193 research outputs found
Global CNS gene transfer for a childhood neurogenetic enzyme deficiency: Canavan disease.
The neurogenetic prototypic disease on which we chose to test our gene therapy strategy is Canavan disease (CD). CD is an autosomal recessive leukodystrophy associated with spongiform degeneration of the brain. At present the disease is uniformly fatal in affected probands. CD is characterized by mutations in the aspartoacylase (ASPA) gene, resulting in loss of enzyme activity. In this review, recent evidence is summarized on the etiology and possible treatments for CD. In particular, we discuss two gene delivery systems representing recent advances in both viral and liposome technology: a novel cationic liposome-polymer-DNA (LPD) complex, DCChol/DOPE-protamine, as well as recombinant adeno-associated virus (AAV) vectors
N-acetylaspartate supports the energetic demands of developmental myelination via oligodendroglial aspartoacylase
Breakdown of neuro-glial N-acetyl-aspartate (NAA) metabolism results in the failure of developmental myelination, manifest in the congenital pediatric leukodystrophy Canavan disease caused by mutations to the sole NAA catabolizing enzyme aspartoacylase. Canavan disease is a major point of focus for efforts to define NAA function, with available evidence suggesting NAA serves as an acetyl donor for fatty acid synthesis during myelination. Elevated NAA is a diagnostic hallmark of Canavan disease, which contrasts with a broad spectrum of alternative neurodegenerative contexts in which levels of NAA are inversely proportional to pathological progression. Recently generated data in the nur7 mouse model of Canavan disease suggests loss of aspartoacylase function results in compromised energetic integrity prior to oligodendrocyte death, abnormalities in myelin content, spongiform degeneration, and motor deficit. The present study utilized a next-generation “oligotropic” adeno-associated virus vector (AAV-Olig001) to quantitatively assess the impact of aspartoacylase reconstitution on developmental myelination. AAV-Olig001-aspartoacylase promoted normalization of NAA, increased bioavailable acetyl-CoA, and restored energetic balance within a window of postnatal development preceding gross histopathology and deteriorating motor function. Long-term effects included increased oligodendrocyte numbers, a global increase in myelination, reversal of vacuolation, and rescue of motor function. Effects on brain energy observed following AAV-Olig001-aspartoacylase gene therapy are shown to be consistent with a metabolic profile observed in mild cases of Canavan disease, implicating NAA in the maintenance of energetic integrity during myelination via oligodendroglial aspartoacylase
Genome-Wide Joint Meta-Analysis of SNP and SNP-by-Smoking Interaction Identifies Novel Loci for Pulmonary Function
The JWST Early Release Science Program for Direct Observations of Exoplanetary Systems IV: NIRISS Aperture Masking Interferometry Performance and Lessons Learned
We present a performance analysis for the aperture masking interferometry
(AMI) mode on board the James Webb Space Telescope Near Infrared Imager and
Slitless Spectrograph (JWST/NIRISS). Thanks to self-calibrating observables,
AMI accesses inner working angles down to and even within the classical
diffraction limit. The scientific potential of this mode has recently been
demonstrated by the Early Release Science (ERS) 1386 program with a deep search
for close-in companions in the HIP 65426 exoplanetary system. As part of ERS
1386, we use the same dataset to explore the random, static, and calibration
errors of NIRISS AMI observables. We compare the observed noise properties and
achievable contrast to theoretical predictions. We explore possible sources of
calibration errors, and show that differences in charge migration between the
observations of HIP 65426 and point-spread function calibration stars can
account for the achieved contrast curves. Lastly, we use self-calibration tests
to demonstrate that with adequate calibration, NIRISS AMI can reach contrast
levels of mag. These tests lead us to observation planning
recommendations and strongly motivate future studies aimed at producing
sophisticated calibration strategies taking these systematic effects into
account. This will unlock the unprecedented capabilities of JWST/NIRISS AMI,
with sensitivity to significantly colder, lower mass exoplanets than
ground-based setups at orbital separations inaccessible to JWST coronagraphy.Comment: 20 pages, 12 figures, submitted to AAS Journal
The \textit{JWST} Early Release Science Program for Direct Observations of Exoplanetary Systems III: Aperture Masking Interferometric Observations of the star HIP\,65426 at
We present aperture masking interferometry (AMI) observations of the star HIP
65426 at as a part of the \textit{JWST} Direct Imaging Early
Release Science (ERS) program obtained using the Near Infrared Imager and
Slitless Spectrograph (NIRISS) instrument. This mode provides access to very
small inner working angles (even separations slightly below the Michelson limit
of for an interferometer), which are inaccessible with the
classical inner working angles of the \textit{JWST} coronagraphs. When combined
with \textit{JWST}'s unprecedented infrared sensitivity, this mode has the
potential to probe a new portion of parameter space across a wide array of
astronomical observations. Using this mode, we are able to achieve a contrast
of \,mag relative to the host star at a separation
of {\sim}0.07\arcsec but detect no additional companions interior to the
known companion HIP\,65426\,b. Our observations thus rule out companions more
massive than 10{-}12\,\rm{M\textsubscript{Jup}} at separations
from HIP\,65426, a region out of reach of ground or
space-based coronagraphic imaging. These observations confirm that the AMI mode
on \textit{JWST} is sensitive to planetary mass companions orbiting at the
water frost line, even for more distant stars at 100\,pc. This result
will allow the planning and successful execution of future observations to
probe the inner regions of nearby stellar systems, opening essentially
unexplored parameter space.Comment: 15 pages, 9 figures, submitted to ApJ Letter
Terrestrial Very-Long-Baseline Atom Interferometry:Workshop Summary
This document presents a summary of the 2023 Terrestrial Very-Long-Baseline Atom Interferometry Workshop hosted by CERN. The workshop brought together experts from around the world to discuss the exciting developments in large-scale atom interferometer (AI) prototypes and their potential for detecting ultralight dark matter and gravitational waves. The primary objective of the workshop was to lay the groundwork for an international TVLBAI proto-collaboration. This collaboration aims to unite researchers from different institutions to strategize and secure funding for terrestrial large-scale AI projects. The ultimate goal is to create a roadmap detailing the design and technology choices for one or more km-scale detectors, which will be operational in the mid-2030s. The key sections of this report present the physics case and technical challenges, together with a comprehensive overview of the discussions at the workshop together with the main conclusions
The JWST Early Release Science Program for Direct Observations of Exoplanetary Systems. IV. NIRISS Aperture Masking Interferometry Performance and Lessons Learned
We present a performance analysis for the aperture masking interferometry (AMI) mode on board the James Webb Space Telescope Near Infrared Imager and Slitless Spectrograph (JWST/NIRISS). Thanks to self-calibrating observables, AMI accesses inner working angles down to and even within the classical diffraction limit. The scientific potential of this mode has recently been demonstrated by the Early Release Science (ERS) 1386 program with a deep search for close-in companions in the HIP 65426 exoplanetary system. As part of ERS 1386, we use the same data set to explore the random, static, and calibration errors of NIRISS AMI observables. We compare the observed noise properties and achievable contrast to theoretical predictions. We explore possible sources of calibration errors and show that differences in charge migration between the observations of HIP 65426 and point-spread function calibration stars can account for the achieved contrast curves. Lastly, we use self-calibration tests to demonstrate that with adequate calibration NIRISS F380M AMI can reach contrast levels of ∼9–10 mag at ≳λ/D. These tests lead us to observation planning recommendations and strongly motivate future studies aimed at producing sophisticated calibration strategies taking these systematic effects into account. This will unlock the unprecedented capabilities of JWST/NIRISS AMI, with sensitivity to significantly colder, lower-mass exoplanets than lower-contrast ground-based AMI setups, at orbital separations inaccessible to JWST coronagraphy
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The JWST Early Release Science Program for Direct Observations of Exoplanetary Systems. V. Do Self-consistent Atmospheric Models Represent JWST Spectra? A Showcase with VHS 1256–1257 b
The unprecedented medium-resolution (R λ ∼ 1500–3500) near- and mid-infrared (1–18 μm) spectrum provided by JWST for the young (140 ± 20 Myr) low-mass (12–20 MJup) L–T transition (L7) companion VHS 1256 b gives access to a catalog of molecular absorptions. In this study, we present a comprehensive analysis of this data set utilizing a forward-modeling approach applying our Bayesian framework, ForMoSA. We explore five distinct atmospheric models to assess their performance in estimating key atmospheric parameters: Teff, log(g), [M/H], C/O, γ, f sed, and R. Our findings reveal that each parameter’s estimate is significantly influenced by factors such as the wavelength range considered and the model chosen for the fit. This is attributed to systematic errors in the models and their challenges in accurately replicating the complex atmospheric structure of VHS 1256 b, notably the complexity of its clouds and dust distribution. To propagate the impact of these systematic uncertainties on our atmospheric property estimates, we introduce innovative fitting methodologies based on independent fits performed on different spectral windows. We finally derived a Teff consistent with the spectral type of the target, considering its young age, which is confirmed by our estimate of log(g). Despite the exceptional data quality, attaining robust estimates for chemical abundances [M/H] and C/O, often employed as indicators of formation history, remains challenging. Nevertheless, the pioneering case of JWST’s data for VHS 1256 b has paved the way for future acquisitions of substellar spectra that will be systematically analyzed to directly compare the properties of these objects and correct the systematics in the models
Data from: Postmating isolation and genetically variable host use in ecologically divergent host forms of Neochlamisus bebbianae leaf beetles
Ecological speciation studies have more thoroughly addressed premating than postmating reproductive isolation. This study examines multiple postmating barriers between host forms of Neochlamisus bebbianae leaf beetles that specialize on Acer versus Salix trees. We demonstrate cryptic isolation and reduced hybrid fitness via controlled matings of these host forms. These findings reveal host-associated postmating isolation, although a non-ecological, ‘intrinsic’ basis for these patterns cannot be ruled out. Host preference and performance results among cross types further suggest sex-linked maternal effects on these traits, while family effects indicate their genetic basis and associated variation. Genes of major effect appear to influence these traits. Together with previous findings of premating isolation and adaptive differentiation in sympatry, our results meet many assumptions of ‘speciation with gene flow’ models. Here, such gene flow is likely asymmetric, with consequences for the dynamics of future ecological divergence and potential ecological speciation of these host forms
Synthesis of 2-(2-Aminopyrimidine)-2,2-difluoroethanols as Potential Bioisosters of Salicylidene Acylhydrazides
molecule
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