Evaluating the New Automatic Method for the Analysis of Absorption Spectra Using Synthetic Spectra

We recently presented a new "artificial intelligence" method for the analysis of high-resolution absorption spectra (Bainbridge and Webb, Mon. Not. R. Astron. Soc. 2017, 468,1639-1670). This new method unifies three established numerical methods: a genetic algorithm (GVPFIT); non-linear least-squares optimisation with parameter constraints (VPFIT); and Bayesian Model Averaging (BMA). In this work, we investigate the performance of GVPFIT and BMA over a broad range of velocity structures using synthetic spectra. We found that this new method recovers the velocity structures of the absorption systems and accurately estimates variation in the fine structure constant. Studies such as this one are required to evaluate this new method before it can be applied to the analysis of large sets of absorption spectra. This is the first time that a sample of synthetic spectra has been utilised to investigate the analysis of absorption spectra. Probing the variation of nature's fundamental constants (such as the fine structure constant), through the analysis of absorption spectra, is one of the most direct ways of testing the universality of physical laws. This "artificial intelligence" method provides a way to avoid the main limiting factor, i.e., human interaction, in the analysis of absorption spectra.Comment: 9 pages, 5 figures, published on 5 April 2017 in Univers

Validation of evidence-Based Fall Prevention Programs for adults with intellectual and/or developmental disorders: a modified otago exercise Program

Introduction: Evidence-based fall prevention (EBFP) programs significantly decrease fall risk, falls, and fall-related injuries in community-dwelling older adults. To date, EBFP programs are only validated for use among people with normal cognition and, therefore, are not evidence-based for adults with intellectual and/or developmental disorders (IDD) such as Alzheimer’s disease and related dementias, cerebral vascular accident, or traumatic brain injury. Background: Adults with IDD experience not only a higher rate of falls than their community-dwelling, cognitively intact peers but also higher rates and earlier onset of chronic diseases, also known to increase fall risk. Adults with IDD experience many barriers to health care and health promotion programs. As the lifespan for people with IDD continues to increase, issues of aging (including falls with associated injury) are on the rise and require effective and efficient prevention. Methods: A modified group-based version of the Otago Exercise Program (OEP) was developed and implemented at a worksite employing adults with IDD in Montana. Participants were tested pre- and post-intervention using the Center for Disease Control and Prevention’s (CDC) Stopping Elderly Accidents Deaths and Injuries (STEADI) tool kit. Participants participated in progressive once weekly, 1-h group exercise classes and home programs over a 7-week period. Discharge planning with consumers and caregivers included home exercise, walking, and an optional home assessment. Results: Despite the limited number of participants (n = 15) and short length of participation, improvements were observed in the 30-s Chair Stand Test, 4-Stage Balance Test, and 2-Minute Walk Test. Additionally, three individuals experienced an improvement in ambulation independence. Participants reported no falls during the study period. Discussion: Promising results of this preliminary project underline the need for further study of this modified OEP among adults with IDD. Future multicenter study should include more participants in diverse geographic regions with longer lengths of participation and follow-up

Quantifying single nucleotide variant detection sensitivity in exome sequencing

BACKGROUND: The targeted capture and sequencing of genomic regions has rapidly demonstrated its utility in genetic studies. Inherent in this technology is considerable heterogeneity of target coverage and this is expected to systematically impact our sensitivity to detect genuine polymorphisms. To fully interpret the polymorphisms identified in a genetic study it is often essential to both detect polymorphisms and to understand where and with what probability real polymorphisms may have been missed. RESULTS: Using down-sampling of 30 deeply sequenced exomes and a set of gold-standard single nucleotide variant (SNV) genotype calls for each sample, we developed an empirical model relating the read depth at a polymorphic site to the probability of calling the correct genotype at that site. We find that measured sensitivity in SNV detection is substantially worse than that predicted from the naive expectation of sampling from a binomial. This calibrated model allows us to produce single nucleotide resolution SNV sensitivity estimates which can be merged to give summary sensitivity measures for any arbitrary partition of the target sequences (nucleotide, exon, gene, pathway, exome). These metrics are directly comparable between platforms and can be combined between samples to give “power estimates” for an entire study. We estimate a local read depth of 13X is required to detect the alleles and genotype of a heterozygous SNV 95% of the time, but only 3X for a homozygous SNV. At a mean on-target read depth of 20X, commonly used for rare disease exome sequencing studies, we predict 5–15% of heterozygous and 1–4% of homozygous SNVs in the targeted regions will be missed. CONCLUSIONS: Non-reference alleles in the heterozygote state have a high chance of being missed when commonly applied read coverage thresholds are used despite the widely held assumption that there is good polymorphism detection at these coverage levels. Such alleles are likely to be of functional importance in population based studies of rare diseases, somatic mutations in cancer and explaining the “missing heritability” of quantitative traits

Spatial variation in the fine-structure constant -- new results from VLT/UVES

(abridged) We present a new analysis of a large sample of quasar absorption-line spectra obtained using UVES (the Ultraviolet and Visual Echelle Spectrograph) on the VLT (Very Large Telescope) in Chile. In the VLT sample (154 absorbers), we find evidence that alpha increases with increasing cosmological distance from Earth. However, as previously shown, the Keck sample (141 absorbers) provided evidence for a smaller alpha in the distant absorption clouds. Upon combining the samples an apparent variation of alpha across the sky emerges which is well represented by an angular dipole model pointing in the direction RA=(17.3 +/- 1.0) hr, dec. = (-61 +/- 10) deg, with amplitude (0.97 +0.22/-0.20) x 10^(-5). The dipole model is required at the 4.1 sigma statistical significance level over a simple monopole model where alpha is the same across the sky (but possibly different to the current laboratory value). The data sets reveal a number of remarkable consistencies: various data cuts are consistent and there is consistency in the overlap region of the Keck and VLT samples. Assuming a dipole-only (i.e. no-monopole) model whose amplitude grows proportionally with `lookback-time distance' (r=ct, where t is the lookback time), the amplitude is (1.1 +/- 0.2) x 10^(-6) GLyr^(-1) and the model is significant at the 4.2 sigma confidence level over the null model [Delta alpha]/alpha = 0). We apply robustness checks and demonstrate that the dipole effect does not originate from a small subset of the absorbers or spectra. We present an analysis of systematic effects, and are unable to identify any single systematic effect which can emulate the observed variation in alpha.Comment: 47 pages, 35 figures. Accepted for publication by Monthly Notices of the Royal Astronomical Society. Please see http://astronomy.swin.edu.au/~mmurphy/pub.html for an ASCII version of table A1 and the full set of Voigt profile fits for appendix

AIFM1 mutation presenting with fatal encephalomyopathy and mitochondrial disease in an infant

Apoptosis-inducing factor mitochondrion-associated 1 (AIFM1), encoded by the gene AIFM1, has roles in electron transport, apoptosis, ferredoxin metabolism, reactive oxygen species generation, and immune system regulation. Here we describe a patient with a novel AIFM1 variant presenting unusually early in life with mitochondrial disease, rapid deterioration, and death. Autopsy, at the age of 4 mo, revealed features of mitochondrial encephalopathy, myopathy, and involvement of peripheral nerves with axonal degeneration. In addition, there was microvesicular steatosis in the liver, thymic noninvolution, follicular bronchiolitis, and pulmonary arterial medial hypertrophy. This report adds to the clinical and pathological spectrum of disease related to AIFM1 mutations and provides insights into the role of AIFM1 in cellular function

Bridging Alone: Religious Conservatism, Marital Homogamy, and Voluntary Association Membership

This study characterizes social insularity of religiously conservative American married couples by examining patterns of voluntary associationmembership. Constructing a dataset of 3938 marital dyads from the second wave of the National Survey of Families and Households, the author investigates whether conservative religious homogamy encourages membership in religious voluntary groups and discourages membership in secular voluntary groups. Results indicate that couples’ shared affiliation with conservative denominations, paired with beliefs in biblical authority and inerrancy, increases the likelihood of religious group membership for husbands and wives and reduces the likelihood of secular group membership for wives, but not for husbands. The social insularity of conservative religious groups appears to be reinforced by homogamy—particularly by wives who share faith with husbands

Modelling Blood Flow and Metabolism in the Preclinical Neonatal Brain during and Following Hypoxic-Ischaemia

Hypoxia-ischaemia (HI) is a major cause of neonatal brain injury, often leading to long-term damage or death. In order to improve understanding and test new treatments, piglets are used as preclinical models for human neonates. We have extended an earlier computational model of piglet cerebral physiology for application to multimodal experimental data recorded during episodes of induced HI. The data include monitoring with near-infrared spectroscopy (NIRS) and magnetic resonance spectroscopy (MRS), and the model simulates the circulatory and metabolic processes that give rise to the measured signals. Model extensions include simulation of the carotid arterial occlusion used to induce HI, inclusion of cytoplasmic pH, and loss of metabolic function due to cell death. Model behaviour is compared to data from two piglets, one of which recovered following HI while the other did not. Behaviourally-important model parameters are identified via sensitivity analysis, and these are optimised to simulate the experimental data. For the non-recovering piglet, we investigate several state changes that might explain why some MRS and NIRS signals do not return to their baseline values following the HI insult. We discover that the model can explain this failure better when we include, among other factors such as mitochondrial uncoupling and poor cerebral blood flow restoration, the death of around 40% of the brain tissue. Copyright

Targeted Sequencing in Chromosome 17q Linkage Region Identifies Familial Glioma Candidates in the Gliogene Consortium

Glioma is a rare, but highly fatal, cancer that accounts for the majority of malignant primary brain tumors. Inherited predisposition to glioma has been consistently observed within non-syndromic families. Our previous studies, which involved non-parametric and parametric linkage analyses, both yielded significant linkage peaks on chromosome 17q. Here, we use data from next generation and Sanger sequencing to identify familial glioma candidate genes and variants on chromosome 17q for further investigation. We applied a filtering schema to narrow the original list of 4830 annotated variants down to 21 very rare (,0.1% frequency), non-synonymous variants. Our findings implicate the MYO19 and KIF18B genes and rare variants in SPAG9 and RUNDC1 as candidates worthy of further investigation. Burden testing and functional studies are planned

De Novo ZMYND8 variants result in an autosomal dominant neurodevelopmental disorder with cardiac malformations

Purpose: ZMYND8 encodes a multidomain protein that serves as a central interactive hub for coordinating critical roles in transcription regulation, chromatin remodeling, regulation of superenhancers, DNA damage response and tumor suppression. We delineate a novel neurocognitive disorder caused by variants in the ZMYND8 gene. Methods: An international collaboration, exome sequencing, molecular modeling, yeast twohybrid assays, analysis of available transcriptomic data and a knockdown Drosophila model were used to characterize the ZMYND8 variants. Results: ZMYND8 variants were identified in 11 unrelated individuals; 10 occurred de novo and one suspected de novo; 2 were truncating, 9 were missense, of which one was recurrent. The disorder is characterized by intellectual disability with variable cardiovascular, ophthalmologic and minor skeletal anomalies. Missense variants in the PWWP domain of ZMYND8 abolish the interaction with Drebrin and missense variants in the MYND domain disrupt the interaction with GATAD2A. ZMYND8 is broadly expressed across cell types in all brain regions and shows highest expression in the early stages of brain development. Neuronal knockdown of the Drosophila ZMYND8 ortholog results in decreased habituation learning, consistent with a role in cognitive function. Conclusion: We present genomic and functional evidence for disruption of ZMYND8 as a novel etiology of syndromic intellectual disability