Resting-state network connectivity has been associated with a variety of cognitive abilities, yet it remains unclear how these connectivity properties might contribute to the neurocognitive ...computations underlying these abilities. We developed a new approach-information transfer mapping-to test the hypothesis that resting-state functional network topology describes the computational mappings between brain regions that carry cognitive task information. Here, we report that the transfer of diverse, task-rule information in distributed brain regions can be predicted based on estimated activity flow through resting-state network connections. Further, we find that these task-rule information transfers are coordinated by global hub regions within cognitive control networks. Activity flow over resting-state connections thus provides a large-scale network mechanism for cognitive task information transfer and global information coordination in the human brain, demonstrating the cognitive relevance of resting-state network topology.
There is increasing interest in discovering mechanisms that mediate the effects of childhood stress on late-life disease morbidity and mortality. Previous studies have suggested one potential ...mechanism linking stress to cellular aging, disease and mortality in humans: telomere erosion. We examined telomere erosion in relation to children's exposure to violence, a salient early-life stressor, which has known long-term consequences for well-being and is a major public-health and social-welfare problem. In the first prospective-longitudinal study with repeated telomere measurements in children while they experienced stress, we tested the hypothesis that childhood violence exposure would accelerate telomere erosion from age 5 to age 10 years. Violence was assessed as exposure to maternal domestic violence, frequent bullying victimization and physical maltreatment by an adult. Participants were 236 children (49% females; 42% with one or more violence exposures) recruited from the Environmental-Risk Longitudinal Twin Study, a nationally representative 1994-1995 birth cohort. Each child's mean relative telomere length was measured simultaneously in baseline and follow-up DNA samples, using the quantitative PCR method for T/S ratio (the ratio of telomere repeat copy numbers to single-copy gene numbers). Compared with their counterparts, the children who experienced two or more kinds of violence exposure showed significantly more telomere erosion between age-5 baseline and age-10 follow-up measurements, even after adjusting for sex, socioeconomic status and body mass index (B=-0.052, s.e.=0.021, P=0.015). This finding provides support for a mechanism linking cumulative childhood stress to telomere maintenance, observed already at a young age, with potential impact for life-long health.
The pregnane X receptor (PXR) detects the presence of a wide variety of endogenous and xenobiotic compounds, and is a master regulator of the expression of genes central to drug metabolism and ...excretion. We present the 2.0Å crystal structure of the human PXR ligand-binding domain (LBD) in complex with the cholesterol-lowering compound SR12813 and a 25 amino acid residue fragment of the human steroid receptor coactivator-1 (SRC-1) containing one LXXLL motif. PXR crystallizes as a homodimer in the asymmetric unit in this structure and possesses a novel α2 helix adjacent to its ligand-binding cavity. The SRC-1 peptide forms two distinct helices and binds adjacent to the ligand-dependent transactivation AF-2 helix on the surface of PXR. In contrast with previous PXR structures, in which SR12813 bound in multiple orientations, the small SR12813 agonist in this structure binds in a single, unique orientation within the receptor's ligand-binding pocket and contacts the AF-2 helix. Thermal denaturation studies reveal that the SR12813 ligand and SRC-1 coactivator peptide each stabilize the LBD of PXR, and that together they exert an additive effect on the stability of the receptor. These results indicate that the binding of coactivator to the surface of PXR limits the ability of this promiscuous receptor to “breathe” and helps to trap a single, active conformation of SR12813. They further reveal that specificity is required for PXR activation.
This study sought to derive age-, sex-, and ethnic-appropriate adult reference values for left atrial (LA) and left ventricular (LV) dimensions and volumes, LV mass, fractional shortening, and ...ejection fraction (EF) derived from geographically diverse population studies.
The current recommended reference values for measurements from echocardiography may not be suitable to the diverse world population to which they are now applied.
Population-based datasets of echocardiographic measurements from 22,404 adults without clinical cardiovascular or renal disease, hypertension, or diabetes were combined in an individual person data meta-analysis. Quantile regression was used to derive reference values at the 95th percentile (upper reference value URV) and fifth percentile (lower reference value LRV) of each measurement against age (treated as linear), separately within sex and ethnic groups.
The URVs for left ventricular end-diastolic volume (LVEDV), LV end-systolic volume, and LV stroke volume (SV) were highest in Europeans and lowest in South Asians. Important sex and ethnic differences remained after indexation by body surface area or height for these measurements, as well as for the LRV for SV. LVEDV and SV decreased with increasing age for all groups. Importantly, the LRV for EF differed by ethnicity; there was a clear apparent difference between Europeans and Asians. The URVs for LV end-diastolic diameter and LV end-systolic diameter were higher for Europeans than those for East Asian, South Asian, and African people, particularly among men. Similarly, the URVs for LA diameter and volume were highest for Europeans.
Sex- and/or ethnic-appropriate echocardiographic reference values are indicated for many measurements of LA and LV size, LV mass, and EF. Reference values for LV volumes and mass also differ across the age range.
We studied the phylogeography of Chinese yew (Taxus wallichiana), a tree species distributed over most of southern China and adjacent regions. A total of 1235 individuals from 50 populations from ...China and North Vietnam were analysed for chloroplast DNA variation using polymerase chain reaction-restriction fragment length polymorphism of the trnL-F intron-spacer region. A total of 19 different haplotypes were distinguished. We found a very high level of population differentiation and a strong phylogeographic pattern, suggesting low levels of recurrent gene flow among populations. Haplotype differentiation was most marked along the boundary between the Sino-Himalayan and Sino-Japanese Forest floristic subkingdoms, with only one haplotype being shared among these two subkingdoms. The Malesian and Sino-Himalayan Forest subkingdoms had five and 10 haplotypes, respectively, while the relatively large Sino-Japanese Forest subkingdom had only eight. The strong geography-haplotype correlation persisted at the regional floristic level, with most regions possessing a unique set of haplotypes, except for the central China region. Strong landscape effects were observed in the Hengduan and Dabashan mountains, where steep mountains and valleys might have been natural dispersal barriers. The molecular phylogenetic data, together with the geographic distribution of the haplotypes, suggest the existence of several localized refugia during the last glaciation from which the present-day distribution may be derived. The pattern of haplotype distribution across China and North Vietnam corresponded well with the current taxonomic delineation of the three intraspecific varieties of T. wallichiana.
Transcriptional differences in interleukin-11 (IL11) after antidepressant treatment have been found to correspond to clinical response in major depressive disorder (MDD) patients. Expression ...differences were partly mediated by a single-nucleotide polymorphism (rs1126757), identified as a predictor of antidepressant response as part of a genome-wide association study. Here we attempt to identify whether DNA methylation, another baseline factor known to affect transcription factor binding, might also predict antidepressant response, using samples collected from the Genome-based Therapeutic Drugs for Depression project (GENDEP). DNA samples from 113 MDD individuals from the GENDEP project, who were treated with either escitalopram (n=80) or nortriptyline (n=33) for 12 weeks, were randomly selected. Percentage change in Montgomery-Åsberg Depression Rating Scale scores between baseline and week 12 were utilized as our measure of antidepressant response. The Sequenom EpiTYPER platform was used to assess DNA methylation across the only CpG island located in the IL11 gene. Regression analyses were then used to explore the relationship between CpG unit methylation and antidepressant response. We identified a CpG unit predictor of general antidepressant response, a drug by CpG unit interaction predictor of response, and a CpG unit by rs1126757 interaction predictor of antidepressant response. The current study is the first to investigate the potential utility of pharmaco-epigenetic biomarkers for the prediction of antidepressant response. Our results suggest that DNA methylation in IL11 might be useful in identifying those patients likely to respond to antidepressants, and if so, the best drug suited to each individual.
Our purpose was to determine reference values and determinants of serum uric acid (SUA) in children and adolescents.
A fasting blood sample was collected from 1750 schoolchildren and adolescents ...(6-17 years). Puberty was defined according to the Tanner scale. Bodyweight, muscle mass, and body fat percentage were determined by bioimpedance. Data are given as cut-offs and mean ± standard deviation.
SUA level was higher in children that had already entered puberty (4.2 ± 1.1 mg/dL) than among prepubescent (3.6 ± 0.8 mg/dL; p < 0.01). Considering the 90 percentile (p90) as the upper reference value, the following values are proposed for boys and girls, respectively: <10 years or prepubescent: ≤4.5 mg/dL and ≤4.8 mg/dL; from 10 to 13 years: ≤5.7 mg/dL and ≤5.2 mg/dL; from 14 to 17 years: ≤6.4 mg/dL and ≤5.3 mg/dL. Muscle mass explained part of the variability in SUA after pubescence, acting as an independent variable for higher levels of SUA.
The sex, age, and phase of puberty influence SUA reference levels, and part of this influence could be explained by the higher muscle mass, mainly after the adolescence onset.
The key message of this study is that high levels of uric acid in the blood are associated with metabolic syndrome and cardiovascular risk factors. These diseases should be prevented since the infancy However, it is necessary to establish reference values of uric acid (SUA) for children and adolescents. The Brazilian population is highly admixed and these values were not determined so far. We studied a robust sample of Brazilian schoolchildren and adolescents (6-17 years) and defined the 90th percentile of uric acid as the upper limit of normality for sex, age, and pubertal stage. These values can be used as a reference for other populations with similar characteristics.
Most extant genus-level radiations in gymnosperms are of Oligocene age or younger, reflecting widespread extinction during climate cooling at the Oligocene/Miocene boundary ∼23 million years ago ...(Ma). Recent biogeographic studies have revealed many instances of long-distance dispersal in gymnosperms as well as in angiosperms. Acting together, extinction and long-distance dispersal are likely to erase historical biogeographic signals. Notwithstanding this problem, we show that phylogenetic relationships in the gymnosperm family Cupressaceae (162 species, 32 genera) exhibit patterns expected from the Jurassic/Cretaceous breakup of Pangea. A phylogeny was generated for 122 representatives covering all genera, using up to 10,000 nucleotides of plastid, mitochondrial, and nuclear sequence per species. Relying on 16 fossil calibration points and three molecular dating methods, we show that Cupressaceae originated during the Triassic, when Pangea was intact. Vicariance between the two subfamilies, the Laurasian Cupressoideae and the Gondwanan Callitroideae, occurred around 153 Ma (124–183 Ma), when Gondwana and Laurasia were separating. Three further intercontinental disjunctions involving the Northern and Southern Hemisphere are coincidental with or immediately followed the breakup of Pangea.
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