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Major depressive disorder (MDD) is a common and disabling condition with well-established heritability and environmental risk factors. Gene–environment interaction studies in MDD have typically investigated candidate genes, though the disorder is known to be highly polygenic. This study aims to test for interaction between polygenic risk and stressful life events (SLEs) or childhood trauma (CT) in the aetiology of MDD.
The RADIANT UK sample consists of 1605 MDD cases and 1064 controls with SLE data, and a subset of 240 cases and 272 controls with CT data. Polygenic risk scores (PRS) were constructed using results from a mega-analysis on MDD by the Psychiatric Genomics Consortium. PRS and environmental factors were tested for association with case/control status and for interaction between them.
PRS significantly predicted depression, explaining 1.1% of variance in phenotype (p = 1.9 × 10−6). SLEs and CT were also associated with MDD status (p = 2.19 × 10−4 and p = 5.12 × 10−20, respectively). No interactions were found between PRS and SLEs. Significant PRSxCT interactions were found (p = 0.002), but showed an inverse association with MDD status, as cases who experienced more severe CT tended to have a lower PRS than other cases or controls. This relationship between PRS and CT was not observed in independent replication samples.
CT is a strong risk factor for MDD but may have greater effect in individuals with lower genetic liability for the disorder. Including environmental risk along with genetics is important in studying the aetiology of MDD and PRS provide a useful approach to investigating gene–environment interactions in complex traits.
Strategies to dissect phenotypic and genetic heterogeneity of major depressive disorder (MDD) have mainly relied on subphenotypes, such as age at onset (AAO) and recurrence/episodicity. Yet, evidence on whether these subphenotypes are familial or heritable is scarce. The aims of this study are to investigate the familiality of AAO and episode frequency in MDD and to assess the proportion of their variance explained by common single nucleotide polymorphisms (SNP heritability).
For investigating familiality, we used 691 families with 2–5 full siblings with recurrent MDD from the DeNt study. We fitted (square root) AAO and episode count in a linear and a negative binomial mixed model, respectively, with family as random effect and adjusting for sex, age and center. The strength of familiality was assessed with intraclass correlation coefficients (ICC). For estimating SNP heritabilities, we used 3468 unrelated MDD cases from the RADIANT and GSK Munich studies. After similarly adjusting for covariates, derived residuals were used with the GREML method in GCTA (genome-wide complex trait analysis) software.
Significant familial clustering was found for both AAO (ICC = 0.28) and episodicity (ICC = 0.07). We calculated from respective ICC estimates the maximal additive heritability of AAO (0.56) and episodicity (0.15). SNP heritability of AAO was 0.17 (p = 0.04); analysis was underpowered for calculating SNP heritability of episodicity.
AAO and episodicity aggregate in families to a moderate and small degree, respectively. AAO is under stronger additive genetic control than episodicity. Larger samples are needed to calculate the SNP heritability of episodicity. The described statistical framework could be useful in future analyses.
The future of centimetre and metre-wave astronomy lies with the Square Kilometre Array (SKA), a telescope under development by a consortium of 17 countries that will be 50 times more sensitive than any existing radio facility. Most of the key science for the SKA will be addressed through large-area imaging of the Universe at frequencies from a few hundred MHz to a few GHz. The Australian SKA Pathfinder (ASKAP) is a technology demonstrator aimed in the mid-frequency range, and achieves instantaneous wide-area imaging through the development and deployment of phased-array feed systems on parabolic reflectors. The large field-of-view makes ASKAP an unprecedented synoptic telescope that will make substantial advances in SKA key science. ASKAP will be located at the Murchison Radio Observatory in inland Western Australia, one of the most radio-quiet locations on the Earth and one of two sites selected by the international community as a potential location for the SKA. In this paper, we outline an ambitious science program for ASKAP, examining key science such as understanding the evolution, formation and population of galaxies including our own, understanding the magnetic Universe, revealing the transient radio sky and searching for gravitational waves.
Although usually thought of as external environmental stressors, a significant heritable component has been reported for measures of stressful life events (SLEs) in twin studies.
We examined the variance in SLEs captured by common genetic variants from a genome-wide association study (GWAS) of 2578 individuals. Genome-wide complex trait analysis (GCTA) was used to estimate the phenotypic variance tagged by single nucleotide polymorphisms (SNPs). We also performed a GWAS on the number of SLEs, and looked at correlations between siblings.
A significant proportion of variance in SLEs was captured by SNPs (30%, p = 0.04). When events were divided into those considered to be dependent or independent, an equal amount of variance was explained for both. This ‘heritability’ was in part confounded by personality measures of neuroticism and psychoticism. A GWAS for the total number of SLEs revealed one SNP that reached genome-wide significance (p = 4 × 10−8), although this association was not replicated in separate samples. Using available sibling data for 744 individuals, we also found a significant positive correlation of R2 = 0.08 in SLEs (p = 0.03).
These results provide independent validation from molecular data for the heritability of reporting environmental measures, and show that this heritability is in part due to both common variants and the confounding effect of personality.
It has been proposed that non-steroidal anti-inflammatory drugs (NSAIDs) may interfere with the efficacy of antidepressants and contribute to treatment resistance in major depressive disorder (MDD). This effect requires replication and a test of whether it is specific to serotonin-reuptake inhibiting (SRI) antidepressants.
We tested the effect of concomitant medication with NSAIDs on the efficacy of escitalopram, a SRI antidepressant, and nortriptyline, a tricyclic antidepressant, among 811 subjects with MDD treated for up to 12 weeks in the GENDEP study. Effects of NSAIDs on improvement of depressive symptoms were tested in mixed-effect linear models. Effects on remission were tested in logistic regression. Age, sex, baseline severity and centre of recruitment were considered as potential confounding factors.
Ten percent (n=78) of subjects were taking NSAIDs during the antidepressant treatment. Older subjects were significantly more likely to take NSAIDs. After controlling for age, sex, centre of recruitment and baseline severity, concomitant medication with NSAIDs did not significantly influence the efficacy of escitalopram [β=0.035, 95% confidence interval (CI) −0.145 to 0.215, p=0.704] or nortriptyline (β=0.075, 95% CI −0.131 to 0.281, p=0.476). Although slightly fewer subjects who took NSAIDs reached remission [odds ratio (OR) 0.80, 95% CI 0.49–1.31, p=0.383], this non-significant effect was reversed after controlling for age, sex, baseline severity and recruitment centre effects (OR 1.04, 95% CI 0.61–1.77, p=0.882).
NSAIDs are unlikely to affect the efficacy of SRI or other antidepressants. Concurrent use of NSAIDs and antidepressants does not need to be avoided.
Despite the increasing development of early intervention services for psychosis, little is known about their cost-effectiveness. We assessed the cost-effectiveness of Outreach and Support in South London (OASIS), a service for people with an at-risk mental state (ARMS) for psychosis.
The costs of OASIS compared to care as usual (CAU) were entered in a decision model and examined for 12- and 24-month periods, using the duration of untreated psychosis (DUP) and rate of transition to psychosis as key parameters. The costs were calculated on the basis of services used following referral and the impact on employment. Sensitivity analysis was used to test the robustness of all the assumptions made in the model.
Over the initial 12 months from presentation, the costs of the OASIS intervention were £1872 higher than CAU. However, after 24 months they were £961 less than CAU.
This model suggests that services that permit early detection of people at high risk of psychosis may be cost saving.
Arsenic is a very common by-product of the processing of Cu, Au and polymetallic ores worldwide, where the ore is roasted (calcined) to remove volatile elements. In southwest England, a diverse range of As-mineral species occur as efflorescent secondary mineral growths on historic calciner buildings. Gypsum occurs as abundant dendritic growths comprising either interlocking blades or tabular crystals. Ca-arsenate minerals are locally very abundant as white colloform masses. Positively identified Ca arsenates include pharmacolite, weilite and haidingerite. Other secondary minerals include arsenolite, scorodite, bukovskyite and an As-bearing potassium alum, together with a wide variety of unidentified minerals, including an Al-As-S phase and As-rich F-bearing phases. Gypsum contains As concentrations up to ~7 wt.%. Efflorescent growth at sites exposed to the prevailing weather systems is less abundant than at sheltered sites. This is interpreted as being due to ‘pressure washing’ of exposed sites by driving rain. Successive concentric growths of gypsum and Ca arsenate on masonry are interpreted as being the result of seasonal crystallization.
Understanding both current and historicalmining and mineralprocessing methods is criticalin the evaluation of the potential impact on the modern environment. In particular, due to the abundance of As-bearing minerals in a wide range of ore types, many buildings worldwide are potentially significantly contaminated with As even though few are directly related to As production or handling. Characterizing the secondary As mineralspecies present at mine and mineralprocessing sites is critical in understanding the potentialheal th risk these sites might pose.
Arsenic-rich magmatic sulphide mineralization is hosted by a diorite intrusion at Talnotry, southwest Scotland. A relatively abundant and diverse platinum-group mineral assemblage is present and is dominated by sperrylite, irarsite and electrum with subordinate merenskyite, michenerite and froodite. Early euhedral gersdorffite is enriched with respect to Rh, Ir and Pt and in some cases contains exsolved blebs of irarsite or euhedral grains of sperrylite. Sperrylite is also enclosed within silicates and sulphides indicating that it crystallized directly from an As-rich sulphide liquid. Pyrrhotite-chalcopyrite mineral assemblages are consistent with the fractional crystallization of monosulphide solid solution and are overlain by PGE-, Ni- and As-rich mineral assemblages indicative of crystallization from a NiAs liquid. Late-stage, cross-cutting, electrum-bearing chalcopyrite veins are consistent with the crystallization of Cu- and Au-rich intermediate solid solution. The chemistry, mineralogy and lithological relationships of the diorite suggest that it may be an appinite and as such is potentially analogous to the Au-rich lamprophyre dykes present within southwest Scotland.
Two generations of sulphide-hosted platinum-group element mineralization occur in the West Sgaorishal ultramafic plug, Rum. Disseminated Cu and Ni sulphides around the margin of the plug host a restricted platinum-group mineral assemblage that is dominated by Pd bismutho-tellurides and sperrylite (PtAs2) with subordinate electrum (AuAg), froodite (PdBi2) and unidentified Pt–Bi–Te phases. Later sulphide-rich dykes cross-cut the plug and host an assemblage dominated by Pd bismutho-tellurides, sperrylite and locally very abundant paolovite (Pd2Sn). Whole rock combined platinum-group element+Au concentrations are proportional to the sulphide abundance with slightly elevated values in disseminated sulphide lithologies (>400 ppb) and very high values (>2000 ppb) in the sulphide-rich dykes. Both generations have relatively flat chondrite-normalized plots indicating a primitive magmatic source. Negative δ34S values (−9.2 to −18.3 ‰) indicate that the disseminated mineralization is due to contamination probably derived from Jurassic sedimentary rocks leading to sulphur saturation and collection of platinum-group elements. The sulphide-rich dykes must have entrained a platinum-group element-rich sulphide liquid collected from a much larger volume of magma. The presence of platinum-group elements and sulphide-rich dykes with δ34S values between −10.8 and −15.0 ‰ indicates that parts of the Rum Layered Suite became sulphur saturated through magmatic contamination. It appears likely that platinum-group element mineralization styles within the southern North Atlantic Igneous Province are diverse and may be present in a wider variety of mineralogical associations than previously recognized.
In recent years, platinum-group mineral deposits have been reported from several of the
Tertiary igneous complexes in East Greenland. These intrusions form part of the same igneous
province as the Tertiary igneous centres in northwest Scotland, and recent work confirmed the
presence of abundant platinum-group minerals in the Rum Central Complex. In this paper we report
for the first time the presence of abundant and diverse platinum-group minerals from the Tertiary Ben
Buie intrusion on Mull and the Cuillin Complex of Skye, Inner Hebrides, Scotland. The platinum-group
minerals in the Ben Buie intrusion are associated with chromitite layers in ultramafic cumulates.
The grains are small (1–2 μm), locally very abundant, and dominated by Pd–Bi–Te–Sb phases. In the
Peridotite Series of the Cuillin Complex, the platinum-group minerals are dominated by laurite
commonly enclosed within chromite or silicate. A combined orthomagmatic–hydromagmatic origin is
proposed for the mineralization. However, the style and type of mineralization differs between each of
the igneous centres. Platinum-group element mineralization is a ubiquitous feature of the Tertiary
Igneous Province in northwest Scotland and in Greenland and is intimately linked to the regional
The effects of low levels of nitrogen addition (7·7 and
N ha−1 yr−1) on plant sensitivity to
biotic and abiotic
stress were studied at a lowland heath in the south of England that
has received N treatments since 1989. Larval
growth rates and adult weights of heather beetles were found to be
significantly higher when insects were reared
on plants that had received additional N, with implications for insect
survival and reproductive success.
Electrolyte leakage measurements failed to reveal any significant
impact of N addition on plant sensitivity to frost
episodes in early winter. In April, however, there was some evidence
of slightly decreased frost hardiness in plants
receiving additional N. Accelerated spring bud burst also suggested
earlier physiological activity in N-treated
plots. The rate of water loss from excised shoots of Calluna vulgaris
(L.) Hull was significantly faster in plants
receiving additional N, although no difference in plant water potential
was measured in the field after a prolonged
dry spell. Whilst experimental N addition had only a small effect on
plant sensitivity to abiotic stress, the
relationship between enhanced deposition and increased insect performance
was clear, with the potential for
substantially increased insect damage at deposition rates around the critical
load contributing to the formation of gaps in the Calluna canopy.
Two hundred and eleven patients with a clinical diagnosis of Turner
syndrome were studied. We
report (i) the cytogenetic results, (ii) the frequency of cryptic mosaicism
and (iii) the parental age and
the parental origin of the abnormality. We scored 100 cells from blood
cultures and found 97 patients
to have a 45,X constitution, 15 to be 45,X/46,XX or 45,X/47,XXX
mosaics, 86 to have a
structurally abnormal X and 13 to have a structurally abnormal Y chromosome.
were used to look for cryptic X and Y chromosome mosaicism in
patients with a 45,X constitution.
Two cryptic X but no cryptic Y mosaics were detected. In 74% of the 45,X
patients the X was
maternal in origin. The i(Xq)s were approximately equally likely
to involve the paternal or maternal
chromosome, while the majority of deletions and rings and virtually
all the abnormal Y chromosomes
were paternal in origin. We suggest that the preponderance of paternal
errors in Turner syndrome
may result from the absence of pairing along the greater part of the
XY bivalent during paternal mei I, which may make the sex chromosomes
particularly susceptible to both structural and
non-disjunctional errors during male gametogenesis.
Male horseshoe crabs, Limulus polyphemus, use their eyes to locate mates day and night. We investigated their ability to detect targets of different size and contrast in a mating area of Buzzards Bay, Cape Cod, MA. We found that males can see large, high-contrast targets better than small, low-contrast ones. For targets of the same size, animals must be about 0.1 m closer to a low-contrast target to see it as well as a high-contrast one. For targets of the same contrast, animals must be approximately 0.2 m closer to a small target to see it as well as one twice as large. A decrease of 0.05 steradians in the size of the retinal image of a target can be compensated by a four-fold increase in contrast. About 60% of the animals detect black targets subtending 0.110 steradians (equivalent to an adult female viewed from about 0.56 m), while only 20% detect targets subtending 0.039 steradians. This study shows that horseshoe crabs maintain about constant contrast sensitivity under diurnal changes in light intensity in their natural environment. As a consequence of circadian and adaptive mechanisms in the retina, male horseshoe crabs can detect female-size objects about equally well day and night.