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Response to lithium in patients with bipolar disorder is associated with clinical and transdiagnostic genetic factors. The predictive combination of these variables might help clinicians better predict which patients will respond to lithium treatment.
Aims
To use a combination of transdiagnostic genetic and clinical factors to predict lithium response in patients with bipolar disorder.
Method
This study utilised genetic and clinical data (n = 1034) collected as part of the International Consortium on Lithium Genetics (ConLi+Gen) project. Polygenic risk scores (PRS) were computed for schizophrenia and major depressive disorder, and then combined with clinical variables using a cross-validated machine-learning regression approach. Unimodal, multimodal and genetically stratified models were trained and validated using ridge, elastic net and random forest regression on 692 patients with bipolar disorder from ten study sites using leave-site-out cross-validation. All models were then tested on an independent test set of 342 patients. The best performing models were then tested in a classification framework.
Results
The best performing linear model explained 5.1% (P = 0.0001) of variance in lithium response and was composed of clinical variables, PRS variables and interaction terms between them. The best performing non-linear model used only clinical variables and explained 8.1% (P = 0.0001) of variance in lithium response. A priori genomic stratification improved non-linear model performance to 13.7% (P = 0.0001) and improved the binary classification of lithium response. This model stratified patients based on their meta-polygenic loadings for major depressive disorder and schizophrenia and was then trained using clinical data.
Conclusions
Using PRS to first stratify patients genetically and then train machine-learning models with clinical predictors led to large improvements in lithium response prediction. When used with other PRS and biological markers in the future this approach may help inform which patients are most likely to respond to lithium treatment.
Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools.
Aims
To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.
Method
Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts.
Results
Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.
Conclusions
AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.
With the recent discovery of a dozen dusty star-forming galaxies and around 30 quasars at z > 5 that are hyper-luminous in the infrared (μ LIR > 1013 L⊙, where μ is a lensing magnification factor), the possibility has opened up for SPICA, the proposed ESA M5 mid-/far-infrared mission, to extend its spectroscopic studies toward the epoch of reionisation and beyond. In this paper, we examine the feasibility and scientific potential of such observations with SPICA’s far-infrared spectrometer SAFARI, which will probe a spectral range (35–230 μm) that will be unexplored by ALMA and JWST. Our simulations show that SAFARI is capable of delivering good-quality spectra for hyper-luminous infrared galaxies at z = 5 − 10, allowing us to sample spectral features in the rest-frame mid-infrared and to investigate a host of key scientific issues, such as the relative importance of star formation versus AGN, the hardness of the radiation field, the level of chemical enrichment, and the properties of the molecular gas. From a broader perspective, SAFARI offers the potential to open up a new frontier in the study of the early Universe, providing access to uniquely powerful spectral features for probing first-generation objects, such as the key cooling lines of low-metallicity or metal-free forming galaxies (fine-structure and H2 lines) and emission features of solid compounds freshly synthesised by Population III supernovae. Ultimately, SAFARI’s ability to explore the high-redshift Universe will be determined by the availability of sufficiently bright targets (whether intrinsically luminous or gravitationally lensed). With its launch expected around 2030, SPICA is ideally positioned to take full advantage of upcoming wide-field surveys such as LSST, SKA, Euclid, and WFIRST, which are likely to provide extraordinary targets for SAFARI.
Oldowan sites in primary geological context are rare in the archaeological record. Here we describe the depositional environment of Oldowan occurrences at Kanjera South, Kenya, based on field descriptions and granulometric analysis. Excavations have recovered a large Oldowan artefact sample as well as the oldest substantial sample of archaeological fauna. The deposits at Kanjera South consist of 30 m of fluvial, colluvial and lacustrine sediments. Magneto- and biostratigraphy indicate the Kanjera South Member of the Kanjera Formation was deposited during 2.3–1.92 Ma, with 2.0 Ma being a likely age for the archaeological occurrences. Oldowan artefacts and associated fauna were deposited in the colluvial and alluvial silts and sands of beds KS1–3, in the margins of a lake basin. Field descriptions and granulometric analysis of the sediment fine fraction indicate that sediments from within the main archaeological horizon were emplaced as a combination of tractional and hyperconcentrated flows with limited evidence of debris-flow deposition. This style of deposition is unlikely to significantly erode or disturb the underlying surface, and therefore promotes preservation of surface archaeological accumulations. Hominins were repeatedly attracted to the site locale, and rapid sedimentation, minimal bone weathering and an absence of bone or artefact rounding further indicate that fossils and artefacts were quickly buried.
We investigate and compare the boundary conditions that are to be applied to free-surface problems involving inlet and outlets of Newtonian fluid, typically found in coating processes. The flux of fluid is a priori known at an inlet, but unknown at an outlet, where it is governed by the local behaviour near the film-forming meniscus. In the limit of vanishing capillary number it is well known that the flux scales with , but this classical result is non-uniform as the contact angle approaches . By examining this limit we find a solution that is uniformly valid for all contact angles. Furthermore, by considering the far-field behaviour of the free surface we show that there exists a critical capillary number above which the problem at an inlet becomes over-determined. The implications of this result for the modelling of coating flows are discussed.
Edited by
Alex S. Evers, Washington University School of Medicine, St Louis,Mervyn Maze, University of California, San Francisco,Evan D. Kharasch, Washington University School of Medicine, St Louis
Staphylococcus aureus (n = 75) isolated from mammary secretions of cows with subclinical and clinical mastitis from several geographic locations in the USA were examined using polymerase chain reaction-based DNA fingerprinting. DNA fingerprints were produced using a synthetic oligonucleotide primer (5‘GTAACGCC3’) to produce a distinct spectrum of amplified DNA fragments facilitating a high degree of resolution for differentiating S. aureus strains. PCR-based DNA fingerprinting grouped the 75 S. aureus isolates into 19 distinct profiles. The technique differentiated closely related strains within and between geographic locations. Findings suggest that certain types are found across geographic regions suggesting a common clonal type. Within herd data suggest heterogeneity among subclinical and clinical isolates of S. aureus strains. Compared to existing typing methods, PCR-based DNA fingerprinting is easy to perform and interpret. Use of PCR-based DNA fingerprinting may allow for a more detailed investigation of the epidemiology of S. aureus mastitis in dairy cows.
The development of the oocytes of Nereis (Hediste) diversicolor and Nereis (Nereis) pelagica takes up to 18 months from their first appearance in the coelom to maturity, and in the natural conditions experienced by the population studied in north-east England the females are in their second year before the oocytes begin to appear. The duration of spermatogenesis is less than that of oogenesis, taking up to 6 months for completion. This information permits a more rigorous interpretation of the size frequency data which have been obtained from a biometrical study of the jaws. In the populations of both species the majority of individuals seem to reach maturity when 3 years old.
Eulalia viridis (L.) is one of a group of polychaete species which are being used in an experimental analysis of the regulation of gametogenesis and reproduction. The back-ground to these studies and some of the preliminary results have been discussed recently by Olive (1980). Despite the abundant data demonstrating the frequent occurrence of well-defined reproductive cycles in marine invertebrates and observations on the correlations between reproductive events and environmental conditions, the mechanisms by which the reproductive cycles of individual species are controlled are very poorly understood. It has generally been accepted since the publication of the important paper of Orton (1920) that the temperature cycle in temperate and boreal regions plays an important role in determining the reproductive cycle, but the nature of the control mechanism is not, in general, understood and is likely to vary markedly between species. Environ-mental conditions such as relative daylength or biological factors such as the quantity and identity of the phytoplankton organisms (Himmelman, 1978, 1979) could also play important roles in regulating the sequence of cellular events which culminates in successful reproduction. These general problems have been discussed by Giese (1959) and more recently by Barnes (1975), Giese & Pearse (1975) and specifically in relation to Polychaeta by Clark (1979) and Olive (1980).
Eulalia viridis is the most common littoral phyllodocid at Cullercoats Bay, where it occupies crevices and small holes in the well-sutured sandstone and limestone rocks. It is particularly common in rocks having a heavy encrustation of barnacles. The reproductive biology of this species in particular, and of phyllodocids in general, is poorly known. Meyer (1938) has described the development of larvae of Eulalia viridis both from artificial fertilizations and from egg cocoons said to belong to Eulalia viridis collected in January at Plymouth, U.K. The observations made during the present investigation differ in a number of important respects from those of Meyer and his conclusions cannot be considered appropriate to all populations of E. viridis.