Land Use Regression Modeling To Estimate Historic (1962−1991) Concentrations of Black Smoke and Sulfur Dioxide for Great Britain

Land-use regression modeling was used to develop maps of annual average black smoke (BS) and sulfur dioxide (SO₂) concentrations in 1962, 1971, 1981, and 1991 for Great Britain on a 1 km grid for use in epidemiological studies. Models were developed in a GIS using data on land cover, the road network, and population, summarized within circular buffers around air pollution monitoring sites, together with altitude and coordinates of monitoring sites to consider global trend surfaces. Models were developed against the log-normal (LN) concentration, yielding R² values of 0.68 (<i>n</i> = 534), 0.68 (<i>n</i> = 767), 0.41 (<i>n</i> = 771), and 0.39 (<i>n</i> = 155) for BS and 0.61 (<i>n</i> = 482), 0.65 (<i>n</i> = 733), 0.38 (<i>n</i> = 756), and 0.24 (<i>n</i> = 153) for SO₂ in 1962, 1971, 1981, and 1991, respectively. Model evaluation was undertaken using concentrations at an independent set of monitoring sites. For BS, values of R² were 0.56 (<i>n</i> = 133), 0.41 (<i>n</i> = 191), 0.38 (<i>n</i> = 193), and 0.34 (<i>n</i> = 37), and for SO₂ values of R² were 0.71 (<i>n</i> = 121), 0.57 (<i>n</i> = 183), 0.26 (<i>n</i> = 189), and 0.31 (<i>n</i> = 38) for 1962, 1971, 1981, and 1991, respectively. Models slightly underpredicted (fractional bias: 0∼−0.1) monitored concentrations of both pollutants for all years. This is the first study to produce historic concentration maps at a national level going back to the 1960s

<i>nhr-49</i> gof strains broadly affect <i>nhr-49</i> dependent activated genes.

<p>Bar graphs show average mRNA fold-changes (<i>vs</i>. wild-type) in L4 stage wild-type N2 worms, <i>nhr-49(nr2041)</i> and <i>nhr-66(ok940)</i> null mutants, and <i>nhr-49(et7)</i>, <i>nhr-49(et8)</i>, and <i>nhr-49(et13)</i> gof mutants (n ≥ 3). Gene expression normalized to <i>act-1</i>, <i>tba-1</i>, and <i>ubc-2</i>. Errors bars show SEM. *, p<0.05; **, p<0.01; ***, p<0.001; and ****, p<0.0001 (unpaired Student's <i>t</i>-test). (A) Fatty acid desaturase genes. (B) Fatty acid β-oxidation enzymes. (C) Non-lipid metabolism genes. (D) Stress response genes.</p

Selective upregulation of NHR-49 repressed genes in <i>nhr-49(et13)</i> mutants.

<p>(A) Bar graphs show average mRNA fold-changes (<i>vs</i>. wild-type) of sphingolipid breakdown and lipid metabolism genes in L4 stage wild-type N2 worms, <i>nhr-49(nr2041)</i> and <i>nhr-66(ok940)</i> null mutants, and <i>nhr-49(et7)</i>, <i>nhr-49(et8)</i>, and <i>nhr-49(et13)</i> gof mutants (n ≥ 3). Gene expression normalized to <i>act-1</i>, <i>tba-1</i>, and <i>ubc-2</i>. Errors bars show SEM. *, p<0.05; **, p<0.01; ***, p<0.001; and ****, p<0.0001 (unpaired Student's <i>t</i>-test). (B) DIC and fluorescence micrographs show <i>plips-6</i>::<i>gfp</i> worms in wild-type, <i>nhr-49(et13)</i>, and <i>nhr-66(ok940)</i> worms. Size bar 200 μm.</p

Biophysical effects of gof point mutations in NHR-49.

<p>(A) Structural homology model of NHR-49C showing the relative locations of the gof (V411E, P479L, S432F) and predicted lof point mutations (E327A) in red with the DBD and LBD (dark grey) and ligand binding zone (grey sphere). (B) Comparison of the biochemical differences between the wild-type V411 (grey) and mutant E411 (red) amino acid residue. The gof mutation has a substantially longer, negatively charged (acidic) side chain, which energetically destabilizes the protein structure.</p

Computational docking of fatty acid ligands to wild-type and mutant NHR-49 LBDs.

<p>(A) Molecular docking of oleoylethanolamide in the NHR-49C WT LBD (black) and the V411E gof LBD (red). The orientation of the long chain lipid molecule is influenced by the structural modifications resulting from the missense mutation. (B) Total number of lipid molecules docked for each NHR-49 mutation (LibDock scores >115) by class. The gof mutations are restricted in both the number and nature of lipid ligands in the modified LBDs compared with the WT or the E327A dimerization mutant. (C) Comparison of the LibDock scores quantifying the energetics and interactions of the lipid ligand (a higher score indicates more favorable binding) within the mutant protein structures by class (FA = fatty acyls; GP = glycerophospholipids; PK = polyketides; PR = prenol lipids; Sx = sterol lipids (ST), sphingolipids (SP), saccharolipids (SL)). Note that ligands that cannot dock within mutant LBDs are not represented as no LibDock score is generated.</p

<i>nhr-49</i> gof alleles differentially affect worm life span.

<p>Population survival curves of wild-type N2 worms and <i>nhr-49(et7)</i>, <i>nhr-49(et8)</i>, and <i>nhr-49(et13)</i> gof mutants. One of three to four individual experiments with similar outcomes is shown; see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0162708#pone.0162708.s007" target="_blank">S4 Table</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0162708#pone.0162708.s003" target="_blank">S3 Fig</a> for details on replicates and statistical analysis. All lifespan experiments were performed at 20°C.</p

<i>In silico</i> modeling of all five NHR-49 isoforms.

<p>(A-B) Homology models of the five NHR-49 isoforms generated using the HNF4α crystal structure (PDB 1M7W) depicted in a structural overlay (A). Strong structural similarity is observed for both the DBD (red) and the LBD (blue) for the longest NHR-49C isoform (B), whereas other regions show variability across isoforms. (C) Overlay of the HNF4α-derived NHR-49C model with models generated using the same modeling parameters but experimentally derived PPARα (PDB 2REW; top) and PPARγ (PDB 3E00; bottom) structures as templates (PPAR derived structure: black; LBD: cyan). Both structures successfully model the NHR-49C-LBD (182 aa homology in both models), but neither has the robustness of the HNF4α-derived NHR-49C model. The PPARα-derived model had a 1.6535 RMSD and the PPARγ-derived model a 1.7144 RMSD from HNF4α-derived NHR-49C, indicating a worse overall fit.</p

Insulin modulates the frequency of Ca²⁺ oscillations in mouse pancreatic islets

<div><p>Pancreatic islets can adapt to oscillatory glucose to produce synchronous insulin pulses. Can islets adapt to other oscillatory stimuli, specifically insulin? To answer this question, we stimulated islets with pulses of exogenous insulin and measured their Ca²⁺ oscillations. We observed that sufficiently high insulin (> 500 nM) with an optimal pulse period (~ 4 min) could make islets to produce synchronous Ca²⁺ oscillations. Glucose and insulin, which are key stimulatory factors of islets, modulate islet Ca²⁺ oscillations differently. Glucose increases the active-to-silent ratio of phases, whereas insulin increases the period of the oscillation. To examine the dual modulation, we adopted a phase oscillator model that incorporated the phase and frequency modulations. This mathematical model showed that out-of-phase oscillations of glucose and insulin were more effective at synchronizing islet Ca²⁺ oscillations than in-phase stimuli. This finding suggests that a phase shift in glucose and insulin oscillations can enhance inter-islet synchronization.</p></div

Drain-Induced Multifunctional Ambipolar Electronics Based on Junctionless MoS₂

Applying a drain bias to a strongly gate-coupled semiconductor influences the carrier density of the channel. However, practical applications of this drain-bias-induced effect in the advancement of switching electronics have remained elusive due to the limited capabilities of its current modulation known to date. Here, we show strategies to largely control the current by utilizing drain-bias-induced carrier type switching in an ambipolar molybdenum disulfide (MoS2) field-effect transistor with Pt bottom contacts. Our CMOS-compatible device architecture, incorporating a partially gate-coupled p–n junction, achieves multifunctionality. The ambipolar MoS2 device operates as an ambipolar transistor (on/off ratios exceeding 107 for both NMOS and PMOS), a rectifier (rectification ratio of ∼3 × 106), a reversible negative breakdown diode with an adjustable breakdown voltage (on/off ratio exceeding 109 with a maximum current as high as 10–4 A), and a photodetector. Finally, we demonstrate a complementary inverter (gain of ∼24 at Vdd = 1.5 V), which is highly facile to fabricate without the need for complex heterostructures and doping processes. Our study provides strategies to achieve high-performance ambipolar MoS2 devices and to effectively utilize drain bias for electrical switching

Dominant periods of Ca²⁺ oscillations under various insulin stimuli.

<p>The relative frequencies of the dominant Ca²⁺ periods for each protocol were plotted for the constant infusion of (A) 0 nM (68 islets), (B) 100 nM (62 islets), and (C) 1000 nM (31 islets) insulin; for the alternating infusion of (D) 100 nM (66 islets), (E) 500 nM (47 islets), and (F) 1000 nM (57 islets) insulin with a 4-min period (2 min with insulin and 2 min without insulin); and for the alternating infusion of (G) 100 nM (60 islets) and 500 nM (71 islets) with a 5-min period (2.5 min with insulin and 2.5 min without insulin).</p