The CCD and readout electronics for the OMC instrument on Integral

The Optical Monitoring Camera (OMC) on ESA's Integral gamma-ray astronomy satellite is devoted to optical wavelength observations simultaneously covering the same field-of-view as the gamma-ray and X-ray instruments. The OMC consists of a refracting telescope with a CCD as the imaging device in the focal plane. Here we describe the CCD and its associated readout electronics, in particular pointing out features of interest to users of the OMC instrument and its data

Knockout of the epilepsy gene Depdc5 in mice causes severe embryonic dysmorphology with hyperactivity of mTORC1 signalling

Published online: 03 October 2017DEPDC5 mutations have recently been shown to cause epilepsy in humans. Evidence from in vitro studies has implicated DEPDC5 as a negative regulator of mTORC1 during amino acid insufficiency as part of the GATOR1 complex. To investigate the role of DEPDC5 in vivo we generated a null mouse model using targeted CRISPR mutagenesis. Depdc5 homozygotes display severe phenotypic defects between 12.5-15.5 dpc, including hypotrophy, anaemia, oedema, and cranial dysmorphology as well as blood and lymphatic vascular defects. mTORC1 hyperactivity was observed in the brain of knockout embryos and in fibroblasts and neurospheres isolated from knockout embryos and cultured in nutrient deprived conditions. Heterozygous mice appeared to be normal and we found no evidence of increased susceptibility to seizures or tumorigenesis. Together, these data support mTORC1 hyperactivation as the likely pathogenic mechanism that underpins DEPDC5 loss of function in humans and highlights the potential utility of mTORC1 inhibitors in the treatment of DEPDC5-associated epilepsy.James Hughes, Ruby Dawson, Melinda Tea, Dale McAninch, Sandra Piltz, Dominique Jackson, Laura Stewart, Michael G. Ricos, Leanne M. Dibbens, Natasha L. Harvey and Paul Thoma

A variant of KCC2 from patients with febrile seizures impairs neuronal Cl- extrusion and dendritic spine formation

Genetic variation in SLC12A5 which encodes KCC2, the neuron‐specific cation‐chloride cotransporter that is essential for hyperpolarizing GABAergic signaling and formation of cortical dendritic spines, has not been reported in human disease. Screening of SLC12A5 revealed a co‐segregating variant (KCC2‐R952H) in an Australian family with febrile seizures. We show that KCC2‐R952H reduces neuronal Cl− extrusion and has a compromised ability to induce dendritic spines in vivo and in vitro. Biochemical analyses indicate a reduced surface expression of KCC2‐R952H which likely contributes to the functional deficits. Our data suggest that KCC2‐R952H is a bona fide susceptibility variant for febrile seizures.Peer reviewe

Chipping away at the common epilepsies with complex genetics: the 15q13.3 microdeletion shows the way

The idiopathic epilepsies are genetically heterogeneous with more than 50 clinical classifications. They are characterized by episodic seizures arising from erratic neuronal discharge in susceptible individuals. The most common predisposing genetic cause is the recently discovered chromosome 15q13.3 microdeletion. Other disorders previously attributed to the same lesion include autism, intellectual disability and schizophrenia. This phenotypic spectrum is most easily imagined as a contiguous gene syndrome with idiopathic generalized epilepsy as the most common clinical manifestation. Expressivity of the microdeletion in carriers is too variable for antenatal prediction of phenotype to be possible; however, when it is detected in living affected cases, it can be taken as the major predisposing cause for the observed phenotype. The discovery of this small 15q13.3 lesion barely scratches the surface that conceals what we ultimately need to know about the molecular genetic mechanisms behind the common epilepsies with complex genetics, but it provides valuable insight into how to proceed toward that goal

Spectroscopic survey of the Galaxy with Gaia I. Design and performance of the Radial Velocity Spectrometer

The definition and optimisation studies for the Gaia satellite spectrograph, the Radial Velocity Spectrometer (RVS), converged in late 2002 with the adoption of the instrument baseline. This paper reviews the characteristics of the selected configuration and presents its expected performance. The RVS is a 2.0 by 1.6 degree integral field spectrograph, dispersing the light of all sources entering its field of view with a resolving power R=11 500 over the wavelength range [848, 874] nm. The RVS will continuously and repeatedly scan the sky during the 5 years of the Gaia mission. On average, each source will be observed 102 times over this period. The RVS will collect the spectra of about 100-150 million stars up to magnitude V~17-18. At the end of the mission, the RVS will provide radial velocities with precisions of ~2 km/s at V=15 and \~15-20 km/s at V=17, for a solar metallicity G5 dwarf. The RVS will also provide rotational velocities, with precisions (at the end of the mission) for late type stars of sigma_vsini ~5 km/s at V~15 as well as atmospheric parameters up to V~14-15. The individual abundances of elements such as Silicon and Magnesium, vital for the understanding of Galactic evolution, will be obtained up to V~12-13. Finally, the presence of the 862.0 nm Diffuse Interstellar Band (DIB) in the RVS wavelength range will make it possible to derive the three dimensional structure of the interstellar reddening.Comment: 17 pages, 9 figures, accepted for publication in MNRAS. Fig. 1,2,4,5, 6 in degraded resolution; available in full resolution at http://blackwell-synergy.com/links/doi/10.1111/j.1365-2966.2004.08282.x/pd

A variant of KCC2 from patients with febrile seizures impairs neuronal Cl- extrusion and dendritic spine formation

Genetic variation in SLC12A5 which encodes KCC2, the neuron‐specific cation‐chloride cotransporter that is essential for hyperpolarizing GABAergic signaling and formation of cortical dendritic spines, has not been reported in human disease. Screening of SLC12A5 revealed a co‐segregating variant (KCC2‐R952H) in an Australian family with febrile seizures. We show that KCC2‐R952H reduces neuronal Cl− extrusion and has a compromised ability to induce dendritic spines in vivo and in vitro. Biochemical analyses indicate a reduced surface expression of KCC2‐R952H which likely contributes to the functional deficits. Our data suggest that KCC2‐R952H is a bona fide susceptibility variant for febrile seizures.Peer reviewe

Spectroscopic survey of the Galaxy with Gaia- I. Design and performance of the Radial Velocity Spectrometer

The definition and optimization studies for the Gaia satellite spectrograph, the ‘radial velocity spectrometer' (RVS), converged in late 2002 with the adoption of the instrument baseline. This paper reviews the characteristics of the selected configuration and presents its expected performance. The RVS is a 2.0 × 1.6 degree integral field spectrograph, dispersing the light of all sources entering its field of view with a resolving power R=λ/Δλ= 11 500 over the wavelength range [848, 874] nm. The RVS will continuously and repeatedly scan the sky during the 5‐yr Gaia mission. On average, each source will be observed 102 times over this period. The RVS will collect the spectra of about 100-150 million stars up to magnitude V≃ 17-18. At the end of the mission, the RVS will provide radial velocities with precisions of ∼2 km s−1 at V= 15 and ∼15-20 km s−1 at V= 17, for a solar‐metallicity G5 dwarf. The RVS will also provide rotational velocities, with precisions (at the end of the mission) for late‐type stars of σvsin i≃ 5 km s−1 at V≃ 15 as well as atmospheric parameters up to V≃ 14-15. The individual abundances of elements such as silicon and magnesium, vital for the understanding of Galactic evolution, will be obtained up to V≃ 12-13. Finally, the presence of the 862.0‐nm diffuse interstellar band (DIB) in the RVS wavelength range will make it possible to derive the three‐dimensional structure of the interstellar reddenin

NF90 Binds the Dengue Virus RNA 3′ Terminus and is a Positive Regulator of Dengue Virus Replication

Background Viral RNA translation and replication are regulated by sequence and structural elements in the 5′ and 3′ untranslated regions (UTR) and by host cell and/or viral proteins that bind them. Dengue virus has a single-stranded RNA genome with positive polarity, a 5′ m7GpppG cap, and a conserved 3′-terminal stem loop (SL) that is linked to proposed functions in viral RNA transcription and translation. Mechanisms explaining the contributions of host proteins to viral RNA translation and replication are poorly defined, yet understanding host protein-viral RNA interactions may identify new targets for therapeutic intervention. This study was directed at identifying functionally significant host proteins that bind the conserved dengue virus RNA 3′ terminus. Methodology/Principal Findings Proteins eluted from a dengue 3′ SL RNA affinity column at increasing ionic strength included two with double-strand RNA binding motifs (NF90/DRBP76 and DEAH box polypeptide 9/RNA helicase A (RHA)), in addition to NF45, which forms a heterodimer with NF90. Although detectable NF90 and RHA proteins localized to the nucleus of uninfected cells, immunofluorescence revealed cytoplasmic NF90 in dengue virus-infected cells, leading us to hypothesize that NF90 has a functional role(s) in dengue infections. Cells depleted of NF90 were used to quantify viral RNA transcript levels and production of infectious dengue virus. NF90 depletion was accompanied by a 50%-70% decrease in dengue RNA levels and in production of infectious viral progeny. Conclusions/Significance The results indicate that NF90 interacts with the 3′ SL structure of the dengue RNA and is a positive regulator of dengue virus replication. NF90 depletion diminished the production of infectious dengue virus by more than 50%, which may have important significance for identifying therapeutic targets to limit a virus that threatens more than a billion people worldwide.Ruth L. Kirschstein National Research Service Award (NIH-NRSA GM64985)UNCF-Merck Postdoctoral FellowshipNational Institute of Allergy and Infectious Diseases (U.S.)Ellison Medical Foundatio

Epileptogenesis after prolonged febrile seizures: mechanisms, biomarkers and therapeutic opportunities.

Epidemiological and recent prospective analyses of long febrile seizures (FS) and febrile status epilepticus (FSE) support the idea that in some children, such seizures can provoke temporal lobe epilepsy (TLE). Because of the high prevalence of these seizures, if epilepsy was to arise as their direct consequence, this would constitute a significant clinical problem. Here we discuss these issues, and describe the use of animal models of prolonged FS and of FSE to address the following questions: Are long FS epileptogenic? What governs this epileptogenesis? What are the mechanisms? Are there any predictive biomarkers of the epileptogenic process, and can these be utilized, together with information about the mechanisms of epileptogenesis, for eventual prevention of the TLE that results from long FS and FSE

Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1, 2q22.3 and 17q21.32

Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% and account for 20-30% of all epilepsies. Despite their high heritability of 80%, the genetic factors predisposing to GGEs remain elusive. To identify susceptibility variants shared across common GGE syndromes, we carried out a two-stage genome-wide association study (GWAS) including 3020 patients with GGEs and 3954 controls of European ancestry. To dissect out syndrome-related variants, we also explored two distinct GGE subgroups comprising 1434 patients with genetic absence epilepsies (GAEs) and 1134 patients with juvenile myoclonic epilepsy (JME). Joint Stage-1 and 2 analyses revealed genome-wide significant associations for GGEs at 2p16.1 (rs13026414, Pmeta = 2.5 × 10−9, OR[T] = 0.81) and 17q21.32 (rs72823592, Pmeta = 9.3 × 10−9, OR[A] = 0.77). The search for syndrome-related susceptibility alleles identified significant associations for GAEs at 2q22.3 (rs10496964, Pmeta = 9.1 × 10−9, OR[T] = 0.68) and at 1q43 for JME (rs12059546, Pmeta = 4.1 × 10−8, OR[G] = 1.42). Suggestive evidence for an association with GGEs was found in the region 2q24.3 (rs11890028, Pmeta = 4.0 × 10−6) nearby the SCN1A gene, which is currently the gene with the largest number of known epilepsy-related mutations. The associated regions harbor high-ranking candidate genes: CHRM3 at 1q43, VRK2 at 2p16.1, ZEB2 at 2q22.3, SCN1A at 2q24.3 and PNPO at 17q21.32. Further replication efforts are necessary to elucidate whether these positional candidate genes contribute to the heritability of the common GGE syndrome