Browsing by Subject "ROS"

Now showing 1 - 10 of 22
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    Circulating Uromodulin inhibits systemic oxidative stress by inactivating the TRPM2 channel
    (American Association for the Advancement of Science, 2019-10) LaFavers, Kaice A.; Macedo, Etienne; Garimella, Pranav S.; Lima, Camila; Khan, Shehnaz; Myslinski, Jered; McClintick, Jeanette; Witzmann, Frank A.; Winfree, Seth; Phillips, Carrie; Hato, Takashi; Dagher, Pierre; Wu, Xue-Ru; El-Achkar, Tarek M.; Micanovic, Radmila; Medicine, School of Medicine
    High serum concentrations of kidney-derived protein uromodulin (Tamm-Horsfall protein or THP) have recently been shown to be independently associated with low mortality in both older adults and cardiac patients, but the underlying mechanism remains unclear. Here, we show that THP inhibits the generation of reactive oxygen species (ROS) both in the kidney and systemically. Consistent with this experimental data, the concentration of circulating THP in patients with surgery-induced acute kidney injury (AKI) correlated with systemic oxidative damage. THP in the serum dropped after AKI, and was associated with an increase in systemic ROS. The increase in oxidant injury correlated with post-surgical mortality and need for dialysis. Mechanistically, THP inhibited the activation of the transient receptor potential cation channel, subfamily M, member 2 (TRPM2) channel. Furthermore, inhibition of TRPM2 in vivo in a mouse model, mitigated the systemic increase in ROS during AKI and THP deficiency. Our results suggest that THP is a key regulator of systemic oxidative stress by suppressing TRPM2 activity and our findings might help to explain how circulating THP deficiency is linked with poor outcomes and increased mortality.
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    Claudin-4 remodeling of nucleus-cell cycle crosstalk maintains ovarian tumor genome stability and drives resistance to genomic instability-inducing agents
    (bioRxiv, 2024-09-07) Villagomez, Fabian R.; Lang, Julie; Nunez-Avellaneda, Daniel; Behbakht, Kian; Dimmick, Hannah L.; Webb, Patricia; Nephew, Kenneth P.; Neville, Margaret; Woodruff, Elizabeth R.; Bitler, Benjamin G.; Anatomy, Cell Biology and Physiology, School of Medicine
    During cancer development, the interplay between the nucleus and the cell cycle leads to a state of genomic instability, often accompanied by observable morphological aberrations. These aberrations can be controlled by tumor cells to evade cell death, either by preventing or eliminating genomic instability. In epithelial ovarian cancer (EOC), overexpression of the multifunctional protein claudin-4 is a key contributor to therapy resistance through mechanisms associated with genomic instability. However, the molecular mechanisms underlying claudin-4 overexpression in EOC remain poorly understood. Here, we altered claudin-4 expression and employed a unique claudin-4 targeting peptide (CMP) to manipulate the function of claudin-4. We found that claudin-4 facilitates genome maintenance by linking the nuclear envelope and cytoskeleton dynamics with cell cycle progression. Claudin-4 caused nuclei constriction by excluding lamin B1 and promoting perinuclear F-actin accumulation, associated with remodeling nuclear architecture, thus altering nuclear envelope dynamics. Consequently, cell cycle modifications due to claudin-4 overexpression resulted in fewer cells entering the S-phase and reduced genomic instability. Importantly, disrupting biological interactions of claudin-4 using CMP and forskolin altered oxidative stress cellular response and increased the efficacy of PARP inhibitor treatment. Our data indicate that claudin-4 protects tumor genome integrity by remodeling the crosstalk between the nuclei and the cell cycle, leading to resistance to genomic instability formation and the effects of genomic instability-inducing agents.
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    Data Acquisition and Processing Pipeline for E-Scooter Tracking Using 3d Lidar and Multi-Camera Setup
    (2020-12) Betrabet, Siddhant S.; Tian, Renran; Zhu, Likun; Anwar, Sohel
    Analyzing behaviors of objects on the road is a complex task that requires data from various sensors and their fusion to recreate the movement of objects with a high degree of accuracy. A data collection and processing system are thus needed to track the objects accurately in order to make an accurate and clear map of the trajectories of objects relative to various coordinate frame(s) of interest in the map. Detection and tracking moving objects (DATMO) and Simultaneous localization and mapping (SLAM) are the tasks that needs to be achieved in conjunction to create a clear map of the road comprising of the moving and static objects. These computational problems are commonly solved and used to aid scenario reconstruction for the objects of interest. The tracking of objects can be done in various ways, utilizing sensors such as monocular or stereo cameras, Light Detection and Ranging (LIDAR) sensors as well as Inertial Navigation systems (INS) systems. One relatively common method for solving DATMO and SLAM involves utilizing a 3D LIDAR with multiple monocular cameras in conjunction with an inertial measurement unit (IMU) allows for redundancies to maintain object classification and tracking with the help of sensor fusion in cases when sensor specific traditional algorithms prove to be ineffectual when either sensor falls short due to their limitations. The usage of the IMU and sensor fusion methods relatively eliminates the need for having an expensive INS rig. Fusion of these sensors allows for more effectual tracking to utilize the maximum potential of each sensor while allowing for methods to increase perceptional accuracy. The focus of this thesis will be the dock-less e-scooter and the primary goal will be to track its movements effectively and accurately with respect to cars on the road and the world. Since it is relatively more common to observe a car on the road than e-scooters, we propose a data collection system that can be built on top of an e-scooter and an offline processing pipeline that can be used to collect data in order to understand the behaviors of the e-scooters themselves. In this thesis, we plan to explore a data collection system involving a 3D LIDAR sensor and multiple monocular cameras and an IMU on an e-scooter as well as an offline method for processing the data to generate data to aid scenario reconstruction.
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    Design and Implementation of Sensing Methods on One-Tenth Scale of an Autonomous Race Car
    (2020-12) Veeramachaneni, Harshitha; Li, Lingxi; Chen, Yaobin; El-Sharkawy, Mohamed; King, Brian
    Self-driving is simply the capacity of a vehicle to drive itself without human intervention. To accomplish this, the vehicle utilizes mechanical and electronic parts, sensors, actuators and an AI computer. The on-board PC runs advanced programming, which permits the vehicle to see and comprehend its current circumstance dependent on sensor input, limit itself in that climate and plan the ideal course from point A to point B. Independent driving is not an easy task, and to create self-sufficient driving arrangements is an exceptionally significant ability in the present programming designing field. ROS is a robust and versatile communication middle ware (framework) tailored and widely used for robotics applications. This thesis work intends to show how ROS could be used to create independent driving programming by investigating self-governing driving issues, looking at existing arrangements and building up a model vehicle utilizing ROS. The main focus of this thesis is to develop and implement a one-tenth scale of an autonomous RACECAR equipped with Jetson Nano board as the on-board computer, PCA9685 as PWM driver, sensors, and a ROS based software architecture. Finally, by following the methods presented in this thesis, it is conceivable to build an autonomous RACECAR that runs on ROS. By following the means portrayed in this theory of work, it is conceivable to build up a self-governing vehicle.
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    An Experimental Distributed Framework for Distributed Simultaneous Localization and Mapping
    (IEEE, 2016-05) Gamage, Ruwan; Tuceryan, Mihran; Department of Computer and Information Science, School of Science
    Simultaneous Localization and Mapping (SLAM) is widely used in applications such as rescue, navigation, semantic mapping, augmented reality and home entertainment applications. Most of these applications would do better if multiple devices are used in a distributed setting. The distributed SLAM research would benefit if there is a framework where the complexities of network communication is already handled. In this paper we introduce such framework utilizing open source Robot Operating System (ROS) and VirtualBox virtualization software. Furthermore, we describe a way to measure communication statistics of the distributed SLAM system.
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    Fluorescence quenching by metal centered porphyrins and poryphyrin enzymes
    (American Physiological Society, 2017-10-01) Olson, Kenneth R.; Gao, Yan; Arif, Faihaan; Arora, Kanika; Patel, Shivali; DeLeon, Eric; Straub, Karl D.; Medicine, School of Medicine
    Fluorescence spectroscopy and microscopy have been used extensively to monitor biomolecules, especially reactive oxygen species (ROS) and, more recently, reactive sulfide (RSS) species. Nearly all fluorophores are either excited by or emit light between 450 and 550 nm, which is similar to the absorbance of heme proteins and metal-centered porphyrins. Here we examined the effects of catalase (Cat), reduced and oxidized hemoglobin (Hb and metHb), albumin (alb), manganese (III) tetrakis (4-benzoic acid) porphyrin chloride (MnTBAP), iron protoporphyrin IX (hemin), and copper protoporphyrin IX (CuPPIX) on the fluorescence properties of fluorescein. We also examined the effects of catalase and MnTBAP on fluorophores for ROS (dichlorofluorescein, DCF), polysulfides (3',6'-di(O-thiosalicyl)fluorescein, SSP4), and H2S (7-azido-4-methylcoumarin, AzMC) previously activated by H2O2, a mixed polysulfide (H2Sn, n = 1-7) and H2S, respectively. All except albumin concentration dependently inhibited fluorophore fluorescence and absorbed light between 450 and 550 nm, suggesting that the inhibitory effect was physical not catalytic. Catalase inhibition of fluorescein fluorescence was unaffected by sodium azide, dithiothreitol, diamide, tris(2-carboxyethyl)phosphine (TCEP), or iodoacetate, supporting a physical inhibitory mechanism. Catalase and TBAP augmented, then inhibited DCF fluorescence, but only inhibited SSP4 and AzMC fluorescence indicative of a substrate-specific catalytic oxidation of DCF and nonspecific fluorescence inhibition of all three fluorophores. These results suggest caution must be exercised when using any fluorescent tracers in the vicinity of metal-centered porphyrins.
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    Genetic Evidence for XPC-KRAS Interactions During Lung Cancer Development.
    (Elsevier, 2015-10-20) Zhang, Xiaoli; He, Nonggao; Gu, Dongsheng; Wickliffe, Jeff; Salazar, James; Boldogh, Istavan; Xie, Jingwu; Department of Pediatrics, IU School of Medicine
    Lung cancer causes more deaths than breast, colorectal and prostate cancers combined. Despite major advances in targeted therapy in a subset of lung adenocarcinomas, the overall 5-year survival rate for lung cancer worldwide has not significantly changed for the last few decades. DNA repair deficiency is known to contribute to lung cancer development. In fact, human polymorphisms in DNA repair genes such as xeroderma pigmentosum group C (XPC) are highly associated with lung cancer incidence. However, the direct genetic evidence for the role of XPC for lung cancer development is still lacking. Mutations of the Kirsten rat sarcoma viral oncogene homolog (Kras) or its downstream effector genes occur in almost all lung cancer cells, and there are a number of mouse models for lung cancer using these mutations. Using activated Kras, KrasLA1, as a driver for lung cancer development in mice, we showed for the first time that mice with KrasLA1 and Xpc knockout had worst outcomes in lung cancer development, and this phenotype was associated with accumulated DNA damage. Using cultured cells, we demonstrated that induced expression of oncogenic KRASG12V led to increased levels of reactive oxygen species (ROS) as well as DNA damage, and both can be suppressed by anti-oxidants. Thus, it appears that XPC may help repair DNA damage caused by KRAS-mediated production of ROS.
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    Implementation of ADAS features on One-Tenth scale of an Autonomous Vehicle
    (2021-12) Davuluri, Yogitha; Li, Lingxi; Chen, Yaobin; King, Brian
    An autonomous car is a self-driving vehicle, that operates without human intervention and has the capability of sensing the environment around it. To achieve this, the autonomous vehicle mostly depends on multiple Sensors, Actuators, Machine learning, complex algorithms and processors for software execution. Developed Software, at that point, processes all the information obtained from sensors, plans the path, and the instructions are passed to the vehicle’s actuators, which are capable of controlling acceleration, steering, and brake systems. The rules that are hard-coded, algorithms for detection of object and obstacle avoidance, and predictive modelling control algorithms assist the software with observing traffic guidelines and navigate the vehicle accordingly. Free driving is anything but a simple assignment, and to make independent driving game plans is an extraordinarily critical capacity in the current programming planning field. Engineers and Researchers have been keeping huge endeavors to develop safe and precise algorithms to be incorporated in autonomous vehicles. ROS is a flexible and perfect middle ware tool for robotic applications. ROS offers the necessary tools to effortlessly get the sensors information, process that information, and produce a suitable response to actuators of the vehicle. This thesis work plans to exhibit how ROS could be utilized as a middle- ware tool to make the vehicle move autonomously by examining the surroundings and taking decision. The main focus of this thesis is to develop a one-tenth scale of an autonomous Racecar equipped with Jetson Nano as the on-board computer, ROS based software architecture, sensors, and a PWM driver and implement ADAS features such as Emergency Brake system, Lane Detection and Lane change on the autonomous Race car vehicle. At last, by following the strategies introduced in this thesis work, it is possible to build and develop an autonomousvehicle that uses ROS framework.
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    Implications of Ape1 in reactive oxygen signaling response following cisplatin treatment of dorsal root ganglion neurons
    (2008-08) Jiang, Yanlin; Guo, Chunlu; Vasko, Michael R.; Kelley, Mark R.
    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.
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    Inhibition of TXNRD or SOD1 overcomes NRF2-mediated resistance to β-lapachone
    (Elsevier, 2020-02) Torrente, Laura; Prieto-Farigua, Nicolas; Falzone, Aimee; Elkins, Cody M.; Boothman, David A.; Haura, Eric B.; DeNicola, Gina M.; Biochemistry and Molecular Biology, School of Medicine
    Alterations in the NRF2/KEAP1 pathway result in the constitutive activation of NRF2, leading to the aberrant induction of antioxidant and detoxification enzymes, including NQO1. The NQO1 bioactivatable agent β-lapachone can target cells with high NQO1 expression but relies in the generation of reactive oxygen species (ROS), which are actively scavenged in cells with NRF2/KEAP1 mutations. However, whether NRF2/KEAP1 mutations influence the response to β-lapachone treatment remains unknown. To address this question, we assessed the cytotoxicity of β-lapachone in a panel of NSCLC cell lines bearing either wild-type or mutant KEAP1. We found that, despite overexpression of NQO1, KEAP1 mutant cells were resistant to β-lapachone due to enhanced detoxification of ROS, which prevented DNA damage and cell death. To evaluate whether specific inhibition of the NRF2-regulated antioxidant enzymes could abrogate resistance to β-lapachone, we systematically inhibited the four major antioxidant cellular systems using genetic and/or pharmacologic approaches. We demonstrated that inhibition of the thioredoxin-dependent system or copper-zinc superoxide dismutase (SOD1) could abrogate NRF2-mediated resistance to β-lapachone, while depletion of catalase or glutathione was ineffective. Interestingly, inhibition of SOD1 selectively sensitized KEAP1 mutant cells to β-lapachone exposure. Our results suggest that NRF2/KEAP1 mutational status might serve as a predictive biomarker for response to NQO1-bioactivatable quinones in patients. Further, our results suggest SOD1 inhibition may have potential utility in combination with other ROS inducers in patients with KEAP1/NRF2 mutations.