Likelihood-ratio ranking of gravitational-wave candidates in a non-Gaussian background

We describe a general approach to detection of transient gravitational-wave signals in the presence of non-Gaussian background noise. We prove that under quite general conditions, the ratio of the likelihood of observed data to contain a signal to the likelihood of it being a noise fluctuation provides optimal ranking for the candidate events found in an experiment. The likelihood-ratio ranking allows us to combine different kinds of data into a single analysis. We apply the general framework to the problem of unifying the results of independent experiments and the problem of accounting for non-Gaussian artifacts in the searches for gravitational waves from compact binary coalescence in LIGO data. We show analytically and confirm through simulations that in both cases the likelihood ratio statistic results in an improved analysis.Comment: 10 pages, 6 figure

Recreating blood-brain barrier physiology and structure on chip: A novel neurovascular microfluidic bioreactor

The blood-brain barrier (BBB) is a critical structure that serves as the gatekeeper between the central nervous system and the rest of the body. It is the responsibility of the BBB to facilitate the entry of required nutrients into the brain and to exclude potentially harmful compounds; however, this complex structure has remained difficult to model faithfully in vitro. Accurate in vitro models are necessary for understanding how the BBB forms and functions, as well as for evaluating drug and toxin penetration across the barrier. Many previous models have failed to support all the cell types involved in the BBB formation and/or lacked the flow-created shear forces needed for mature tight junction formation. To address these issues and to help establish a more faithful in vitro model of the BBB, we have designed and fabricated a microfluidic device that is comprised of both a vascular chamber and a brain chamber separated by a porous membrane. This design allows for cell-to-cell communication between endothelial cells, astrocytes, and pericytes and independent perfusion of both compartments separated by the membrane. This NeuroVascular Unit (NVU) represents approximately one-millionth of the human brain, and hence, has sufficient cell mass to support a breadth of analytical measurements. The NVU has been validated with both fluorescein isothiocyanate (FITC)-dextran diffusion and transendothelial electrical resistance. The NVU has enabled in vitro modeling of the BBB using all human cell types and sampling effluent from both sides of the barrier

Widespread genomic influences on phenotype in Dravet syndrome, a 'monogenic' condition

Dravet syndrome is an archetypal rare severe epilepsy, considered "monogenic", typically caused by loss-of-function SCN1A variants. Despite a recognisable core phenotype, its marked phenotypic heterogeneity is incompletely explained by differences in the causal SCN1A variant or clinical factors. In 34 adults with SCN1A-related Dravet syndrome, we show additional genomic variation beyond SCN1A contributes to phenotype and its diversity, with an excess of rare variants in epilepsy-related genes as a set and examples of blended phenotypes, including one individual with an ultra-rare DEPDC5 variant and focal cortical dysplasia. Polygenic risk scores for intelligence are lower, and for longevity, higher, in Dravet syndrome than in epilepsy controls. The causal, major-effect, SCN1A variant may need to act against a broadly compromised genomic background to generate the full Dravet syndrome phenotype, whilst genomic resilience may help to ameliorate the risk of premature mortality in adult Dravet syndrome survivors

Nebulin nemaline myopathy recapitulated in a compound heterozygous mouse model with both a missense and a nonsense mutation in Neb

Nemaline myopathy (NM) caused by mutations in the gene encoding nebulin (NEB) accounts for at least 50% of all NM cases worldwide, representing a significant disease burden. Most NEB-NM patients have autosomal recessive disease due to a compound heterozygous genotype. Of the few murine models developed for NEB-NM, most are Neb knockout models rather than harbouring Neb mutations. Additionally, some models have a very severe phenotype that limits their application for evaluating disease progression and potential therapies. No existing murine models possess compound heterozygous Neb mutations that reflect the genotype and resulting phenotype present in most patients. We aimed to develop a murine model that more closely matched the underlying genetics of NEB-NM, which could assist elucidation of the pathogenetic mechanisms underlying the disease. Here, we have characterised a mouse strain with compound heterozygous Neb mutations; one missense (p.Tyr2303His), affecting a conserved actin-binding site and one nonsense mutation (p.Tyr935*), introducing a premature stop codon early in the protein. Our studies reveal that this compound heterozygous model, Neb(Y2303H, Y935X), has striking skeletal muscle pathology including nemaline bodies. In vitro whole muscle and single myofibre physiology studies also demonstrate functional perturbations. However, no reduction in lifespan was noted. Therefore, Neb(Y2303H,Y935X) mice recapitulate human NEB-NM and are a much needed addition to the NEB-NM mouse model collection. The moderate phenotype also makes this an appropriate model for studying NEB-NM pathogenesis, and could potentially be suitable for testing therapeutic applications.Peer reviewe

Nebulin nemaline myopathy recapitulated in a compound heterozygous mouse model with both a missense and a nonsense mutation in Neb

Nemaline myopathy (NM) caused by mutations in the gene encoding nebulin (NEB) accounts for at least 50% of all NM cases worldwide, representing a significant disease burden. Most NEB-NM patients have autosomal recessive disease due to a compound heterozygous genotype. Of the few murine models developed for NEB-NM, most are Neb knockout models rather than harbouring Neb mutations. Additionally, some models have a very severe phenotype that limits their application for evaluating disease progression and potential therapies. No existing murine models possess compound heterozygous Neb mutations that reflect the genotype and resulting phenotype present in most patients. We aimed to develop a murine model that more closely matched the underlying genetics of NEB-NM, which could assist elucidation of the pathogenetic mechanisms underlying the disease. Here, we have characterised a mouse strain with compound heterozygous Neb mutations; one missense (p.Tyr2303His), affecting a conserved actin-binding site and one nonsense mutation (p.Tyr935*), introducing a premature stop codon early in the protein. Our studies reveal that this compound heterozygous model, Neb(Y2303H, Y935X), has striking skeletal muscle pathology including nemaline bodies. In vitro whole muscle and single myofibre physiology studies also demonstrate functional perturbations. However, no reduction in lifespan was noted. Therefore, Neb(Y2303H,Y935X) mice recapitulate human NEB-NM and are a much needed addition to the NEB-NM mouse model collection. The moderate phenotype also makes this an appropriate model for studying NEB-NM pathogenesis, and could potentially be suitable for testing therapeutic applications.Peer reviewe

Managing Incidental Genomic Findings in Clinical Trials: Fulfillment of the Principle of Justice

<p>Managing Incidental Genomic Findings in Clinical Trials: Fulfillment of the Principle of Justice</p

Testing for pharmacogenomic predictors of ppRNFL thinning in individuals exposed to vigabatrin

BACKGROUND: The anti-seizure medication vigabatrin (VGB) is effective for controlling seizures, especially infantile spasms. However, use is limited by VGB-associated visual field loss (VAVFL). The mechanisms by which VGB causes VAVFL remains unknown. Average peripapillary retinal nerve fibre layer (ppRNFL) thickness correlates with the degree of visual field loss (measured by mean radial degrees). Duration of VGB exposure, maximum daily VGB dose, and male sex are associated with ppRNFL thinning. Here we test the hypothesis that common genetic variation is a predictor of ppRNFL thinning in VGB exposed individuals. Identifying pharmacogenomic predictors of ppRNFL thinning in VGB exposed individuals could potentially enable safe prescribing of VGB and broader use of a highly effective drug. METHODS: Optical coherence topography (OCT) and GWAS data were processed from VGB-exposed individuals (n = 71) recruited through the EpiPGX Consortium. We conducted quantitative GWAS analyses for the following OCT measurements: (1) average ppRNFL, (2) inferior quadrant, (3) nasal quadrant, (4) superior quadrant, (5) temporal quadrant, (6) inferior nasal sector, (7) nasal inferior sector, (8) superior nasal sector, and (9) nasal superior sector. Using the summary statistics from the GWAS analyses we conducted gene-based testing using VEGAS2. We conducted nine different PRS analyses using the OCT measurements. To determine if VGB-exposed individuals were predisposed to having a thinner RNFL, we calculated their polygenic burden for retinal thickness. PRS alleles for retinal thickness were calculated using published summary statistics from a large-scale GWAS of inner retinal morphology using the OCT images of UK Biobank participants. RESULTS: The GWAS analyses did not identify a significant association after correction for multiple testing. Similarly, the gene-based and PRS analyses did not reveal a significant association that survived multiple testing. CONCLUSION: We set out to identify common genetic predictors for VGB induced ppRNFL thinning. Results suggest that large-effect common genetic predictors are unlikely to exist for ppRNFL thinning (as a marker of VAVFL). Sample size was a limitation of this study. However, further recruitment is a challenge as VGB is rarely used today because of this adverse reaction. Rare variants may be predictors of this adverse drug reaction and were not studied here

Neural Activity Patterns in Response to Interspecific and Intraspecific Variation in Mating Calls in the Túngara Frog

During mate choice, individuals must classify potential mates according to species identity and relative attractiveness. In many species, females do so by evaluating variation in the signals produced by males. Male túngara frogs (Physalaemus pustulosus) can produce single note calls (whines) and multi-note calls (whine-chucks). While the whine alone is sufficient for species recognition, females greatly prefer the whine-chuck when given a choice.To better understand how the brain responds to variation in male mating signals, we mapped neural activity patterns evoked by interspecific and intraspecific variation in mating calls in túngara frogs by measuring expression of egr-1. We predicted that egr-1 responses to conspecific calls would identify brain regions that are potentially important for species recognition and that at least some of those brain regions would vary in their egr-1 responses to mating calls that vary in attractiveness. We measured egr-1 in the auditory brainstem and its forebrain targets and found that conspecific whine-chucks elicited greater egr-1 expression than heterospecific whines in all but three regions. We found no evidence that preferred whine-chuck calls elicited greater egr-1 expression than conspecific whines in any of eleven brain regions examined, in contrast to predictions that mating preferences in túngara frogs emerge from greater responses in the auditory system.Although selectivity for species-specific signals is apparent throughout the túngara frog brain, further studies are necessary to elucidate how neural activity patterns vary with the attractiveness of conspecific mating calls

Female Sex and Gender in Lung/Sleep Health and Disease. Increased Understanding of Basic Biological, Pathophysiological, and Behavioral Mechanisms Leading to Better Health for Female Patients with Lung Disease

Female sex/gender is an undercharacterized variable in studies related to lung development and disease. Notwithstanding, many aspects of lung and sleep biology and pathobiology are impacted by female sex and female reproductive transitions. These may manifest as differential gene expression or peculiar organ development. Some conditions are more prevalent in women, such as asthma and insomnia, or, in the case of lymphangioleiomyomatosis, are seen almost exclusively in women. In other diseases, presentation differs, such as the higher frequency of exacerbations experienced by women with chronic obstructive pulmonary disease or greater cardiac morbidity among women with sleep-disordered breathing. Recent advances in -omics and behavioral science provide an opportunity to specifically address sex-based differences and explore research needs and opportunities that will elucidate biochemical pathways, thus enabling more targeted/personalized therapies. To explore the status of and opportunities for research in this area, the NHLBI, in partnership with the NIH Office of Research on Women's Health and the Office of Rare Diseases Research, convened a workshop of investigators in Bethesda, Maryland on September 18 and 19, 2017. At the workshop, the participants reviewed the current understanding of the biological, behavioral, and clinical implications of female sex and gender on lung and sleep health and disease, and formulated recommendations that address research gaps, with a view to achieving better health outcomes through more precise management of female patients with nonneoplastic lung disease. This report summarizes those discussions

Transcranial Electrical Currents to Probe EEG Brain Rhythms and Memory Consolidation during Sleep in Humans

Previously the application of a weak electric anodal current oscillating with a frequency of the sleep slow oscillation (∼0.75 Hz) during non-rapid eye movement sleep (NonREM) sleep boosted endogenous slow oscillation activity and enhanced sleep-associated memory consolidation. The slow oscillations occurring during NonREM sleep and theta oscillations present during REM sleep have been considered of critical relevance for memory formation. Here transcranial direct current stimulation (tDCS) oscillating at 5 Hz, i.e., within the theta frequency range (theta-tDCS) is applied during NonREM and REM sleep. Theta-tDCS during NonREM sleep produced a global decrease in slow oscillatory activity conjoint with a local reduction of frontal slow EEG spindle power (8–12 Hz) and a decrement in consolidation of declarative memory, underlining the relevance of these cortical oscillations for sleep-dependent memory consolidation. In contrast, during REM sleep theta-tDCS appears to increase global gamma (25–45 Hz) activity, indicating a clear brain state-dependency of theta-tDCS. More generally, results demonstrate the suitability of oscillating-tDCS as a tool to analyze functions of endogenous EEG rhythms and underlying endogenous electric fields as well as the interactions between EEG rhythms of different frequencies