Analytic Relations for Magnifications and Time Delays in Gravitational Lenses with Fold and Cusp Configurations

Gravitational lensing provides a unique and powerful probe of the mass distributions of distant galaxies. Four-image lens systems with fold and cusp configurations have two or three bright images near a critical point. Within the framework of singularity theory, we derive analytic relations that are satisfied for a light source that lies a small but finite distance from the astroid caustic of a four-image lens. Using a perturbative expansion of the image positions, we show that the time delay between the close pair of images in a fold lens scales with the cube of the image separation, with a constant of proportionality that depends on a particular third derivative of the lens potential. We also apply our formalism to cusp lenses, where we develop perturbative expressions for the image positions, magnifications and time delays of the images in a cusp triplet. Some of these results were derived previously for a source asymptotically close to a cusp point, but using a simplified form of the lens equation whose validity may be in doubt for sources that lie at astrophysically relevant distances from the caustic. Along with the work of Keeton et al. (2005), this paper demonstrates that perturbation theory plays an important role in theoretical lensing studies.Comment: 10 pages, 3 figures; reference added, minor correction

Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP

Background In genome-wide screening studies for de novo mutations underlying autism and intellectual disability, mutations in the ADNP gene are consistently reported among the most frequent. ADNP mutations have been identified in children with autism spectrum disorder comorbid with intellectual disability, distinctive facial features, and deficits in multiple organ systems. However, a comprehensive clinical description of the Helsmoortel-Van der Aa syndrome is lacking. Methods We identified a worldwide cohort of 78 individuals with likely disruptive mutations in ADNP from January 2014 to October 2016 through systematic literature search, by contacting collaborators, and through direct interaction with parents. Clinicians filled in a structured questionnaire on genetic and clinical findings to enable correlations between genotype and phenotype. Clinical photographs and specialist reports were gathered. Parents were interviewed to complement the written questionnaires. Results We report on the detailed clinical characterization of a large cohort of individuals with an ADNP mutation and demonstrate a distinctive combination of clinical features, including mild to severe intellectual disability, autism, severe speech and motor delay, and common facial characteristics. Brain abnormalities, behavioral problems, sleep disturbance, epilepsy, hypotonia, visual problems, congenital heart defects, gastrointestinal problems, short stature, and hormonal deficiencies are common comorbidities. Strikingly, individuals with the recurrent p.Tyr719* mutation were more severely affected. Conclusions This overview defines the full clinical spectrum of individuals with ADNP mutations, a specific autism subtype. We show that individuals with mutations in ADNP have many overlapping clinical features that are distinctive from those of other autism and/or intellectual disability syndromes. In addition, our data show preliminary evidence of a correlation between genotype and phenotype.This work was supported by grants from the European Research Area Networks Network of European Funding for Neuroscience Research through the Research Foundation–Flanders and the Chief Scientist Office–Ministry of Health (to RFK, GV, IG). This research was supported, in part, by grants from the Simons Foundation Autism Research Initiative (Grant No. SFARI 303241 to EEE) and National Institutes of Health (Grant No. R01MH101221 to EEE). This work was also supported by the Italian Ministry of Health and ‘5 per mille’ funding (to CR). For many individuals, sequencing was provided by research initiatives like the Care4Rare Research Consortium in Canada or the Deciphering Developmental Disorders (DDD) study in the UK. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (Grant No. HICF-1009–003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (Grant No. WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of the Wellcome Trust or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South Research Ethics Committee, and GEN/284/12 granted by the Republic of Ireland Research Ethics Committee). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network

Solving patients with rare diseases through programmatic reanalysis of genome-phenome data.

Funder: EC | EC Seventh Framework Programm | FP7 Health (FP7-HEALTH - Specific Programme "Cooperation": Health); doi: https://doi.org/10.13039/100011272; Grant(s): 305444, 305444Funder: Ministerio de Economía y Competitividad (Ministry of Economy and Competitiveness); doi: https://doi.org/10.13039/501100003329Funder: Generalitat de Catalunya (Government of Catalonia); doi: https://doi.org/10.13039/501100002809Funder: EC | European Regional Development Fund (Europski Fond za Regionalni Razvoj); doi: https://doi.org/10.13039/501100008530Funder: Instituto Nacional de Bioinformática ELIXIR Implementation Studies Centro de Excelencia Severo OchoaFunder: EC | EC Seventh Framework Programm | FP7 Health (FP7-HEALTH - Specific Programme "Cooperation": Health)Reanalysis of inconclusive exome/genome sequencing data increases the diagnosis yield of patients with rare diseases. However, the cost and efforts required for reanalysis prevent its routine implementation in research and clinical environments. The Solve-RD project aims to reveal the molecular causes underlying undiagnosed rare diseases. One of the goals is to implement innovative approaches to reanalyse the exomes and genomes from thousands of well-studied undiagnosed cases. The raw genomic data is submitted to Solve-RD through the RD-Connect Genome-Phenome Analysis Platform (GPAP) together with standardised phenotypic and pedigree data. We have developed a programmatic workflow to reanalyse genome-phenome data. It uses the RD-Connect GPAP's Application Programming Interface (API) and relies on the big-data technologies upon which the system is built. We have applied the workflow to prioritise rare known pathogenic variants from 4411 undiagnosed cases. The queries returned an average of 1.45 variants per case, which first were evaluated in bulk by a panel of disease experts and afterwards specifically by the submitter of each case. A total of 120 index cases (21.2% of prioritised cases, 2.7% of all exome/genome-negative samples) have already been solved, with others being under investigation. The implementation of solutions as the one described here provide the technical framework to enable periodic case-level data re-evaluation in clinical settings, as recommended by the American College of Medical Genetics

Structural studies of organic monolayer and protein -membrane systems via molecular dynamics computer simulations

Great interest exists among chemists, physicists, biologists, materials scientists and others, in learning more about the microscopic structure of organic thin films and protein-membrane complexes. In this work, we undertook structural investigations into two such systems, using molecular dynamics simulations as our tool. On the one hand, we studied different models of an alkane self-assembled monolayer, in order to improve our understanding of the structural effects of such parameters as the chain packing density in the monolayer plane, and the strength of the interactions between the chains and the model substrate surface. We found that the SAM-substrate interaction is very important to the SAM structure, and that by varying the strength of this interaction alone, we could produce SAMs either with or without long-range in-plane order (much like alkylthiol and alkylsilane SAMs, respectively). On the other hand, we performed extensive analysis of a family of model hydrated protein-membrane systems, in order to better understand the structural interrelation of a membrane protein, its associated membrane, and the surrounding solvent. Our basic model was a cytochrome c molecule attached to an alkane SAM and surrounded by water; we explored models with different amounts of water, different SAM endgroups, and differing coordination number of the heme iron atom. We found that the overall protein structure is largely conserved, that a polar-endgroup SAM interacts more strongly with the protein than does a nonpolar SAM, and that increased hydration tends to mitigate the effects of changing other parameters. Structural measurements from our models, such as the electron density profile and the protein\u27s orientation and radius of gyration, were in reasonable agreement with experimental spectroscopic and scattering measurements

Structural studies of organic monolayer and protein -membrane systems via molecular dynamics computer simulations

Great interest exists among chemists, physicists, biologists, materials scientists and others, in learning more about the microscopic structure of organic thin films and protein-membrane complexes. In this work, we undertook structural investigations into two such systems, using molecular dynamics simulations as our tool. On the one hand, we studied different models of an alkane self-assembled monolayer, in order to improve our understanding of the structural effects of such parameters as the chain packing density in the monolayer plane, and the strength of the interactions between the chains and the model substrate surface. We found that the SAM-substrate interaction is very important to the SAM structure, and that by varying the strength of this interaction alone, we could produce SAMs either with or without long-range in-plane order (much like alkylthiol and alkylsilane SAMs, respectively). On the other hand, we performed extensive analysis of a family of model hydrated protein-membrane systems, in order to better understand the structural interrelation of a membrane protein, its associated membrane, and the surrounding solvent. Our basic model was a cytochrome c molecule attached to an alkane SAM and surrounded by water; we explored models with different amounts of water, different SAM endgroups, and differing coordination number of the heme iron atom. We found that the overall protein structure is largely conserved, that a polar-endgroup SAM interacts more strongly with the protein than does a nonpolar SAM, and that increased hydration tends to mitigate the effects of changing other parameters. Structural measurements from our models, such as the electron density profile and the protein\u27s orientation and radius of gyration, were in reasonable agreement with experimental spectroscopic and scattering measurements

Direct evidence of conformational changes associated with voltage gating in a voltage sensor protein by time-resolved X-ray/neutron interferometry.

The voltage sensor domain (VSD) of voltage-gated cation (e.g., Na(+), K(+)) channels central to neurological signal transmission can function as a distinct module. When linked to an otherwise voltage-insensitive, ion-selective membrane pore, the VSD imparts voltage sensitivity to the channel. Proteins homologous with the VSD have recently been found to function themselves as voltage-gated proton channels or to impart voltage sensitivity to enzymes. Determining the conformational changes associated with voltage gating in the VSD itself in the absence of a pore domain thereby gains importance. We report the direct measurement of changes in the scattering-length density (SLD) profile of the VSD protein, vectorially oriented within a reconstituted phospholipid bilayer membrane, as a function of the transmembrane electric potential by time-resolved X-ray and neutron interferometry. The changes in the experimental SLD profiles for both polarizing and depolarizing potentials with respect to zero potential were found to extend over the entire length of the isolated VSD's profile structure. The characteristics of the changes observed were in qualitative agreement with molecular dynamics simulations of a related membrane system, suggesting an initial interpretation of these changes in terms of the VSD's atomic-level 3-D structure

Direct evidence of conformational changes associated with voltage gating in a voltage sensor protein by time-resolved X-ray/neutron interferometry.

The voltage sensor domain (VSD) of voltage-gated cation (e.g., Na(+), K(+)) channels central to neurological signal transmission can function as a distinct module. When linked to an otherwise voltage-insensitive, ion-selective membrane pore, the VSD imparts voltage sensitivity to the channel. Proteins homologous with the VSD have recently been found to function themselves as voltage-gated proton channels or to impart voltage sensitivity to enzymes. Determining the conformational changes associated with voltage gating in the VSD itself in the absence of a pore domain thereby gains importance. We report the direct measurement of changes in the scattering-length density (SLD) profile of the VSD protein, vectorially oriented within a reconstituted phospholipid bilayer membrane, as a function of the transmembrane electric potential by time-resolved X-ray and neutron interferometry. The changes in the experimental SLD profiles for both polarizing and depolarizing potentials with respect to zero potential were found to extend over the entire length of the isolated VSD's profile structure. The characteristics of the changes observed were in qualitative agreement with molecular dynamics simulations of a related membrane system, suggesting an initial interpretation of these changes in terms of the VSD's atomic-level 3-D structure

Soft x-ray absorption and emission spectra and the electronic structure of the Ba2YCu3O7−xBa_{2}YCu_{3}O_{7-x} superconductor

We present e-beam-excited soft-x-ray emission spectra and total-photoelectron-yield spectra in the 20–600 eV photon energy range for $Ba_2YCu_3O_{7−x}$. In soft x-ray emission, the N4,5 structure of Ba, the M4,5 spectrum of Y, and the K spectrum of O provide a direct measure of the p-type partial density of states (p-PDOS) localized on the respective atomic sites. In each case the p-PDOS is very small at the Fermi energy ɛF. The maximum in the O K spectrum is 2.6±0.5 eV below ɛF. This result provides direct confirmation that the shoulder previously found at ɛ$_F$-2.3 eV in photoelectron emission spectra is associated with O p orbitals. No changes are observed between spectra taken above and below Tc. .A