Stochastic Differential Equation Model for Cerebellar Granule Cell Excitability

Neurons in the brain express intrinsic dynamic behavior which is known to be stochastic in nature. A crucial question in building models of neuronal excitability is how to be able to mimic the dynamic behavior of the biological counterpart accurately and how to perform simulations in the fastest possible way. The well-established Hodgkin-Huxley formalism has formed to a large extent the basis for building biophysically and anatomically detailed models of neurons. However, the deterministic Hodgkin-Huxley formalism does not take into account the stochastic behavior of voltage-dependent ion channels. Ion channel stochasticity is shown to be important in adjusting the transmembrane voltage dynamics at or close to the threshold of action potential firing, at the very least in small neurons. In order to achieve a better understanding of the dynamic behavior of a neuron, a new modeling and simulation approach based on stochastic differential equations and Brownian motion is developed. The basis of the work is a deterministic one-compartmental multi-conductance model of the cerebellar granule cell. This model includes six different types of voltage-dependent conductances described by Hodgkin-Huxley formalism and simple calcium dynamics. A new model for the granule cell is developed by incorporating stochasticity inherently present in the ion channel function into the gating variables of conductances. With the new stochastic model, the irregular electrophysiological activity of an in vitro granule cell is reproduced accurately, with the same parameter values for which the membrane potential of the original deterministic model exhibits regular behavior. The irregular electrophysiological activity includes experimentally observed random subthreshold oscillations, occasional spontaneous spikes, and clusters of action potentials. As a conclusion, the new stochastic differential equation model of the cerebellar granule cell excitability is found to expand the range of dynamics in comparison to the original deterministic model. Inclusion of stochastic elements in the operation of voltage-dependent conductances should thus be emphasized more in modeling the dynamic behavior of small neurons. Furthermore, the presented approach is valuable in providing faster computation times compared to the Markov chain type of modeling approaches and more sophisticated theoretical analysis tools compared to previously presented stochastic modeling approaches

Explainable Artificial Intelligence and Machine Learning: A reality rooted perspective

We are used to the availability of big data generated in nearly all fields of science as a consequence of technological progress. However, the analysis of such data possess vast challenges. One of these relates to the explainability of artificial intelligence (AI) or machine learning methods. Currently, many of such methods are non-transparent with respect to their working mechanism and for this reason are called black box models, most notably deep learning methods. However, it has been realized that this constitutes severe problems for a number of fields including the health sciences and criminal justice and arguments have been brought forward in favor of an explainable AI. In this paper, we do not assume the usual perspective presenting explainable AI as it should be, but rather we provide a discussion what explainable AI can be. The difference is that we do not present wishful thinking but reality grounded properties in relation to a scientific theory beyond physics

A clarification of misconceptions, myths and desired status of artificial intelligence

The field artificial intelligence (AI) has been founded over 65 years ago. Starting with great hopes and ambitious goals the field progressed though various stages of popularity and received recently a revival in the form of deep neural networks. Some problems of AI are that so far neither 'intelligence' nor the goals of AI are formally defined causing confusion when comparing AI to other fields. In this paper, we present a perspective on the desired and current status of AI in relation to machine learning and statistics and clarify common misconceptions and myths. Our discussion is intended to uncurtain the veil of vagueness surrounding AI to see its true countenance

Ensuring Quality Standards and Reproducible Research for Data Analysis Services in Oncology: A Cooperative Service Model.

Modern molecular high-throughput devices, e.g., next-generation sequencing, have transformed medical research. Resulting data sets are usually high-dimensional on a genomic-scale providing multi-factorial information from intertwined molecular and cellular activities of genes and their products. This genomics-revolution installed precision medicine offering breathtaking opportunities for patient\u27s diagnosis and treatment. However, due to the speed of these developments the quality standards of the involved data analyses are lacking behind, as exemplified by the infamous Duke Saga. In this paper, we argue in favor of a two-stage cooperative serve model that couples data generation and data analysis in the most beneficial way from the perspective of a patient to ensure data analysis quality standards including reproducible research

Anticancer activity of THMPP: Downregulation of PI3K/ S6K1 in breast cancer cell line.

Breast cancer is the most common cancer that majorly affects female. The present study is focused on exploring the potential anticancer activity of 2-((1, 2, 3, 4-Tetrahydroquinolin-1-yl) (4 methoxyphenyl) methyl) phenol (THMPP), against human breast cancer. The mechanism of action, activation of specific signaling pathways, structural activity relationship and drug-likeness properties of THMPP remains elusive. Cell proliferation and viability assay, caspase enzyme activity, DNA fragmentation and FITC/Annexin V, AO/EtBr staining, RT-PCR, QSAR and ADME analysis were executed to understand the mode of action of the drug. The effect of THMPP on multiple breast cancer cell lines (MCF-7 and SkBr3), and non-tumorigenic cell line (H9C2) was assessed by MTT assay. THMPP at I

What Is a Digital Twin? Experimental Design for a Data-Centric Machine Learning Perspective in Health

The idea of a digital twin has recently gained widespread attention. While, so far, it has been used predominantly for problems in engineering and manufacturing, it is believed that a digital twin also holds great promise for applications in medicine and health. However, a problem that severely hampers progress in these fields is the lack of a solid definition of the concept behind a digital twin that would be directly amenable for such big data-driven fields requiring a statistical data analysis. In this paper, we address this problem. We will see that the term ’digital twin’, as used in the literature, is like a Matryoshka doll. For this reason, we unstack the concept via a data-centric machine learning perspective, allowing us to define its main components. As a consequence, we suggest to use the term Digital Twin System instead of digital twin because this highlights its complex interconnected substructure. In addition, we address ethical concerns that result from treatment suggestions for patients based on simulated data and a possible lack of explainability of the underling models.publishedVersionPeer reviewe

Alkylaminophenol Induces G1/S Phase Cell Cycle Arrest in Glioblastoma Cells Through p53 and Cyclin-Dependent Kinase Signaling Pathway

Glioblastoma (GBM) is the most common type of malignant brain tumor in adults. We show here that small molecule 2-[(3,4-dihydroquinolin-1(2H)-yl)(p-tolyl)methyl]phenol (THTMP), a potential anticancer agent, increases the human glioblastoma cell death. Its mechanism of action and the interaction of selective signaling pathways remain elusive. Three structurally related phenolic compounds were tested in multiple glioma cell lines in which the potential activity of the compound, THTMP, was further validated and characterized. Upon prolonged exposer to THTMP, all glioma cell lines undergo p53 and cyclin-dependent kinase mediated cell death with the IC50 concentration of 26.5 and 75.4 μM in LN229 and Snb19, respectively. We found that THTMP strongly inhibited cell growth in a dose and in time dependent manner. THTMP treatment led to G1/S cell cycle arrest and apoptosis induction of glioma cell lines. Furthermore, we identified 3,714 genes with significant changes at the transcriptional level in response to THTMP. Further, a transcriptional analysis (RNA-seq) revealed that THTMP targeted the p53 signaling pathway specific genes causing DNA damage and cell cycle arrest at G1/S phase explained by the decrease of cyclin-dependent kinase 1, cyclin A2, cyclin E1 and E2 in glioma cells. Consistently, THTMP induced the apoptosis by regulating the expression of Bcl-2 family genes and reactive oxygen species while it also changed the expression of several anti-apoptotic genes. These observations suggest that THTMP exerts proliferation activity inhibition and pro-apoptosis effects in glioma through affecting cell cycle arrest and intrinsic apoptosis signaling. Importantly, THTMP has more potential at inhibiting GBM cell proliferation compared to TMZ, the current chemotherapy treatment administered to GBM patients; thus, we propose that THTMP may be an alternative therapeutic option for glioblastoma