R31C GNRH1 mutation and congenital hypogonadotropic hypogonadism

Normosmic congenital hypogonadotropic hypogonadism (nCHH) is a rare reproductive disease leading to lack of puberty and infertility. Loss-of-function mutations of GNRH1 gene are a very rare cause of autosomal recessive nCHH. R31C GNRH1 is the only missense mutation that affects the conserved GnRH decapeptide sequence. This mutation was identified in a CpG islet in nine nCHH subjects from four unrelated families, giving evidence for a putative “hot spot”. Interestingly, all the nCHH patients carry this mutation in heterozygosis that strikingly contrasts with the recessive inheritance associated with frame shift and non-sense mutations. Therefore, after exclusion of a second genetic event, a comprehensive functional characterization of the mutant R31C GnRH was undertaken. Using different cellular models, we clearly demonstrate a dramatic reduction of the mutant decapeptide capacity to bind GnRH-receptor, to activate MAPK pathway and to trigger inositol phosphate accumulation and intracellular calcium mobilization. In addition it is less able than wild type to induce lh-beta transcription and LH secretion in gonadotrope cells. Finally, the absence of a negative dominance in vitro offers a unique opportunity to discuss the complex in vivo patho-physiology of this form of nCHH

Quantifying sources of variability in infancy research using the infant-directed-speech preference

Psychological scientists have become increasingly concerned with issues related to methodology and replicability, and infancy researchers in particular face specific challenges related to replicability: For example, high-powered studies are difficult to conduct, testing conditions vary across labs, and different labs have access to different infant populations. Addressing these concerns, we report on a large-scale, multisite study aimed at (a) assessing the overall replicability of a single theoretically important phenomenon and (b) examining methodological, cultural, and developmental moderators. We focus on infants’ preference for infant-directed speech (IDS) over adult-directed speech (ADS). Stimuli of mothers speaking to their infants and to an adult in North American English were created using seminaturalistic laboratory-based audio recordings. Infants’ relative preference for IDS and ADS was assessed across 67 laboratories in North America, Europe, Australia, and Asia using the three common methods for measuring infants’ discrimination (head-turn preference, central fixation, and eye tracking). The overall meta-analytic effect size (Cohen’s d) was 0.35, 95% confidence interval = [0.29, 0.42], which was reliably above zero but smaller than the meta-analytic mean computed from previous literature (0.67). The IDS preference was significantly stronger in older children, in those children for whom the stimuli matched their native language and dialect, and in data from labs using the head-turn preference procedure. Together, these findings replicate the IDS preference but suggest that its magnitude is modulated by development, native-language experience, and testing procedure. (This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 798658.

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Observation of near-podal P0P0 precursors: Evidence for back scattering from the 150–220 km zone in the Earth’s upper mantle

[1] P0P0 (PKPPKP) are P waves that travel from a hypocenter through the Earth’s core, reflect from the free surface and travel back through the core to a recording station on the surface. Here we report the observations of hitherto unobserved near-podal P0P0 waves (at epicentral distance <10) and very prominent precursors preceding the main energy by as much as 60 s. We interpret these precursors as a back-scattered energy from horizontally connected small-scale heterogeneity in the upper mantle beneath the oceans in a zone between 150 and 220 km depth beneath the Earth’s surface. From these observations, we identify a frequency dependence of attenuation quality factor Q in the lithosphere through forward modeling of the observed amplitude spectra of the main and back-scattere

Obesrvation of near-podal P'P' precursors: Evidence for back scattering from the 150-220 km zone in the Earth's upper mantle

P′P′ (PKPPKP) are P waves that travel from a hypocenter through the Earth's core, reflect from the free surface and travel back through the core to a recording station on the surface. Here we report the observations of hitherto unobserved near-podal

Evidence for back scattering of near-podal seismic P'P' waves from the 150-220 km zone in Earth's upper mantle Evidence for back scattering of near-podal seismic P'P' waves from the 150-220 km zone in Earth's upper mantle

The deepest and most inaccessible parts of Earth's interior -the core and coremantle boundary regions can be studied from compressional waves that turn in the core and are routinely observed following large earthquakes at epicentral distances between 145° and 180° (also called P', PKIKP or PKP waves) 10 . Our understanding of Earth's composition and dynamics has evolved dramatically in the last several decades, especially with the expansion of modern broadband seismic networks and development of seismological methods such as tomographic imaging. Many details about Earth's deep interior, however, remain elusive or completely unknown. Faster progress toward understanding of Earth's lowermost mantle and core regions has been hindered by the difficulty of observing and analyzing core-sensitive seismic phases. For example, core-mantle and inner-outer core boundaries can be studied from P waves that reflect from these boundaries (PcP and PKiKP waves, respectively). These phases, however, are not widely observed on seismograms, particularly at very short epicentral distances 12? . Moreover, with the current configuration of stations and the world's seismicity, the existing collection of PKP waves does not sample equally well all parts of the inner core. For this reason seismic phases with more complex geometry, like PnKP (where n is a number of multiple reflections from the inner side of the core mantle boundary) and P'P' An alternative scattering hypotheses 26? A common characteristic of early observations of P'P' and their precursors was that they were mostly assembled at epicentral distances of about 50°-70°. This characteristic, considered with the geometry of two separate single legs of PKP, can be explained by the fact that a maximum amplitude of PKP waves due to triplication (simultaneous arrivals and interference of 3 branches of PKP waves) is observed between 145° and 155°. Thus, 360°-2Δ={70°,50°} for PKP epicentral distance Δ={145°,155°}. Unlike the majority of these earlier observations of P'P' precursors, we report unprecedented observations at near-podal epicentral distances (less then 10°) of very clear and energetic P'P' precursor arrivals An example of P'P' precursor observations at the short-period ILAR array network in Alaska is illustrated in Scattering of P'P' waves could take place anywhere along the ray path beneath the receiver, core-mantle boundary, inner-core boundary, or antipodal bounce point area. If P'P' waves were forward-scattered, simple travel time calculations reveal that all forward scattering would arrive as energy following P'P' rather than as a precursor. This is a distinguishing property of such short epicentral distance geometry and corresponding seismic wave arrivals and is true regardless of the location or distribution of scatterers in the mantle. For some strong velocity anomalies conncentrated near the receiver, it is possible to create some P'P' precursors but they would arrive with very different slowness or apparent angle of incidence than the main P'P' phase. It is feasible that a specific near-source geometry-related effect, such as a dipping slab, could cause multi-pathing, in which case a denser lithospheric slab would propagate compressional energy faster in the direction of the slab. It is highly unlikely, however, that this is the case in our observations. First, mechanisms with a compressional energy radiation pattern favorable to produce a podal P'P' phase are thrust faulting source mechanisms, where one lobe with maximum compressional energy extends vertically downward from the source region. The seismic energy that is released in the direction of the slab and travels through it is thus much smaller than the main P'P' energy (unless the slab itself is not vertical). Even if this were the case in our observations at ILAR, which were recorded in Alaska above the subducting Pacific plate, it would be difficult to acquire as much as 55 seconds of advance time. We also observed similar P'P' precursors on another, independent set of broadband recordings, for an Afghanistan-Tajikistan border earthquake, recorded at the Kazakhstan regional seismic network. The precursor in the recordings from the Afganistan-Tajikistan border earthquake had advance times similar to that observed at ILAR, also inconsistent with forward scattering from any dipping structure associated with the intermediate depth earthquakes in this region. Further evidence against forward scattering or multipathing near the receiver is given by a slowness analysis from beams formed at the ILAR array, which found strikingly similar slowness and back-azimuth for both the precursor and main P'P' phase that agree well with those predicted for from the location of the earthquake Results of our slowness analyses are also inconsistent with precursor origin from scattering near the core-mantle boundary. It has been suggested that various scattered phases of PKP as well as PK(KKP) or PKK(KP) (where parentheses indicated scattered part of the signal) might account for precursors of PKKKP (double reflection from the inner side of the core mantle boundary) and P'P' waves, and could be an alternative explanation to underside reflections from 410-and 660-km discontinuities at epicentral distances equal and longer than 30°2 Therefore, we suggest that the observed P'P' precursors are back-scattered energy from reflectors in the upper mantle (see illustration in One curiosity is that we do not observe any 410-or 660-km related precursors to P'P'. Because PKP waves have maximum amplitudes near 150º, it is not surprising that most observations of P'P' and their precursors are made near epicentral distances of 60º (see previous comments and a note on relationship between geometry of P'P' and PKP). An interesting factor to consider is the observability of reflections off upper mantle discontinuities having topography The observation of different frequency content between the main P'P' phase and the precursors as well as high amplitudes of the observed precursors persisting at higher frequencies motivated us to investigate this phenomenon more closely. The higher frequency content of the precursors to P'P' could be explained by a combination of the effects of higher attenuation in the uppermost mantle and the frequency dependence of backscattered energy from small-scale heterogeneities. The effects of upper mantle attenuation are relatively simple to model. The modeling of the effects of the backscattered radiation pattern of small-scale heterogeneities is necessarily more speculative. The largest effect on frequency content, however, will undoubtedly be the effect of the exponential attenuation of amplitude with frequency due to intrinsic attenuation rather than the simple first and second power law increase in amplitude with frequency due to scattering by heterogeneities of varying scale length and shape. Hence, we first consider the effects of mantle attenuation on the backscattered attenuation. The difference in the attenuation experienced by P'P' relative to the back-scattered precursors is simply given by the effect of the travel time accumulated by the additional two legs that the main P'P' phase spends in the attenuating uppermost 150-220 km of the mantle. In while in In conclusion, we interpret our best fit to the frequency content and slowness of nearpodal P'P' precursor as backscattering from horizontally connected small-scale heterogeneity concentrated in the uppermost 150-220 km of the mantle. Possible candidate scatterers include compositional blobs of variable size and elastic impedance or lenses of partial melt. Compositional heterogeneities may be eclogitic slab fragments. The impedance contrasts of the heterogeneities may also be associated with a rheologic change from dislocation creep to diffusion creep, which Karato 35 has proposed as a mechanism to account for a transition from an isotropic uppermost mantle to an isotropic lower mantle. Partial melt lenses will be more effective than either compositional or solid-solid phase changes in accounting for the large impedance contrasts needed to account for the amplitude of the observed P'P' precursors at ILAR. Our best observations of P'P' precursors back-scattered from this depth range at ILAR occur beneath oceanic regions, far from mid-ocean ridge. Little or no partial melt, however, has ever been postulated in the upper mantle as deep as 150-220 km, far from mid-ocean ridges. Compared to P'P' precursors observed at ILAR, however, precursors observed from P'P' in the Afganistan-Tajikistan Border region have relatively lower frequency content, perhaps related to an antipodal bounce point near a mid-ocean ridge. Important future observations include an assessment in regional variations in the frequency content of P'P' precursors, especially whether similar back-scattering is observed beneath continental regions. Perhaps the mechanism producing the backscattering from a diffuse depth 150 km zone beneath oceanic regions is identical to the mechanism producing occasional observations of a Lehmann discontinuity near 220 km depth beneath continental regions. The vertical cross-section shows main subdivisions and discontinuities as well as podal P'P'df ray-paths connecting the source with the receiver. A podal P'P'-DF ray-path consists of two antipodal PKIKP ray-paths with bottoming points in the inner core very close to Earth's center. b, Theoretical travel time curves of P'P' and PKKKP seismic phases from a source at 0 km depth, shown by thick and thin lines, respectively. The P'P'-DF branch corresponds to the waves bottoming in the inner core. The BC branch corresponds to the waves bottoming in the lower, while the AB branch corresponds to the waves bottoming in the middle parts of the outer core. PKKKP waves could be observed in the same epicentral distance range preceding the arrivals of P'P' waves, although with significantly different slowness. Also shown (by dashed line) is a theoretical P'P' travel time curve from a 500 km deep source. Reference model ak135 11 was used. c, Map of Earth with surface projections of P'P' raypaths for the observed podal P'P' precursors. Locations of 9 earthquakes as well as the location of ILAR short period network in Alaska are shown by stars and a triangle, respectively. Also shown (by stars in the southern hemisphere) are reflection points near the antipode. Circles are surface projections of the corresponding bottoming points in the inner core (one on the source, and one on the receiver side). d, Schematic representation of the reflection of P'P' waves in the antipodal mantle (indicated by a rectangle in part a). Thin lines show geometry of back-scattered P'P' responsible for the observed precursor energy. Back scattering originates in a zone between 150 and 220 km in the upper mantle. P'P' waves continue their way through the lithosphere to the surface, reflect from it and travel to the receiver with similar slowness to P'P' precursors. They are attenuated, however, significantly with respect to the precursors, owing to two additional leg paths through the antipodal lithosphere. Figure 2 P'P' observations at podal epicentral distance. Vertical component records at the short-period ILAR array are shown for two bandpass filters: a, 0.2-0.7 Hz and b, 1.0-1.5 Hz. This earthquake was located in the southern Alaska, about 7 degrees southwest of the ILAR seismic network. Both the main P'P' phase and precursors are visible at lower frequencies. Precursors to P'P' are characterized by several distinct arrivals in 55-30 second interval before P'P'. Note a difference in frequency content between the precursor and the main P'P' energy. At higher frequencies, the main P'P' phase is below the noise level and not visible. Figure 3 Amplitude spectra for the observed main P'P' phase (thick black line), P'P' precursor (thick gray line) and noise preceeding the precursors (dashed gray line). The spectrum of the main phase was used to calculate predictions of precursor spectra (thin black lines). Only frequency effect of Q (quality factor) without frequency dependence on scattering was taken into account. a, Q was assumed to be constant in the antipodal lithosphere, with values used shown above the theoretical curves. b, Q has a flat relaxation spectrum for frequencies below 0.1 Hz and increases with as the first power of frequency above a given corner frequency. For Q=200, frequency corners of 0.1 (Qf 1 ) and 0.05 Hz (Qf 2 ) were used. c. Q varies with frequency in the same way as in b, but with frequency dependence proportional to the first power of frequency in order to account for integrated effect of connected small-scale heterogeneity or lenses of partial melt. References

Effects of oxytocin on stress reactivity and craving in veterans with co-occurring PTSD and alcohol use disorder

© 2018 American Psychological Association. Posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD) are highly prevalent and commonly co-occur. The dual diagnosis of PTSD/AUD is associated with serious negative sequalae, and there are currently no effective pharmacological treatments for this comorbidity. Both PTSD and AUD are characterized by dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, which helps modulate stress reactivity. Oxytocin, a neuropeptide that attenuates HPA axis dysregulation, may be beneficial for individuals with co-occurring PTSD/AUD. Thus, the current study examined the effects of intranasal oxytocin (40 IU) as compared with placebo on stress reactivity (e.g., cortisol) as well as subjective alcohol craving in response to a laboratory stress task (Trier Social Stress Task). Participants were 67 male U.S. military veterans with current PTSD and AUD (oxytocin n = 32, placebo n = 35; overall mean age = 49.06 years). Baseline cortisol levels were examined as a moderator of outcome. The findings revealed that oxytocin marginally attenuated cortisol reactivity in response to the stress task. Furthermore, oxytocin\u27s effect was moderated by baseline cortisol level, such that oxytocin mitigated cortisol reactivity to a greater extent among participants with higher, as compared with lower, baseline cortisol. Oxytocin did not reduce craving. Although preliminary, the findings are the first to examine oxytocin in co-occurring PTSD/AUD. The findings from this study contribute to the growing literature examining the potential utility of oxytocin among individuals with psychiatric disorders, such as PTSD and substance use disorders