Use of single-component wind speed in Rankine-Hugoniot analysis of interplanetary shocks

We have extended and deployed a routine designed to run independently on the Web providing real-time analysis of interplanetary shock observations from L_1. The program accesses real-time magnetic field, solar wind speed, and proton density data from the Advanced Composition Explorer (ACE) spacecraft, searches for interplanetary shocks, analyzes shocks according to the Rankine-Hugoniot (R-H) jump conditions, and provides shock solutions on the Web for space weather applications. Because the ACE real-time data stream contains the wind speed but not the three-component wind velocity, we describe modifications to the R-H analysis that use the scalar wind speed and show successful results for analyses of strong interplanetary shocks at 1 AU. We compare the three-component and one-component solutions and find the greatest disagreement between the two rests in estimations of the shock speed rather than the shock propagation direction. Uncertainties in magnetic quantities such as magnetic compression and shock normal angle relative to the upstream magnetic field show large uncertainties in both analyses when performed using an automated routine whereas analyses of the shock normal alone do not. The automated data point selection scheme, together with the natural variability of the magnetic field, is inferred to be a problem in a few instances for this and other reasons. For a broad range of interplanetary shocks that arrive 30 to 60 min after passing L_1, this method will provide 15 to 45 min of advanced warning prior to the shock's collision with the Earth's magnetopause. The shock, in turn, provides advance warning of the approaching driver gas

An integrated clinical program and crowdsourcing strategy for genomic sequencing and Mendelian disease gene discovery.

Despite major progress in defining the genetic basis of Mendelian disorders, the molecular etiology of many cases remains unknown. Patients with these undiagnosed disorders often have complex presentations and require treatment by multiple health care specialists. Here, we describe an integrated clinical diagnostic and research program using whole-exome and whole-genome sequencing (WES/WGS) for Mendelian disease gene discovery. This program employs specific case ascertainment parameters, a WES/WGS computational analysis pipeline that is optimized for Mendelian disease gene discovery with variant callers tuned to specific inheritance modes, an interdisciplinary crowdsourcing strategy for genomic sequence analysis, matchmaking for additional cases, and integration of the findings regarding gene causality with the clinical management plan. The interdisciplinary gene discovery team includes clinical, computational, and experimental biomedical specialists who interact to identify the genetic etiology of the disease, and when so warranted, to devise improved or novel treatments for affected patients. This program effectively integrates the clinical and research missions of an academic medical center and affords both diagnostic and therapeutic options for patients suffering from genetic disease. It may therefore be germane to other academic medical institutions engaged in implementing genomic medicine programs

Survey of Saturn auroral storms observed by the Hubble Space Telescope: Implications for storm time scales

We examine the ultraviolet images of Saturn obtained by the Hubble Space Telescope (HST) between 1997 and 2013 for the presence of auroral storm signatures, consisting of 2060 individual images over 74.4 h of exposure time. We find 12 storm intervals in these data, identified by bright high-latitude auroras spanning the dawn sector, which previous studies have shown are excited by strong magnetospheric compressions by the solar wind. While most of these events have previously been discussed individually, here we consider what may be deduced about the lifetime of storms, yet unobserved directly for a given event, by examining the ensemble. Specifically, we examine the presence or absence of storm signatures in successive HST observing “visits” separated by varying intervals of time. We show that the observations are consistent with a typical lifetime of ~1.5 Saturn rotations (~16 h), within a likely range between ~1 and ~2 rotations. We suggest that this time scale and the storm evolution morphology relate to the time for hot plasma subcorotation around the planet, following injection postmidnight after a major burst of tail reconnection excited by the solar wind compression. From the overall observed ~12% occurrence frequency of storm signatures, we further infer an averaged storm recurrence time of ~5.5 days (~4-7 days), although this averaged value could be shortened by the occurrence of successive storm activations within few-day disturbed solar wind intervals as observed directly in two cases

Identification of a Proline-rich Inositol Polyphosphate 5-Phosphatase (PIPP)center dot Collapsin Response Mediator Protein 2 (CRMP2) Complex That Regulates Neurite Elongation

Neuron polarization is essential for the formation of one axon and multiple dendrites, establishing the neuronal circuitry. Phosphoinositide 3-kinase (PI3K) signaling promotes axon selection and elongation. Here we report in hippocampal neurons siRNA knockdown of the proline-rich inositol polyphosphate 5-phosphatase (PIPP), which degrades PI3K-generated PtdIns(3,4,5)P3, results in multiple hyperelongated axons consistent with a polarization defect. We identify collapsin response mediator protein 2 (CRMP2), which regulates axon selection by promoting WAVE1 delivery via Kinesin-1 motors to the axon growth cone, as a PIPP-interacting protein by Y2H screening, direct binding studies, and coimmunoprecipitation of an endogenous PIPP, CRMP2, and Kinesin-1 complex from brain lysates. The C-terminal growth cone-targeting domain of PIPP facilitates its interaction with CRMP2. PIPP growth cone localization is CRMP2-dependent. PIPP knockdown in PC12 cells promotes neurite elongation, WAVE1 and Kinesin-1 growth cone localization, whereas knockdown of CRMP2 exhibits the opposite phenotype, with shorter neurites and decreased WAVE1/Kinesin-1 at the growth cone. In contrast, CRMP2 overexpression promotes neurite elongation, a phenotype rescued by full-length PIPP, or expression of the CRMP2-binding PIPP domain. Therefore this study identifies PIPP and CRMP2 exert opposing roles in promoting axon selection and neurite elongation and the complex between these proteins serves to regulate the localization of effectors that promote neurite extension

An integrated clinical program and crowdsourcing strategy for genomic sequencing and Mendelian disease gene discovery.

Despite major progress in defining the genetic basis of Mendelian disorders, the molecular etiology of many cases remains unknown. Patients with these undiagnosed disorders often have complex presentations and require treatment by multiple health care specialists. Here, we describe an integrated clinical diagnostic and research program using whole-exome and whole-genome sequencing (WES/WGS) for Mendelian disease gene discovery. This program employs specific case ascertainment parameters, a WES/WGS computational analysis pipeline that is optimized for Mendelian disease gene discovery with variant callers tuned to specific inheritance modes, an interdisciplinary crowdsourcing strategy for genomic sequence analysis, matchmaking for additional cases, and integration of the findings regarding gene causality with the clinical management plan. The interdisciplinary gene discovery team includes clinical, computational, and experimental biomedical specialists who interact to identify the genetic etiology of the disease, and when so warranted, to devise improved or novel treatments for affected patients. This program effectively integrates the clinical and research missions of an academic medical center and affords both diagnostic and therapeutic options for patients suffering from genetic disease. It may therefore be germane to other academic medical institutions engaged in implementing genomic medicine programs

Spectrum of neurodevelopmental disease associated with the GNAO1 guanosine triphosphate-binding region

Objective To characterize the phenotypic spectrum associated with GNAO1 variants and establish genotype-protein structure-phenotype relationships. Methods We evaluated the phenotypes of 14 patients with GNAO1 variants, analyzed their variants for potential pathogenicity, and mapped them, along with those in the literature, on a three-dimensional structural protein model. Results The 14 patients in our cohort, including one sibling pair, had 13 distinct, heterozygous GNAO1 variants classified as pathogenic or likely pathogenic. We attributed the same variant in two siblings to parental mosaicism. Patients initially presented with seizures beginning in the first 3 months of life (8/14), developmental delay (4/14), hypotonia (1/14), or movement disorder (1/14). All patients had hypotonia and developmental delay ranging from mild to severe. Nine had epilepsy, and nine had movement disorders, including dystonia, ataxia, chorea, and dyskinesia. The 13 GNAO1 variants in our patients are predicted to result in amino acid substitutions or deletions in the GNAO1 guanosine triphosphate (GTP)-binding region, analogous to those in previous publications. Patients with variants affecting amino acids 207-221 had only movement disorder and hypotonia. Patients with variants affecting the C-terminal region had the mildest phenotypes.

Spectrum of neurodevelopmental disease associated with the GNAO1 guanosine triphosphate-binding region

OBJECTIVE: To characterize the phenotypic spectrum associated with GNAO1 variants and establish genotype-protein structure-phenotype relationships. METHODS: We evaluated the phenotypes of 14 patients with GNAO1 variants, analyzed their variants for potential pathogenicity, and mapped them, along with those in the literature, on a three-dimensional structural protein model. RESULTS: The 14 patients in our cohort, including one sibling pair, had 13 distinct, heterozygous GNAO1 variants classified as pathogenic or likely pathogenic. We attributed the same variant in two siblings to parental mosaicism. Patients initially presented with seizures beginning in the first 3 months of life (8/14), developmental delay (4/14), hypotonia (1/14), or movement disorder (1/14). All patients had hypotonia and developmental delay ranging from mild to severe. Nine had epilepsy, and nine had movement disorders, including dystonia, ataxia, chorea, and dyskinesia. The 13 GNAO1 variants in our patients are predicted to result in amino acid substitutions or deletions in the GNAO1 guanosine triphosphate (GTP)-binding region, analogous to those in previous publications. Patients with variants affecting amino acids 207-221 had only movement disorder and hypotonia. Patients with variants affecting the C-terminal region had the mildest phenotypes. SIGNIFICANCE: GNAO1 encephalopathy most frequently presents with seizures beginning in the first 3 months of life. Concurrent movement disorders are also a prominent feature in the spectrum of GNAO1 encephalopathy. All variants affected the GTP-binding domain of GNAO1, highlighting the importance of this region for G-protein signaling and neurodevelopment.status: publishe