Displacement of the corneal apex (mm) as a function of the corneal thickness (CCT).

<p>Patient’s pachymetry was constantly decreased for the simulations. Results show a cubic relation between displacement and pachymetry (CCT) when the material was fixed (large stifnees material—C) and three levels of IOP were considered: 10 mmHg (dotted-dashed green line), 19 mHg (solid green line), and 28 mmHg (doted green line). Results also show a cubic relation between displacement and pachymetry (CCT) when the IOP was kept at 19 mmHg and the three corneal stiffnesses were considered: low (material A) solid red line, intermediate (material B) solid blue line, and large (material C) solid green line. The right panel shows the accuracy of the fit (minimum mean squares) and the constants of the cubic polynomial.</p

Stress strain response of anterior and posterior apical points during non-contact tonometry.

<p>Normal Cauchy Stress vs. stretch path along the meridional direction followed by two points on the anterior and posterior surface of the cornea during air-puff for an IOP = 19 mmHg and the stiffest material (C). Blue color is associated with compression whereas red color is associated with tension. At the physiological configuration when the eye is subjected to IOP (open circle at the beginning of the air jet profile, shown in the inset) the cornea only experiences traction (membrane tensional state). As the air-pulse progresses (black filled circle in the pressure profile inset), the anterior corneal surface (inverted open triangle) experiences compression (<i>λ</i><1) whereas, the posterior corneal surface (open square) experiences a larger tensional stress (<i>λ</i>>1).</p

Non-contact tonometer air-puff loading and CFD results.

<p>a) Temporal pressure profile applied on the center of the cornea (corneal apex region). Solid black line represents the temporal profile used in the simulations. Dashed black line was no considered since only the maximum displacement of the corneal apex was studied; b) Spatial profile of pressure applied on cornea obtained with the CFD simulation shown in c) and d); c) Symmetrical pressure profile obtained from the CFD simulation; d) Symmetrical velocity streamline plot result from the CFD simulation.</p

Material parameters for cornea, limbus, and sclera.

<p>Material parameters for cornea, limbus, and sclera.</p

Displacement—Time response of the corneal apex.

<p>Time course of the apex displacement for the conducted simulations. Displacement’s region 10–28 mmHg (mat. A) (red colored area) are the results for low stiffness material (A) for all three different IOP (10, 19 and 28 mmHg); Displacement’s region 10–28 mmHg (mat. B) (blue colored area) are the results for intermediate stiffness material (B) for all three different IOP (10, 19 and 28 mmHg); Displacement’s region 10–28 mmHg (mat. C) (green colored area) are the results for large stiffness material (C) for all three different IOP (10, 19 and 28 mmHg). Different overlapping zones, at different loading time, can be observed in figure. Inverted triangles correspond to simulations performed with the real IOP (12 mmHg) and the three different corneal material models.</p

Displacement—Pressure: response overlapping.

<p>Overlapping zone in the corneal response (grey zone) where different combinations of IOP and material lead to the same displacement.</p

Right healthy eye data provided by the Pentacam.

<p>Right healthy eye data provided by the Pentacam.</p

Corneal response in the meridional plane (FE results).

<p>Meridional cutting plane of the cornea. a) Displacement field along the optical axis at first applanation time (mm), b) Vertical displacement field at high concavity time (mm), c) Circumferential logarithmic strain field (-) at first applanation time, d) Hoop stress field (MPa) at first applanation time (spherical coordinate system). c) and d) show the bending mode of deformation at which the cornea is subjected during a non-contact tonometry test. Results correspond to IOP = 19 mmHg and material C.</p

MTA exerts its activity in different pathways increasing the apoptotic stimulus.

<p>Firstly, there is an accumulation of the AMP analogue ZMP that induces the activation of the AMPK pathway, starting a cascade of signalling that affects mTOR and PI3P/Akt pathways; mTOR is inactivated and the accumulation of its downstream unphosphorylated substrates facilitates the apoptosis process. Akt also remains inactive, unable to block p53 and to activate mTOR. On the other hand, the inhibition of TS, DHFR, GARFT and AICART induces oxidative stress and DNA damage which in turn is detected by p53 and caspase-dependent and independent mitochondrial apoptosis that is activated as has been previously reported. Together all processes lead to an imbalance between cell death and survival stimuli that result in enhanced apoptotic signalling.</p

Viability and proliferation XTT after 48 h of exposure to MTA alone or in combination with dTh, Hx, or/and AICA.

<p>The percentage of viable cells is shown relative to viability of MTA-unexposed cells (control conditions). These results are representative of three independent experiments. <b>A)</b> Viability assays before and after MTA exposure with the pyrimidine biosynthesis pathway restored by addition of Hx alone or in combination with dTh. <b>B)</b> Viability assays before and after MTA exposure with purine biosynthesis pathway restored through the addition of AICA alone or in combination with dTh. <b>C)</b> Heatmap of six MTA-related genes where up- and down-regulation fold changes corresponding to each colour are indicated on the scale on the right of the figure.</p