Variability and origin of seismic anisotropy across eastern Canada: evidence from shear-wave splitting measurements

Measurements of seismic anisotropy in continental regions are frequently interpreted with respect to past tectonic processes, preserved in the lithosphere as “fossil” fabrics. Models of the present-day sublithospheric flow (often using absolute plate motion as a proxy) are also used to explain the observations. Discriminating between these different sources of seismic anisotropy is particularly challenging beneath shields, whose thick (≥200 km) lithospheric roots may record a protracted history of deformation and strongly influence underlying mantle flow. Eastern Canada, where the geological record spans ∼3 Ga of Earth history, is an ideal region to address this issue. We use shear wave splitting measurements of core phases such as SKS to define upper mantle anisotropy using the orientation of the fast-polarization direction ϕ and delay time δt between fast and slow shear wave arrivals. Comparison with structural trends in surface geology and aeromagnetic data helps to determine the contribution of fossil lithospheric fabrics to the anisotropy. We also assess the influence of sublithospheric mantle flow via flow directions derived from global geodynamic models. Fast-polarization orientations are generally ENE-WSW to ESE-WNW across the region, but significant lateral variability in splitting parameters on a ≤100 km scale implies a lithospheric contribution to the results. Correlations with structural geologic and magnetic trends are not ubiquitous, however, nor are correlations with geodynamically predicted mantle flow directions. We therefore consider that the splitting parameters likely record a combination of the present-day mantle flow and older lithospheric fabrics. Consideration of both sources of anisotropy is critical in shield regions when interpreting splitting observations

A recurrent p.Arg92Trp variant in steroidogenic factor-1 (NR5A1) can act as a molecular switch in human sex development

Cell lineages of the early human gonad commit to one of the two mutually antagonistic organogenetic fates, the testis or the ovary. Some individuals with a 46,XX karyotype develop testes or ovotestes (testicular or ovotesticular disorder of sex development; TDSD/OTDSD), due to the presence of the testis-determining gene, SRY Other rare complex syndromic forms of TDSD/OTDSD are associated with mutations in pro-ovarian genes that repress testis development (e.g. WNT4); however, the genetic cause of the more common non-syndromic forms is unknown. Steroidogenic factor-1 (known as NR5A1) is a key regulator of reproductive development and function. Loss-of-function changes in NR5A1 in 46,XY individuals are associated with a spectrum of phenotypes in humans ranging from a lack of testis formation to male infertility. Mutations in NR5A1 in 46,XX women are associated with primary ovarian insufficiency, which includes a lack of ovary formation, primary and secondary amenorrhoea as well as early menopause. Here, we show that a specific recurrent heterozygous missense mutation (p.Arg92Trp) in the accessory DNA-binding region of NR5A1 is associated with variable degree of testis development in 46,XX children and adults from four unrelated families. Remarkably, in one family a sibling raised as a girl and carrying this NR5A1 mutation was found to have a 46,XY karyotype with partial testicular dysgenesis. These unique findings highlight how a specific variant in a developmental transcription factor can switch organ fate from the ovary to testis in mammals and represents the first missense mutation causing isolated, non-syndromic 46,XX testicular/ovotesticular DSD in humans

The gene encoding the ketogenic enzyme HMGCS2 displays a unique expression during gonad development in mice

Disorders/differences of sex development (DSD) cause profound psychological and reproductive consequences for the affected individuals, however, most are still unexplained at the molecular level. Here, we present a novel gene, 3-hydroxy-3-methylglutaryl coenzyme A synthase 2 (HMGCS2), encoding a metabolic enzyme in the liver important for energy production from fatty acids, that shows an unusual expression pattern in developing fetal mouse gonads. Shortly after gonadal sex determination it is up-regulated in the developing testes following a very similar spatial and temporal pattern as the male-determining gene Sry in Sertoli cells before switching to ovarian enriched expression. To test if Hmgcs2 is important for gonad development in mammals, we pursued two lines of investigations. Firstly, we generated Hmgcs2-null mice using CRISPR/Cas9 and found that these mice had gonads that developed normally even on a sensitized background. Secondly, we screened 46,XY DSD patients with gonadal dysgenesis and identified two unrelated patients with a deletion and a deleterious missense variant in HMGCS2 respectively. However, both variants were heterozygous, suggesting that HMGCS2 might not be the causative gene. Analysis of a larger number of patients in the future might shed more light into the possible association of HMGCS2 with human gonadal development.Stefan Bagheri-Fam, Huijun Chen, Sean Wilson, Katie Ayers, James Hughes, Frederique Sloan-Bena, Pierre Calvel, Gorjana Robevska, Beatriz Puisac, Kamila Kusz-Zamelczyk, Stefania Gimelli, Anna Spik, Jadwiga Jaruzelska, Alina Warenik-Szymankiewicz, Sultana Faradz, Serge Nef, Juan Pie, Paul Thomas, Andrew Sinclair, Dagmar Wilhel

Combined Effects of <formula formulatype="inline"> <tex Notation="TeX">60^{60}</tex></formula>Co Dose and High Frequency Interferences on a Discrete Bipolar Transistor

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Impact of Total Ionizing Dose on the Electromagnetic Susceptibility of a single bipolar transistor

International audienceSpace or military electronic components are subject to both electromagnetic fields and total ionizing dose. This paper deals with the modification in the susceptibility to 100 MHz – 1.5 GHz signals of a discrete low frequency transistor subsequently to total ionizing dose deposition. The electromagnetic susceptibility is investigated on both non-irradiated and irradiated transistors mounted in common emitter configuration. A synergy effect between near field electromagnetic interferences and total ionizing dose is observed

HP26: Electrophysiological properties of electrical brain stimulations and their impact on neuronal activity during stereoelectroencephalography in epilepsy

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Loss of function mutation in the palmitoyl-transferase HHAT leads to syndromic 46,XY disorder of sex development by impeding Hedgehog protein palmitoylation and signaling

The Hedgehog (Hh) family of secreted proteins act as morphogens to control embryonic patterning and development in a variety of organ systems. Post-translational covalent attachment of cholesterol and palmitate to Hh proteins are critical for multimerization and long range signaling potency. However, the biological impact of lipid modifications on Hh ligand distribution and signal reception in humans remains unclear. In the present study, we report a unique case of autosomal recessive syndromic 46,XY Disorder of Sex Development (DSD) with testicular dysgenesis and chondrodysplasia resulting from a homozygous G287V missense mutation in the hedgehog acyl-transferase (HHAT) gene. This mutation occurred in the conserved membrane bound O-acyltransferase (MBOAT) domain and experimentally disrupted the ability of HHAT to palmitoylate Hh proteins such as DHH and SHH. Consistent with the patient phenotype, HHAT was found to be expressed in the somatic cells of both XX and XY gonads at the time of sex determination, and Hhat loss of function in mice recapitulates most of the testicular, skeletal, neuronal and growth defects observed in humans. In the developing testis, HHAT is not required for Sertoli cell commitment but plays a role in proper testis cord formation and the differentiation of fetal Leydig cells. Altogether, these results shed new light on the mechanisms of action of Hh proteins. Furthermore, they provide the first clinical evidence of the essential role played by lipid modification of Hh proteins in human testicular organogenesis and embryonic development

Gaia basic angle monitoring system

The Gaia mission will create an extraordinarily precise three-dimensional map of more than one billion stars in our Galaxy. The Gaia spacecraft2, built by EADS Astrium, is part of ESA's Cosmic Vision programme and scheduled for launch in 2013. Gaia measures the position, distance and motion of stars with an accuracy of 24 micro-arcsec using two telescopes at a fixed mutual angle of 106.5°, named the ‘Basic Angle’, at an operational temperature of 100 K. This accuracy requires ultra-high stability at cryogenic conditions, which can only be achieved by using Silicon Carbide for both the optical bench and the telescopes. TNO has developed, built and space qualified the Silicon carbide Basic Angle Monitoring (BAM) on-board metrology system3 for this mission, measuring the relative motion of Gaia’s telescopes with accuracies in the range of 0.5 micro-arcsec. This is achieved by a system of two laser interferometers able to detect Optical Path Differences (OPD) as small as 1.5 picometer rms. Following a general introduction on Gaia and the use of Silicon Carbide as base material this paper addresses the specific challenges towards the cryogenic application of the Gaia BAM including design, integration and verification/qualification by testing

The Role of Feedback Resistors and TID Effects in the ASET Response of a High Speed Current Feedback Amplifier

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