Implications of Ape1 in reactive oxygen signaling response following cisplatin treatment of dorsal root ganglion neurons

Peripheral neuropathy is one of the major side-effects of the anticancer drug, cisplatin. Although previous work suggests that this neuropathy correlates with formation of DNA adducts in sensory neurons, growing evidence suggests that cisplatin also increases the generation of reactive oxygen species (ROS), which could cause DNA damage. Apurinic/apyrimidinic endonuclease/redox factor-1 (Ape1/Ref-1) is a multifunctional protein involved in DNA base excision repair (BER) of oxidative DNA damage and in redox regulation of a number of transcription factors. Therefore, we asked whether altering Ape1 functions would influence cisplatin induced neurotoxicity. Sensory neurons in culture were exposed to cisplatin for 24 hrs and several endpoints of toxicity were measured including production of ROS, cell death, apoptosis, and release of the immunoreactive calcitonin gene-related peptide (iCGRP). Reducing expression of Ape1 in neuronal cultures using siRNA enhances cisplatin-induced cell killing, apoptosis, ROS generation and the cisplatin-induced reduction in iCGRP release. Overexpressing wild-type (WT)-Ape1 attenuates all the toxic effects of cisplatin in cells containing normal endogenous levels of Ape1 and in cells with reduced Ape1 levels following Ape1siRNA treatment. Overexpressing the redox deficient/repair competent C65-Ape1 provides partial rescue, while the repair deficient Ape1 (N226A+R177A) does not protect neurons from cisplatin toxicity. We also observe an increase in phosphorylation of p53 following a decrease in Ape1 levels in sensory neuronal cultures. These results strongly support the notion that Ape1 is a potential translational target such that protecting Ape1 levels and particularly its DNA repair function could reduce peripheral neuropathy in patients undergoing cisplatin treatment

Epidermal growth factor receptor restoration rescues the fatty liver regeneration in mice

Hepatic steatosis is a common histological finding in obese patients. Even mild steatosis is associated with delayed hepatic regeneration and poor outcomes following liver resection or transplantation. We sought to identify and target molecular pathways that mediate this dysfunction. Lean mice and mice made obese through feeding of a high-fat, hypercaloric diet underwent 70 or 80% hepatectomy. After 70% resection, obese mice demonstrated 100% survival but experienced increased liver injury, reduced energy stores, reduced mitoses, increased necroapoptosis, and delayed recovery of liver mass. Increasing liver resection to 80% was associated with mortality of 40% in lean and 80% in obese mice (P < 0.05). Gene expression profiling showed decreased epidermal growth factor receptor (EGFR) in fatty liver. Meta-analysis of expression studies in mice, rats, and patients also demonstrated reduction of EGFR in fatty liver. In mice, both EGFR and phosphorylated EGFR decreased with increasing percent body fat. Hydrodynamic transfection of EGFR plasmids in mice corrected fatty liver regeneration, reducing liver injury, increasing proliferation, and improving survival after 80% resection. Loss of EGFR expression is rate limiting for liver regeneration in obesity. Therapies directed at increasing EGFR in steatosis might promote liver regeneration and survival following hepatic resection or transplantation

Reduced Expression of DNA Repair and Redox Signaling Protein APE1/Ref-1 Impairs Human Pancreatic Cancer Cell Survival, Proliferation, and Cell Cycle Progression

Pancreatic cancer is a deadly disease that is virtually never cured. Understanding the chemoresistance intrinsic to this cancer will aid in developing new regimens. High expression of APE1/Ref-1, a DNA repair and redox signaling protein, is associated with resistance, poor outcome, and angiogenesis; little is known in pancreatic cancer. Immunostaining of adenocarcinoma shows greater APE1/Ref-1 expression than in normal pancreas tissue. A decrease in APE1/Ref-1 protein levels results in pancreatic cancer cell growth inhibition, increased apoptosis, and altered cell cycle progression. Endogenous cell cycle inhibitors increase when APE1/ Ref-1 is reduced, demonstrating its importance to proliferation and growth of pancreatic cancer

Text Classification Using Novel Term Weighting Scheme-Based Improved TF-IDF for Internet Media Reports

With the rapid development of the internet technology, a large amount of internet text data can be obtained. The text classification (TC) technology plays a very important role in processing massive text data, but the accuracy of classification is directly affected by the performance of term weighting in TC. Due to the original design of information retrieval (IR), term frequency-inverse document frequency (TF-IDF) is not effective enough for TC, especially for processing text data with unbalanced distributions in internet media reports. Therefore, the variance between the DF value of a particular term and the average of all DFs , namely, the document frequency variance (ADF), is proposed to enhance the ability in processing text data with unbalanced distribution. Then, the normal TF-IDF is modified by the proposed ADF for processing unbalanced text collection in four different ways, namely, TF-IADF, TF-IADF+, TF-IADFnorm, and TF-IADF+norm. As a result, an effective model can be established for the TC task of internet media reports. A series of simulations have been carried out to evaluate the performance of the proposed methods. Compared with TF-IDF on state-of-the-art classification algorithms, the effectiveness and feasibility of the proposed methods are confirmed by simulation results

To Explain or Not to Explain: A Study on the Necessity of Explanations for Autonomous Vehicles

Explainable AI, in the context of autonomous systems, like self driving cars, has drawn broad interests from researchers. Recent studies have found that providing explanations for an autonomous vehicle actions has many benefits, e.g., increase trust and acceptance, but put little emphasis on when an explanation is needed and how the content of explanation changes with context. In this work, we investigate which scenarios people need explanations and how the critical degree of explanation shifts with situations and driver types. Through a user experiment, we ask participants to evaluate how necessary an explanation is and measure the impact on their trust in the self driving cars in different contexts. We also present a self driving explanation dataset with first person explanations and associated measure of the necessity for 1103 video clips, augmenting the Berkeley Deep Drive Attention dataset. Additionally, we propose a learning based model that predicts how necessary an explanation for a given situation in real time, using camera data inputs. Our research reveals that driver types and context dictates whether or not an explanation is necessary and what is helpful for improved interaction and understanding.Comment: 9.5 pages, 7 figures, submitted to UIST202

Numerical analysis of initial imperfection influence on the performance of buckling-restrained brace

Potrebno je razmotriti interakciju između jezgre i vanjskih ograničavajućih elemenata kod spojnice ograničenog izvijanja (buckling-restrained brace - BRB) zbog značajnog učinka na ukupnu performansu spojnica. Mehanizam deformacije elementa jezgre u obliku nekoliko valova, po prvi se puta analizira u ovom istraživanju i predstavlja element jezgre kao savojni valoviti oblik s povećavajućim aksijalnim opterećenjem te pokazuje distribuciju i razvoj dodirne sile između vanjskih i ograničavajućih elemenata jezgre analizom konačnih elemenata. Objektno orijentiran programski jezik Python primijenjen je u ABAQUS parametrijskoj analizi, a također se analiziraju utjecaji inicijalne nesavršenosti jezgre i vanjskih elemenata ograničenja kao i amplitude razmaka na performansu BRB. Rezultati numeričke simulacije pokazuju da je povratno savijanje elementa jezgre rezultiralo iznenadnim izvijanjem kod viših tipova oscilacije kao i sveukupno smanjenje naprezanja u vanjskom ograničavajućem elementu, dok je lokalno naprezanje poraslo s razvojem valovitog oblika deformacije jezgre. Spojnica (BRB) s jezgrom simetrične inicijalne nesavršenosti funkcionirala je lošije od one s jezgrom protu-simetrične početne nesavršenosti u kompresiji. Nadalje, manji početni progib vanjskih ograničavajućih elemenata i amplitude razmaka rezultira manjom dodirnom silom te spojnica može stoga učinkovitije funkcionirati.The interaction between the core and external restraining members of the buckling-restrained brace (BRB) should be considered because of the significant effect it may cause on the overall performance of BRBs. The mechanism of core member multi-wave deformation is studied for the first time in this research, which presents an actual flexural wave-shape development of core member with increasing axial load and reveals the contact force distribution and development between the core and external restraining members by employing the refined finite element (FE) analysis. The object-oriented programming language Python is applied in the ABAQUS parameter analysis, and the influences of initial imperfection of the core and external restraining members, as well as that of the gap amplitude, on BRB performance are also investigated. Numerical simulation results show that the reverse bending of core member triggered sudden buckling in high-order modes, as well as the overall stress decrease in the external restraining member, whereas the local stress increased with the development of the core deformation waveform. The BRB with the core of symmetric initial imperfection performed worse than that with the core of anti-symmetric initial imperfection in compression. Furthermore, less initial deflection of external restraining members and gap amplitude leads to smaller contact force, thus the BRB can perform more effectively

Role of APE1 in differentiated neuroblastoma SH-SY5Y cells in response to oxidative stress; Use of APE1 small molecule inhibitors to delineate APE1 functions

Oxidative DNA damage has been implicated in a number of central nervous system pathologies. The base excision repair (BER) pathway is one of the most important cellular protection mechanisms that respond to oxidative DNA damage. Human apurinic (apyrimidinic) endonuclease/redox effector factor (APE1/Ref-1 or APE1) is an essential enzyme in the BER pathway and is expressed in both mitotic and post-mitotic cells in humans. In neurons, a reduction of APE1 expression increases chemotherapy-induced cytotoxicity, while overexpression of APE1 protects cells against the cytotoxicity. However, given the multiple functions of APE1, knockdown of total APE1 is not completely informative of whether it is the redox or DNA repair activity, or interactions with other proteins. Therefore, the use of selective small molecules that can block each function independent of the other is of great benefit in ascertaining APE1 function in post-mitotic cells. In this study, we chose differentiated SH-SY5Y cells as our post-mitotic cell line model to investigate whether a drug-induced decrease in APE1 DNA repair or redox activity contributes to the growth and survival of post-mitotic cells under oxidative DNA damaging conditions. Here, we demonstrate that overexpression of WT-APE1 or C65-APE1 (repair competent) results in significant increase in cell viability after exposure to H2O2. However, the 177/226-APE1 (repair deficient) did not show a protective effect. This phenomenon was further confirmed by the use of methoxyamine (MX), which blocks the repair activity of APE1 that results in enhanced cell killing and apoptosis in differentiated SH-SY5Y cells and in neuronal cultures after oxidative DNA damaging treatments. Blocking APE1 redox function by a small molecule inhibitor, BQP did not decrease viability of SH-SY5Y cells or neuronal cultures following oxidative DNA damaging treatments. Our results demonstrate that the DNA repair function of APE1 contributes to the survival of nondividing post-mitotic cells following oxidative DNA damage