39 research outputs found

    Cryo-EM structure of nucleotide-bound Tel1ATM unravels the molecular basis of inhibition and structural rationale for disease-associated mutations

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    Yeast Tel1 and its highly conserved human ortholog ataxia-telangiectasia mutated (ATM) are large protein kinases central to the maintenance of genome integrity. Mutations in ATM are found in ataxia-telangiectasia (A-T) patients and ATM is one of the most frequently mutated genes in many cancers. Using cryoelectron microscopy, we present the structure of Tel1 in a nucleotide-bound state. Our structure reveals molecular details of key residues surrounding the nucleotide binding site and provides a structural and molecular basis for its intrinsically low basal activity. We show that the catalytic residues are in a productive conformation for catalysis, but the phosphatidylinositol 3-kinase-related kinase (PIKK) regulatory domain insert restricts peptide substrate access and the N-lobe is in an open conformation, thus explaining the requirement for Tel1 activation. Structural comparisons with other PIKKs suggest a conserved and common allosteric activation mechanism. Our work also provides a structural rationale for many mutations found in A-T and cancer

    Modeling cancer genomic data in yeast reveals selection against ATM function during tumorigenesis

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    The DNA damage response (DDR) comprises multiple functions that collectively preserve genomic integrity and suppress tumorigenesis. The Mre11 complex and ATM govern a major axis of the DDR and several lines of evidence implicate that axis in tumor suppression. Components of the Mre11 complex are mutated in approximately five percent of human cancers. Inherited mutations of complex members cause severe chromosome instability syndromes, such as Nijmegen Breakage Syndrome, which is associated with strong predisposition to malignancy. And in mice, Mre11 complex mutations are markedly more susceptible to oncogene- induced carcinogenesis. The complex is integral to all modes of DNA double strand break (DSB) repair and is required for the activation of ATM to effect DNA damage signaling. To understand which functions of the Mre11 complex are important for tumor suppression, we undertook mining of cancer genomic data from the clinical sequencing program at Memorial Sloan Kettering Cancer Center, which includes the Mre11 complex among the 468 genes assessed. Twenty five mutations in MRE11 and RAD50 were modeled in S. cerevisiae and in vitro. The mutations were chosen based on recurrence and conservation between human and yeast. We found that a significant fraction of tumor-borne RAD50 and MRE11 mutations exhibited separation of function phenotypes wherein Tel1/ATM activation was severely impaired while DNA repair functions were mildly or not affected. At the molecular level, the gene products of RAD50 mutations exhibited defects in ATP binding and hydrolysis. The data reflect the importance of Rad50 ATPase activity for Tel1/ATM activation and suggest that inactivation of ATM signaling confers an advantage to burgeoning tumor cells

    CHROMIUM STATUS IN DIABETES MELLITUS

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    Fasting serum chromium, total cholesterol HDL-cholesterol, LDL-cholesterol, triacytglycerot and blood sugar were determined in fifty two diabetic patients with no other organic diseases anil compared with those obtained from a control group including fourty two healthy volunteers matched for age, sex ami body mass irutex (BMI). Fasting serum chromium and HDL-cholesterol were significantly lower in patients than in controls (p<0.0001 and p<0.001 respectively), but the mean triacytglycerot concentration was significantly higher in patients than in controls (p<002). Mean total cholesterol and LDL-cholesterol values were not significantly different in the two groups. Mean intake of energy, proteins, fats and chromium, estimated by the 24 hr dietary recall method were not significantly different in the two groups. We demonstrated that despite an adequate intake of chromium, the fasting serum chromium was lower in diabetic patients than in control subjects. Chromium deficiency in diabetic patients may act as a contributing factor in aggravating the disease's complications

    RS_DCNN: a novel distributed convolutional-neural-networks based-approach for big remote-sensing image classification

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    Developments in remote sensing technology have led to a continuous increase in the volume of remote-sensing data, which can be qualified as big remote sensing data. A wide range of potential applications is using these data including land cover classification, regional planning, catastrophe prediction and management, and climate-change estimation. Big remote sensing data are characterized by different types of resolutions (radiometric, spatial, spectral, and temporal), modes of imaging, and sensor types, and this range of options often makes the process of analyzing and interpreting such data more difficult. In this paper, which is the first study of its kind, we propose a novel distributed deep learning-based approach for the classification of big remote sensing images. Specifically, we propose Distributed Convolutional-Neural-Networks for handling RS image classification (RS-DCNN). The first step is to prepare the training dataset for RS-DCNN. Then, to ensure a data-parallel training on the top of the Apache Spark framework, a pixel-based convolutional-neural-network model across the big data cluster is performed using BigDL. Experiments are conducted on a real dataset covering many regions of Saudi Arabia and the results demonstrate high classification accuracy at a faster speed than other state-of-the-art classification methods

    Misbehavior-aware on-demand collaborative intrusion detection system using distributed ensemble learning for VANET

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    Vehicular ad hoc networks (VANETs) play an important role as enabling technology for future cooperative intelligent transportation systems (CITSs). Vehicles in VANETs share real-time information about their movement state, traffic situation, and road conditions. However, VANETs are susceptible to the cyberattacks that create life threatening situations and/or cause road congestion. Intrusion detection systems (IDSs) that rely on the cooperation between vehicles to detect intruders, were the most suggested security solutions for VANET. Unfortunately, existing cooperative IDSs (CIDSs) are vulnerable to the legitimate yet compromised collaborators that share misleading and manipulated information and disrupt the IDSsā€™ normal operation. As such, this paper proposes a misbehavior-aware on-demand collaborative intrusion detection system (MA-CIDS) based on the concept of distributed ensemble learning. That is, vehicles individually use the random forest algorithm to train local IDS classifiers and share their locally trained classifiers on-demand with the vehicles in their vicinity, which reduces the communication overhead. Once received, the performance of the classifiers is evaluated using the local testing dataset in the receiving vehicle. The evaluation values are used as a trustworthiness factor and used to rank the received classifiers. The classifiers that deviate much from the box-and-whisker plot lower boundary are excluded from the set of the collaborators. Then, each vehicle constructs an ensemble of weighted random forest-based classifiers that encompasses the locally and remotely trained classifiers. The outputs of the classifiers are aggregated using a robust weighted voting scheme. Extensive simulations were conducted utilizing the network security laboratory-knowledge discovery data mining (NSL-KDD) dataset to evaluate the performance of the proposed MA-CIDS model. The obtained results show that MA-CIDS performs better than the other existing models in terms of effectiveness and efficiency for VANET

    The particle size of drug nanocarriers dictates the fate of neurons; Critical points in neurological therapeutics

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    Neurological disorders and diseases are on the rise in the world, while pharmacists are being encouraged to encapsulate drugs into the nanocarriers. The critical key question is which size of nanocarrier has a promising neurotherapeutic effect. In the present study, FTY-720, an FDA approved drug, was encapsulated into O/W nanocarriers. SEM and DLS data indicated in ultrasonication and stirring methods resulted in spherical nanocarriers with a particle size of 60 and 195 nm (nF60 and nF195), respectively. Further to investigate the effect of particle size on neuronal cells, MTT assay, PI flow-cytometry, LDH release, and NO production examinations were performed. Results showed that small nanocarriers increased cell viability along with the decline of dead cells, while both nanocarriers decreased LDH release and NO production as compared to the conventional drug. Notably, qRT-PCR and western blotting data related to apoptotic markers indicated in the increase of cell mortality in cells treated by nF190 was not due to the increase of apoptosis and Bax/Bcl2 ratio. It is worth mentioning that integrin ƎĀ±5 as a cell surface receptor involves in neuritogenesis was over-expressed in neuronal cells treated by small nanocarriers. However, nF60 increased PTK2 over-expression along with neurite outgrowth, as well. In other words, nanocarriers at the size of 60 nm are preferred to 195 nm as a drug carrier in neurotherapy due to profound impacts on neural cells. Thanks to small nanocarrier broad positive action on neural viability and neurite outgrowth. The present study discloses a pharmaceutical strategy to design drugs based on their particle size efficiency. ƂĀ© 2020 IOP Publishing Ltd
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