Non‐consumptive effects of predation: does perceived risk strengthen the genetic integration of behaviour and morphology in stickleback?

Predators can shape genetic correlations in prey by altering prey perception of risk. We manipulated perceived risk to test whether such non‐consumptive effects tightened behavioural trait correlations in wild‐caught stickleback from high‐ compared to low‐risk environments due to genetic variation in plasticity. We expected tighter genetic correlations within perceived risk treatments than across them, and tighter genetic correlations in high‐risk than in low‐risk treatments. We identified genetic variation in plasticity, with genetic correlations between boldness, sociality, and antipredator morphology, as expected, being tighter within treatments than across them, for both of two populations. By contrast, genetic correlations did not tighten with exposure to risk. Tighter phenotypic correlations in wild stickleback may thus arise because predators induce correlational selection on environmental components of these traits, or because predators tighten residual correlations by causing environmental heterogeneity that is controlled in the laboratory. Our study places phenotypic integration firmly into an ecological context.     

Host behaviour alteration by its parasite: from brain gene expression to functional test

Many parasites with complex life cycles modify their intermediate hosts'' behaviour, presumably to increase transmission to their final host. The threespine stickleback (Gasterosteus aculeatus) is an intermediate host in the cestode Schistocephalus solidus life cycle, which ends in an avian host, and shows increased risky behaviours when infected. We studied brain gene expression profiles of sticklebacks infected with S. solidus to determine the proximal causes of these behavioural alterations. We show that infected fish have altered expression levels in genes involved in the inositol pathway. We thus tested the functional implication of this pathway and successfully rescued normal behaviours in infected sticklebacks using lithium exposure. We also show that exposed but uninfected fish have a distinct gene expression profile from both infected fish and control individuals, allowing us to separate gene activity related to parasite exposure from consequences of a successful infection. Finally, we find that selective serotonin reuptake inhibitor-treated sticklebacks and infected fish do not have similarly altered gene expression, despite their comparable behaviours, suggesting that the serotonin pathway is probably not the main driver of phenotypic changes in infected sticklebacks. Taken together, our results allow us to predict that if S. solidus directly manipulates its host, it could target the inositol pathway.     

Modelling the distribution of larval fish in a western boundary current using a multi-voyage database

Reviews in Fish Biology and Fisheries - Across the world’s oceans, western boundary currents are strengthening and warming faster than the global average. This is expected to have large...     

A Panel of 4 microRNAs Facilitates the Prediction of Left Ventricular Contractility after Acute Myocardial Infarction

Background

Prediction of clinical outcome after acute myocardial infarction (AMI) is challenging and would benefit from new biomarkers. We investigated the prognostic value of 4 circulating microRNAs (miRNAs) after AMI.

Methods

We enrolled 150 patients after AMI. Blood samples were obtained at discharge for determination of N-terminal pro-brain natriuretic peptide (Nt-proBNP) and levels of miR-16, miR-27a, miR-101 and miR-150. Patients were assessed by echocardiography at 6 months follow-up and the wall motion index score (WMIS) was used as an indicator of left ventricular (LV) contractility. We assessed the added predictive value of miRNAs against a multi-parameter clinical model including Nt-proBNP.

Results

Patients with anterior AMI and elevated Nt-proBNP levels at discharge from the hospital were at high risk of subsequent impaired LV contractility (follow-up WMIS>1.2, n = 71). A combination of the 4 miRNAs (miR-16/27a/101/150) improved the prediction of LV contractility based on clinical variables (P = 0.005). Patients with low levels of miR-150 (odds ratio [95% confidence interval] 0.08 [0.01–0.48]) or miR-101 (0.19 [0.04–0.97]) and elevated levels of miR-16 (15.9 [2.63–95.91]) or miR-27a (4.18 [1.36–12.83]) were at high risk of impaired LV contractility. The 4 miRNA panel reclassified a significant proportion of patients with a net reclassification improvement of 66% (P = 0.00005) and an integrated discrimination improvement of 0.08 (P = 0.001).

Conclusion

Our results indicate that panels of miRNAs may aid in prognostication of outcome after AMI.     

Conformational Changes in Talin on Binding to Anionic Phospholipid Membranes Facilitate Signaling by Integrin Transmembrane Helices

Integrins are heterodimeric (αβ) cell surface receptors that are activated to a high affinity state by the formation of a complex involving the α/β integrin transmembrane helix dimer, the head domain of talin (a cytoplasmic protein that links integrins to actin), and the membrane. The talin head domain contains four sub-domains (F0, F1, F2 and F3) with a long cationic loop inserted in the F1 domain. Here, we model the binding and interactions of the complete talin head domain with a phospholipid bilayer, using multiscale molecular dynamics simulations. The role of the inserted F1 loop, which is missing from the crystal structure of the talin head, PDB:3IVF, is explored. The results show that the talin head domain binds to the membrane predominantly via cationic regions on the F2 and F3 subdomains and the F1 loop. Upon binding, the intact talin head adopts a novel V-shaped conformation which optimizes its interactions with the membrane. Simulations of the complex of talin with the integrin α/β TM helix dimer in a membrane, show how this complex promotes a rearrangement, and eventual dissociation of, the integrin α and β transmembrane helices. A model for the talin-mediated integrin activation is proposed which describes how the mutual interplay of interactions between transmembrane helices, the cytoplasmic talin protein, and the lipid bilayer promotes integrin inside-out activation.     

Non-Homologous End-Joining Pathway Associated with Occurrence of Myocardial Infarction: Gene Set Analysis of Genome-Wide Association Study Data

Purpose

DNA repair deficiencies have been postulated to play a role in the development and progression of cardiovascular disease (CVD). The hypothesis is that DNA damage accumulating with age may induce cell death, which promotes formation of unstable plaques. Defects in DNA repair mechanisms may therefore increase the risk of CVD events. We examined whether the joints effect of common genetic variants in 5 DNA repair pathways may influence the risk of CVD events.

Methods

The PLINK set-based test was used to examine the association to myocardial infarction (MI) of the DNA repair pathway in GWAS data of 866 subjects of the GENetic DEterminants of Restenosis (GENDER) study and 5,244 subjects of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) study. We included the main DNA repair pathways (base excision repair, nucleotide excision repair, mismatch repair, homologous recombination and non-homologous end-joining (NHEJ)) in the analysis.

Results

The NHEJ pathway was associated with the occurrence of MI in both GENDER (P = 0.0083) and PROSPER (P = 0.014). This association was mainly driven by genetic variation in the MRE11A gene (P_GENDER = 0.0001 and P_PROSPER = 0.002). The homologous recombination pathway was associated with MI in GENDER only (P = 0.011), for the other pathways no associations were observed.

Conclusion

This is the first study analyzing the joint effect of common genetic variation in DNA repair pathways and the risk of CVD events, demonstrating an association between the NHEJ pathway and MI in 2 different cohorts.     

Make Vitamin D While the Sun Shines,Take Supplements When It Doesn′t: A Longitudinal,Observational Study of Older Adults in Tasmania,Australia

Low vitamin D status has been associated with a number of chronic conditions, particularly in older adults. The aim of this study was to identify how best to maintain optimum vitamin D status throughout the year in this high-risk population. The main objectives of the study were to assess seasonal vitamin D status; identify the main determinants of vitamin D status; determine if taking part in the study led to alterations in participant behaviour and vitamin D status. A longitudinal design across four consecutive seasons observed ninety-one 60–85 year old community-dwelling adults in Tasmania (41π S) over 13 consecutive months, with a follow-up assessment at next winter''s end. Associations between solar UVB exposure, sun protection behaviours, dietary and supplemental vitamin D with serum 25(OH)D concentrations were assessed. Variation in serum 25(OH)D demonstrated an identical pattern to solar UVB, lagging 8–10 weeks. Serum 25(OH)D was positively associated with summer UVB (mean 15.9 nmol/L; 95%CI 11.8–19.9 nmol/L, p<0.001) and vitamin D supplementation (100–600 IU/day: 95%CI 10.2 nmol/L; 0.8–19.6 nmol/L; p = 0.03; 800 IU/day: 21.0 nmol/L; 95%CI 8.1–34.0 nmol/L; p = 0.001). Seasonal variation in serum 25(OH)D was greatly diminished in supplement users. The most common alteration in participant behaviour after the study was ingesting vitamin D supplements. Post-study vitamin D supplementation ℘800 IU/day was seven times more likely than during the study resulting in mean difference in serum 25(OH)D between supplement and non-supplement users of 30.1 nmol/L (95%CI 19.4–40.8 nmol/L; p<0.001). The main limitation was homogeneity of participant ethnicity. Solar exposure in summer and ingestion of vitamin D supplements in other seasons are the most effective ways of achieving and maintaining year-round vitamin D sufficiency in older adults in the Southern hemisphere. Vitamin D supplementation has greatest effect on vitamin D status if ingested during and after winter, i.e. between the autumn and spring equinoxes.     

Structural Context of Disease-Associated Mutations and Putative Mechanism of Autoinhibition Revealed by X-Ray Crystallographic Analysis of the EZH2-SET Domain

The enhancer-of-zeste homolog 2 (EZH2) gene product is an 87 kDa polycomb group (PcG) protein containing a C-terminal methyltransferase SET domain. EZH2, along with binding partners, i.e., EED and SUZ12, upon which it is dependent for activity forms the core of the polycomb repressive complex 2 (PRC2). PRC2 regulates gene silencing by catalyzing the methylation of histone H3 at lysine 27. Both overexpression and mutation of EZH2 are associated with the incidence and aggressiveness of various cancers. The novel crystal structure of the SET domain was determined in order to understand disease-associated EZH2 mutations and derive an explanation for its inactivity independent of complex formation. The 2.00 Å crystal structure reveals that, in its uncomplexed form, the EZH2 C-terminus folds back into the active site blocking engagement with substrate. Furthermore, the S-adenosyl-L-methionine (SAM) binding pocket observed in the crystal structure of homologous SET domains is notably absent. This suggests that a conformational change in the EZH2 SET domain, dependent upon complex formation, must take place for cofactor and substrate binding activities to be recapitulated. In addition, the data provide a structural context for clinically significant mutations found in the EZH2 SET domain.