ALBERT

Description: We investigate the influence of the glacial isostatic adjustment (GIA) on the deformation at the surface and at seismogenic depths in Fennoscandia. The surface strain rate field, derived from geodetic data, is controlled by GIA which causes NW–SE extension of up to 4  x  10 –9  yr –1 in most of mainland Fennoscandia, surrounded by regions of radial shortening towards the centre of uplift. The seismic deformation field, derived from a new compilation of focal mechanisms, shows consistent NW–SE compression on the Norwegian continental margin and a tendency towards tension in mainland Fennoscandia. The seismic moment rate is at least two orders of magnitude smaller than the geodetic moment rate. We propose that the low level of seismicity and the tendency towards tensional focal mechanisms in mainland Fennoscandia may be explained by the destructive interference of the regional stress from ridge push with the flexural stress due to GIA.

Description: Patients with chronic kidney disease (CKD) have signs of genomic instability and, as a consequence, extensive genetic damage, possibly due to accumulation of uraemic toxins, oxidative stress mediators and other endogenous substances with genotoxic properties. We explored factors associated with the presence and background levels of genetic damage in CKD. A cross-sectional study was performed in 91 CKD patients including pre-dialysis (CKD patients; n = 23) and patients undergoing peritoneal dialysis (PD; n = 33) or haemodialysis (HD; n = 35) and with 61 healthy subjects, divided into two subgroups with the older group being in the age range of the patients, serving as controls. Alkaline comet assay and cytokinesis-block micronucleus assay in peripheral blood lymphocytes were used to determine DNA and chromosome damage, respectively, present in CKD. Markers of oxidative stress [malondialdehyde (MDA), advanced glycation end products (AGEs), thiols, advanced oxidation protein products and 8-hydroxy-2'-deoxyguanosine] and markers of inflammation (C-reactive protein, interleukin-6 and tumour necrosis factor alpha) were also measured. Micronucleus (MN) frequency was significantly higher ( P 〈 0.05) in the CKD group (46±4) when compared with the older control (oC) group (27.7±14). A significant increase in MN frequency ( P 〈 0.05) was also seen in PD patients (41.9±14) versus the oC group. There was no statistically significant difference for the HD group (29.7±15.6; P = NS) versus the oC group. Comet assay data showed a significant increase ( P 〈 0.001) of tail DNA intensity in cells of patients with CKD (15.6±7%) with respect to the total control (TC) group (11±1%). PD patients (14.8±7%) also have a significant increase ( P 〈 0.001) versus the TC group. Again, there was no statistically significant difference for the HD group (12.5±3%) compared with the TC group. Patients with MN values in the upper quartile had increased cholesterol, triglycerides, AGEs and MDA levels and lower albumin levels. Multiple logistic regression analysis showed that male gender, diabetes and treatment modality were independently associated with higher levels of DNA damage. Our results suggest that oxidative stress, diabetes, gender and dialysis modality in CKD patients increased DNA and chromosome damage. To confirm these data, prospective clinical trials need to be performed.

Description: Polyandry is widespread across animal taxa and subjects males to intense postcopulatory sexual selection which favors adaptations that enhance a male’s paternity success, either by decreasing the risk of sperm competition and/or by increasing the competitiveness of the ejaculate. Copulatory plugs deposited by males are thought to have evolved in the context of sperm competition. However, experimental studies that assess the function of copulatory plugs remain scarce. Moreover, most studies have used unnatural manipulations, such as ablating plug-producing male glands or interrupting copulations. Here, we investigated whether repeated ejaculation affects plug size in a mammalian model species, the house mouse. When males experience short periods of sexual rest we found that plug size decreased over repeated ejaculations so that time since last ejaculation can be applied as an approximation for plug size. We induced natural variation in plug size arising from variation in male sexual restedness and investigated the behavior and paternity success of rival males. Male behavior in the offensive mating role (second) was influenced, albeit not significantly, by the sexual restedness of the first male to mate, and therefore the size of his plug. However, second males sired a significantly greater proportion of embryos when competing against a male that had recently mated compared with a male that had not. This supports a potential role of the plug in promoting a male’s competitive fertilization success when remating occurs, which could be mediated both by delaying female remating and by ensuring efficient sperm transport through the female reproductive tract.

Description: Huntington's disease (HD) is an autosomal inherited neurological disease caused by a CAG-repeat expansion in the first exon of huntingtin gene encoding for the huntingtin protein (Htt). In HD, there is an accumulation of intracellular aggregates of mutant Htt that negatively influence cellular functions. The aggregates contain ubiquitin, and part of the HD pathophysiology could result from an imbalance in cellular ubiquitin levels. Deubiquitinating enzymes are important for replenishing the ubiquitin pool, but less is known about their roles in brain diseases. We show here that overexpression of the ubiquitin-specific protease-14 (Usp14) reduces cellular aggregates in mutant Htt-expressing cells mainly via the ubiquitin proteasome system. We also observed that the serine–threonine kinase IRE1 involved in endoplasmic reticulum (ER) stress responses is activated in mutant Htt-expressing cells in culture as well as in the striatum of mutant Htt transgenic (BACHD) mice. Usp14 interacted with IRE1 in control cells but less in mutant Htt-expressing cells. Overexpression of Usp14 in turn was able to inhibit phosphorylation of IRE1α in mutant Htt-overexpressing cells and to protect against cell degeneration and caspase-3 activation. These results show that ER stress-mediated IRE1 activation is part of mutant Htt toxicity and that this is counteracted by Usp14 expression. Usp14 effectively reduced cellular aggregates and counteracted cell degeneration indicating an important role of this protein in mutant Htt-induced cell toxicity.

Description: In many species, females have evolved behavioral strategies to reduce the risk of infanticide. For instance, polyandry can create paternity confusion that inhibits males from killing offspring they could have sired. Here, the authors propose that females could socially obtain the same benefits by nesting communally. Singly sired litters could be perceived as a large multiply sired litter once pooled together in a single nest. Long-term data from a wild house mouse population showed that monandrous litters (singly sired) were more common in communal than in solitary nests and 85% of them were raised with litters sired by different males hence becoming effectively polyandrous (multiply sired). These socially polyandrous litters had significantly higher offspring survival than genetically or socially monandrous litters and reached a similar survival to that of multiply sired litters raised in solitary or communal nests. Furthermore, the number of sires within nests significantly improved offspring survival whereas the number of mothers did not. These results suggest that the survival benefits associated with communal nesting are driven by polyandry and not communal defense. This socially mediated polyandry was as efficient as multiple paternity in preventing infanticide, and may also occur in other infanticidal and polytocous species where the caring parent exhibits social behavior.

Description: Proxies of solar activity, based on radiocarbon and beryllium, covering most of the Holocene were statistically analysed using both wavelet and Fourier approaches. It was shown that a significant tri-centennial (300–400 yr) cyclicity is present in the both series. Evidence for the same kind of variation was found in data on flux of 10 Be in Dye-3 (South Greenland, ad 1424–1985) and NGRIP (Central Greenland, ad 1389–1994) ice cores. Possible origins of the revealed quasi-300-year periodicity are discussed.

Description: Red, orange, and yellow carotenoid-based ornaments, which are widely used as sexual signals in many birds, fish, and reptiles, are known to exhibit multidimensional chromatic variation as a result of both the concentration and relative proportions of different constituent carotenoids with differing spectral properties. This is thought to reflect intrinsic variation in signaler quality, making it a useful basis for female choice. However, whether females are able to discriminate relevant variation in carotenoid concentration and/or composition independently of each other, and of other phenotypic or behavior traits, and if so, how this mediates their choice, is poorly understood. Here, female 3-spined sticklebacks ( Gasterosteus aculeatus ) were presented with computer-animated courting males that varied exclusively in the appearance of their carotenoid-based coloration; specifically, each male’s signal provided a perceptual match for carotenoid coloration expressed by live males with known underlying carotenoid content, thereby providing a biologically-relevant signal while precluding confounding traits influencing female choice. Females were able to discriminate between prospective mates solely on the basis of perceived variation in the allocation of carotenoids to males’ sexual signals, and exhibited a strong preference for males with coloration indicative of higher concentrations of carotenoids in their signal, rather than in response to perceived variation in the relative proportion of constituent carotenoids. This has important implications for our understanding of male signaling strategies and the information content of carotenoid-based sexual signals.

Description: N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a strong predictor of mortality in coronary artery disease and is widely employed as a prognostic biomarker. However, a causal relationship between NT-proBNP and clinical endpoints has not been established. We have performed a genome-wide association and Mendelian randomization study of NT-proBNP. We used a discovery set of 3740 patients from the PLATelet inhibition and patient Outcomes (PLATO) trial, which enrolled 18 624 patients with acute coronary syndrome (ACS). A further set of 5492 patients, from the same trial, was used for replication. Genetic variants at two novel loci ( SLC39A8 and POC1B/GALNT4 ) were associated with NT-proBNP levels and replicated together with the previously known NPPB locus. The most significant SNP (rs198389, pooled P = 1.07 x 10 –15 ) in NPPB interrupts an E-box consensus motif in the gene promoter. The association in SLC39A8 is driven by a deleterious variant (rs13107325, pooled P = 5.99 x 10 –10 ), whereas the most significant SNP in POC1B/GALNT4 (rs11105306, pooled P = 1.02 x 10 –16 ) is intronic. The SLC39A8 SNP was associated with higher risk of cardiovascular (CV) death (HR = 1.39, 95% CI: 1.08–1.79, P = 0.0095), but the other loci were not associated with clinical endpoints. We have identified two novel loci to be associated with NT-proBNP in patients with ACS. Only the SLC39A8 variant, but not the NPPB variant, was associated with a clinical endpoint. Due to pleotropic effects of SLC39A8 , these results do not suggest that NT-proBNP levels have a direct effect on mortality in ACS patients. PLATO Clinical Trial Registration: www.clinicaltrials.gov ; NCT00391872.

Description: A selective sweep is the result of strong positive selection driving newly occurring or standing genetic variants to fixation, and can dramatically alter the pattern and distribution of allelic diversity in a population. Population-level sequencing data have enabled discoveries of selective sweeps associated with genes involved in recent adaptations in many species. In contrast, much debate but little evidence addresses whether "selfish" genes are capable of fixation—thereby leaving signatures identical to classical selective sweeps—despite being neutral or deleterious to organismal fitness. We previously described R2d2 , a large copy-number variant that causes nonrandom segregation of mouse Chromosome 2 in females due to meiotic drive. Here we show population-genetic data consistent with a selfish sweep driven by alleles of R2d2 with high copy number ( R2d2 HC ) in natural populations. We replicate this finding in multiple closed breeding populations from six outbred backgrounds segregating for R2d2 alleles. We find that R2d2 HC rapidly increases in frequency, and in most cases becomes fixed in significantly fewer generations than can be explained by genetic drift. R2d2 HC is also associated with significantly reduced litter sizes in heterozygous mothers, making it a true selfish allele. Our data provide direct evidence of populations actively undergoing selfish sweeps, and demonstrate that meiotic drive can rapidly alter the genomic landscape in favor of mutations with neutral or even negative effects on overall Darwinian fitness. Further study will reveal the incidence of selfish sweeps, and will elucidate the relative contributions of selfish genes, adaptation and genetic drift to evolution.

Description: Linkage, association and expression studies previously pointed to the human QKI , KH domain containing , RNA-binding ( QKI ) as a candidate gene for schizophrenia. Functional studies of the mouse orthologue Qk focused mainly on its role in oligodendrocyte development and myelination, while its function in astroglia remained unexplored. Here, we show that QKI is highly expressed in human primary astrocytes and that its splice forms encode proteins targeting different subcellular localizations. Uncovering the role of QKI in astrocytes is of interest in light of growing evidence implicating astrocyte dysfunction in the pathogenesis of several disorders of the central nervous system. We selectively silenced QKI splice variants in human primary astrocytes and used RNA sequencing to identify differential expression and splice variant composition at the genome-wide level. We found that an mRNA expression of Glial fibrillary acidic protein ( GFAP ), encoding a major component of astrocyte intermediate filaments, was down-regulated after QKI7 splice variant silencing. Moreover, we identified a potential QKI-binding site within the 3' untranslated region of human GFAP. This sequence was not conserved between mice and humans, raising the possibility that GFAP is a target for QKI in humans but not rodents. Haloperidol treatment of primary astrocytes resulted in coordinated increases in QKI7 and GFAP expression. Taken together, our results provide the first link between QKI and GFAP , two genes with alterations previously observed independently in schizophrenic patients. Our findings for QKI , together with its well-known role in myelination, suggest that QKI is a hub regulator of glia function in humans.