Effect of incidence of visceral arteries arising from the FL on intraluminal flows.

<p>Changes in flow patterns with changes in the percentage of abdominal side branches connected to the false lumen (FL). Antegrade flows are positive and retrograde flows are negative. TL, True lumen.</p

Effect of wall stiffness on intraluminal flows and pressures.

<p>Changes in flow patterns (Left) and pressure profiles (Right) with changes in wall stiffness. Antegrade flows are positive and retrograde flows are negative. TL, True lumen; FL, False lumen.</p

Quantitative flow assessment at the proximal, diaphragm and distal levels of the dissected segment for the baseline case of a chronic dissection.

<p>Quantitative flow assessment at the proximal, diaphragm and distal levels of the dissected segment for the baseline case of a chronic dissection.</p

Effect of tear size distribution along the dissection on flows.

<p>Changes in intraluminal flow patterns with changes in the distribution of total communicating area between the proximal and distal tears. The color scale represents the percentage of total area distributed at the proximal site. Antegrade flows are positive and retrograde flows are negative. TL, True lumen; FL, False lumen.</p

Quantification of flow profiles derived from the parametric study.

<p>Percentage of total volume flow into the false lumen (FL) (%TVF), percentage of systolic (%RSF_FL) and diastolic (%RDF_FL) FL retrograde flow for changes in (A) wall stiffness of the dissected segment; (B) percentage of FL side branches; (C) distribution of total area between the proximal and distal tear; (D) increase and (E) decrease in cumulative tear area.</p

Lumped-parameter computational model of an aortic dissection.

<p>(A) Diagram of the lumped-parameter model of an aortic dissection including the presence of abdominal side branches (sb) and the modeling of the thoracic (ThAo) and abdominal (AbAo) aorta; (B) Clinical appearance of an aortic dissection with magnetic resonance imaging and the equivalent dissection geometry proposed; (C) Imposed inflow curve; (D) Value of interluminal resistance plotted as a function of the cumulative tear area, resulting from the calibration of the lumped-parameter model to the experimental in-vitro one [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0170888#pone.0170888.ref017" target="_blank">17</a>]. Each data point corresponds to the cumulative value of the tear resistances in the numerical model related to the cumulative tear area in the experimental model for a specific scenario S_P,D; P, proximal tear diameter; D, distal tear diameter; FL, False lumen; TL, True lumen; PT, Proximal tear; DT, Distal tear.</p

Comparison between in-vivo observations and model predictions.

<p>Comparison between the 4 characteristic FL flow patterns (B_A, B_R, M_A, M_R) identified in the study population and the findings from the parametric study. The different FL flow profiles at the level of the diaphragm can be explained by the percentage of visceral arteries arising from the FL and the location (before/after) of the dominant interluminal communication respect to the place of measurement. Signs illustrate the level of incidence of each property in each FL flow pattern determination: <b>(-)</b> absent property; <b>(++)</b> existent property; <b>(+/-)</b> possible existent property. Antegrade flows are positive and retrograde flows are negative.</p

Effect of decrease in cumulative tear area on intraluminal flows and pressures.

<p>Variations in flow patterns (Left) and pressure profiles (Right) for a decrease in the cumulative tear area (from 300 to 25 mm²) and resultant true lumen (TL) vasodilatation. Antegrade flows are positive and retrograde flows are negative. FL, False lumen.</p

Transaldolase inhibition impairs mitochondrial respiration and induces a starvation-like longevity response in <i>Caenorhabditis elegans</i>

<div><p>Mitochondrial dysfunction can increase oxidative stress and extend lifespan in <i>Caenorhabditis elegans</i>. Homeostatic mechanisms exist to cope with disruptions to mitochondrial function that promote cellular health and organismal longevity. Previously, we determined that decreased expression of the cytosolic pentose phosphate pathway (PPP) enzyme transaldolase activates the mitochondrial unfolded protein response (UPR^mt) and extends lifespan. Here we report that transaldolase (<i>tald-1</i>) deficiency impairs mitochondrial function <i>in vivo</i>, as evidenced by altered mitochondrial morphology, decreased respiration, and increased cellular H₂O₂ levels. Lifespan extension from knockdown of <i>tald-1</i> is associated with an oxidative stress response involving p38 and c-Jun N-terminal kinase (JNK) MAPKs and a starvation-like response regulated by the transcription factor EB (TFEB) homolog HLH-30. The latter response promotes autophagy and increases expression of the flavin-containing monooxygenase 2 (<i>fmo-2</i>). We conclude that cytosolic redox established through the PPP is a key regulator of mitochondrial function and defines a new mechanism for mitochondrial regulation of longevity.</p></div

The flavin-containing monooxygenase FMO-2 is upregulated in a HLH-30 and PMK-1 dependent fashion and regulates the lifespan extension from <i>tald-1(RNAi)</i>.

<p><b>(A)</b><i>fmo-2p</i>::<i>mCherry</i> reporter expression is increased by <i>tald-1(RNAi)</i> or BD in a HLH-30 and PMK-1 dependent fashion. BD animals were starved for 24 hours on FUDR plates prior to imaging. Scale bar, 200 μm. <b>(B)</b> Mean relative fluorescence of <i>fmo-2p</i>::<i>mCherry</i> reporter animals in the context of the <i>hlh-30(tm1978)</i> mutation. Fluorescence is calculated relative to N2 <i>EV(RNAi)</i> controls (N = 3 independent experiments, pooled individual worm values, error bars indicate s.e.m., ANOVA with Bonferroni’s post-hoc). <b>(C)</b> Mean relative fluorescence of <i>fmo-2p</i>::<i>mCherry</i> reporter animals in the context of the <i>pmk-1(km25)</i> mutation. Fluorescence is calculated relative to N2 <i>EV(RNAi)</i> controls (N = 5 independent experiments, pooled individual worm values, error bars indicate s.e.m., ANOVA with Bonferroni’s post-hoc). <b>(D)</b> Gene expression of <i>fmo-2</i> is upregulated by <i>tald-1(RNAi)</i> or <i>cco-1(RNAi)</i> (N = 11 biological replicates, error bars indicate s.e.m., student’s t-test with Bonferroni’s correction). <b>(E)</b> Gene expression of <i>fmo-2</i> is upregulated by <i>tald-1(RNAi)</i> in a HLH-30 and PMK-1 dependent fashion (N = 3–6 biological replicates, error bars indicate s.e.m., ANOVA with Bonferroni’s post-hoc). <b>(F)</b> Percent of animals displaying HLH-30 nuclear localization. BD animals were starved for 8 hours on FUDR plates prior to imaging (N = 5 independent experiments, error bars indicate s.e.m., ANOVA with Bonferroni’s post-hoc). <b>(G)</b> FMO-2 is required for the lifespan extension from <i>tald-1(RNAi)</i>. N2 fed <i>EV(RNAi)</i> (mean 15.3±0.1 days, n = 341), N2 fed <i>tald-1(RNAi)</i> (mean 17.8±0.1 days, n = 353), <i>fmo-2(ok2147)</i> fed <i>EV(RNAi)</i> (mean 18±0.2 days, n = 314), <i>fmo-2(ok2147)</i> fed <i>tald-1(RNAi)</i> (mean 17.4±0.2 days, n = 382). Lifespans were performed at 25°C, with pooled data from three independent experiments shown. <b>(H)</b> FMO-2 is partially required for the lifespan extension from <i>cco-1(RNAi)</i>. N2 fed <i>EV(RNAi)</i> (mean 15.7±0.1 days, n = 562), N2 fed <i>cco-1(RNAi)</i> (mean 23.3±0.2 days, n = 616), <i>fmo-2(ok2147)</i> fed <i>EV(RNAi)</i> (mean 18.3±0.1 days, n = 474), <i>fmo-2(ok2147)</i> fed <i>cco-1(RNAi)</i> (mean 20.5±0.2 days, n = 473). Lifespans were performed at 25°C, with pooled data from five independent experiments shown. <b>(I)</b> Lifespan extension from <i>fmo-2</i> overexpression is not additive with <i>tald-1(RNAi)</i>. N2 fed <i>EV(RNAi)</i> (mean 16.5±0.1 days, n = 453), N2 fed <i>tald-1(RNAi)</i> (mean 20.6±0.1 days, n = 421), <i>eft-3p</i>::<i>fmo-2</i> fed <i>EV(RNAi)</i> (mean 18.2±0.1 days, n = 439), <i>eft-3p</i>::<i>fmo-2</i> fed <i>tald-1(RNAi)</i> (mean 19.1±0.1 days, n = 435). Lifespans were performed at 25°C, with pooled data from three independent experiments shown. <b>(J)</b> Lifespan extension from <i>fmo-2</i> overexpression is additive with <i>cco-1(RNAi)</i>. N2 fed <i>EV(RNAi)</i> (mean 16.5±0.1 days, n = 453), N2 fed <i>cco-1(RNAi)</i> (mean 23.3±0.2 days, n = 259), <i>eft-3p</i>::<i>fmo-2</i> fed <i>EV(RNAi)</i> (mean 18.2±0.1 days, n = 439), <i>eft-3p</i>::<i>fmo-2</i> fed <i>cco-1(RNAi)</i> (mean 25.5±0.2 days, n = 352). Lifespans were performed at 25°C, with pooled data from three independent experiments shown. Lifespans in this figure are indicated as mean±s.e.m. and statistical analysis is provided in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1006695#pgen.1006695.s011" target="_blank">S1 Table</a>. In this figure, statistics are displayed as: * <i>p</i><0.05, ** <i>p</i><0.01, *** <i>p</i><0.001.</p