Role of PARP-1 and PARP-2 in the expression of apoptosis-regulating genes in HeLa cells

Poly (ADP-ribose) polymerase-1 (PARP-1) is a DNA-binding enzyme involved in DNA damage processing, apoptosis, and genetic stability. Many lines of evidence suggest that PARP-1 is implicated in transcriptional regulation of various genes through the modulation of chromatin structure or through direct interaction with transcription factors and/or transcription factor-binding sites. In the present study, we applied TaqMan Low-Density Array analyses to investigate the expression of genes involved in apoptotic cell death induced by an alkylating agent. Using RNA interference, we determined the roles of PARP-1 and PARP-2 in transcriptional regulation during apoptosis in HeLa cells. Of the 93 genes monitored, 33 differentially expressed genes were identified after induction of apoptosis. Whereas the down-regulation of PARP-1 and PARP-2 had no impact on gene expression per se, we observed that Bcl10, c-Rel, and tumor necrosis factor-related apoptosis-inducing ligand receptor-1 and -2 are differentially expressed after induction of apoptosis in a PARP-1-dependent manner. These findings suggest that PARP-1—but not PARP-2—is required for proper expression of major genes involved in regulation of apoptosi

Towards real interpretability of student success prediction combining methods of XAI and social science

Despite calls to increase the focus on explainability and interpretability in EDM and, in particular, student success prediction, so that it becomes useful for personalized intervention systems, only few efforts have been undertaken in that direction so far. In this paper, we argue that this is mainly due to the limitations of current Explainable Artificial Intelligence (XAI) approaches regarding interpretability. We further argue that the issue, thus, calls for a a combination of AI and social science methods utilizing the strengths of both. For this, we introduce a step-wise model of interpretability where the first step constitutes of knowing important features, the second step of understanding counterfactuals regarding a particular person’s prediction, and the third step of uncovering causal relations relevant for a set of similar students. We show that LIME, a current XAI method, reaches the first but not subsequent steps. To reach step two, we propose an extension to LIME, Minimal Counterfactual-LIME, finding the smallest number of changes necessary to change a prediction. Reaching step three, however, is more involved and additionally requires theoretical and causal reasoning - to this end, we construct an easily applicable framework. Using artificial data, we showcase that our methods can recover connections among features; additionally, we demonstrate its applicability on real-life data. Limitations of our methods are discussed and collaborations with social scientists encouraged

Planning Landmark Based Goal Recognition Revisited: Does Using Initial State Landmarks Make Sense?

Goal recognition is an important problem in many application domains (e.g., pervasive computing, intrusion detection, computer games, etc.). In many application scenarios, it is important that goal recognition algorithms can recognize goals of an observed agent as fast as possible. However, many early approaches in the area of Plan Recognition As Planning, require quite large amounts of computation time to calculate a solution. Mainly to address this issue, recently, Pereira et al. developed an approach that is based on planning landmarks and is much more computationally efficient than previous approaches. However, the approach, as proposed by Pereira et al., also uses trivial landmarks (i.e., facts that are part of the initial state and goal description are landmarks by definition). In this paper, we show that it does not provide any benefit to use landmarks that are part of the initial state in a planning landmark based goal recognition approach. The empirical results show that omitting initial state landmarks for goal recognition improves goal recognition performance.Comment: Will be presented at KI 202

The roles of poly(ADP-ribose)-metabolizing enzymes in alkylation-induced cell death

Abstract.: Poly(ADP-ribose) (PAR) has been identified as a DNA damage-inducible cell death signal upstream of apoptosis-inducing factor (AIF). PAR causes the translocation of AIF from mitochondria to the nucleus and triggers cell death. In living cells, PAR molecules are subject to dynamic changes pending on internal and external stress factors. Using RNA interference (RNAi), we determined the roles of poly(ADP-ribose) polymerases-1 and -2 (PARP-1, PARP-2) and poly(ADP-ribose) glycohydrolase (PARG), the key enzymes configuring PAR molecules, in cell death induced by an alkylating agent. We found that PARP-1, but not PARP-2 and PARG, contributed to alkylation-induced cell death. Likewise, AIF translocation was only affected by PARP-1. PARP-1 seems to play a major role configuring PAR as a death signal involving AIF translocation regardless of the death pathway involve

When probabilities are not enough - A framework for causal explanations of student success models

Student success and drop-out predictions have gained increased attention in recent years, connected to the hope that by identifying struggling students, it is possible to intervene and provide early help and design programs based on patterns discovered by the models. Though by now many models exist achieving remarkable accuracy-values, models outputting simple probabilities are not enough to achieve these ambitious goals. In this paper, we argue that they can be a first exploratory step of a pipeline aiming to be capable of reaching the mentioned goals. By using Explainable Artificial Intelligence (XAI) methods, such as SHAP and LIME, we can understand what features matter for the model and make the assumption that features important for successful models are also important in real life. By then additionally connecting this with an analysis of counterfactuals and a theory-driven causal analysis, we can begin to reasonably understand not just if a student will struggle but why and provide fitting help. We evaluate the pipeline on an artificial dataset to show that it can, indeed, recover complex causal mechanisms and on a real-life dataset showing the method’s applicability. We further argue that collaborations with social scientists are mutually beneficial in this area but also discuss the potential negative effects of personal intervention systems and call for careful designs

The roles of poly(ADP-ribose)-metabolizing enzymes in alkylation-induced cell death

Poly(ADP-ribose) (PAR) has been identified as a DNA damage-inducible cell death signal upstream of apoptosis-inducing factor (AIF). PAR causes the translocation of AIF from mitochondria to the nucleus and triggers cell death. In living cells, PAR molecules are subject to dynamic changes pending on internal and external stress factors. Using RNA interference (RNAi), we determined the roles of poly(ADP-ribose) polymerases-1 and -2 (PARP-1, PARP-2) and poly(ADP-ribose) glycohydrolase (PARG), the key enzymes configuring PAR molecules, in cell death induced by an alkylating agent. We found that PARP-1, but not PARP-2 and PARG, contributed to alkylation-induced cell death. Likewise, AIF translocation was only affected by PARP-1. PARP-1 seems to play a major role configuring PAR as a death signal involving AIF translocation regardless of the death pathway involved

Rapid regulation of telomere length is mediated by poly(ADP-ribose) polymerase-1

Shelterin/telosome is a multi-protein complex at mammalian telomeres, anchored to the double-stranded region by the telomeric-repeat binding factors-1 and -2. In vitro modification of these proteins by poly(ADP-ribosyl)ation through poly(ADP-ribose) polymerases-5 (tankyrases) and -1/-2, respectively, impairs binding. Thereafter, at least telomeric-repeat binding factor-1 is degraded by the proteasome. We show that pharmacological inhibition of poly(ADP-ribose) polymerase activity in cells from two different species leads to rapid decrease in median telomere length and stabilization at a lower setting. Specific knockdown of poly(ADP-ribose) polymerase-1 by RNA interference had the same effect. The length of the single-stranded telomeric overhang as well as telomerase activity were not affected. Release of inhibition led to a fast re-gain in telomere length to control levels in cells expressing active telomerase. We conclude that poly(ADP-ribose) polymerase-1 activity and probably its interplay with telomeric-repeat binding factor-2 is an important determinant in telomere regulation. Our findings reinforce the link between poly(ADP-ribosyl)ation and aging/longevity and also impact on the use of poly(ADP-ribose) polymerase inhibitors in tumor therapy