Search

Time-fractional partial differential equations are nonlocal-in-time and show an innate memory effect. Previously, examples like the time-fractional Cahn-Hilliard and Fokker-Planck equations have been studied. In this work, we propose a general framework of time-fractional gradient flows and we provide a rigorous analysis of well-posedness using the Faedo-Galerkin approach. Furthermore, we investigate the monotonicity of the energy functional of time-fractional gradient flows. Interestingly, it is still an open problem whether the energy is dissipating in time. This property is essential for integer-order gradient flows and many numerical schemes exploit this steepest descent characterization. We propose an augmented energy functional, which includes the history of the solution. Based on this new energy, we prove the equivalence of a time-fractional gradient flow to an integer-order one. This correlation guarantees the dissipating character of the augmented energy. The state function of the integer-order gradient flow acts on an extended domain similar to the Caffarelli-Silvestre extension for the fractional Laplacian. Additionally, we present a numerical scheme for solving time-fractional gradient flows, which is based on kernel compressing methods and reduces the problem to a system of ordinary differential equations. We illustrate the behavior of the original and augmented energy in the case of the Ginzburg-Landau energy.

Abstract The EGF receptor (EGFR) has been extensively studied in tumor biology and recently a role in cardiovascular pathophysiology was suggested. The mineralocorticoid receptor (MR) is an important effector of the renin–angiotensin–aldosterone-system and elicits pathophysiological effects in the cardiovascular system; however, the underlying molecular mechanisms are unclear. Our aim was to investigate the importance of EGFR for MR-mediated cardiovascular pathophysiology because MR is known to induce EGFR expression. We identified a SNP within the EGFR promoter that modulates MR-induced EGFR expression. In RNA-sequencing and qPCR experiments in heart tissue of EGFR KO and WT mice, changes in EGFR abundance led to differential expression of cardiac ion channels, especially of the T-type calcium channel CACNA1H. Accordingly, CACNA1H expression was increased in WT mice after in vivo MR activation by aldosterone but not in respective EGFR KO mice. Aldosterone- and EGF-responsiveness of CACNA1H expression was confirmed in HL-1 cells by Western blot and by measuring peak current density of T-type calcium channels. Aldosterone-induced CACNA1H protein expression could be abrogated by the EGFR inhibitor AG1478. Furthermore, inhibition of T-type calcium channels with mibefradil or ML218 reduced diameter, volume and BNP levels in HL-1 cells. In conclusion the MR regulates EGFR and CACNA1H expression, which has an effect on HL-1 cell diameter, and the extent of this regulation seems to depend on the SNP-216 (G/T) genotype. This suggests that the EGFR may be an intermediate for MR-mediated cardiovascular changes and that SNP analysis can help identify subgroups of patients that will benefit most from MR antagonists.

Numerical simulations are increasingly often involved in developing new and improving existing medical therapies. While the models involved in those simulations are designed to resemble a specific phenomenon realistically, the results of the interplay of those models are often not sufficiently validated. We created a plugin for a cardiac simulation framework to validate the simulation results using clinical MRI data. The MRI data were used to create a static wholeheart mesh as well as slices from the left ventricular short axis, providing the motion over time. The static heart was a starting point for a simulation of the heart’s motion. From the simulation result, we created slices and compared them to the clinical MRI slices using two different metrics: the area of the slices and the point distances. The comparison showed global similarities in the deformation of simulated and clinical data, but also indicated points for potential improvements. Performing this comparison with more clinical data could lead to personalized modeling of elastomechanics of the heart.

Enumerating protonation states and calculating microstate pKa values of small molecules is an important yet challenging task for lead optimization and molecular modeling. Commercial and non-commercial solutions have notable limitations such as restrictive and expensive licenses, high CPU/GPU hour requirements, or the need for expert knowledge to set up and use. We present a graph neural network model that is trained on 714,906 calculated microstate pKa predictions from molecules obtained from the ChEMBL database. The model is fine-tuned on a set of 5,994 experimental pKa values significantly improving its performance on two challenging test sets. Combining the graph neural network model with Dimorphite-DL, an open-source program for enumerating ionization states, we have developed the open-source Python package pkasolver, which is able to generate and enumerate protonation states and calculate pKa values with high accuracy.

The P2X5 receptor, an ATP-gated cation channel, is believed to be involved in tumor development, inflammatory bone loss and inflammasome activation after bacterial infection. Therefore, it is a worthwhile pharmacological target to treat the corresponding diseases, especially in minority populations that have a gene variant coding for functional homotrimeric P2X5 channels. Here, we investigated the effects of dihydropyridines on the human full-length P2X5 receptor (hP2X5FL) heterologously expressed in Xenopus oocytes using the two-microelectrode voltage clamp method. Agonist dependency, kinetics and permeation behavior, including Cl− permeability, were similar to hP2X5FL expressed in HEK293 or 1321N1 cells. Additionally, 1,4-dihydropyridines have been shown to interact with various other purinergic receptors, and we have examined them as potential hP2X5 modulators. Of seven commercially available and four newly synthesized dihydropyridines tested at hP2X5FL, only amlodipine exerted an inhibitory effect, but only at a high concentration of 300 µM. Isradipine and—even more—nimodipine stimulated ATP-induced currents in the low micromolar range. We conclude that common dihydropyridines or four new derivatives of amlodipine are not suitable as hP2X5 antagonists, but amlodipine might serve as a lead for future synthesis to increase its affinity. Furthermore, a side effect of nimodipine therapy could be a stimulatory effect on inflammatory processes.

Background: There is very limited information about the amount of information that cancer patients retain after a fertility preservation (FP) consultation (FPC). Our objective was to assess patients' knowledge following FPC and to examine predictors of increased knowledge.Methods: We conducted a multi-center, cross-sectional, web-based survey at academic IVF centers, including women aged 18-43 years seen for comprehensive FPC between April 2009 and December 2010. The primary outcome measure was a knowledge score designed to assess comprehension of FP options. Analysis was performed to assess which patient variables were associated with higher knowledge scores. A 13-item knowledge tool about FP was developed (Kuder-Richardson 20=0.64).Result(s): Among 90 eligible subjects, 66 were successfully contacted and 52 completed the survey (79% response rate). Participant's median age was 30.7 (interquartile range (IQR) 24.9-36.9) years and most were Caucasian, college graduates, nulliparous and in a committed relationship. The median knowledge post-FPC score was 6 (IQR: 5-9). Higher knowledge scores were associated with a college education, higher income, a primary diagnosis of breast cancer, additional contact with the FP specialist following the initial FPC and use of specific reference websites such as www.fertilehope.org. Parity, marital status and completion of FP treatment were not associated with knowledge scores.Conclusions: FP knowledge following comprehensive FPC remains limited. Modifications to the current single visit FPC, such as a standard follow-up visit or additional educational tools, may be needed to improve patient comprehension of complex FP treatment options. Further research is needed to validate the knowledge scale in broader populations of cancer patients receiving FPC. [ABSTRACT FROM AUTHOR]

Multiple births related to infertility treatment have increased dramatically in recent years and are associated with significant personal, economic, and social costs. The causes are many and complicated and no easy solution is at hand. Acknowledging the problem, introducing new initiatives, and supporting those already under way are the keys to success. [ABSTRACT FROM AUTHOR]