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The Psychiatric Genomics Consortium (PGC) has made major advances in the molecular etiology of MDD, confirming that MDD is highly polygenic. Pathway enrichment results from PGC meta-analyses can also be used to help inform molecular drug targets. Prior to any knowledge of molecular biomarkers for MDD, drugs targeting molecular pathways (MPs) proved successful in treating MDD. It is possible that examining polygenicity within specific MPs implicated in MDD can further refine molecular drug targets.
Using a large case–control GWAS based on low-coverage whole genome sequencing (N = 10 640) in Han Chinese women, we derived polygenic risk scores (PRS) for MDD and for MDD specific to each of over 300 MPs previously shown to be relevant to psychiatric diagnoses. We then identified sets of PRSs, accounting for critical covariates, significantly predictive of case status.
Over and above global MDD polygenic risk, polygenic risk within the GO: 0017144 drug metabolism pathway significantly predicted recurrent depression after multiple testing correction. Secondary transcriptomic analysis suggests that among genes in this pathway, CYP2C19 (family of Cytochrome P450) and CBR1 (Carbonyl Reductase 1) might be most relevant to MDD. Within the cases, pathway-based risk was additionally associated with age at onset of MDD.
Results indicate that pathway-based risk might inform etiology of recurrent major depression. Future research should examine whether polygenicity of the drug metabolism gene pathway has any association with clinical presentation or treatment response. We discuss limitations to the generalizability of these preliminary findings, and urge replication in future research.
Despite established clinical associations among major depression (MD), alcohol dependence (AD), and alcohol consumption (AC), the nature of the causal relationship between them is not completely understood. We leveraged genome-wide data from the Psychiatric Genomics Consortium (PGC) and UK Biobank to test for the presence of shared genetic mechanisms and causal relationships among MD, AD, and AC.
Linkage disequilibrium score regression and Mendelian randomization (MR) were performed using genome-wide data from the PGC (MD: 135 458 cases and 344 901 controls; AD: 10 206 cases and 28 480 controls) and UK Biobank (AC-frequency: 438 308 individuals; AC-quantity: 307 098 individuals).
Positive genetic correlation was observed between MD and AD (rgMD−AD = + 0.47, P = 6.6 × 10−10). AC-quantity showed positive genetic correlation with both AD (rgAD−AC quantity = + 0.75, P = 1.8 × 10−14) and MD (rgMD−AC quantity = + 0.14, P = 2.9 × 10−7), while there was negative correlation of AC-frequency with MD (rgMD−AC frequency = −0.17, P = 1.5 × 10−10) and a non-significant result with AD. MR analyses confirmed the presence of pleiotropy among these four traits. However, the MD-AD results reflect a mediated-pleiotropy mechanism (i.e. causal relationship) with an effect of MD on AD (beta = 0.28, P = 1.29 × 10−6). There was no evidence for reverse causation.
This study supports a causal role for genetic liability of MD on AD based on genetic datasets including thousands of individuals. Understanding mechanisms underlying MD-AD comorbidity addresses important public health concerns and has the potential to facilitate prevention and intervention efforts.
Legionnaires’ disease (LD) incidence in the USA has quadrupled since 2000. Health departments must detect LD outbreaks quickly to identify and remediate sources. We tested the performance of a system to prospectively detect simulated LD outbreaks in Allegheny County, Pennsylvania, USA. We generated three simulated LD outbreaks based on published outbreaks. After verifying no significant clusters existed in surveillance data during 2014–2016, we embedded simulated outbreak-associated cases into 2016, assigning simulated residences and report dates. We mimicked daily analyses in 2016 using the prospective space-time permutation scan statistic to detect clusters of ⩽30 and ⩽180 days using 365-day and 730-day baseline periods, respectively. We used recurrence interval (RI) thresholds of ⩾20, ⩾100 and ⩾365 days to define significant signals. We calculated sensitivity, specificity and positive and negative predictive values for daily analyses, separately for each embedded outbreak. Two large, simulated cooling tower-associated outbreaks were detected. As the RI threshold was increased, sensitivity and negative predictive value decreased, while positive predictive value and specificity increased. A small, simulated potable water-associated outbreak was not detected. Use of a RI threshold of ⩾100 days minimised time-to-detection while maximizing positive predictive value. Health departments should consider using this system to detect community-acquired LD outbreaks.
Objectives: To evaluate prospective and retrospective memory abilities in Operation Enduring Freedom (OEF), Operation Iraqi Freedom (OIF), and Operation New Dawn (OND) Veterans with and without a self-reported history of blast-related mild traumatic brain injury (mTBI). Methods: Sixty-one OEF/OIF/OND Veterans, including Veterans with a self-reported history of blast-related mTBI (mTBI group; n=42) and Veterans without a self-reported history of TBI (control group; n=19) completed the Memory for Intentions Test, a measure of prospective memory (PM), and two measures of retrospective memory (RM), the California Verbal Learning Test-II and the Brief Visuospatial Memory Test-Revised. Results: Veterans in the mTBI group exhibited significantly lower PM performance than the control group, but the groups did not differ in their performance on RM measures. Further analysis revealed that Veterans in the mTBI group with current PTSD (mTBI/PTSD+) demonstrated significantly lower performance on the PM measure than Veterans in the control group. PM performance by Veterans in the mTBI group without current PTSD (mTBI/PTSD-) was intermediate between the mTBI/PTSD+ and control groups, and results for the mTBI/PTSD- group were not significantly different from either of the other two groups. Conclusions: Results suggest that PM performance may be a sensitive marker of cognitive dysfunction among OEF/OIF/OND Veterans with a history of self-reported blast-related mTBI and comorbid PTSD. Reduced PM may account, in part, for complaints of cognitive difficulties in this Veteran cohort, even years post-injury. (JINS, 2018, 24, 324–334)
Identifying genetic relationships between complex traits in emerging adulthood can provide useful etiological insights into risk for psychopathology. College-age individuals are under-represented in genomic analyses thus far, and the majority of work has focused on the clinical disorder or cognitive abilities rather than normal-range behavioral outcomes.
This study examined a sample of emerging adults 18–22 years of age (N = 5947) to construct an atlas of polygenic risk for 33 traits predicting relevant phenotypic outcomes. Twenty-eight hypotheses were tested based on the previous literature on samples of European ancestry, and the availability of rich assessment data allowed for polygenic predictions across 55 psychological and medical phenotypes.
Polygenic risk for schizophrenia (SZ) in emerging adults predicted anxiety, depression, nicotine use, trauma, and family history of psychological disorders. Polygenic risk for neuroticism predicted anxiety, depression, phobia, panic, neuroticism, and was correlated with polygenic risk for cardiovascular disease.
These results demonstrate the extensive impact of genetic risk for SZ, neuroticism, and major depression on a range of health outcomes in early adulthood. Minimal cross-ancestry replication of these phenomic patterns of polygenic influence underscores the need for more genome-wide association studies of non-European populations.
Previous studies have demonstrated that several major psychiatric disorders are influenced by shared genetic factors. This shared liability may influence clinical features of a given disorder (e.g. severity, age at onset). However, findings have largely been limited to European samples; little is known about the consistency of shared genetic liability across ethnicities.
The relationship between polygenic risk for several major psychiatric diagnoses and major depressive disorder (MDD) was examined in a sample of unrelated Han Chinese women. Polygenic risk scores (PRSs) were generated using European discovery samples and tested in the China, Oxford, and VCU Experimental Research on Genetic Epidemiology [CONVERGE (maximum N = 10 502)], a sample ascertained for recurrent MDD. Genetic correlations between discovery phenotypes and MDD were also assessed. In addition, within-case characteristics were examined.
European-based polygenic risk for several major psychiatric disorder phenotypes was significantly associated with the MDD case status in CONVERGE. Risk for clinically significant indicators (neuroticism and subjective well-being) was also associated with case–control status. The variance accounted for by PRS for both psychopathology and for well-being was similar to estimates reported for within-ethnicity comparisons in European samples. However, European-based PRS were largely unassociated with CONVERGE family history, clinical characteristics, or comorbidity.
The shared genetic liability across severe forms of psychopathology is largely consistent across European and Han Chinese ethnicities, with little attenuation of genetic signal relative to within-ethnicity analyses. The overall absence of associations between PRS for other disorders and within-MDD variation suggests that clinical characteristics of MDD may arise due to contributions from ethnicity-specific factors and/or pathoplasticity.
The MCSA is a special-purpose digital signal processor. Its main function is to filter a wide-band signal into many narrower bands, so that each of the output bands has a bandwidth that is a better match to the signal being searched for.
The basic MCSA provides simultaneous output bandwidths of approximately 1 HZ, 32 Hz, 1024 Hz, and 74 kHz over a spectrum that is about 8 MHz wide. The input to the MCSA consists of a complex signal sampled at 10 MHz, and the outputs consist of either complex samples or power (square-law-detected) samples. In addition, the MCSA provides an accumulator for taking the integral of the power of the output bands for periods up to 1000 sec.
The MCSA hardware is constructed using wire-wrap technology. The implementation of the hardware is done with the aid of a computer program developed specifically for the design of the MCSA. Care has been taken in the MCSA design to ensure that engineering tradeoffs do not adversely affect the performance of the system.
The aim of the survey is to sample a relatively large, randomly chosen volume of the Universe in order to study the large-scale distribution of galaxies using the two-point correlation function, the peculiar velocities between galaxy pairs and to provide an estimate of the galaxian luminosity function that is unaffected by density inhomogeneities and Virgo infall.
We are investigating a complete sample of flat-spectrum extragalactic radio quasars drawn from the Parkes 2.7 GHz survey. The sample is being used to map the space distribution of radio quasars and to determine their luminosity function. Accurate positions are being measured for a selection of the brighter quasars in order to establish an extragalactic position reference frame in the Southern Hemisphere.
We are investigating complete samples of southern hemisphere flat spectrum extra-galactic radio sources drawn from the Parkes 2.7 GHz Survey (see Bolton et al. 1979 and references therein). These samples are being used for a variety of investigations, including a determination of the space distribution and luminosity function of radio QSOs, their radio size distribution, as well as the structures of the individual sources. Accurate positions are being determined, as well, in order to establish an extra-galactic position reference frame in the southern hemisphere.
Antigenic variation in malaria was discovered in Plasmodium knowlesi studies involving longitudinal infections of rhesus macaques (M. mulatta). The variant proteins, known as the P. knowlesi Schizont Infected Cell Agglutination (SICA) antigens and the P. falciparum Erythrocyte Membrane Protein 1 (PfEMP1) antigens, expressed by the SICAvar and var multigene families, respectively, have been studied for over 30 years. Expression of the SICA antigens in P. knowlesi requires a splenic component, and specific antibodies are necessary for variant antigen switch events in vivo. Outstanding questions revolve around the role of the spleen and the mechanisms by which the expression of these variant antigen families are regulated. Importantly, the longitudinal dynamics and molecular mechanisms that govern variant antigen expression can be studied with P. knowlesi infection of its mammalian and vector hosts. Synchronous infections can be initiated with established clones and studied at multi-omic levels, with the benefit of computational tools from systems biology that permit the integration of datasets and the design of explanatory, predictive mathematical models. Here we provide an historical account of this topic, while highlighting the potential for maximizing the use of P. knowlesi – macaque model systems and summarizing exciting new progress in this area of research.
Experiments on the National Ignition Facility show that multi-dimensional effects currently dominate the implosion performance. Low mode implosion symmetry and hydrodynamic instabilities seeded by capsule mounting features appear to be two key limiting factors for implosion performance. One reason these factors have a large impact on the performance of inertial confinement fusion implosions is the high convergence required to achieve high fusion gains. To tackle these problems, a predictable implosion platform is needed meaning experiments must trade-off high gain for performance. LANL has adopted three main approaches to develop a one-dimensional (1D) implosion platform where 1D means measured yield over the 1D clean calculation. A high adiabat, low convergence platform is being developed using beryllium capsules enabling larger case-to-capsule ratios to improve symmetry. The second approach is liquid fuel layers using wetted foam targets. With liquid fuel layers, the implosion convergence can be controlled via the initial vapor pressure set by the target fielding temperature. The last method is double shell targets. For double shells, the smaller inner shell houses the DT fuel and the convergence of this cavity is relatively small compared to hot spot ignition. However, double shell targets have a different set of trade-off versus advantages. Details for each of these approaches are described.
The foetal mammary gland is sensitive to maternal weight and nutrition during gestation, which could affect offspring milk production. It has previously been shown that ewes born to dams offered maintenance nutrition during pregnancy (day 21 to 140 of gestation) produced greater milk, lactose and CP yields in their first lactation when compared with ewes born to dams offered ad libitum nutrition. In addition, ewes born to heavier dams produced greater milk and lactose yields when compared with ewes born to lighter dams. The objective of this study was to analyse and compare the 5-year lactation performance of the previously mentioned ewes, born to heavy or light dams that were offered maintenance or ad libitum pregnancy nutrition. Ewes were milked once per week, for the first 6 weeks of their lactation, for 5 years. Using milk yield and composition data, accumulated yields were calculated over a 42-day period for each year for milk, milk fat, CP, true protein, casein and lactose using a Legendre orthogonal polynomial model. Over the 5-year period, ewes born to heavy dams produced greater average milk (P=0.04), lactose (P=0.01) and CP (P=0.04) yields than offspring born to light dams. In contrast, over the 5-year period dam nutrition during pregnancy did not affect average (P>0.05) offspring milk yields or composition, but did increase milk and lactose accumulated yield (P=0.03 and 0.01, respectively) in the first lactation. These results indicate that maternal gestational nutrition appears to only affect the first lactational performance of ewe offspring. Neither dam nutrition nor size affected grand-offspring live weight gain to, or live weight at weaning (P>0.05). Combined these data indicate that under the conditions of the present study, manipulating dam weight or nutrition in pregnancy can have some effects of offspring lactational performance, however, these effects are not large enough to alter grand-offspring growth to weaning. Therefore, such manipulations are not a viable management tool for farmers to influence lamb growth to weaning.
We have analyzed a sample of 1150 type ab, and 550 type c RR Lyrae stars found in 24 of 94 bulge fields of the MACHO database. These fields cover a range in Galactocentric distances from 0.3 to 1.6 kpc. In combination with the data on the outer bulge fields of Alard (1997) and Wesselink (1987), here we present the surface density distribution of bulge RR Lyrae between 0.3 and 3 kpc.
The MACHO microlensing experiment's time-sampled photometry database contains blue and red lightcurves for nearly 9 million stars in the central bar region of the Large Magellanic Cloud (LMC). We have identified known LMC Planetary Nebulae (PN) in the database and find one, Jacoby 5, to be variable. We additionally present data on the “parent populations” of LMC PN, and discuss the star formation history of the LMC bar.
A review of the properties of Type II Cepheids and RV Tauri stars in the Magellanic Clouds is presented. In the behaviour of their light and colour curves, the RV Tauri stars appear to be a direct extension of the Type II Cepheids to longer periods. A single P – L – C relationship describes both the Type II Cepheids and RV Tauri stars in the LMC. The derived high intrinsic magnitudes for the RV Tauri variables supports the proposition that these objects are luminous stars evolving off the AGB. Preliminary analysis of the long time-series MACHO photometry indicates one star (MACHO*05:37:45.0–69:54:16) has an obvious ‘period-quadrupled’ periodicity, which is supporting evidence for a period-doubling bifurcation transition to chaotic pulsations.
We present Chandra HETG spectra of seven cataclysmic variables, including four intermediate polars. We find that they divide unambiguously into two distinct types. Spectra of the first type (nonmagnetic systems and EX Hya) are remarkably well fit by a simple cooling flow model, which assumes only steady-state isobaric radiative cooling. The maximum temperature, kTmax, and the normalization, which provides a highly precise measurement of the accretion rate, are the only free parameters of this model. Spectra of the second type (the three other IPs) are grossly inconsistent with a cooling flow model. They instead exhibit a hard continuum, and show strong H-like and He-like ion emission but little Fe L-shell emission, which is consistent with expectations for line emission from a photoionized plasma. Using a simple photoionization model, we argue that the observed line emission for these sources can be driven entirely by the hard continuum. The physical significance of these two distinct types of X-ray spectra is also explored.
We present the first results of the analysis of 22 Blazhko stars. We find: 1) Blazhko RRab stars that are nearly pure amplitude modulators; 2) Blazhko RRab stars that have both amplitude and phase modulation; 3) A Blazhko RRab star that has an abrupt period change; 4) Proof of the Blazhko effect in RRc stars. Our data show the character of the amplitude and phase modulations of the light curves over the Blazhko cycles far better than has been previously possible.
We present the preliminary results of a frequency analysis of 1457 fundamental mode RR Lyrae (RR0) stars in the Large Magellanic Cloud (LMC) from MACHO Project photometry. We find the same classes of pulsational behavior as were found in our earlier survey of first overtone RR Lyrae (RR1) stars. Variables whose prewhitened power spectra contain one or two peaks close to the main frequency component in the original power spectra are commonly known as Blazhko-type variables. The present analysis shows the overall frequency of Blazhko-type stars in the total RR0 population analysed to date to be ≈ 10%. This is lower than the often cited Galactic field/globular rate of 20-30% (Szeidl, 1988).
The incidence rate of Blazhko-type variability in the LMC appears to be about three times higher in RR0 stars than in RR1 stars. This puts important constraints on possible models of the Blazhko effect.
We present the first massive frequency analysis of the 1200 first overtone RR Lyrae stars in the Large Magellanic Cloud observed in the first 4.3 yr of the MACHO project. Besides the many new double-mode variables, we also discovered stars with closely spaced frequencies. These variables are most probably nonradial pulsators.