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Background: SMA is characterized by reduced levels of survival of motor neuron (SMN) protein from deletions and/or mutations of the SMN1 gene. While SMN1 produces full-length SMN protein, a second gene, SMN2, produces low levels of functional SMN protein. Risdiplam (RG7916/RO7034067) is an investigational, orally administered, centrally and peripherally distributed small molecule that modulates pre-mRNA splicing of SMN2 to increase SMN protein levels. Methods: FIREFISH (NCT02913482) is an ongoing, multicenter, open-label operationally seamless study of risdiplam in infants aged 1–7 months with Type 1 SMA and two SMN2 gene copies. Exploratory Part 1 (n=21) assesses the safety, tolerability, pharmacokinetics and pharmacodynamics of different risdiplam dose levels. Confirmatory Part 2 (n=40) is assessing the safety and efficacy of risdiplam. Results: In a Part 1 interim analysis (data-cut 09/07/18), 93% (13/14) of babies had ≥4-point improvement in CHOP-INTEND total score from baseline at Day 245, with a median change of 16 points. The number of infants meeting HINE-2 motor milestones (baseline to Day 245) increased. To date (data-cut 09/07/18), no drug-related safety findings have led to patient withdrawal. No significant ophthalmological findings have been observed. Conclusions: In FIREFISH Part 1, risdiplam improved motor function in infants with Type 1 SMA.
Background: There is currently no accepted classification of recessive cerebellar ataxias, a group of disorders characterized by important genetic heterogeneity and complex phenotypes. The objective of this task force was to build a consensus and develop a clinical and pathophysiological classification for recessive ataxias. Methods: The work of this task force was based on a scoping systematic review of the literature that identified recessive disorders characterized primarily by a cerebellar motor syndrome and cerebellar degeneration. The task force regrouped 12 international ataxia experts who decided on general orientation and specific issues. Results: We identified 59 disorders that are classified as primary recessive ataxias. For each of these disorders, we present geographical and ethnical specificities along with distinctive clinical and imagery features. The primary recessive ataxias were organized in a clinical and a pathophysiological classification, and we present a general clinical approach to the patient presenting with ataxia. We also identified a list of 48 complex multisystem disorders in which ataxia is a secondary feature. Conclusions: This classification is based on a scoping systematic review of the literature and results from a sconsensus among a panel of international experts. It promotes a unified understanding of recessive cerebellar disorders for clinicians and researchers.
While our fascination with understanding the past is sufficient to warrant an increased focus on synthesis, solutions to important problems facing modern society require understandings based on data that only archaeology can provide. Yet, even as we use public monies to collect ever-greater amounts of data, modes of research that can stimulate emergent understandings of human behavior have lagged behind. Consequently, a substantial amount of archaeological inference remains at the level of the individual project. We can more effectively leverage these data and advance our understandings of the past in ways that contribute to solutions to contemporary problems if we adapt the model pioneered by the National Center for Ecological Analysis and Synthesis to foster synthetic collaborative research in archaeology. We propose the creation of the Coalition for Archaeological Synthesis coordinated through a U.S.-based National Center for Archaeological Synthesis. The coalition will be composed of established public and private organizations that provide essential scholarly, cultural heritage, computational, educational, and public engagement infrastructure. The center would seek and administer funding to support collaborative analysis and synthesis projects executed through coalition partners. This innovative structure will enable the discipline to address key challenges facing society through evidentially based, collaborative synthetic research.
In the framework of our multi-frequency study of Virgo A we have performed observations of Vir A at 10.55 GHz with the Effelsberg 100-m telescope. Using our improved CLEAN procedure for single dish data we have increased the dynamic range to some 40 dB.
By applying our newly developed polarization CLEANing technique we are able to diminish instrumental polarization effects. Since Faraday rotation is negligible at λ2.8 cm the measured linear polarization is a direct trace of the projected magnetic field in Vir A. In combination with low-frequency data obtained with the VLA it is possible to determine parameters like spectral indices, break frequencies, and spectral ages.
Although adolescence is marked by increased negative life events and internalizing problems, few studies investigate this association as an ongoing longitudinal process. Moreover, while there are considerable individual differences in the degree to which these phenomena are linked, little is known about the origins of these differences. The present study examines early life stress (ELS) exposure and early-adolescent longitudinal afternoon cortisol level as predictors of the covariation between internalizing symptoms and negative life events across high school. ELS was assessed by maternal report during infancy, and the measure of cortisol was derived from assessments at ages 11, 13, and 15 years. Life events and internalizing symptoms were assessed at ages 15, 17, and 18 years. A two-level hierarchical linear model revealed that ELS and cortisol were independent predictors of the covariation of internalizing symptoms and negative life events. Compared to those with lower levels of ELS, ELS-exposed adolescents displayed tighter covariation between internalizing symptoms and negative life events. Adolescents with lower longitudinal afternoon cortisol displayed tighter covariation between negative life events and internalizing symptoms, while those with higher cortisol demonstrated weaker covariation, partially due to increased levels of internalizing symptoms when faced with fewer negative life events.
Single layer regions of MoS2 on SiO2 and SrTiO3 were identified by Raman spectroscopy and μ-photoluminescence before Kelvin probe force microscopy was performed. For the already known system MoS2/SiO2 we find 1.839 eV for the direct bandgap, in good agreement with earlier results. On MoS2/SrTiO3 the direct bandgap was determined to be 1.829 eV. From our Kelvin probe data we infer that the SrTiO3 substrate leads to a dipole layer at the interface of the MoS2 single layer. The corresponding μ-PL measurements however show no significant decrease of the bandgap. This shows, that in the case of MoS2 the carrier type as well as concentration is not significantly influenced by the choice of SrTiO3 as the substrate compared to SiO2.
The luminescence of erbium implanted in hydrogenated amorphous silicon (a-Si : H) is presented. For the first time an intense and relatively sharp luminescence at 1.54 mm is observed in a-Si : H, using implanted erbium. The Er+ emission intensity strongly depends on the hydrogen film content and on the measurement temperature. A direct correlation between the optical gap energy of the semiconductor and the hydrogen film content is observed.
CL spectroscopy studies at varying temperatures and excitation power densities as well as depth-resolved CL imaging were conducted to investigate the impact of low energy electron beam irradiation (LEEBI) on native defects and residual impurities in metal-organic vapor phase epitaxy (MOVPE) grown Mg-doped p-type GaN. Due to the dissociation of (Mg-H)0 complexes, LEEBI significantly increases the (e,Mg0) emission (3.26 eV) at 300 K and substantially decreases the H-Mg donor-acceptor-pair (DAP) emission (3.27 eV) at 80 K. In-plane and depth-resolved CL imaging indicates that hydrogen dissociation results from electron-hole recombination at H-defect complexes rather than heating by the electron beam. The dissociated hydrogen atoms associate with nitrogen vacancies, forming a deeper donor, i.e. a (H-VN) complex. The corresponding deeper DAP emission with Mg centered at 3.1 eV is clearly observed between 160 and 220 K. Moreover, a broad yellow luminescence (YL) band centered at 2.2 eV is observed in MOVPE-grown Mg-doped GaN after LEEBI-treatment. It is suggested that a combination of LEEBI-induced Fermi-level downshift due to Mg-acceptor activation and simultaneous dissociation of gallium vacancy-impurity complexes, i.e. (VGa-H), is responsible for the observed YL.
Cooperative self-assembly processes of inorganic species and amphiphilic molecules have experienced major advances over the past six years. The ability to design these materials with spatially controlled combinations of different mesophases or compositions, and therefore different properties, would greatly enhance their utility as nanofunctional surfaces.
We present a simple lithographic procedure, which allows a deliberate control of structure and properties of a meso-ordered silica film through optical mediation. This nanostructural lithography process exploits the pH sensitivity of supra-molecular self-assembly which allows spatial control over mesophases in the thin film and a selective etching capability. Through the addition of a photoacid generator in the coating sol along with surfactant and silica source, dip coating results in continuous, ordered photosensitive films. Exposure to UV light through a mask produces local pH changes, inducing mesostructural phase transitions and an increase in the acidcatalyzed siloxane condensation rate in the exposed regions. Two surfactant systems, CTAB (CH3(CH2)15N+(CH3)3Br–) and Brij 56 (CH3(CH2)15(OCH2CH2)10OH) have been studied. X-ray diffraction, transmission and scanning electron microscopy, optical microscopy, ellipsometry, MAS-NMR and atomic force microscopy are used to characterize the patterned nanostructured surfaces.
Classical approaches to modeling fracture have proved successful in applications for which the highly deformed region near a crack tip is small compared to any other relevant dimensions in the structure. The classical theory relies on phenomenological criteria for material failure that lack a physics-based description of the fracture process itself. Small scale, thin film structures pose difficulties for analysis by these approaches because they contain complicated geometry and many interfaces within the fracture process zone itself. Moreover, plastic flow in metal layers is often severely constrained by the surrounding structure, causing the plastic dissipation part of the overall fracture energy consumed by debonding to be a strong function of geometry. Therefore, it can no longer be regarded as an intrinsic material property. To improve the fracture characterization of these structures, one must develop a physically sound methodology capable of separating the contribution of plastic flow, and other sources of dissipation, from the work of adhesion consumed at the crack tip. In this study, we investigate the parameters affecting energy dissipation by interfacial debonding in a multilayered structure. Interlayer decohesion is modeled using the Virtual Internal Bond constitutive model. We compare our predicted variations in the macroscopic fracture energy with experimental results for varying layer geometry. We also characterize the effect of variations in material properties and other experimental uncertainties in the resulting debonding behavior.
In this work we present steady-state characteristics and low-frequency noise spectra of AlGaN/GaN based high electron mobility transistors (HEMTs) exposed to gamma ray radiation. The devices with a variety of gate length (150-350 nm) and width (100-400 νm) were irradiated by 60Co gamma rays with doses in the range of 104-109 Rad and flux of 102 Rad/s. Dose dependencies of basic operating parameters of the transistors, such as saturation current (Isat), transconductance (gm), channel conductance (gc), and threshold voltage (VT) are analysed. Our study show that visible changes of above mentioned parameters are observed under relatively small doses (105 Rad) and strongly depend on the HEMT's topology. The transconductance decreases and threshold voltage becomes more negative for all devices while deviation of these parameters from its initial values does not exceed 20% at highest irradiation dose. At the same time variation of the channel conductance as well as saturation current depends to a high extent on the gate voltage (Vg). At |Vg| < |Vcr|, both Isat and gc show a reversal proportional to the cumulative dosage of radiation. However, at |Vg| > |Vcr|, drain saturation current and channel conductance increase with the cumulative dosage of radiation. The effect is more pronounced in short-length-gate devices.
The Balloon-borne Large Aperture Submillimeter Telescope (BLAST) has recently conducted an extragalactic submillimetric survey of the Chandra Deep Field South region of unprecedented size, depth, and angular resolution in three wavebands centered at 250,
350, and 500 µm. BLAST wavelengths are chosen to study the Cosmic Infrared Background near its peak at 200 µm.
We find that most of the CIB at these wavelengths is contributed by galaxies detected at 24 µm by the MIPS instrument on Spitzer, and that the source counts distribution shows a population with strongly evolving density and luminosity. These results anticipate what can be expected from the surveys that will be conducted with the SPIRE instrument on the Herschel space observatory.
Dyadic discord, while common in depression, has not been specifically evaluated as an outcome predictor in chronic major depressive disorder. This study investigated pretreatment dyadic discord as a predictor of non-remission and its relationship to depressive symptom change during acute treatment for chronic depression.
Out-patients with chronic depression were randomized to 12 weeks of treatment with nefazodone, the Cognitive Behavioral Analysis System of Psychotherapy or their combination. Measures included the Marital Adjustment Scale (MAS) and the Inventory of Depressive Symptomatology – Self Report (IDS-SR30). Of 681 original patients, 316 were partnered and 171 of these completed a baseline and exit MAS, and at least one post-baseline IDS-SR30. MAS scores were analysed as continuous and categorical variables (‘dyadic discord’ v. ‘no dyadic discord’ defined as an MAS score >2.36. Remission was defined as an IDS-SR30 of ⩽14 at exit (equivalent to a 17-item Hamilton Rating Scale for Depression of ⩽7).
Patients with dyadic discord at baseline had lower remission rates (34.1%) than those without dyadic discord (61.2%) (all three treatment groups) (χ2=12.6, df=1, p=0.0004). MAS scores improved significantly with each of the treatments, although the change was reduced by controlling for improvement in depression. Depression remission at exit was associated with less dyadic discord at exit than non-remission for all three groups [for total sample, 1.8 v. 2.4, t(169)=7.3, p<0.0001].
Dyadic discord in chronically depressed patients is predictive of a lower likelihood of remission of depression. Couple therapy for those with dyadic discord may increase remission rates.