Circumnuclear Structures in Megamaser Host Galaxies

Using the Hubble Space Telescope, we identify circumnuclear (100-500 pc scale) structures in nine new H2O megamaser host galaxies to understand the flow of matter from kpc-scale galactic structures down to the supermassive black holes (SMBHs) at galactic centers. We double the sample analyzed in a similar way by Greene et al. and consider the properties of the combined sample of 18 sources. We find that disk-like structure is virtually ubiquitous when we can resolve <200 pc scales, in support of the notion that non-axisymmetries on these scales are a necessary condition for SMBH fueling. We perform an analysis of the orientation of our identified nuclear regions and compare it with the orientation of megamaser disks and the kpc-scale disks of the hosts. We find marginal evidence that the disk-like nuclear structures show increasing misalignment from the kpc-scale host galaxy disk as the scale of the structure decreases. In turn, we find that the orientation of both the similar to 100 pc scale nuclear structures and their host galaxy large-scale disks is consistent with random with respect to the orientation of their respective megamaser disks

GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture

Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment

Ultra-Rare Genetic Variation in the Epilepsies : A Whole-Exome Sequencing Study of 17,606 Individuals

Sequencing-based studies have identified novel risk genes associated with severe epilepsies and revealed an excess of rare deleterious variation in less-severe forms of epilepsy. To identify the shared and distinct ultra-rare genetic risk factors for different types of epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,436 controls of European ancestry. We focused on three phenotypic groups: severe developmental and epileptic encephalopathies (DEEs), genetic generalized epilepsy (GGE), and non-acquired focal epilepsy (NAFE). We observed that compared to controls, individuals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in constrained genes and in genes previously associated with epilepsy; we saw the strongest enrichment in individuals with DEEs and the least strong in individuals with NAFE. Moreover, we found that inhibitory GABA(A) receptor genes were enriched for missense variants across all three classes of epilepsy, whereas no enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEEs and GGE. Although no single gene surpassed exome-wide significance among individuals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the lead associations; such genes included CACNAIG, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and GABRG2 for NAFE. Our study, the largest epilepsy WES study to date, confirms a convergence in the genetics of severe and less-severe epilepsies associated with ultra-rare coding variation, and it highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology.Peer reviewe

Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals

Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control individuals. While prior Epi25 studies focused on gene-based collapsing analyses, we asked how the pattern of variation within genes differs by epilepsy type. Specifically, we compared the genetic architectures of severe developmental and epileptic encephalopathies (DEEs) and two generally less severe epilepsies, genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). Our gene-based rare variant collapsing analysis used geographic ancestry-based clustering that included broader ancestries than previously possible and revealed novel associations. Using the missense intolerance ratio (MTR), we found that variants in DEE-affected individuals are in significantly more intolerant genic sub-regions than those in NAFE-affected individuals. Only previously reported pathogenic variants absent in available genomic datasets showed a significant burden in epilepsy-affected individuals compared with control individuals, and the ultra-rare pathogenic variants associated with DEE were located in more intolerant genic sub-regions than variants associated with non-DEE epilepsies. MTR filtering improved the yield of ultra-rare pathogenic variants in affected individuals compared with control individuals. Finally, analysis of variants in genes without a disease association revealed a significant burden of loss-of-function variants in the genes most intolerant to such variation, indicating additional epilepsy-risk genes yet to be discovered. Taken together, our study suggests that genic and sub-genic intolerance are critical characteristics for interpreting the effects of variation in genes that influence epilepsy

Stochastic model predictive control with joint chance constraints

This article investigates model predictive control (MPC) of linear systems subject to arbitrary (possibly unbounded) stochastic disturbances. An MPC approach is presented to account for hard input constraints and joint state chance constraints in the presence of unbounded additive disturbances. The Cantelli–Chebyshev inequality is used in combination with risk allocation to obtain computationally tractable but accurate surrogates for the joint state chance constraints when only the mean and variance of the arbitrary disturbance distributions are known. An algorithm is presented for determining the optimal feedback gain and optimal risk allocation by iteratively solving a series of convex programs. The proposed stochastic MPC approach is demonstrated on a continuous acetone–butanol–ethanol fermentation process, which is used in the production of biofuels

Stochastic model predictive control with joint chance constraints

This article investigates model predictive control (MPC) of linear systems subject to arbitrary (possibly unbounded) stochastic disturbances. An MPC approach is presented to account for hard input constraints and joint state chance constraints in the presence of unbounded additive disturbances. The Cantelli–Chebyshev inequality is used in combination with risk allocation to obtain computationally tractable but accurate surrogates for the joint state chance constraints when only the mean and variance of the arbitrary disturbance distributions are known. An algorithm is presented for determining the optimal feedback gain and optimal risk allocation by iteratively solving a series of convex programs. The proposed stochastic MPC approach is demonstrated on a continuous acetone–butanol–ethanol fermentation process, which is used in the production of biofuels

Drink and Drugs and Your Body - (Book review)

We present results of an HST survey in Hα and continuum filters of a sample of H2O megamaser galaxies compiled by Braatz et al., all of which contain AGN. These observations allow us to study the AGN/host-galaxy connection, e.g. study the relation between the parsec scale masing disk/torus, bipolar outflows, and large scale properties of the galaxies such as dust lanes, signs for interaction, and galaxy types. A number of galaxies indeed show large-scale bi-polar Hα structures which, however, are more reminiscent of outflows then excitation cones. Most megamaser galaxies are found in spiral galaxies. Only one galaxy in the original sample is known to be an elliptical and one galaxy imaged by us shows clear signs of interactions. In all cases we see evidence for obscuration of the nucleus (e.g. dust-lanes) in our color maps and the disk galaxies are preferentially edge on. This suggests that the nuclear masing disk has some relation to the large scale properties of the galaxy and the dust distribution

Model Predictive Control of an Integrated Continuous Pharmaceutical Manufacturing Pilot Plant

This paper considers the model predictive control (MPC) of critical quality attributes (CQAs) of products in an end-to-end continuous pharmaceutical manufacturing pilot plant, which was designed and constructed at the Novartis-MIT Center for Continuous Manufacturing. Feedback control is crucial for achieving the stringent regulatory requirements on CQAs of pharmaceutical products in the presence of process uncertainties and disturbances. To this end, a key challenge arises from complex plant-wide dynamics of the integrated process units in a continuous pharmaceutical process, that is, dynamical interactions between several process units. This paper presents two plant-wide MPC designs for the end-to-end continuous pharmaceutical manufacturing pilot plant using the quadratic dynamic matrix control algorithm. The plant-wide MPC designs are based on different modeling approaches - subspace identification and linearization of nonlinear differential-algebraic equations that yield, respectively, linear low-dimensional and high-dimensional state-space models for the plant-wide dynamics. The closed-loop performance of the plant-wide MPC designs is evaluated using a nonlinear plant simulator equipped with a stabilizing control layer. The closed-loop simulation results demonstrate that the plant-wide MPC systems can facilitate effective regulation of CQAs and flexible process operation in the presence of uncertainties in reaction kinetics, persistent drifts in efficiency of filtration units, temporary disturbances in purity of intermediate compounds, and set point changes. The plant-wide MPC allows for incorporating quality-by-design considerations into the control problem through input and output constraints to ensure regulatory compliant process operation

Measuring Supermassive Black Hole Peculiar Motion Using H2O Megamasers

H2O megamasers residing in the accretion disks of active galactic nuclei (AGNs) exhibit Keplerian rotation about the central supermassive black hole (SMBH). Such disk maser systems are excellent tools for diagnosing the kinematic status of the SMBH, and they currently provide the only direct and unambiguous measure of SMBH velocities outside the Milky Way. We have measured the galaxy recession velocities for a sample of 10 maser disk systems using a combination of spatially resolved H I disk modeling, spatially integrated H I profile fitting, and optical spectral line and continuum fitting. In comparing the SMBH velocities to those of their host galaxies, we find two (out of 10) systems-J0437+2456 and NGC 6264-for which the SMBH and galaxy velocities show a statistically significant (>3 sigma) difference. For NGC 6264 the apparent velocity offset can likely be explained by ionized gas motion within the host galaxy (e.g., from AGN-driven shocks). The velocity measurements for J0437+2456, however, imply a SMBH peculiar velocity of 69.6 +/- 12.7 km s(-1) (5.5 sigma). We thus consider J0437+2456 to be a promising candidate for hosting either a recoiling or binary SMBH, though additional observations are necessary to exclude the possibility of a systematic offset between the galactic recession velocity and that measured using the optical spectrum