273 research outputs found

    Gene-history correlation and population structure

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    Correlation of gene histories in the human genome determines the patterns of genetic variation (haplotype structure) and is crucial to understanding genetic factors in common diseases. We derive closed analytical expressions for the correlation of gene histories in established demographic models for genetic evolution and show how to extend the analysis to more realistic (but more complicated) models of demographic structure. We identify two contributions to the correlation of gene histories in divergent populations: linkage disequilibrium, and differences in the demographic history of individuals in the sample. These two factors contribute to correlations at different length scales: the former at small, and the latter at large scales. We show that recent mixing events in divergent populations limit the range of correlations and compare our findings to empirical results on the correlation of gene histories in the human genome.Comment: Revised and extended version: 26 pages, 5 figures, 1 tabl

    Multisensory information facilitates reaction speed by enlarging activity difference between superior colliculus hemispheres in rats

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    Animals can make faster behavioral responses to multisensory stimuli than to unisensory stimuli. The superior colliculus (SC), which receives multiple inputs from different sensory modalities, is considered to be involved in the initiation of motor responses. However, the mechanism by which multisensory information facilitates motor responses is not yet understood. Here, we demonstrate that multisensory information modulates competition among SC neurons to elicit faster responses. We conducted multiunit recordings from the SC of rats performing a two-alternative spatial discrimination task using auditory and/or visual stimuli. We found that a large population of SC neurons showed direction-selective activity before the onset of movement in response to the stimuli irrespective of stimulation modality. Trial-by-trial correlation analysis showed that the premovement activity of many SC neurons increased with faster reaction speed for the contraversive movement, whereas the premovement activity of another population of neurons decreased with faster reaction speed for the ipsiversive movement. When visual and auditory stimuli were presented simultaneously, the premovement activity of a population of neurons for the contraversive movement was enhanced, whereas the premovement activity of another population of neurons for the ipsiversive movement was depressed. Unilateral inactivation of SC using muscimol prolonged reaction times of contraversive movements, but it shortened those of ipsiversive movements. These findings suggest that the difference in activity between the SC hemispheres regulates the reaction speed of motor responses, and multisensory information enlarges the activity difference resulting in faster responses

    Stochastic population growth in spatially heterogeneous environments

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    Classical ecological theory predicts that environmental stochasticity increases extinction risk by reducing the average per-capita growth rate of populations. To understand the interactive effects of environmental stochasticity, spatial heterogeneity, and dispersal on population growth, we study the following model for population abundances in nn patches: the conditional law of Xt+dtX_{t+dt} given Xt=xX_t=x is such that when dtdt is small the conditional mean of Xt+dtiXtiX_{t+dt}^i-X_t^i is approximately [xiμi+j(xjDjixiDij)]dt[x^i\mu_i+\sum_j(x^j D_{ji}-x^i D_{ij})]dt, where XtiX_t^i and μi\mu_i are the abundance and per capita growth rate in the ii-th patch respectivly, and DijD_{ij} is the dispersal rate from the ii-th to the jj-th patch, and the conditional covariance of Xt+dtiXtiX_{t+dt}^i-X_t^i and Xt+dtjXtjX_{t+dt}^j-X_t^j is approximately xixjσijdtx^i x^j \sigma_{ij}dt. We show for such a spatially extended population that if St=(Xt1+...+Xtn)S_t=(X_t^1+...+X_t^n) is the total population abundance, then Yt=Xt/StY_t=X_t/S_t, the vector of patch proportions, converges in law to a random vector YY_\infty as tt\to\infty, and the stochastic growth rate limtt1logSt\lim_{t\to\infty}t^{-1}\log S_t equals the space-time average per-capita growth rate \sum_i\mu_i\E[Y_\infty^i] experienced by the population minus half of the space-time average temporal variation \E[\sum_{i,j}\sigma_{ij}Y_\infty^i Y_\infty^j] experienced by the population. We derive analytic results for the law of YY_\infty, find which choice of the dispersal mechanism DD produces an optimal stochastic growth rate for a freely dispersing population, and investigate the effect on the stochastic growth rate of constraints on dispersal rates. Our results provide fundamental insights into "ideal free" movement in the face of uncertainty, the persistence of coupled sink populations, the evolution of dispersal rates, and the single large or several small (SLOSS) debate in conservation biology.Comment: 47 pages, 4 figure

    Activation of superior colliculi in humans during visual exploration

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    <p>Abstract</p> <p>Background</p> <p>Visual, oculomotor, and – recently – cognitive functions of the superior colliculi (SC) have been documented in detail in non-human primates in the past. Evidence for corresponding functions of the SC in humans is still rare. We examined activity changes in the human tectum and the lateral geniculate nuclei (LGN) in a visual search task using functional magnetic resonance imaging (fMRI) and anatomically defined regions of interest (ROI). Healthy subjects conducted a free visual search task and two voluntary eye movement tasks with and without irrelevant visual distracters. Blood oxygen level dependent (BOLD) signals in the SC were compared to activity in the inferior colliculi (IC) and LGN.</p> <p>Results</p> <p>Neural activity increased during free exploration only in the SC in comparison to both control tasks. Saccade frequency did not exert a significant effect on BOLD signal changes. No corresponding differences between experimental tasks were found in the IC or the LGN. However, while the IC revealed no signal increase from the baseline, BOLD signal changes at the LGN were consistently positive in all experimental conditions.</p> <p>Conclusion</p> <p>Our data demonstrate the involvement of the SC in a visual search task. In contrast to the results of previous studies, signal changes could not be seen to be driven by either visual stimulation or oculomotor control on their own. Further, we can exclude the influence of any nearby neural structures (e.g. pulvinar, tegmentum) or of typical artefacts at the brainstem on the observed signal changes at the SC. Corresponding to findings in non-human primates, our data support a dependency of SC activity on functions beyond oculomotor control and visual processing.</p

    Genome-wide linkage analysis of 972 bipolar pedigrees using single-nucleotide polymorphisms.

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    Because of the high costs associated with ascertainment of families, most linkage studies of Bipolar I disorder (BPI) have used relatively small samples. Moreover, the genetic information content reported in most studies has been less than 0.6. Although microsatellite markers spaced every 10 cM typically extract most of the genetic information content for larger multiplex families, they can be less informative for smaller pedigrees especially for affected sib pair kindreds. For these reasons we collaborated to pool family resources and carried out higher density genotyping. Approximately 1100 pedigrees of European ancestry were initially selected for study and were genotyped by the Center for Inherited Disease Research using the Illumina Linkage Panel 12 set of 6090 single-nucleotide polymorphisms. Of the ~1100 families, 972 were informative for further analyses, and mean information content was 0.86 after pruning for linkage disequilibrium. The 972 kindreds include 2284 cases of BPI disorder, 498 individuals with bipolar II disorder (BPII) and 702 subjects with recurrent major depression. Three affection status models (ASMs) were considered: ASM1 (BPI and schizoaffective disorder, BP cases (SABP) only), ASM2 (ASM1 cases plus BPII) and ASM3 (ASM2 cases plus recurrent major depression). Both parametric and non-parametric linkage methods were carried out. The strongest findings occurred at 6q21 (non-parametric pairs LOD 3.4 for rs1046943 at 119 cM) and 9q21 (non-parametric pairs logarithm of odds (LOD) 3.4 for rs722642 at 78 cM) using only BPI and schizoaffective (SA), BP cases. Both results met genome-wide significant criteria, although neither was significant after correction for multiple analyses. We also inspected parametric scores for the larger multiplex families to identify possible rare susceptibility loci. In this analysis, we observed 59 parametric LODs of 2 or greater, many of which are likely to be close to maximum possible scores. Although some linkage findings may be false positives, the results could help prioritize the search for rare variants using whole exome or genome sequencing

    Elevated MicroRNA-33 in Sarcoidosis and a Carbon Nanotube Model of Chronic Granulomatous Disease

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    We established a murine model of multiwall carbon nanotube (MWCNT)–induced chronic granulomatous disease, which resembles human sarcoidosis pathology. At 60 days after oropharyngeal MWCNT instillation, bronchoalveolar lavage (BAL) cells from wild-type mice exhibit an M1 phenotype with elevated proinflammatory cytokines and reduced peroxisome proliferator–activated receptor γ (PPARγ)—characteristics also present in human sarcoidosis. Based upon MWCNT-associated PPARγ deficiency, we hypothesized that the PPARγ target gene, ATP-binding cassette (ABC) G1, a lipid transporter with antiinflammatory properties, might also be repressed. Results after MWCNT instillation indicated significantly repressed ABCG1, but, surprisingly, lipid transporter ABCA1 was also repressed, suggesting a possible second pathway. Exploration of potential regulators revealed that microRNA (miR)-33, a lipid transporter regulator, was strikingly elevated (13.9 fold) in BAL cells from MWCNT-instilled mice but not sham control mice. Elevated miR-33 was also detected in murine granulomatous lung tissue. In vitro studies confirmed that lentivirus–miR-33 overexpression repressed both ABCA1 and ABCG1 (but not PPARγ) in cultured murine alveolar macrophages. BAL cells of patients with sarcoidosis also displayed elevated miR-33 together with reduced ABCA1 and ABCG1 messenger RNA and protein compared with healthy control subjects. Moreover, miR-33 was elevated within sarcoidosis granulomatous tissue. The findings suggest that alveolar macrophage miR-33 is up-regulated by proinflammatory cytokines and may perpetuate chronic inflammatory granulomatous disease by repressing antiinflammatory functions of ABCA1 and ABCG1 lipid transporters. The results also suggest two possible pathways for transporter dysregulation in granulomatous disease—one associated with intrinsic PPARγ status and the other with miR-33 up-regulation triggered by environmental challenges, such as MWCNT
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