Search results for: copy number variations

Authors: Cheng-Yang Lee, Petrus Tang, Tzu-Hao Chang

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Copy number variations (CNVs) have played an important role in many kinds of human diseases, such as Autism, Schizophrenia and a number of cancers. Many diseases are found in genome coding regions and whole exome sequencing (WES) is a cost-effective and powerful technology in detecting variants that are enriched in exons and have potential applications in clinical setting. Although several algorithms have been developed to detect CNVs using WES and compared with other algorithms for finding the most suitable methods using their own samples, there were not consistent datasets across most of algorithms to evaluate the ability of CNV detection. On the other hand, most of algorithms is using command line interface that may greatly limit the analysis capability of many laboratories. We create a series of simulated WES datasets from UCSC hg19 chromosome 22, and then evaluate the CNV detective ability of 19 algorithms from OMICtools database using our simulated WES datasets. We compute the sensitivity, specificity and accuracy in each algorithm for validation of the exome-derived CNVs. After comparison of 19 algorithms from OMICtools database, we construct a platform to install all of the algorithms in a virtual machine like VirtualBox which can be established conveniently in local computers, and then create a simple script that can be easily to use for detecting CNVs using algorithms selected by users. We also build a table to elaborate on many kinds of events, such as input requirement, CNV detective ability, for all of the algorithms that can provide users a specification to choose optimum algorithms.

Keywords: whole exome sequencing, copy number variations, omictools, pipeline

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Authors: S. Fahiminiya, J. Nadaf, F. Rauch, L. Jerome-Majewska, J. Majewski

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Background: Sequencing of protein coding regions of human genome (Whole Exome Sequencing; WES), has demonstrated a great success in the identification of causal mutations for several rare genetic disorders in human. Generally, most of WES studies have focused on rare variants in coding exons and splicing-sites where missense substitutions lead to the alternation of protein product. Although focusing on this category of variants has revealed the mystery behind many inherited genetic diseases in recent years, a subset of them remained still inconclusive. Here, we present the result of our WES studies where analyzing only rare variants in coding regions was not conclusive but further investigation revealed the involvement of non-coding variants and copy number variations (CNV) in etiology of the diseases. Methods: Whole exome sequencing was performed using our standard protocols at Genome Quebec Innovation Center, Montreal, Canada. All bioinformatics analyses were done using in-house WES pipeline. Results: To date, we successfully identified several disease causing mutations within gene coding regions (e.g. SCARF2: Van den Ende-Gupta syndrome and SNAP29: 22q11.2 deletion syndrome) by using WES. In addition, we showed that variants in non-coding regions and CNV have also important value and should not be ignored and/or filtered out along the way of bioinformatics analysis on WES data. For instance, in patients with osteogenesis imperfecta type V and in patients with glucocorticoid deficiency, we identified variants in 5'UTR, resulting in the production of longer or truncating non-functional proteins. Furthermore, CNVs were identified as the main cause of the diseases in patients with metaphyseal dysplasia with maxillary hypoplasia and brachydactyly and in patients with osteogenesis imperfecta type VII. Conclusions: Our study highlights the importance of considering non-coding variants and CNVs during interpretation of WES data, as they can be the only cause of disease under investigation.

Keywords: whole exome sequencing data, non-coding variants, copy number variations, rare diseases

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Authors: Chen Wang, Jared Evans, Yan Asmann

Abstract:

With the quick evolvement of next-generation sequencing techniques, whole-exome or exome-panel data have become a cost-effective way for detection of small exonic mutations, but there has been a growing desire to accurately detect copy number variations (CNVs) as well. In order to address this research and clinical needs, we developed a sequencing coverage pattern-based method not only for copy number detections, data integrity checks, CNV calling, and visualization reports. The developed methodologies include complete automation to increase usability, genome content-coverage bias correction, CNV segmentation, data quality reports, and publication quality images. Automatic identification and removal of poor quality outlier samples were made automatically. Multiple experimental batches were routinely detected and further reduced for a clean subset of samples before analysis. Algorithm improvements were also made to improve somatic CNV detection as well as germline CNV detection in trio family. Additionally, a set of utilities was included to facilitate users for producing CNV plots in focused genes of interest. We demonstrate the somatic CNV enhancements by accurately detecting CNVs in whole exome-wide data from the cancer genome atlas cancer samples and a lymphoma case study with paired tumor and normal samples. We also showed our efficient reuses of existing exome sequencing data, for improved germline CNV calling in a family of the trio from the phase-III study of 1000 Genome to detect CNVs with various modes of inheritance. The performance of the developed method is evaluated by comparing CNV calling results with results from other orthogonal copy number platforms. Through our case studies, reuses of exome sequencing data for calling CNVs have several noticeable functionalities, including a better quality control for exome sequencing data, improved joint analysis with single nucleotide variant calls, and novel genomic discovery of under-utilized existing whole exome and custom exome panel data.

Keywords: bioinformatics, computational genetics, copy number variations, data reuse, exome sequencing, next generation sequencing

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Authors: Khaled M. Alqahtani

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Copy number alterations (CNA) are variations in the structure of the genome, where certain regions deviate from the typical two chromosomal copies. These alterations are pivotal in understanding tumor progression and are indicative of patients' survival outcomes. However, effectively modeling patients' survival based on their genomic CNA profiles while identifying relevant genomic regions remains a statistical challenge. Various methods, such as the Cox proportional hazard (PH) model with ridge, lasso, or elastic net penalties, have been proposed but often overlook the inherent dependencies between genomic regions, leading to results that are hard to interpret. In this study, we enhance the elastic net penalty by incorporating an additional penalty that accounts for these dependencies. This approach yields smooth parameter estimates and facilitates variable selection, resulting in a sparse solution. Our findings demonstrate that this method outperforms other models in predicting survival outcomes, as evidenced by our simulation study. Moreover, it allows for a more meaningful interpretation of genomic regions associated with patients' survival. We demonstrate the efficacy of our approach using both real data from a lung cancer cohort and simulated datasets.

Keywords: copy number alterations, cox proportional hazard, lung cancer, regression, sparse solution

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Authors: Habtamu Abera Goshu, Ping Yan

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Copy number variation (CNV) is a significant marker of the genetic and phenotypic diversity among individuals that accounts for complex quantitative traits of phenotype and diseases via modulating gene dosage, position effects, alteration of downstream pathways, modification of chromosome structure, and position within the nucleus and disrupting coding regions in the genome. Associating copy number variations (CNVs) with growth and gene expression are a powerful approach for identifying genomic characteristics that contribute to phenotypic and genotypic variation. A previous study using next-generation sequencing illustrated that the choline kinase beta (CHKB), Krüpple-like factor 6 (KLF6), glypican 1(GPC1), and cholinergic receptor muscarinic 3 (CHRM3) genes reside within copy number variable regions (CNVRs) of yak populations that overlap with quantitative trait loci (QTLs) of meat quality and growth. As a result, this research aimed to determine the association of CNVs of the KLF6, CHKB, GPC1, and CHRM3 genes with growth traits in the Datong yak breed. The association between the CNV types of the KLF6, CHKB, GPC1, and CHRM3 genes and the growth traits in the Datong yak breed was determined by one-way analysis of variance (ANOVA) using SPSS software. The CNV types were classified as a loss (a copy number of 0 or 1), gain (a copy number >2), and normal (a copy number of 2) relative to the reference gene, BTF3 in the 387 individuals of Datong yak. These results indicated that the normal CNV types of the CHKB and GPC1 genes were significantly (P<0.05) associated with high body length, height and weight, and chest girth in six-month-old and five-year-old Datong yaks. On the other hand, the loss CNV types of the KLF6 gene is significantly (P<0.05) associated with body weight and length and chest girth at six-month-old and five-year-old Datong yaks. In the contrary, the gain CNV type of the CHRM3 gene is highly (P<0.05) associated with body weight, length, height, and chest girth in six-month-old and five-year-old. This work provides the first observation of the biological role of CNVs of the CHKB, KLF6, GPC1, and CHRM3 genes in the Datong yak breed and might, therefore, provide a novel opportunity to utilize data on CNVs in designing molecular markers for the selection of animal breeding programs for larger populations of various yak breeds. Therefore, we hypothesized that this study provided inclusive information on the application of CNVs of the CHKB, KLF6, GPC1, and CHRM3 genes in growth traits in Datong yaks and its possible function in bovine species.

Keywords: Copy number variation, growth traits, yak, genes

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Authors: Kang Zijian, Zhang Tingyu, Burra Venkata Durga Kumar

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This article investigates the challenges in memory migration during the live migration of virtual machines. We found three challenges probably existing in pre-copy technology. One of the main challenges is the challenge of downtime migration. Decrease the downtime could promise the normal work for a virtual machine. Although pre-copy technology is greatly decreasing the downtime, we still need to shut down the machine in order to finish the last round of data transfer. This paper provides an optimization scheme for the problems existing in pro-copy technology, mainly the optimization of the dirty page migration mechanism. The typical pre-copy technology copy n-1th’s dirty pages in nth turn. However, our idea is to create a double iteration method to solve this problem.

Keywords: virtual machine, pre-copy technology, memory migration process, downtime, dirty pages migration method

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Authors: Eirini Konstanta, Cedric Gouedard, Aggeliki Delimitsou, Stefania Patera, Samuel Murray

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Introduction: Quality reference DNA standards (QRS) for molecular testing by next-generation sequencing (NGS) are essential for accurate quantitation of copy number variations (CNV) for germline and variant allelic frequencies (VAF) for somatic analyses. Objectives: Presently, several molecular analytics for oncology patients are reliant upon quantitative metrics. Test validation and standardisation are also reliant upon the availability of surrogate control materials allowing for understanding test LOD (limit of detection), sensitivity, specificity. We have developed a dual calibration platform allowing for QRS pairs to be included in analysed DNA samples, allowing for accurate quantitation of CNV and VAF metrics within and between patient samples. Methods: QRS™ blocks up to 500nt were designed for common NGS panel targets incorporating ≥ 2 identification tags (IDTDNA.com). These were analysed upon spiking into gDNA, somatic, and ctDNA using a proprietary CalSuite™ platform adaptable to common LIMS. Results: We demonstrate QRS™ calibration reproducibility spiked to 5–25% at ± 2.5% in gDNA and ctDNA. Furthermore, we demonstrate CNV and VAF within and between samples (gDNA and ctDNA) with the same reproducibility (± 2.5%) in a clinical sample of lung cancer and HBOC (EGFR and BRCA1, respectively). CNV analytics was performed with similar accuracy using a single pair of QRS calibrators when using multiple single targeted sequencing controls. Conclusion: Dual paired QRS™ calibrators allow for accurate and reproducible quantitative analyses of CNV, VAF, intrinsic sample allele measurement, inter and intra-sample measure not only simplifying NGS analytics but allowing for monitoring clinically relevant biomarker VAF across patient ctDNA samples with improved accuracy.

Keywords: calibrator, CNV, gene copy number, VAF

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Authors: Maria Lopez-Ibarra, Ana Velazquez-Wong, Lucelli Yañez-Gutierrez, Maria Araujo-Solis, Fabio Salamanca-Gomez, Alfonso Mendez-Tenorio, Haydeé Rosas-Vargas

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Congenital heart diseases (CHD) are the most common congenital abnormalities. These conditions can occur as both an element of distinct chromosomal malformation syndromes or as non-syndromic forms. Their etiology is not fully understood. Genetic variants such copy number variants have been associated with CHD. The aim of our study was to analyze these genomic variants in peripheral blood from Mexican children diagnosed with non-syndromic CHD. We included 16 children with atrial and ventricular septal defects and 5 healthy subjects without heart malformations as controls. To exclude the most common heart disease-associated syndrome alteration, we performed a fluorescence in situ hybridization test to identify the 22q11.2, responsible for congenital heart abnormalities associated with Di-George Syndrome. Then, a microarray based comparative genomic hybridization was used to identify global copy number variants. The identification of copy number variants resulted from the comparison and analysis between our results and data from main genetic variation databases. We identified copy number variants gain in three chromosomes regions from pediatric patients, 4q13.2 (31.25%), 9q34.3 (25%) and 20q13.33 (50%), where several genes associated with cellular, biosynthetic, and metabolic processes are located, UGT2B15, UGT2B17, SNAPC4, SDCCAG3, PMPCA, INPP6E, C9orf163, NOTCH1, C20orf166, and SLCO4A1. In addition, after a hierarchical cluster analysis based on the fluorescence intensity ratios from the comparative genomic hybridization, two congenital heart disease groups were generated corresponding to children with atrial or ventricular septal defects. Further analysis with a larger sample size is needed to corroborate these copy number variants as possible biomarkers to differentiate between heart abnormalities. Interestingly, the 20q13.33 gain was present in 50% of children with these CHD which could suggest that alterations in both coding and non-coding elements within this chromosomal region may play an important role in distinct heart conditions.

Keywords: aCGH, bioinformatics, congenital heart diseases, copy number variants, fluorescence in situ hybridization

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Authors: A. Delimitsou, C. Gouedard, E. Konstanta, A. Koletis, S. Patera, E. Manou, K. Spaho, S. Murray

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Background: There remains a lack of International Standard Control Reference materials for Next Generation Sequencing-based approaches or device calibration. We have designed and validated dsDNA biomimetic reference materials for targeted such approaches incorporating proprietary motifs (patent pending) for device/test calibration. They enable internal single-sample calibration, alleviating sample comparisons to pooled historical population-based data assembly or statistical modelling approaches. We have validated such an approach for BRCA Copy Number Variation analytics using iQRS™-CNVSUITE versus Mixed Ligation-dependent Probe Amplification. Methods: Standard BRCA Copy Number Variation analysis was compared between mixed ligation-dependent probe amplification and next generation sequencing using a cohort of 198 breast/ovarian cancer patients. Next generation sequencing based copy number variation analysis of samples spiked with iQRS™ dsDNA biomimetics were analysed using proprietary CNVSUITE software. Mixed ligation-dependent probe amplification analyses were performed on an ABI-3130 Sequencer and analysed with Coffalyser software. Results: Concordance of BRCA – copy number variation events for mixed ligation-dependent probe amplification and CNVSUITE indicated an overall sensitivity of 99.88% and specificity of 100% for iQRS™-CNVSUITE. The negative predictive value of iQRS-CNVSUITE™ for BRCA was 100%, allowing for accurate exclusion of any event. The positive predictive value was 99.88%, with no discrepancy between mixed ligation-dependent probe amplification and iQRS™-CNVSUITE. For device calibration purposes, precision was 100%, spiking of patient DNA demonstrated linearity to 1% (±2.5%) and range from 100 copies. Traditional training was supplemented by predefining the calibrator to sample cut-off (lock-down) for amplicon gain or loss based upon a relative ratio threshold, following training of iQRS™-CNVSUITE using spiked iQRS™ calibrator and control mocks. BRCA copy number variation analysis using iQRS™-CNVSUITE™ was successfully validated and ISO15189 accredited and now enters CE-IVD performance evaluation. Conclusions: The inclusion of a reference control competitor (iQRS™ dsDNA mimetic) to next generation sequencing-based sequencing offers a more robust sample-independent approach for the assessment of copy number variation events compared to mixed ligation-dependent probe amplification. The approach simplifies data analyses, improves independent sample data analyses, and allows for direct comparison to an internal reference control for sample-specific quantification. Our iQRS™ biomimetic reference materials allow for single sample copy number variation analytics and further decentralisation of diagnostics to single patient sample assessment.

Keywords: validation, diagnostics, oncology, copy number variation, reference material, calibration

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Authors: Grishma D. Solanki, Karshan Kandoriya

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In modern era of information age, digitalization has revolutionized like never before. Powerful computers, advanced photo editing software packages and high resolution capturing devices have made manipulation of digital images incredibly easy. As per as image forensics concerns, one of the most actively researched area are detection of copy move forgeries. Higher computational complexity is one of the major component of existing techniques to detect such tampering. Moreover, copy move forgery is usually performed in three steps. First, copying of a region in an image then pasting the same one in the same respective image and finally doing some post-processing like rotation, scaling, shift, noise, etc. Consequently, pseudo Zernike moment is used as a features extraction method for matching image blocks and as a primary factor on which performance of detection algorithms depends.

Keywords: copy-move image forgery, digital forensics, image forensics, image forgery

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Authors: L. M. Al-Harbi, A. M. Shokry, J. S. M. Sabir, A. Chaudhary, J. Manikandan, K. S. Saini

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Breast cancer is the second most common cause of cancer death worldwide and is the most common malignancy among Saudi females. During breast carcinogenesis, a wide-array of cytogenetic changes involving deletions, or amplification, or translocations, of part or whole of chromosome regions have been observed. Because of the limitations of various earlier technologies, newer tools are developed to scan for changes at the genomic level. Recently, Array Comparative Genomic Hybridization (aCGH) technique has been applied for detecting segmental genomic alterations at molecular level. In this study, aCGH was performed on twenty breast cancer tumors and their matching non-tumor (normal) counterparts using the Agilent 2x400K. Several regions were identified to be either amplified or deleted in a tumor-specific manner. Most frequent alterations were amplification of chromosome 1q, chromosome 8q, 20q, and deletions at 16q were also detected. The amplification of genetic events at 1q and 8q were further validated using FISH analysis using probes targeting 1q25 and 8q (MYC gene). The copy number changes at these loci can potentially cause a significant change in the tumor behavior, as deletions in the E-Cadherin (CDH1)-tumor suppressor gene as well as amplification of the oncogenes-Aurora Kinase A. (AURKA) and MYC could make these tumors highly metastatic. This study validates the use of aCGH in Saudi breast cancer patients and sets the foundations necessary for performing larger cohort studies searching for ethnicity-specific biomarkers and gene copy number variations.

Keywords: breast cancer, molecular biology, ecology, environment

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Authors: N. Chaitawittanun, M. Munlin

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Due to rapid advancement of powerful image processing software, digital images are easy to manipulate and modify by ordinary people. Lots of digital images are edited for a specific purpose and more difficult to distinguish form their original ones. We propose a clustering method to detect a copy-move image forgery of JPEG, BMP, TIFF, and PNG. The process starts with reducing the color of the photos. Then, we use the clustering technique to divide information of measuring data by Hausdorff Distance. The result shows that the purposed methods is capable of inspecting the image file and correctly identify the forgery.

Keywords: image detection, forgery image, copy-paste, attack detection

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Authors: Michael Zimba

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A novel set of features for copy-move image forgery, CMIF, detection method is proposed. The proposed set presents a new approach which relies on electrostatic field theory, EFT. Solely for the purpose of reducing the dimension of a suspicious image, firstly performs discrete wavelet transform, DWT, of the suspicious image and extracts only the approximation subband. The extracted subband is then bijectively mapped onto a virtual electrostatic field where concepts of EFT are utilised to extract robust features. The extracted features are shown to be invariant to additive noise, JPEG compression, and affine transformation. The proposed features can also be used in general object matching.

Keywords: virtual electrostatic field, features, affine transformation, copy-move image forgery

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Authors: John M. Ikome, Martha E. Ikome, Therese Van Wyk

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Productivity optimization of a company can significantly increase the company’s output and productivity which can be in the form of corrective actions of ineffective activities, process simplification, and reduction of variations, responsiveness, and reduction of set-up-time which are all under the classification of waste within the manufacturing environment. Deriving a means to eliminate a number of these issues has a key importance for manufacturing organization. This paper focused on a number of industrial engineering techniques which include a cause and effect diagram, to identify and optimize the method or systems being used. Based on our results, it shows that there are a number of variations within the production processes that can significantly disrupt the expected output.

Keywords: optimization, fishbone, diagram, productivity

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Authors: Jaco Oosthuizen, Nerina C. Van Der Merwe

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The National Health Laboratory Services in Bloemfontien has been the diagnostic testing facility for 1830 patients for familial breast cancer since 1997. From the cohort, 540 were comprehensively screened using High-Resolution Melting Analysis or Next Generation Sequencing for the presence of point mutations and/or indels. Approximately 90% of these patients stil remain undiagnosed as they are BRCA1/2 negative. Multiplex ligation-dependent probe amplification was initially added to screen for copy number variation detection, but with the introduction of next generation sequencing in 2017, was substituted and is currently used as a confirmation assay. The aim was to investigate the viability of utilizing internationally designed copy number variation detection assays based on mostly European/Caucasian genomic data for use within a South African context. The multiplex ligation-dependent probe amplification technique is based on the hybridization and subsequent ligation of multiple probes to a targeted exon. The ligated probes are amplified using conventional polymerase chain reaction, followed by fragment analysis by means of capillary electrophoresis. The experimental design of the assay was performed according to the guidelines of MRC-Holland. For BRCA1 (P002-D1) and BRCA2 (P045-B3), both multiplex assays were validated, and results were confirmed using a secondary probe set for each gene. The next generation sequencing technique is based on target amplification via multiplex polymerase chain reaction, where after the amplicons are sequenced parallel on a semiconductor chip. Amplified read counts are visualized as relative copy numbers to determine the median of the absolute values of all pairwise differences. Various experimental parameters such as DNA quality, quantity, and signal intensity or read depth were verified using positive and negative patients previously tested internationally. DNA quality and quantity proved to be the critical factors during the verification of both assays. The quantity influenced the relative copy number frequency directly whereas the quality of the DNA and its salt concentration influenced denaturation consistency in both assays. Multiplex ligation-dependent probe amplification produced false positives due to ligation failure when ligation was inhibited due to a variant present within the ligation site. Next generation sequencing produced false positives due to read dropout when primer sequences did not meet optimal multiplex binding kinetics due to population variants in the primer binding site. The analytical sensitivity and specificity for the South African population have been proven. Verification resulted in repeatable reactions with regards to the detection of relative copy number differences. Both multiplex ligation-dependent probe amplification and next generation sequencing multiplex panels need to be optimized to accommodate South African polymorphisms present within the genetically diverse ethnic groups to reduce the false copy number variation positive rate and increase performance efficiency.

Keywords: familial breast cancer, multiplex ligation-dependent probe amplification, next generation sequencing, South Africa

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Authors: Shih-Yan Chen, Shin-Shin Kao

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In this paper, a thorough review about dual-cubes, DCn, the related studies and their variations are given. DCn was introduced to be a network which retains the pleasing properties of hypercube Qn but has a much smaller diameter. In fact, it is so constructed that the number of vertices of DCn is equal to the number of vertices of Q2n +1. However, each vertex in DCn is adjacent to n + 1 neighbors and so DCn has (n + 1) × 2^2n edges in total, which is roughly half the number of edges of Q2n+1. In addition, the diameter of any DCn is 2n +2, which is of the same order of that of Q2n+1. For selfcompleteness, basic definitions, construction rules and symbols are provided. We chronicle the results, where eleven significant theorems are presented, and include some open problems at the end.

Keywords: dual-cubes, dual-cube extensive networks, dual-cube-like networks, hypercubes, fault-tolerant hamiltonian property

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Authors: Ghada Al-Kafaji, Mohamed Sabry

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Mitochondria are the site of cellular respiration and produce energy in the form of adenosine triphosphate (ATP) via oxidative phosphorylation. They are the major source of intracellular reactive oxygen species (ROS) and are also direct target to ROS attack. Oxidative stress and ROS-mediated disruptions of mitochondrial function are major components involved in the pathogenicity of diabetic complications. In this work, the changes in mitochondrial DNA (mtDNA) copy number, biogenesis, gene expression of mtDNA-encoded subunits of electron transport chain (ETC) complexes, and mitochondrial function in response to hyperglycemia-induced ROS and the effect of direct inhibition of ROS on mitochondria were investigated in an in vitro model of diabetic nephropathy using human renal mesangial cells. The cells were exposed to normoglycemic and hyperglycemic conditions in the presence and absence of Mn(III)tetrakis(4-benzoic acid) porphyrin chloride (MnTBAP) or catalase for 1, 4 and 7 days. ROS production was assessed by the confocal microscope and flow cytometry. mtDNA copy number and PGC-1a, NRF-1, and TFAM, as well as ND2, CYTB, COI, and ATPase 6 transcripts, were all analyzed by real-time PCR. PGC-1a, NRF-1, and TFAM, as well as ND2, CYTB, COI, and ATPase 6 proteins, were analyzed by Western blotting. Mitochondrial function was determined by assessing mitochondrial membrane potential and adenosine triphosphate (ATP) levels. Hyperglycemia-induced a significant increase in the production of mitochondrial superoxide and hydrogen peroxide at day 1 (P < 0.05), and this increase remained significantly elevated at days 4 and 7 (P < 0.05). The copy number of mtDNA and expression of PGC-1a, NRF-1, and TFAM as well as ND2, CYTB, CO1 and ATPase 6 increased after one day of hyperglycemia (P < 0.05), with a significant reduction in all those parameters at 4 and 7 days (P < 0.05). The mitochondrial membrane potential decreased progressively at 1 to 7 days of hyperglycemia with the parallel progressive reduction in ATP levels over time (P < 0.05). MnTBAP and catalase treatment of cells cultured under hyperglycemic conditions attenuated ROS production reversed renal mitochondrial oxidative stress and improved mtDNA, mitochondrial biogenesis, and function. These results show that hyperglycemia-induced ROS caused an early increase in mtDNA copy number, mitochondrial biogenesis and mtDNA-encoded gene expression of the ETC subunits in human mesangial cells as a compensatory response to the decline in mitochondrial function, which precede the mtDNA defect and mitochondrial dysfunction with a progressive oxidative response. Protection from ROS-mediated damage to renal mitochondria induced by hyperglycemia may be a novel therapeutic approach for the prevention/treatment of DN.

Keywords: diabetic nephropathy, hyperglycemia, reactive oxygen species, oxidative stress, mtDNA, mitochondrial dysfunction, manganese superoxide dismutase, catalase

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Authors: Aishwarya Shekhar, Himanshu Sharma

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Data deduplication is one of important data compression techniques for eliminating duplicate copies of repeating data, and has been widely used in cloud storage to reduce the amount of storage space and save bandwidth. In this process, duplicate data is expunged, leaving only one copy means single instance of the data to be accumulated. Though, indexing of each and every data is still maintained. Data deduplication is an approach for minimizing the part of storage space an organization required to retain its data. In most of the company, the storage systems carry identical copies of numerous pieces of data. Deduplication terminates these additional copies by saving just one copy of the data and exchanging the other copies with pointers that assist back to the primary copy. To ignore this duplication of the data and to preserve the confidentiality in the cloud here we are applying the concept of hybrid nature of cloud. A hybrid cloud is a fusion of minimally one public and private cloud. As a proof of concept, we implement a java code which provides security as well as removes all types of duplicated data from the cloud.

Keywords: confidentiality, deduplication, data compression, hybridity of cloud

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Authors: Akterono Budiyati, Gita Kusumo, Teguh Putra, Fritzie Rexana, Antonius Kurniawan, Aru Sudoyo, Ahmad Utomo, Andi Utama

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The presence of the programmed death ligand-1 (PD-L1) has been used in multiple clinical trials and approved as biomarker for selecting patients more likely to respond to immune checkpoint inhibitors. However, the expression of PD-L1 is regulated in different ways, which leads to a different significance of its presence. Positive PD-L1 within tumors may result from two mechanisms, induced PD-L1 expression by T-cell presence or genetic mechanism that lead to constitutive PD-L1 expression. Amplification of PD-L1 genes was found as one of genetic mechanism which causes an increase in PD-L1 expression. In case of colorectal cancer (CRC), targeting immune checkpoint inhibitor has been recommended for patients with microsatellite instable (MSI). Although the correlation between PD-L1 expression and MSI status has been widely studied, so far the precise mechanism of PD-L1 gene activation in CRC patients, particularly in MSI population have yet to be clarified. In this present study we have profiled 61 archived formalin fixed paraffin embedded CRC specimens of patients from Medistra Hospital, Jakarta admitted in 2010 - 2016. Immunohistochemistry was performed to measure expression of PD-L1 in tumor cells as well as MSI status using antibodies against PD-L1 and MMR (MLH1, MSH2, PMS2 and MSH6), respectively. PD-L1 expression was measured on tumor cells with cut off of 1% whereas loss of nuclear MMR protein expressions in tumor cells but not in normal or stromal cells indicated presence of MSI. Subset of PD-L1 positive patients was then assessed for copy number variations (CNVs) using single Tube TaqMan Copy Number Assays Gene CD247PD-L1. We also observed KRAS mutation to profile possible genetic mechanism leading to the presence or absence of PD-L1 expression. Analysis of 61 CRC patients revealed 15 patients (24%) expressed PD-L1 on their tumor cell membranes. The prevalence of surface membrane PD-L1 was significantly higher in patients with MSI (87%; 7/8) compared to patients with microsatellite stable (MSS) (15%; 8/53) (P=0.001). Although amplification of PD-L1 gene was not found among PD-L1 positive patients, low-level amplification of PD-L1 gene was commonly observed in MSS patients (75%; 6/8) than in MSI patients (43%; 3/7). Additionally, we found 26% of CRC patients harbored KRAS mutations (16/61), so far the distribution of KRAS status did not correlate with PD-L1 expression. Our data suggest genetic mechanism through amplification of PD-L1 seems not to be the mechanism underlying upregulation of PD-L1 expression in CRC patients. However, further studies are warranted to confirm the results.

Keywords: colorectal cancer, gene amplification, microsatellite instable, programmed death ligand-1

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Authors: Ercan Ceyhan, Ali Kahraman, Hasan Dalgıç

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This research was made during the 2011 and 2012 growing periods according to “Randomized Blocks Design” with 3 replications. Research material was the following chickpea genotype: CA119, CA128, CA149, CA150, CA222, CA250, CA254 and other 2 commercial varieties named as Gökçe and Yaşa. Some agronomical characteristics such as plant height (cm), number of pod per plant, number of seed per pod, number of seed per plant, 1000 seed weight (g) and seed yield (kg ha-1) were determined. Statistically significant variations were found amongst the genotypes for all variables except seeds per pod. Means of the two years showed the range for plant height was from 52.83 cm (Gökçe) to 73.00 cm (CA150), number of pod per plant was from 14.00 (CA149) to 26.83 (CA261), number of seed per pod was from 1.10 (Gökçe) to 1.19 (CA149 ve CA250), number of seed per plant was from 16.28 (CA149) to 31.65 (CA261), 1000 seed weight was from 295.85 g (CA149) to 437.80 g (CA261) and seed yield was from 1342.73 kg ha-1 (CA261) to 2161.50 kg ha-1 (CA128). Results of the research implicated that the new developed lines were superior compared with the control (commercial) varieties by means of most of the characteristics.

Keywords: agricultural characters, chickpea, seed yield, genotype variations

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Authors: Hanaa A. S. Oraby, Amal A. M. Hassan, Mahmoud M. Sakr, Atef A. A. Haiba

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Applying the profiling approach for the assessment of proteomic variations due to genetic modification of the Egyptian tomato cultivar "Edkawy", three complementary approaches were used. These methods are amino acids analysis, gel electrophoresis, and Gas chromatography coupled with mass spectrometry (GC/MS). The results of the present study Show evidence of proteomic variations between both modified tomato and its non-modified counterpart. Amino acids concentrations, and the protein patterns separation on the 1D SDS-PAGE were not similar in the case of transformed tomato compared to that of the non-transformed counterpart. These detected differences are most likely derived from the process of transformation. Results also revealed that the efficiency of GC/MS approach to identify a mixture of unknown proteins is limited. GC/MS analysis was only able to identify few number of protein molecules. Therefore, more advanced and specific technologies like MALDI-TOF-MS are recommended to be employed.

Keywords: GMOs, unintended effects, proteomic variations, 1D SDS-PAGE, GC/MS

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Authors: Ashrafosadat Mousavi Lar, Elahe Moravej

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To investigate and explain the history of each copy, we must refer to its past because it highlights parts of the civilization of people among which this copy has been codified. In this paper, eight Ferdowsi’s Shahnameh of Safavid era of Tabriz doctrine available in Iranian libraries and museums are studied. Undoubtedly, it can be said that Ferdowsi’s Shahnameh is one of the most important books that has been transcribed many times in different eras because it explains the Iranian champions’ prowess and it includes the history of Iran from Pishdadian to Sasanian dynasty. In addition, it has been attractive for governors and artists. The research methodology of this article is based on the analytical-descriptive arguments. The research hypothesis is based on papers used in Shahnameh writing in Safavid era of Tabriz doctrine were mostly Isfahanian papers existed. At that time, Isfahanian paper was unique in terms of quality, clarity, flatness of the sheets, volume, shape, softness and elegance, strength, and smoothness. This paper was mostly used to prepare the courtier and exquisite copies. This shows that the prepared copies in Safavid era of Tabriz doctrine were very important because the artists and people who ordered and were out of the court have ordered Isfahanian paper for writing their books.

Keywords: paper, Shahnameh, Safavid era, Tabriz doctrine

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Authors: Doaa Hashad, Amany Elyamany, Perihan Salem

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Introduction: Hepatitis C virus infection (HCV) constitutes a serious dilemma that has an impact on the health of millions of Egyptians. Hepatitis C virus related hepatocellular carcinoma (HCV-HCC) is a crucial consequence of HCV that represents the third cause of cancer-related deaths worldwide. Aim of the study: assess the use of mitochondrial DNA (mtDNA) content as a non-invasive molecular biomarker in hepatitis c virus related hepatocellular carcinoma (HCV-HCC). Methods: A total of 135 participants were enrolled in the study. Volunteers were assigned to one of three groups equally; a group of HCV related cirrhosis (HCV-cirrhosis), a group of HCV-HCC and a control group of age- and sex- matched healthy volunteers with no evidence of liver disease. mtDNA was determined using a quantitative real-time PCR technique. Results: mtDNA content was lowest in HCV-HCC cases. No statistically significant difference was observed between the group of HCV-cirrhosis and the control group as regards mtDNA level. HCC patients with multi-centric hepatic lesions had significantly lower mtDNA content. On using receiver operating characteristic curve analysis, a cutoff of 34 was assigned for mtDNA content to distinguish between HCV-HCC and HCV-cirrhosis patients who are not yet complicated by malignancy. Lower mtDNA was associated with greater HCC risk on using healthy controls, HCV-cirrhosis, or combining both groups as a reference group. Conclusions: mtDNA content might constitute a non-invasive molecular biomarker that reflects tumor burden in HCV-HCC cases and could be used as a predictor of HCC risk in patients of HCV-cirrhosis. In addition, the non significant difference of mtDNA level between HCV-cirrhosis patients and healthy controls could eliminate the grey zone created by the use of AFP in some cirrhotic patients.

Keywords: DNA copy number, HCC, HCV, mitochondrial

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Authors: Fatma Sümer

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Introduction: This case report aims to report myopic anisometropia with copy-image in monozygotic twins. Methods: In February 2021, a 6-year-old identical twin was seen, who was referred to us with the diagnosis of amblyopia in their left eye from an external center. Both twins had a full ophthalmic examination, which included visual acuity testing, ocular motility testing, cycloplegic refraction, and fundus examination. Results: On examination, “copy image” myopic anisometropia was discovered. Twin 1 had anisometropia with myopic astigmatism in the left eye. His cycloplegic refraction was +1.00 (-0.75x 75) in the right eye and -8.0 (-1.50x175) in the left eye. Similarly, twin 2 had anisometropia with myopic astigmatism in the left eye. His cycloplegic refraction was -7.75 (-1.50x180) in the left eye and +1.25 (-0.75x90 ) in the right eye. The best-corrected visual acuity was 20/60 in the amblyopic eyes and 20/20 in the unaffected eyes. There was no ocular deviation. In either patient, a slit-lamp microscopic examination revealed no abnormalities in the anterior parts of either eye. Fundoscopic examination revealed no abnormalities. No abnormal ocular movements were demonstrated. Conclusion: As far as we have reviewed in the literature, previous studies with twins were mostly concerned with mirror-effect myopic anisometropia and myopic anisometropia, whereas ipsilateral amblyopia and anisometropia were not reported in monozygotic twins. This case underscores the possible genetic basis of myopic anisometropia.

Keywords: amblyopia, anisometropia, myopia, twins

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Authors: Salma M. Wakil

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Advances in the field of genetics overwhelmed detecting large number of inherited disorders at the molecular level and directed to the development of innovative technologies. These innovations have led to gene sequencing, prenatal mutation detection, pre-implantation genetic diagnosis; population based carrier screening and genome wide analyses using microarrays. Microarrays are widely used in establishing clinical and diagnostic setup for genetic anomalies at a massive level, with the advent of cytoscan molecular karyotyping as a clinical utility card for detecting chromosomal aberrations with high coverage across the entire human genome. Unlike a regular karyotype that relies on the microscopic inspection of chromosomes, molecular karyotyping with cytoscan constructs virtual chromosomes based on the copy number analysis of DNA which improves its resolution by 100-fold. We have been investigating a large number of patients with Developmental Delay and Intellectual disability with this platform for establishing micro syndrome deletions and have detected number of novel CNV’s in the Arabian population with the clinical relevance.

Keywords: microarrays, molecular karyotyping, developmental delay, genetics

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Authors: Kenny Raharjo, Ramon Lawrence

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Game designers have the challenging task of building games that engage players to spend their time and money on the game. There are an infinite number of game variations and design choices, and it is hard to systematically determine game design choices that will have positive experiences for players. In this work, we demonstrate how multi-arm bandits can be used to automatically explore game design variations to achieve improved player metrics. The advantage of multi-arm bandits is that they allow for continuous experimentation and variation, intrinsically converge to the best solution, and require no special infrastructure to use beyond allowing minor game variations to be deployed to users for evaluation. A user study confirms that applying multi-arm bandits was successful in determining the preferred game variation with highest play time metrics and can be a useful technique in a game designer's toolkit.

Keywords: game design, multi-arm bandit, design exploration and data mining, player metric optimization and analytics

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Authors: Masoumeh Moghbel

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Nowadays, carbon dioxide which is produced by human activities is considered as the main effective factor in the global warming occurrence. Regarding to the role of CO2 and its ability in trapping the heat, the main objective of this research is study the effect of atmospheric CO2 (which is recorded in Manaloa) on variations of temperature parameters (daily mean temperature, minimum temperature and maximum temperature) in 5 meteorological stations in Iran which were selected according to the latitude and altitude in 40 years statistical period. Firstly, the trend of temperature parameters was studied by Regression and none-graphical Man-Kendal methods. Then, relation between temperature variations and CO2 were studied by Correlation technique. Also, the impact of CO2 amount on temperature in different atmospheric levels (850 and 500 hpa) was analyzed. The results illustrated that correlation coefficient between temperature variations and CO2 in low latitudes and high altitudes is more significant rather than other regions. it is important to note that altitude as the one of the main geographic factor has limitation in affecting the temperature variations, so that correlation coefficient between these two parameters in 850 hpa (r=0.86) is more significant than 500 hpa (r = 0.62).

Keywords: altitude, atmospheric carbon dioxide, latitude, temperature variations

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Authors: Alirıza Kaleli, M. Akif Ceviz, Erdoğan Güner, Köksal Erentürk

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The cyclic variations in spark ignition engines occurring especially under specific engine operating conditions make the maximum pressure variable for successive in-cylinder pressure cycles. Minimization of cyclic variations has a great importance in effectively operating near to lean limit, or at low speed and load. The cyclic variations may reduce the power output of the engine, lead to operational instabilities, and result in undesirable engine vibrations and noise. In this study, spark timing is controlled in order to reduce the cyclic variations in spark ignition engines. Firstly, an ARMAX model has developed between spark timing and maximum pressure using system identification techniques. By using this model, the maximum pressure of the next cycle has been predicted. Then, self-tuning minimum variance controller has been designed to change the spark timing for consecutive cycles of the first cylinder of test engine to regulate the in-cylinder maximum pressure. The performance of the proposed controller is illustrated in real time and experimental results show that the controller has a reliable effect on cycle to cycle variations of maximum cylinder pressure when the engine works under low speed conditions.

Keywords: cyclic variations, cylinder pressure, SI engines, self tuning controller

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Authors: Reza Shakoori

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This paper presents a structural correction of Arabic and Persian strokes using manipulation of their chain codes in order to improve the rate and performance of Persian and Arabic handwritten word recognition systems. It collects pure and effective features to represent a character with one consolidated feature vector and reduces variations in order to decrease the number of training samples and increase the chance of successful classification. Our results also show that how the proposed approaches can simplify classification and consequently recognition by reducing variations and possible noises on the chain code by keeping orientation of characters and their backbone structures.

Keywords: Arabic, chain code normalization, OCR systems, image processing

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Authors: Arthi Ganapathy, Rati Tandon, Saroj Kaler

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Introduction: A thorough knowledge of variations in lung anatomy is of prime significance during surgical procedures like lobectomy, pneumonectomy, and segmentectomy of lungs. The arrangement of structures in the lung hilum act as a guide in performing such procedures. The normal pattern of arrangement of hilar structures in the right lung is eparterial bronchus, pulmonary artery, hyparterial bronchus and pulmonary veins from above downwards. In the left lung, it is pulmonary artery, principal bronchus and pulmonary vein from above downwards. The arrangement of hilar structures from anterior to posterior in both the lungs is pulmonary vein, pulmonary artery, and principal bronchus. The bronchial arteries are very small and usually the posterior most structures in the hilum of lungs. Aim: The present study aims at reporting the variations in hilar anatomy (arrangement and number) of lungs. Methodology: 75 adult formalin fixed cadaveric lungs from the department of Anatomy AIIMS New Delhi were observed for variations in the lobar anatomy. Arrangement of pulmonary hilar structures was meticulously observed, and any deviation in the pattern of presentation was recorded. Results: Among the 75 adult lung specimens observed 36 specimens were of right lung and the rest of left lung. Seven right lung specimens showed only 2 lobes with an oblique fissure dividing them and one left lung showed 3 lobes. The normal pattern of arrangement of hilar structures was seen in 22 right lungs and 23 left lungs. Rest of the lung specimens (14 right and 16 left) showed a varied pattern of arrangement of hilar structures. Some of them showed alterations in the sequence of arrangement of pulmonary artery, pulmonary veins, bronchus, and others in the number of these structures. Conclusion: Alterations in the pattern of arrangement of structures in the lung hilum are quite frequent. A compromise in knowledge of such variations will result in inadvertent complications like intraoperative bleeding during surgical procedures.

Keywords: fissures, hilum, lobes, pulmonary

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