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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.
Few studies have investigated the patterns of posttraumatic stress disorder (PTSD) symptom change in prolonged exposure (PE) therapy. In this study, we aimed to understand the patterns of PTSD symptom change in both PE and present-centered therapy (PCT).
Participants were active duty military personnel (N = 326, 89.3% male, 61.2% white, 32.5 years old) randomized to spaced-PE (S-PE; 10 sessions over 8 weeks), PCT (10 sessions over 8 weeks), or massed-PE (M-PE; 10 sessions over 2 weeks). Using latent profile analysis, we determined the optimal number of PTSD symptom change classes over time and analyzed whether baseline and follow-up variables were associated with class membership.
Five classes, namely rapid responder (7–17%), steep linear responder (14–22%), gradual responder (30–34%), non-responder (27–33%), and symptom exacerbation (7–13%) classes, characterized each treatment. No baseline clinical characteristics predicted class membership for S-PE and M-PE; in PCT, more negative baseline trauma cognitions predicted membership in the non-responder v. gradual responder class. Class membership was robustly associated with PTSD, trauma cognitions, and depression up to 6 months after treatment for both S-PE and M-PE but not for PCT.
Distinct profiles of treatment response emerged that were similar across interventions. By and large, no baseline variables predicted responder class. Responder status was a strong predictor of future symptom severity for PE, whereas response to PCT was not as strongly associated with future symptoms.
The development of laser wakefield accelerators (LWFA) over the past several years has led to an interest in very compact sources of X-ray radiation – such as “table-top” free electron lasers. However, the use of conventional undulators using permanent magnets also implies system sizes which are large. In this work, we assess the possibilities for the use of novel mini-undulators in conjunction with a LWFA so that the dimensions of the undulator become comparable with the acceleration distances for LWFA experiments (i.e., centimeters). The use of a prototype undulator using laser machining of permanent magnets for this application is described and the emission characteristics and limitations of such a system are determined. Preliminary electron propagation and X-ray emission measurements are taken with a LWFA electron beam at the University of Michigan.
Animal and cross-sectional epidemiological studies suggest that prenatal lead exposure is related to delayed menarche, but this has not been confirmed in longitudinal studies. We analyzed this association among 200 girls from Mexico City who were followed since the first trimester of gestation. Maternal blood lead levels were analyzed once during each trimester of pregnancy, and daughters were asked about their first menstrual cycle at a visit between the ages of 9.8 and 18.1 years. We estimated hazard ratios (HRs) and 95% confidence intervals (CI) for probability of menarche over the follow-up period using interval-censored Cox models, comparing those with prenatal blood lead level ⩾5 µg/dl to those with prenatal blood lead <5 µg/dl. We also estimated HRs and 95% CI with conventional Cox regression models, which utilized the self-reported age at menarche. In adjusted analyses, we accounted for maternal age, maternal parity, maternal education, and prenatal calcium treatment status. Across trimesters, 36−47% of mothers had blood lead levels ⩾5 µg/dl. Using interval-censored models, we found that during the second trimester only, girls with ⩾5 µg/dl prenatal blood lead had a later age at menarche compared with girls with prenatal blood lead levels <5 µg/dl (confounder-adjusted HR=0.59, 95% CI 0.28–0.90; P=0.05). Associations were in a similar direction, although not statistically significant, in the conventional Cox regression models, potentially indicating measurement error in the self-recalled age at menarche. In summary, higher prenatal lead exposure during the second trimester could be related to later onset of sexual maturation.
Exotic annual grasses such as medusahead [Taeniatherum caput-medusae (L.) Nevski] and downy brome (Bromus tectorum L.) dominate millions of hectares of grasslands in the western United States. Applying picloram, aminopyralid, and other growth regulator herbicides at late growth stages reduces seed production of most exotic annual grasses. In this study, we applied aminopyralid to T. caput-medusae to determine how reducing seed production in the current growing season influenced cover in the subsequent growing season. At eight annual grassland sites, we applied aminopyralid at 55, 123, and 245 g ae ha−1 in spring just before T. caput-medusae heading. The two higher rates were also applied pre-emergence (PRE) in fall to allow comparisons with this previously tested timing. When applied in spring during the roughly 10-d period between the flag leaf and inflorescence first becoming visible, just 55 g ae ha−1 of aminopyralid greatly limited seed production and subsequently reduced T. caput-medusae cover to nearly zero. Fall aminopyralid applications were less effective against T. caput-medusae, even at a rate of 245 g ae ha−1. The growing season of application, fall treatments, but not spring treatments, sometimes reduced cover of desirable winter annual forage grasses. The growing season after application, both spring and fall treatments tended to increase forage grasses, though spring treatments generally caused larger increases. Compared with other herbicide treatment options, preheading aminopyralid treatments are a relatively inexpensive, effective approach for controlling T. caput-medusae and increasing forage production.
Habits are behavioral routines that are automatic and frequent, relatively independent of any desired outcome, and have potent antecedent cues. Among individuals with anorexia nervosa (AN), behaviors that promote the starved state appear habitual, and this is the foundation of a recent neurobiological model of AN. In this proof-of-concept study, we tested the habit model of AN by examining the impact of an intervention focused on antecedent cues for eating disorder routines.
The primary intervention target was habit strength; we also measured clinical impact via eating disorder psychopathology and actual eating. Twenty-two hospitalized patients with AN were randomly assigned to 12 sessions of either Supportive Psychotherapy or a behavioral intervention aimed at cues for maladaptive behavioral routines, Regulating Emotions and Changing Habits (REaCH).
Covarying for baseline, REaCH was associated with a significantly lower Self-Report Habit Index (SRHI) score and significantly lower Eating Disorder Examination-Questionnaire (EDE-Q) global score at the end-of-treatment. The end-of-treatment effect size for SRHI was d = 1.28, for EDE-Q was d = 0.81, and for caloric intake was d = 1.16.
REaCH changed habit strength of maladaptive routines more than an active control therapy, and targeting habit strength yielded improvement in clinically meaningful measures. These findings support a habit-based model of AN, and suggest habit strength as a mechanism-based target for intervention.
The re-emergence of debates on the decolonisation of knowledge has revived interest in the National Question, which began over a century ago and remains unresolved. Tensions that were suppressed and hidden in the past are now being openly debated. Despite this, the goal of one united nation living prosperously under a constitutional democracy remains elusive. This edited volume examines the way in which various strands of left thought have addressed the National Question, especially during the apartheid years, and goes on to discuss its relevance for South Africa today and in the future. Instead of imposing a particular understanding of the National Question, the editors identified a number of political traditions and allowed contributors the freedom to define the question as they believed appropriate – in other words, to explain what they thought was the Unresolved National Question. This has resulted in a rich tapestry of interweaving perceptions. The volume is structured in two parts. The first examines four foundational traditions: Marxism-Leninism (the Colonialism of a Special Type thesis); the Congress tradition; the Trotskyist tradition; and Africanism. The second part explores the various shifts in the debate from the 1960s onwards, and includes chapters on Afrikaner nationalism, ethnic issues, black consciousness, feminism, workerism and constitutionalism. The editors hope that by revisiting the debates not popularly known among the scholarly mainstream, this volume will become a catalyst for an enriched debate on our identity and our future.
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 genesis of some types of patterned ground, including hummocks, frost boils and sorted stone circles, has been attributed to differential frost heave (DFH). However, a theoretical model that adequately describes DFH has yet to be developed and validated. In this paper, we present a mathematical model for the initiation of DFH, and discuss how variations in physical (i.e. soil/vegetation properties) and environmental (i.e. ground/air temperatures) properties affect its occurrence and length scale. Using the Fowler and Krantz multidimensional frost-heave equations, a linear stability analysis anda quasi-steady-state real-time analysis are performed. Results indicate that the following conditions positively affect the spontaneous initiation of DFH: silty soil, small Young’s modulus, small non-uniform surface heat transfer or cold uniform surface temperatures, and small freezing depths. The initiating mechanism for DFH is multidimensional heat transfer within the freezing soil. Numerical integration of the linear growth rates indicates that expression of surface patterns can become evident on the 10–100 year time-scale.
Variability of the emission-line spectra of broad-line AGNs is now a well-established phenomenon (see Peterson 1988 for a review). The rapid variability of the emission lines and the strong correlation between continuum and line fluxes suggests broad-line region (BLR) dimensions too small to be consistent with theoretical estimates based on photoionization equilibrium considerations.
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 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.