Characterization of the anisotropic deformation of the right ventricle during open heart surgery.

Digital Image Correlation (DIC) was used for studying the anisotropic behavior of the thin walled right ventricle of the human heart. Strains measured with Speckle Tracking Echocardiography (STE) were compared with the DIC data. Both DIC and STE were used to measure longitudinal strains of the right ventricle in the beginning of an open-heart surgery as well as after the cardiopulmonary bypass. Based on the results, the maximum end-systolic strains obtained with the DIC and STE change similarly during the surgery with less than 10% difference. The difference is largely due to the errors in matching the longitudinal direction in the two methods, sensitivity of the measurement to the positioning of the virtual extensometer of in both STE and DIC, and physiological difference of the measurements as the DIC measures the top surface of the heart whereas the STE obtains the data from below. The anisotropy of the RV was measured using full field principal strains acquired from the DIC displacement fields. The full field principal strains cover the entire region of interest instead of just two points as the virtual extensometer approach used by the STE. The principal strains are not direction dependent measures, and therefore are more independent of the anatomy of the patient and the exact positioning of the virtual strain gage or the STE probe. The results show that the longitudinal strains alone are not enough to fully characterize the behavior of the heart, as the deformation of the heart can be very anisotropic, and the anisotropy changes during the surgery, and from patient to patient.

Pore space extraction and characterization of sack paper using µ-CT.

We show that attenuation X-ray microcomputed tomography (µ-CT) offers a route to extract the three-dimensional pore space of paper reliably enough to distinguish samples of the same kind of paper. Here, we consider two sack kraft papers for cement bags with different basis weights and thicknesses. Sample areas of approximately 5 mm2 with a resolution of 1.5 µm are considered, i.e. sizes that exceed sample areas of 2 mm2 for which the pore structure was previously studied in the literature. The image segmentation is based on indicator kriging as a local method that removes ambiguities in assigning voxels as pore or as fibre. The microstructures of the two samples are statistically compared in terms of descriptors such as sheet thickness, porosity, fractions of externally accessible pores and mean geodesic tortuosity. We demonstrate that a quantitative comparison of samples in terms of porosity and thickness requires a common definition of the sheet surfaces. Finally, the statistical pore space analysis based on the µ-CT scans reliably reveals structural differences between the two paper samples, but only when several descriptors are used. LAY DESCRIPTION: This paper is a seemingly abundant material. Its intrinsic porosity enables a vast number of commercial applications. Particularly packing products, e.g. cement bags, often incorporate sack kraft paper due to its high porosity and its additional mechanical strength. A direct quantification of the porosity of sack kraft papers is, hence, particularly desirable. However, experimental quantification of paper porosity or its pore network properties is difficult and often highly indirect. A nondestructive statistical analysis of the 3D microstructure holds the promise to directly assess the pores. In particular, X-ray microcomputed tomography (µ-CT), frequently with sub-µm resolution, has been established as a method to study the fibre and pore structure of paper. The question arises, whether statistical analysis of the microstructure based on µ-CT imaging is sufficient to reliably distinguish between different sack kraft papers. Here, we explore whether the pore structure of paper can be extracted and statistically analysed for larger sample areas despite the fact that a larger sample size directly translates into a lower resolution of the µ-CT scan. We expect that a large sample size increases the region of interest on the basis of which samples can be better distinguished. A lowered resolution poses a severe challenge for the reliable identification of voxel data as pores or as fibres, because the contrast between paper fibres (made of cellulose) and air, which is established due to X-ray absorption, is weak. We show that we can reliably assign each voxel by using an indicator kriging as a two-step method. This method performs an initial voxel identification based on the overall distribution of measured grey values and refines the identification by inspecting the local environment of each voxel. For the pore space extracted in such a way, we can then compute quantities that are related to the geometry and connectivity properties of the pores. Furthermore, we address a paper-born challenge for such an analysis, i.e. we cannot always unambiguously tell whether a pore is located inside the paper sheet or at the surface of the paper. The way the paper surfaces are extracted from the microstructure decisively determines the final specifications of the predicted properties. A significant distinction of the samples is only possible when comparing the properties of the pore network.

An Optical Method for the In-Vivo Characterization of the Biomechanical Response of the Right Ventricle.

The intraoperative in-vivo mechanical function of the left ventricle has been studied thoroughly using echocardiography in the past. However, due to technical and anatomical issues, the ultrasound technology cannot easily be focused on the right side of the heart during open-heart surgery, and the function of the right ventricle during the intervention remains largely unexplored. We used optical imaging and digital image correlation for the characterization of the right ventricle motion and deformation during open-heart surgery. This work is a pilot study focusing on one patient only with the aim of establishing the framework for long term research. These experiments show that optical imaging and the analysis of the images can be used to obtain similar parameters, and partly at higher accuracy, for describing the mechanical functioning of the heart as the ultrasound technology. This work describes the optical imaging based method to characterize the mechanical response of the heart in-vivo, and offers new insight into the mechanical function of the right ventricle.

Association between breastfeeding and better preserved cognitive ability in an elderly cohort of Finnish men.

BACKGROUND: Being breastfed in infancy has been shown to benefit neurodevelopment. However, whether the benefits persist to old age remains unclear. METHODS: We examined the associations between breastfeeding and its duration on cognitive ability in young adulthood and old age, and on aging-related cognitive change over five decades. In total, 931 men from the Helsinki Birth Cohort Study born in 1934-1944 in Finland took the Finnish Defence Forces Basic Intellectual Ability Test (total and verbal, arithmetic and visuospatial subtest scores) twice, at ages 20.2 and 67.9 years, and had data on breastfeeding (yes v. no) and its duration ('never breastfed', 'up to 3', '3 to 6' and '6 or more months'). Linear and mixed model regressions tested the associations. RESULTS: At 20.2 years, breastfed men had higher cognitive ability total and visuospatial subtest scores [mean differences (MDs) ranged between 3.0-3.9, p values < 0.013], and its longer duration predicted higher cognitive ability total and arithmetic and visuospatial subtest scores (MDs ranged between 3.0 and 4.8, p values < 0.039). At 67.9 years, breastfed men had higher total cognitive ability and all subtest scores (MDs ranged between 2.6 and 3.4, p values < 0.044) and its longer duration predicted all cognitive ability scores (MDs ranged between 3.1 and 4.7, p values < 0.050). Verbal subtest scores decreased over five decades in men who were never breastfed or were breastfed for 3 months or less, and increased in those breastfed for longer than 3 months. CONCLUSIONS: Neurodevelopmental advantages of breastfeeding and its longer duration persist into old age, and longer duration of breastfeeding may benefit aging-related change, particularly in verbal reasoning ability.

An epigenome-wide association study meta-analysis of educational attainment.

The epigenome is associated with biological factors, such as disease status, and environmental factors, such as smoking, alcohol consumption and body mass index. Although there is a widespread perception that environmental influences on the epigenome are pervasive and profound, there has been little evidence to date in humans with respect to environmental factors that are biologically distal. Here we provide evidence on the associations between epigenetic modifications-in our case, CpG methylation-and educational attainment (EA), a biologically distal environmental factor that is arguably among the most important life-shaping experiences for individuals. Specifically, we report the results of an epigenome-wide association study meta-analysis of EA based on data from 27 cohort studies with a total of 10 767 individuals. We find nine CpG probes significantly associated with EA. However, robustness analyses show that all nine probes have previously been found to be associated with smoking. Only two associations remain when we perform a sensitivity analysis in the subset of never-smokers, and these two probes are known to be strongly associated with maternal smoking during pregnancy, and thus their association with EA could be due to correlation between EA and maternal smoking. Moreover, the effect sizes of the associations with EA are far smaller than the known associations with the biologically proximal environmental factors alcohol consumption, body mass index, smoking and maternal smoking during pregnancy. Follow-up analyses that combine the effects of many probes also point to small methylation associations with EA that are highly correlated with the combined effects of smoking. If our findings regarding EA can be generalized to other biologically distal environmental factors, then they cast doubt on the hypothesis that such factors have large effects on the epigenome.

Autism spectrum traits and visual processing in young adults with very low birth weight: the Helsinki Study of Very Low Birth Weight adults.

Visual processing problems may be one underlying factor for cognitive impairments related to autism spectrum disorders (ASDs). We examined associations between ASD-traits (Autism-Spectrum Quotient) and visual processing performance (Rey-Osterrieth Complex Figure Test; Block Design task of the Wechsler Adult Intelligence Scale-III) in young adults (mean age=25.0, s.d.=2.1 years) born preterm at very low birth weight (VLBW; <1500 g) (n=101) or at term (n=104). A higher level of ASD-traits was associated with slower global visual processing speed among the preterm VLBW, but not among the term-born group (P<0.04 for interaction). Our findings suggest that the associations between ASD-traits and visual processing may be restricted to individuals born preterm, and related specifically to global, not local visual processing. Our findings point to cumulative social and neurocognitive problems in those born preterm at VLBW.

Changes in leisure-time physical activity and physical and mental health functioning: a follow-up study.

Functioning will be an increasingly important issue in Finland over the coming decades as the proportion of the population aged 65 and older is growing significantly. However, the associations between changes in physical activity and subsequent health functioning are poorly understood. The aim of this study was to examine how changes in physical activity relate to concurrent and prospective levels of health functioning. Cohort data from the Helsinki Health Study were used. Phase 1 (n = 8960, response rate 67%, 80% women) was conducted among 40- to 60-year-old employees of the City of Helsinki in 2000-2002, phase 2 in 2007 (n = 7332, response rate 83%), and phase 3 in 2012 (n = 6814, response rate 79%). Linear mixed models were used as the main statistical method. Increasing physical activity was associated with higher concurrent and prospective levels of physical health functioning, whereas decreasing activity was associated with lower levels of physical health functioning. The associations were stronger with physical than with mental health functioning. Promoting physical activity among aging people may help to maintain their level of health functioning.

Common mental disorders in young adults born late-preterm.

BACKGROUND: Results of adulthood mental health of those born late-preterm (34 + 0-36 + 6 weeks + days of gestation) are mixed and based on national registers. We examined if late-preterm birth was associated with a higher risk for common mental disorders in young adulthood when using a diagnostic interview, and if this risk decreased as gestational age increased. METHOD: A total of 800 young adults (mean = 25.3, s.d. = 0.62 years), born 1985-1986, participated in a follow-up of the Arvo Ylppö Longitudinal Study. Common mental disorders (mood, anxiety and substance use disorders) during the past 12 months were defined using the Composite International Diagnostic Interview (Munich version). Gestational age was extracted from hospital birth records and categorized into early-preterm (<34 + 0, n = 37), late-preterm (34 + 0-36 + 6, n = 106), term (37 + 0-41 + 6, n = 617) and post-term (⩾42 + 0, n = 40). RESULTS: Those born late-preterm and at term were at a similar risk for any common mental disorder [odds ratio (OR) 1.11, 95% confidence interval (CI) 0.67-1.84], for mood (OR 1.11, 95% CI 0.54-2.25), anxiety (OR 1.00, 95% CI 0.40-2.50) and substance use (OR 1.31, 95% CI 0.74-2.32) disorders, and co-morbidity of these disorders (p = 0.38). While the mental disorder risk decreased significantly as gestational age increased, the trend was driven by a higher risk in those born early-preterm. CONCLUSIONS: Using a cohort born during the advanced neonatal and early childhood care, we found that not all individuals born preterm are at risk for common mental disorders in young adulthood - those born late-preterm are not, while those born early-preterm are at a higher risk. Available resources for prevention and intervention should be targeted towards the preterm group born the earliest.

Somatic, positive and negative domains of the Center for Epidemiological Studies Depression (CES-D) scale: a meta-analysis of genome-wide association studies.

BACKGROUND: Major depressive disorder (MDD) is moderately heritable, however genome-wide association studies (GWAS) for MDD, as well as for related continuous outcomes, have not shown consistent results. Attempts to elucidate the genetic basis of MDD may be hindered by heterogeneity in diagnosis. The Center for Epidemiological Studies Depression (CES-D) scale provides a widely used tool for measuring depressive symptoms clustered in four different domains which can be combined together into a total score but also can be analysed as separate symptom domains. METHOD: We performed a meta-analysis of GWAS of the CES-D symptom clusters. We recruited 12 cohorts with the 20- or 10-item CES-D scale (32 528 persons). RESULTS: One single nucleotide polymorphism (SNP), rs713224, located near the brain-expressed melatonin receptor (MTNR1A) gene, was associated with the somatic complaints domain of depression symptoms, with borderline genome-wide significance (p discovery = 3.82 × 10-8). The SNP was analysed in an additional five cohorts comprising the replication sample (6813 persons). However, the association was not consistent among the replication sample (p discovery+replication = 1.10 × 10-6) with evidence of heterogeneity. CONCLUSIONS: Despite the effort to harmonize the phenotypes across cohorts and participants, our study is still underpowered to detect consistent association for depression, even by means of symptom classification. On the contrary, the SNP-based heritability and co-heritability estimation results suggest that a very minor part of the variation could be captured by GWAS, explaining the reason of sparse findings.

GWAS for executive function and processing speed suggests involvement of the CADM2 gene.

To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32,070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 × 10(-8)) and in the joint discovery and replication meta-analysis (P-value=3.28 × 10(-9) after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 × 10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 × 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value=1.36 × 10(-11)) and neuron cell-cell adhesion (P-value=1.48 × 10(-13)). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed.

Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53949).

General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53,949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10(-9), MIR2113; rs17522122, P=2.55 × 10(-8), AKAP6; rs10119, P=5.67 × 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10(-6)). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10(-17)). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer's disease: TOMM40, APOE, ABCG1 and MEF2C.

Novel loci associated with usual sleep duration: the CHARGE Consortium Genome-Wide Association Study.

Usual sleep duration is a heritable trait correlated with psychiatric morbidity, cardiometabolic disease and mortality, although little is known about the genetic variants influencing this trait. A genome-wide association study (GWAS) of usual sleep duration was conducted using 18 population-based cohorts totaling 47 180 individuals of European ancestry. Genome-wide significant association was identified at two loci. The strongest is located on chromosome 2, in an intergenic region 35- to 80-kb upstream from the thyroid-specific transcription factor PAX8 (lowest P=1.1 × 10(-9)). This finding was replicated in an African-American sample of 4771 individuals (lowest P=9.3 × 10(-4)). The strongest combined association was at rs1823125 (P=1.5 × 10(-10), minor allele frequency 0.26 in the discovery sample, 0.12 in the replication sample), with each copy of the minor allele associated with a sleep duration 3.1 min longer per night. The alleles associated with longer sleep duration were associated in previous GWAS with a more favorable metabolic profile and a lower risk of attention deficit hyperactivity disorder. Understanding the mechanisms underlying these associations may help elucidate biological mechanisms influencing sleep duration and its association with psychiatric, metabolic and cardiovascular disease.

Late preterm birth, post-term birth, and abnormal fetal growth as risk factors for severe mental disorders from early to late adulthood.

BACKGROUND: Late preterm births constitute the majority of preterm births. However, most evidence suggesting that preterm birth predicts the risk of mental disorders comes from studies on earlier preterm births. We examined if late preterm birth predicts the risks of severe mental disorders from early to late adulthood. We also studied whether adulthood mental disorders are associated with post-term birth or with being born small (SGA) or large (LGA) for gestational age, which have been previously associated with psychopathology risk in younger ages. METHOD: Of 12 597 Helsinki Birth Cohort Study participants, born 1934-1944, 664 were born late preterm, 1221 post-term, 287 SGA, and 301 LGA. The diagnoses of mental disorders were identified from national hospital discharge and cause of death registers from 1969 to 2010. In total, 1660 (13.2%) participants had severe mental disorders. RESULTS: Individuals born late preterm did not differ from term-born individuals in their risk of any severe mental disorder. However, men born late preterm had a significantly increased risk of suicide. Post-term birth predicted significantly increased risks of any mental disorder in general and particularly of substance use and anxiety disorders. Individuals born SGA had significantly increased risks of any mental and substance use disorders. Women born LGA had an increased risk of psychotic disorders. CONCLUSIONS: Although men born late preterm had an increased suicide risk, late preterm birth did not exert widespread effects on adult psychopathology. In contrast, the risks of severe mental disorders across adulthood were increased among individuals born SGA and individuals born post-term.

Maternal hypertensive disorders during pregnancy: adaptive functioning and psychiatric and psychological problems of the older offspring.

OBJECTIVE: To study whether pre-eclampsia and hypertension without proteinuria during pregnancy are associated with adaptive functioning, and psychiatric and psychological problems, of older offspring. DESIGN: Retrospective longitudinal cohort study. SETTING: Participants in the Helsinki Birth Cohort 1934-44 Study. POPULATION: A cohort of 778 participants born after normotensive, pre-eclamptic, or hypertensive pregnancies, defined based on the mother's blood pressure and urinary protein measurements at maternity clinics and birth hospitals. METHODS: Pearson's chi-squared tests and multivariable logistic regression. MAIN OUTCOME MEASURES: Achenbach System of Empirically Based Assessment Older Adult Self-Report scores, completed at age 69.3 years (SD 3.1 years). RESULTS: Compared with offspring born after normotensive pregnancies, offspring born after pre-eclamptic pregnancies had increased odds of reporting total problems (aOR 4.00, 95%CI 1.64-9.77) and problems of particular concern to clinicians (critical items; aOR 5.28, 95%CI 1.87-14.96), as well as: anxious/depressed, functional impairment, memory, thought, and irritable/disinhibited problems on syndrome scales; depressive, somatic, and psychotic problems on Diagnostic and Statistical Manual of Mental Disorders scales; and adjustment problems in relationship satisfaction with spouse/partner. Maternal hypertension without proteinuria was not consistently associated with adjustment and problems (total problems, aOR 1.08, 95%CI 0.75-1.57; critical items, aOR 1.58, 95%CI 0.91-2.72). CONCLUSIONS: Maternal hypertensive disorders in pregnancy, during a period of expectant treatment, carry an increased risk of problems in adaptive functioning and mental wellbeing in the offspring seven decades later. Being the longest follow-up on transgenerational consequences of maternal hypertensive disorders reported thus far, our study points to the life-time increased risk of an adverse intrauterine environment.

CDK/CK1 inhibitors roscovitine and CR8 downregulate amplified MYCN in neuroblastoma cells.

To understand the mechanisms of action of (R)-roscovitine and (S)-CR8, two related pharmacological inhibitors of cyclin-dependent kinases (CDKs), we applied a variety of '-omics' techniques to the human neuroblastoma SH-SY5Y and IMR32 cell lines: (1) kinase interaction assays, (2) affinity competition on immobilized broad-spectrum kinase inhibitors, (3) affinity chromatography on immobilized (R)-roscovitine and (S)-CR8, (4) whole genome transcriptomics analysis and specific quantitative PCR studies, (5) global quantitative proteomics approach and western blot analysis of selected proteins. Altogether, the results show that the major direct targets of these two molecules belong to the CDKs (1,2,5,7,9,12), DYRKs, CLKs and CK1s families. By inhibiting CDK7, CDK9 and CDK12, these inhibitors transiently reduce RNA polymerase 2 activity, which results in downregulation of a large set of genes. Global transcriptomics and proteomics analysis converge to a central role of MYC transcription factors downregulation. Indeed, CDK inhibitors trigger rapid and massive downregulation of MYCN expression in MYCN-amplified neuroblastoma cells as well as in nude mice xenografted IMR32 cells. Inhibition of casein kinase 1 may also contribute to the antitumoral activity of (R)-roscovitine and (S)-CR8. This dual mechanism of action may be crucial in the use of these kinase inhibitors for the treatment of MYC-dependent cancers, in particular neuroblastoma where MYCN amplification is a strong predictor factor for high-risk disease.

Molecular genetic evidence for overlap between general cognitive ability and risk for schizophrenia: a report from the Cognitive Genomics consorTium (COGENT).

It has long been recognized that generalized deficits in cognitive ability represent a core component of schizophrenia (SCZ), evident before full illness onset and independent of medication. The possibility of genetic overlap between risk for SCZ and cognitive phenotypes has been suggested by the presence of cognitive deficits in first-degree relatives of patients with SCZ; however, until recently, molecular genetic approaches to test this overlap have been lacking. Within the last few years, large-scale genome-wide association studies (GWAS) of SCZ have demonstrated that a substantial proportion of the heritability of the disorder is explained by a polygenic component consisting of many common single-nucleotide polymorphisms (SNPs) of extremely small effect. Similar results have been reported in GWAS of general cognitive ability. The primary aim of the present study is to provide the first molecular genetic test of the classic endophenotype hypothesis, which states that alleles associated with reduced cognitive ability should also serve to increase risk for SCZ. We tested the endophenotype hypothesis by applying polygenic SNP scores derived from a large-scale cognitive GWAS meta-analysis (~5000 individuals from nine nonclinical cohorts comprising the Cognitive Genomics consorTium (COGENT)) to four SCZ case-control cohorts. As predicted, cases had significantly lower cognitive polygenic scores compared to controls. In parallel, polygenic risk scores for SCZ were associated with lower general cognitive ability. In addition, using our large cognitive meta-analytic data set, we identified nominally significant cognitive associations for several SNPs that have previously been robustly associated with SCZ susceptibility. Results provide molecular confirmation of the genetic overlap between SCZ and general cognitive ability, and may provide additional insight into pathophysiology of the disorder.

CHK2 kinase promotes pre-mRNA splicing via phosphorylating CDK11(p110).

Checkpoint kinase 2 (CHK2) kinase is a key mediator in many cellular responses to genotoxic stresses, including ionizing radiation (IR) and topoisomerase inhibitors. Upon IR, CHK2 is activated by ataxia telangiectasia mutated kinase and regulates the S-phase and G1-S checkpoints, apoptosis and DNA repair by phosphorylating downstream target proteins, such as p53 and Brca1. In addition, CHK2 is thought to be a multi-organ cancer susceptibility gene. In this study, we used a tandem affinity purification strategy to identify proteins that interact with CHK2 kinase. Cyclin-dependent kinase 11 (CDK11)(p110) kinase, implicated in pre-mRNA splicing and transcription, was identified as a CHK2-interacting protein. CHK2 kinase phosphorylated CDK11(p110) on serine 737 in vitro. Unexpectedly, CHK2 kinase constitutively phosphorylated CDK11(p110) in a DNA damage-independent manner. At a molecular level, CDK11(p110) phosphorylation was required for homodimerization without affecting its kinase activity. Overexpression of CHK2 promoted pre-mRNA splicing. Conversely, CHK2 depletion decreased endogenous splicing activity. Mutation of the phosphorylation site in CDK11(p110) to alanine abrogated its splicing-activating activity. These results provide the first evidence that CHK2 kinase promotes pre-mRNA splicing via phosphorylating CDK11(p110).

A genome-wide meta-analysis of association studies of Cloninger's Temperament Scales.

Temperament has a strongly heritable component, yet multiple independent genome-wide studies have failed to identify significant genetic associations. We have assembled the largest sample to date of persons with genome-wide genotype data, who have been assessed with Cloninger's Temperament and Character Inventory. Sum scores for novelty seeking, harm avoidance, reward dependence and persistence have been measured in over 11,000 persons collected in four different cohorts. Our study had >80% power to identify genome-wide significant loci (P<1.25 × 10(-8), with correction for testing four scales) accounting for ≥0.4% of the phenotypic variance in temperament scales. Using meta-analysis techniques, gene-based tests and pathway analysis we have tested over 1.2 million single-nucleotide polymorphisms (SNPs) for association to each of the four temperament dimensions. We did not discover any SNPs, genes, or pathways to be significantly related to the four temperament dimensions, after correcting for multiple testing. Less than 1% of the variability in any temperament dimension appears to be accounted for by a risk score derived from the SNPs showing strongest association to the temperament dimensions. Elucidation of genetic loci significantly influencing temperament and personality will require potentially very large samples, and/or a more refined phenotype. Item response theory methodology may be a way to incorporate data from cohorts assessed with multiple personality instruments, and might be a method by which a large sample of a more refined phenotype could be acquired.

OS103. Hypertensive disorders during pregnancy and cognitive decline of the offspring up to old age: the helsinki birth cohort study.

INTRODUCTION: Hypertensive disorders affect the fetal developmental milieu and may point to mechanisms by which prenatal adversity is associated with lower cognitive ability in subsequent life. OBJECTIVES: We tested whether hypertensive disorders during pregnancy predict age-related change in cognitive ability in the offspring up to old age. METHODS: Using mothers' blood pressure and urinary protein measurements from the maternity clinics and birth hospitals, we defined normotensive or hypertensive pregnancies in mothers of 398 men, who participated in the Helsinki Birth Cohort 1934-44 Study. The men underwent the Finnish Defense Forces basic ability test twice, first, during compulsory military service at age 20.1 (SD=1.4) years and, then, in a re-test at age 68.5 (SD=2.9) years. The test yields a total score and subscores for tests measuring verbal, arithmetic and visuospatial reasoning. Scores were standardized with a mean of 100 and standard deviation of 15. RESULTS: Men born after pregnancies complicated by a hypertensive disorder, compared with men born after normotensive pregnancies, scored 3.84 (95% Confidence Interval, 0.77 to 6.91) points lower on total cognitive ability at 68.5 years, and displayed a greater decline in total cognitive ability (2.31, 0.23 to 4.39) after 20.1 years. Of the subscores, associations were strongest for arithmetic reasoning. CONCLUSION: Maternal hypertensive disorders in pregnancy predict lower cognitive ability and greater cognitive decline up to old age. Multidisciplinary research is essential in order to uncover the mechanisms linking hypertensive pregnancy disorders with lower cognitive abilities in the offspring.

Neurocognitive abilities in young adults with very low birth weight.

OBJECTIVE: Although severely preterm birth has been associated with impaired neurocognitive abilities in children, follow-up studies in adulthood are scarce. We set out to study whether adults born with very low birth weight (VLBW) (<1,500 g), either small for gestational age (SGA) (birth weight ≤-2 SD) or appropriate for gestational age (AGA), differ in a range of neurocognitive abilities and academic performance from adults born at term and not SGA. METHODS: As part of the Helsinki Study of Very Low Birth Weight Adults, 103 VLBW (37 SGA) and 105 term-born control adults (mean age 25.0, range 21.4-29.7 years) without major neurosensory impairments participated in the follow-up study in 2007-2008. The test battery included measures of general cognitive ability as well as executive functioning and related abilities. Academic performance was self-reported. RESULTS: With adjustment for sex and age, the VLBW group scored lower or performed slower than the control group in some indices of all tests (these mean differences ranged from 0.3 to 0.5 SD units, p ≤ 0.03) and they had received remedial education at school more frequently; however, no differences existed in self-reported academic performance. The differences were evident in both VLBW-SGA and VLBW-AGA groups. Further covariate adjustments for parental education, current head circumference, and head circumference at birth and, in tests of executive functioning and related abilities, adjustment for IQ estimate had minor effects on the results. CONCLUSIONS: In comparison with control adults, VLBW adults scored lower on several neurocognitive tests. Poorer neurocognitive performance is associated with VLBW irrespective of the intrauterine growth pattern.