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When a dad says \I love you\
Explores some of the many and varied ways a father can express his love, even without saying the words, such as by making pancakes, playing games, and reading a favorite story using special voices for each character.
Book
Distinct Epigenetic Effects of Tobacco Smoking in Whole Blood and among Leukocyte Subtypes
Tobacco smoke exposure dramatically alters DNA methylation in blood cells and may mediate smoking-associated complex diseases through effects on immune cell function. However, knowledge of smoking effects in specific leukocyte subtypes is limited. To better characterize smoking-associated methylation changes in whole blood and leukocyte subtypes, we used Illumina 450K arrays and Reduced Representation Bisulfite Sequencing (RRBS) to assess genome-wide DNA methylation. Differential methylation analysis in whole blood DNA from 172 smokers and 81 nonsmokers revealed 738 CpGs, including 616 previously unreported CpGs, genome-wide significantly associated with current smoking (p <1.2x10-7, Bonferroni correction). Several CpGs (MTSS1, NKX6-2, BTG2) were associated with smoking duration among heavy smokers (>22 cigarettes/day, n = 86) which might relate to long-term heavy-smoking pathology. In purified leukocyte subtypes from an independent group of 20 smokers and 14 nonsmokers we further examined methylation and gene expression for selected genes among CD14+ monocytes, CD15+ granulocytes, CD19+ B cells, and CD2+ T cells. In 10 smokers and 10 nonsmokers we used RRBS to fine map differential methylation in CD4+ T cells, CD8+ T cells, CD14+, CD15+, CD19+, and CD56+ natural killer cells. Distinct cell-type differences in smoking-associated methylation and gene expression were identified. AHRR (cg05575921), ALPPL2 (cg21566642), GFI1 (cg09935388), IER3 (cg06126421) and F2RL3 (cg03636183) showed a distinct pattern of significant smoking-associated methylation differences across cell types: granulocytes> monocytes>> B cells. In contrast GPR15 (cg19859270) was highly significant in T and B cells and ITGAL (cg09099830) significant only in T cells. Numerous other CpGs displayed distinctive cell-type responses to tobacco smoke exposure that were not apparent in whole blood DNA. Assessing the overlap between these CpG sites and differential methylated regions (DMRs) with RRBS in 6 cell types, we confirmed cell-type specificity in the context of DMRs. We identified new CpGs associated with current smoking, pack-years, duration, and revealed unique profiles of smoking-associated DNA methylation and gene expression among immune cell types, providing potential clues to hematopoietic lineage-specific effects in disease etiology.
Journal Article
Effects of Wind Turbine Curtailment on Bird and Bat Fatalities
Bird and bat fatalities increase with wind energy expansion and the only effective fatality-reduction measure has been operational curtailment, which has been documented for bats but not for birds. We performed opportune before-after, control-impact (BACI) experiments of curtailment effects on bird and bat fatalities and nocturnal passage rates during fall migration at 2 wind projects, where 1 continued operating and the other shut down from peak migration to the study’s end (study 1). We also performed BACI experiments during a 3-year study of curtailment and operational effects on bird fatalities among wind turbines of varying operational status (study 2). In study 1, wind turbine curtailment significantly reduced near-misses and rotor-disrupted flights of bats, and it significantly reduced fatalities of bats but not of birds. In study 2, converting wind turbines from inoperable to operable status did not significantly increase bird fatalities, and bird species of hole or sheltered-ledge nesters or roosters on human-made structures died in substantial numbers at vacant towers. Of bird species represented by fatalities in study 2, 79% were found at inoperable wind turbines. Because the migration season is relatively brief, seasonal curtailment would greatly reduce bat fatalities for a slight loss in annual energy generation, but it might not benefit many bird species.
Journal Article
Hillock assisted p-type enhancement in N-polar GaN:Mg films grown by MOCVD
We report on the enhanced incorporation efficiency of magnesium dopants into facets of hexagonal hillock structures in N-polar GaN, studied by comparative analysis of GaN:Mg films grown by MOCVD on high and low hillock density GaN template layers. Total magnesium concentration in planar regions surrounding a hillock structure is comparable to that within hillock sidewall facets measured at 1.3 × 10
19
cm
−3
by atom probe tomography, and clustering of Mg atoms is seen in all regions of the film. Within individual hillock structures a decreased Mg cluster density is observed within hillock structures as opposed to the planar regions surrounding a hillock. Additionally, the Mg cluster radius is decreased within the hillock sidewall. The favorable incorporation of Mg is attributed to Mg dopants incorporating substitutionally for Ga during growth of semi-polar facets of the hillock structures. Enhanced p-type conductivity of GaN:Mg films grown on high hillock density template layers is verified by optical and electrical measurement.
Journal Article
Interactions of Chromatin Context, Binding Site Sequence Content, and Sequence Evolution in Stress-Induced p53 Occupancy and Transactivation
Cellular stresses activate the tumor suppressor p53 protein leading to selective binding to DNA response elements (REs) and gene transactivation from a large pool of potential p53 REs (p53REs). To elucidate how p53RE sequences and local chromatin context interact to affect p53 binding and gene transactivation, we mapped genome-wide binding localizations of p53 and H3K4me3 in untreated and doxorubicin (DXR)-treated human lymphoblastoid cells. We examined the relationships among p53 occupancy, gene expression, H3K4me3, chromatin accessibility (DNase 1 hypersensitivity, DHS), ENCODE chromatin states, p53RE sequence, and evolutionary conservation. We observed that the inducible expression of p53-regulated genes was associated with the steady-state chromatin status of the cell. Most highly inducible p53-regulated genes were suppressed at baseline and marked by repressive histone modifications or displayed CTCF binding. Comparison of p53RE sequences residing in different chromatin contexts demonstrated that weaker p53REs resided in open promoters, while stronger p53REs were located within enhancers and repressed chromatin. p53 occupancy was strongly correlated with similarity of the target DNA sequences to the p53RE consensus, but surprisingly, inversely correlated with pre-existing nucleosome accessibility (DHS) and evolutionary conservation at the p53RE. Occupancy by p53 of REs that overlapped transposable element (TE) repeats was significantly higher (p<10-7) and correlated with stronger p53RE sequences (p<10-110) relative to nonTE-associated p53REs, particularly for MLT1H, LTR10B, and Mer61 TEs. However, binding at these elements was generally not associated with transactivation of adjacent genes. Occupied p53REs located in L2-like TEs were unique in displaying highly negative PhyloP scores (predicted fast-evolving) and being associated with altered H3K4me3 and DHS levels. These results underscore the systematic interaction between chromatin status and p53RE context in the induced transactivation response. This p53 regulated response appears to have been tuned via evolutionary processes that may have led to repression and/or utilization of p53REs originating from primate-specific transposon elements.
Journal Article
Activation of Nrf2 in the liver is associated with stress resistance mediated by suppression of the growth hormone-regulated STAT5b transcription factor
The transcription factor Nrf2 (encoded by Nfe2l2) induces expression of numerous detoxifying and antioxidant genes in response to oxidative stress. The cytoplasmic protein Keap1 interacts with and represses Nrf2 function. Computational approaches were developed to identify factors that modulate Nrf2 in a mouse liver gene expression compendium. Forty-eight Nrf2 biomarker genes were identified using profiles from the livers of mice in which Nrf2 was activated genetically in Keap1-null mice or chemically by a potent activator of Nrf2 signaling. The rank-based Running Fisher statistical test was used to determine the correlation between the Nrf2 biomarker genes and a test set of 81 profiles with known Nrf2 activation status demonstrating a balanced accuracy of 96%. For a large number of factors examined in the compendium, we found consistent relationships between activation of Nrf2 and feminization of the liver transcriptome through suppression of the male-specific growth hormone (GH)-regulated transcription factor STAT5b. The livers of female mice exhibited higher Nrf2 activation than male mice in untreated or chemical-treated conditions. In male mice, Nrf2 was activated by treatment with ethinyl estradiol, whereas in female mice, Nrf2 was suppressed by treatment with testosterone. Nrf2 was activated in 5 models of disrupted GH signaling containing mutations in Pit1, Prop1, Ghrh, Ghrhr, and Ghr. Out of 59 chemical treatments that activated Nrf2, 36 exhibited STAT5b suppression in the male liver. The Nrf2-STAT5b coupling was absent in in vitro comparisons of chemical treatments. Treatment of male and female mice with 11 chemicals that induce oxidative stress led to activation of Nrf2 to greater extents in females than males. The enhanced basal and inducible levels of Nrf2 activation in females relative to males provides a molecular explanation for the greater resistance often seen in females vs. males to age-dependent diseases and chemical-induced toxicity.
Journal Article
Mining a human transcriptome database for chemical modulators of NRF2
Nuclear factor erythroid-2 related factor 2 (NRF2) encoded by the NFE2L2 gene is a transcription factor critical for protecting cells from chemically-induced oxidative stress. We developed computational procedures to identify chemical modulators of NRF2 in a large database of human microarray data. A gene expression biomarker was built from statistically-filtered gene lists derived from microarray experiments in primary human hepatocytes and cancer cell lines exposed to NRF2-activating chemicals (oltipraz, sulforaphane, CDDO-Im) or in which the NRF2 suppressor Keap1 was knocked down by siRNA. Directionally consistent biomarker genes were further filtered for those dependent on NRF2 using a microarray dataset from cells after NFE2L2 siRNA knockdown. The resulting 143-gene biomarker was evaluated as a predictive tool using the correlation-based Running Fisher algorithm. Using 59 gene expression comparisons from chemically-treated cells with known NRF2 activating potential, the biomarker gave a balanced accuracy of 93%. The biomarker was comprised of many well-known NRF2 target genes (AKR1B10, AKR1C1, NQO1, TXNRD1, SRXN1, GCLC, GCLM), 69% of which were found to be bound directly by NRF2 using ChIP-Seq. NRF2 activity was assessed across ~9840 microarray comparisons from ~1460 studies examining the effects of ~2260 chemicals in human cell lines. A total of 260 and 43 chemicals were found to activate or suppress NRF2, respectively, most of which have not been previously reported to modulate NRF2 activity. Using a NRF2-responsive reporter gene in HepG2 cells, we confirmed the activity of a set of chemicals predicted using the biomarker. The biomarker will be useful for future gene expression screening studies of environmentally-relevant chemicals.
Journal Article
Microbiota-derived acetate protects against respiratory syncytial virus infection through a GPR43-type 1 interferon response
Severe respiratory syncytial virus (RSV) infection is a major cause of morbidity and mortality in infants <2 years-old. Here we describe that high-fiber diet protects mice from RSV infection. This effect was dependent on intestinal microbiota and production of acetate. Oral administration of acetate mediated interferon-β (IFN-β) response by increasing expression of interferon-stimulated genes in the lung. These effects were associated with reduction of viral load and pulmonary inflammation in RSV-infected mice. Type 1 IFN signaling via the IFN-1 receptor (IFNAR) was essential for acetate antiviral activity in pulmonary epithelial cell lines and for the acetate protective effect in RSV-infected mice. Activation of Gpr43 in pulmonary epithelial cells reduced virus-induced cytotoxicity and promoted antiviral effects through IFN-β response. The effect of acetate on RSV infection was abolished in
Gpr43
−
/
−
mice. Our findings reveal antiviral effects of acetate involving IFN-β in lung epithelial cells and engagement of GPR43 and IFNAR.
Dietary fibers and SCFAs can exert a protective effect against respiratory syncytial virus (RSV). Here, the authors report that microbiota-derived acetate protects mice against RSV infection via GPR43- mediated type 1 interferon response induction in the lungs.
Journal Article
On the Spatial Distribution of Eagle Carcasses Around Wind Turbines: Implications for Collision Mortality Estimation
With worldwide development of wind energy, birds have grown increasingly vulnerable to collisions with wind turbines. For several species of eagles, which in many countries are accorded special protection due to a host of anthropogenic threats, accurate estimates of collision mortality are needed to assess impacts and to formulate appropriate mitigation strategies. Unfortunately, estimates of wind turbine collision mortality are often biased low by failing to account for carcasses that fall beyond the fatality search area boundary, B. In some instances, carcass density is modeled across the fatality search area to adjust for these undetected fatalities. Yet for more accurate fatality estimates, it is important to determine B^, the search area boundary within which all carcasses could be found. We used eagle carcass data from multi-year fatality studies conducted at the Island of Smøla, Norway, and the Altamont Pass Wind Resource Area, California, USA, to assess carcass density (i) as a contributor to mortality estimation (ii) as a predictor variable of B, and (iii) to test whether the cumulative carcass counts with increasing distance from the wind turbine can predict B^. We found that carcass counts within 5 m annuli change little with increasing distance from modern wind turbines, and that carcass density is largely a function of the area calculated. Characterization of the spatial distribution of carcasses within the search area varies with the search radius that determines B. However, this may not represent the true spatial distribution of carcasses, including those found beyond B. We assert that the available data are unsuitable for predicting the number of eagle carcasses within and beyond a given search area, nor for determining B^, but they do indicate that B^ lies much farther from wind turbines than previously assumed. Ultimately, modeling available carcass distribution data cannot replace the need for searching farther from wind turbines to account for the true number of eagle collision victims at any given wind project.
Journal Article
Dogs Detect Larger Wind Energy Effects on Bats and Birds
As wind turbine-caused mortality of birds and bats increases with increasing wind energy capacity, accurate fatality estimates are needed to assess effects, identify collision factors, and formulate mitigation. Finding a larger proportion of collision victims reduces the magnitude of adjustment for the proportion not found, thus reducing opportunities for bias. We tested detection dogs in trials of bat and small-bird carcasses placed randomly in routine fatality monitoring at the Buena Vista and Golden Hills Wind Energy projects, California, USA, 2017. Of trial carcasses placed and confirmed available before next-day fatality searches, dogs detected 96% of bats and 90% of small birds, whereas humans at a neighboring wind project detected 6% of bats and 30% of small birds. At Golden Hills dogs found 71 bat fatalities in 55 searches compared to 1 bat found by humans in 69 searches within the same search plots over the same season. Dog detection rates of trial carcasses remained unchanged with distance from turbine, and dogs found more fatalities than did humans at greater distances from turbines. Patterns of fatalities found by dogs within search plots indicated 20% of birds and 4–14% of bats remained undetected outside search plots at Buena Vista and Golden Hills. Dogs also increased estimates of carcass persistence by finding detection trial carcasses that the trial administrator had erroneously concluded were removed. Compared to human searches, dog searches resulted in fatality estimates up to 6.4 and 2.7 times higher for bats and small birds, respectively, along with higher relative precision and >90% lower cost per fatality detection.
Journal Article