Application of oligonucleotide array CGH to the simultaneous detection of a deletion in the nuclear TK2 gene and mtDNA depletion.

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Zhang, Shulin; Li, Fang-Yuan; Bass, Harold N; Pursley, Amber; Schmitt, Eric S; Brown, Blaire L; Brundage, Ellen K; Mardach, Rebecca; Wong, Lee-Jun

2010-01-01

Thymidine kinase 2 (TK2), encoded by the TK2 gene on chromosome 16q22, is one of the deoxyribonucleoside kinases responsible for the maintenance of mitochondrial deoxyribonucleotide pools. Defects in TK2 mainly cause a myopathic form of the mitochondrial DNA depletion syndrome (MDDS). Currently, only point mutations and small insertions and deletions have been reported in TK2 gene; gross rearrangements of TK2 gene and possible hepatic involvement in patients with TK2 mutations have not been described. We report a non-consanguineous Jordanian family with three deceased siblings due to mtDNA depletion. Sequence analysis of the father detected a heterozygous c.761T>A (p.I254N) mutation in his TK2 gene; however, point mutations in the mother were not detected. Subsequent gene dosage analysis using oligonucleotide array CGH identified an intragenic approximately 5.8-kb deletion encompassing the 5'UTR to intron 2 of her TK2 gene. Sequence analysis confirmed that the deletion spans c.1-495 to c.283-2899 of the TK2 gene (nucleotide 65,136,256-65,142,086 of chromosome 16). Analysis of liver and muscle specimens from one of the deceased infants in this family revealed compound heterozygosity for the paternal point mutation and maternal intragenic deletion. In addition, a significant reduction of the mtDNA content in liver and muscle was detected (10% and 20% of age- and tissue-matched controls, respectively). Prenatal diagnosis was performed in the third pregnancy. The fetus was found to carry both the point mutation and the deletion. This child died 6months after birth due to myopathy. A serum specimen demonstrated elevated liver transaminases in two of the infants from whom results were available. This report expands the mutation spectrum associated with TK2 deficiency. While the myopathic form of MDDS appears to be the main phenotype of TK2 mutations, liver dysfunction may also be a part of the mitochondrial depletion syndrome caused by TK2 gene defects.

Novel and differential accumulation of mitochondrial DNA deletions in Swedish and vietnamese patients with colorectal cancer.

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Dimberg, Jan; Hong, Thai Trinh; Skarstedt, Marita; Löfgren, Sture; Zar, Niklas; Matussek, Andreas

2014-01-01

Mitochondrial DNA (mtDNA) has been proposed to be involved in carcinogenesis and aging. The mtDNA 4977 bp deletion is one of the most frequently observed mtDNA mutations in human tissues and may play a role in colorectal cancer (CRC). In the present study, we aimed to evaluate the frequency of mtDNA 4977 bp deletion in CRC tissues and its association with clinical factors. We determined the presence of the 4977 bp common deletion in cancer and normal paired tissue samples from 105 Swedish and 88 Vietnamese patients with CRC using polymerase chain reaction (PCR) assays. The mtDNA 4977 bp deletion was shown to be significantly more frequent in normal tissues in comparison with paired cancer tissues in both Swedish and Vietnamese patients. The 4977 bp common deletion was significantly more frequent in cancer tissues of the Vietnamese patients compared to the Swedish patients, and in Vietnamese cancer tissues, the 4977 bp deletion was significantly over represented in those with localized disease compared to those with disseminated disease. Moreover, we detected nine novel mtDNA deletions and found a significantly higher rate of these in CRC tissues in Swedish in comparison to Vietnamese patients. The mtDNA 4977 bp deletion seems to have an impact on the clinical outcome of CRC in Vietnamese patients, that the Swedish patients accumulate more of the detected novel deletions in CRC tissue compared to Vietnamese patients probably indicates divergent mechanisms in colorectal carcinogenesis.

The mitochondrial DNA 4,977-bp deletion and its implication in copy number alteration in colorectal cancer

Science.gov (United States)

2011-01-01

Background Qualitative and quantitative changes in human mitochondrial DNA (mtDNA) have been implicated in various cancer types. A 4,977 bp deletion in the major arch of the mitochondrial genome is one of the most common mutations associated with a variety of human diseases and aging. Methods We conducted a comprehensive study on clinical features and mtDNA of 104 colorectal cancer patients in the Wenzhou area of China. In particular, using a quantitative real time PCR method, we analyzed the 4,977 bp deletion and mtDNA content in tumor tissues and paired non-tumor areas from these patients. Results We found that the 4,977 bp deletion was more likely to be present in patients of younger age (≤65 years, p = 0.027). In patients with the 4,977 bp deletion, the deletion level decreased as the cancer stage advanced (p = 0.031). Moreover, mtDNA copy number in tumor tissues of patients with this deletion increased, both compared with that in adjacent non-tumor tissues and with in tumors of patients without the deletion. Such mtDNA content increase correlated with the levels of the 4,977 bp deletion and with cancer stage (p deletion may play a role in the early stage of colorectal cancer, and it is also implicated in alteration of mtDNA content in cancer cells. PMID:21232124

Human mitochondrial DNA (mtDNA) types in Malaysia

International Nuclear Information System (INIS)

Lian, L.H.; Koh, C.L.; Lim, M.E.

2000-01-01

Each human cell contains hundreds of mitochondria and thousands of double-stranded circular mtDNA. The delineation of human mtDNA variation and genetics over the past decade has provided unique and often startling insights into human evolution, degenerative diseases, and aging. Each mtDNA of 16,569 base pairs, encodes 13 polypeptides essential to the enzymes of the mitochondrial energy generating pathway, plus the necessary tRNAs and rRNAs. The highly polymorphic noncoding D-(displacement) loop region, also called the control region, is approximately 1.2 kb long. It contains two well-characterized hypervariable (HV-) regions, HV1 and HV2. MtDNA identification is usually based on these sequence differences. According to the TWTGDAM (Technical Working Group for DNA Analysis Methods), the minimum requirement for a mtDNA database for HV1 is from positions 16024 to 16365 and for HV2, from positions 00073 to 00340. The targeted Malaysian population subgroups for this study were mainly the Malays, Chinese, Indians, and indigenous Ibans, Bidayuhs, Kadazan-Dusuns, and Bajaus. Research methodologies undertaken included DNA extraction of samples from unrelated individuals, amplification of the specific regions via the polymerase chain reaction (PCR), and preparation of template DNA for sequencing by using an automated DNA sequencer. Sufficient nucleotide sequence data were generated from the mtDNA analysis. When the sequences were analyzed, sequence variations were found to be caused by nucleotide substitutions, insertions, and deletions. Of the three causes of the sequence variations, nucleotide substitutions (86.1%) accounted for the vast majority of polymorphism. It is noted that transitions (83.5%) were predominant when compared to the significantly lower frequencies of transversions (2.6%). Insertions (0.9%) and deletions (13.0%) were rather rare and found only in HV2. The data generated will also form the basis of a Malaysian DNA sequence database of mtDNA D

Prediction of radiosensitivity of human tumor cell lines in vitro by determining 4977bp deletion in mitochondrial DNA

International Nuclear Information System (INIS)

Rong Qinglin; Cao Yongzhen; Zhang Yaowen; Zhao Xinran; Wang Qin; Li Jin; Liu Qiang

2008-01-01

Objective: To evaluate the possibility of predicting the radiosensitivity of tumor cell lines using the assay of the mtDNA4977bp deletion. Methods: The mtDNA4977bp deletion of HepG 2 cells and PC-3 cells were detected by nested PCR after irradiated by various doses of x-ray. Results: The radiation-induced mtDNA4977bp deletion of the tumor cell lines of HepG 2 and PC-3 were detected after irradiated. There was a dose dependent in the mtDNA4977bp deletion of two tumor cell lines. The deletion rate of HepG 2 was higher significantly than that of PC-3 at each point of radiation dose (P 2 was higher than that of PC-3. Conclusion: The assay of the mtDNA4977bp deletion may be an approach to predict the radiosensitivity of tumor cells. (authors)

Mitochondrial common deletion is elevated in blood of breast cancer patients mediated by oxidative stress.

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Nie, Hezhongrong; Chen, Guorong; He, Jing; Zhang, Fengjiao; Li, Ming; Wang, Qiufeng; Zhou, Huaibin; Lyu, Jianxin; Bai, Yidong

2016-01-01

The 4977 bp common deletion is one of the most frequently observed mitochondrial DNA (mtDNA) mutations in human tissues and has been implicated in various human cancer types. It is generally believed that continuous generation of intracellular reactive oxygen species (ROS) during oxidative phosphorylation (OXPHOS) is a major underlying mechanism for generation of such mtDNA deletions while antioxidant systems, including Manganese superoxide dismutase (MnSOD), mitigating the deleterious effects of ROS. However, the clinical significance of this common deletion remains to be explored. A comprehensive investigation on occurrence and accumulation of the common deletion and mtDNA copy number was carried out in breast carcinoma (BC) patients, benign breast disease (BBD) patients and age-matched healthy donors in our study. Meanwhile, the representative oxidative (ROS production, mtDNA and lipid oxidative damage) and anti-oxidative features (MnSOD expression level and variation) in blood samples from these groups were also analyzed. We found that the mtDNA common deletion is much more likely to be detected in BC patients at relatively high levels while the mtDNA content is lower. This alteration has been associated with a higher MnSOD level and higher oxidative damages in both BC and BBD patients. Our results indicate that the mtDNA common deletion in blood may serve a biomarker for the breast cancer. Copyright © 2015 Elsevier B.V. and Mitochondria Research Society. All rights reserved.

Accurate measurement of mitochondrial DNA deletion level and copy number differences in human skeletal muscle.

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John P Grady

Full Text Available Accurate and reliable quantification of the abundance of mitochondrial DNA (mtDNA molecules, both wild-type and those harbouring pathogenic mutations, is important not only for understanding the progression of mtDNA disease but also for evaluating novel therapeutic approaches. A clear understanding of the sensitivity of mtDNA measurement assays under different experimental conditions is therefore critical, however it is routinely lacking for most published mtDNA quantification assays. Here, we comprehensively assess the variability of two quantitative Taqman real-time PCR assays, a widely-applied MT-ND1/MT-ND4 multiplex mtDNA deletion assay and a recently developed MT-ND1/B2M singleplex mtDNA copy number assay, across a range of DNA concentrations and mtDNA deletion/copy number levels. Uniquely, we provide a specific guide detailing necessary numbers of sample and real-time PCR plate replicates for accurately and consistently determining a given difference in mtDNA deletion levels and copy number in homogenate skeletal muscle DNA.

Heterozygous SSBP1 start loss mutation co-segregates with hearing loss and the m.1555A>G mtDNA variant in a large multigenerational family.

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Kullar, Peter J; Gomez-Duran, Aurora; Gammage, Payam A; Garone, Caterina; Minczuk, Michal; Golder, Zoe; Wilson, Janet; Montoya, Julio; Häkli, Sanna; Kärppä, Mikko; Horvath, Rita; Majamaa, Kari; Chinnery, Patrick F

2018-01-01

The m.1555A>G mtDNA variant causes maternally inherited deafness, but the reasons for the highly variable clinical penetrance are not known. Exome sequencing identified a heterozygous start loss mutation in SSBP1, encoding the single stranded binding protein 1 (SSBP1), segregating with hearing loss in a multi-generational family transmitting m.1555A>G, associated with mtDNA depletion and multiple deletions in skeletal muscle. The SSBP1 mutation reduced steady state SSBP1 levels leading to a perturbation of mtDNA metabolism, likely compounding the intra-mitochondrial translation defect due to m.1555A>G in a tissue-specific manner. This family demonstrates the importance of rare trans-acting genetic nuclear modifiers in the clinical expression of mtDNA disease. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.

Somatic mtDNA mutation spectra in the aging human putamen.

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Siôn L Williams

Full Text Available The accumulation of heteroplasmic mitochondrial DNA (mtDNA deletions and single nucleotide variants (SNVs is a well-accepted facet of the biology of aging, yet comprehensive mutation spectra have not been described. To address this, we have used next generation sequencing of mtDNA-enriched libraries (Mito-Seq to investigate mtDNA mutation spectra of putamen from young and aged donors. Frequencies of the "common" deletion and other "major arc" deletions were significantly increased in the aged cohort with the fold increase in the frequency of the common deletion exceeding that of major arc deletions. SNVs also increased with age with the highest rate of accumulation in the non-coding control region which contains elements necessary for translation and replication. Examination of predicted amino acid changes revealed a skew towards pathogenic SNVs in the coding region driven by mutation bias. Levels of the pathogenic m.3243A>G tRNA mutation were also found to increase with age. Novel multimeric tandem duplications that resemble murine control region multimers and yeast ρ(- mtDNAs, were identified in both young and aged specimens. Clonal ∼50 bp deletions in the control region were found at high frequencies in aged specimens. Our results reveal the complex manner in which the mitochondrial genome alters with age and provides a foundation for studies of other tissues and disease states.

Detection of large scale 3' deletions in the PMS2 gene amongst Colon-CFR participants: have we been missing anything?

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Clendenning, Mark; Walsh, Michael D; Gelpi, Judith Balmana; Thibodeau, Stephen N; Lindor, Noralane; Potter, John D; Newcomb, Polly; LeMarchand, Loic; Haile, Robert; Gallinger, Steve; Hopper, John L; Jenkins, Mark A; Rosty, Christophe; Young, Joanne P; Buchanan, Daniel D

2013-09-01

Current screening practices have been able to identify PMS2 mutations in 78 % of cases of colorectal cancer from the Colorectal Cancer Family Registry (Colon CFR) which showed solitary loss of the PMS2 protein. However the detection of large-scale deletions in the 3' end of the PMS2 gene has not been possible due to technical difficulties associated with pseudogene sequences. Here, we utilised a recently described MLPA/long-range PCR-based approach to screen the remaining 22 % (n = 16) of CRC-affected probands for mutations in the 3' end of the PMS2 gene. No deletions encompassing any or all of exons 12 through 15 were identified; therefore, our results suggest that 3' deletions in PMS2 are not a frequent occurrence in such families.

The detection of large deletions or duplications in genomic DNA.

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Armour, J A L; Barton, D E; Cockburn, D J; Taylor, G R

2002-11-01

While methods for the detection of point mutations and small insertions or deletions in genomic DNA are well established, the detection of larger (>100 bp) genomic duplications or deletions can be more difficult. Most mutation scanning methods use PCR as a first step, but the subsequent analyses are usually qualitative rather than quantitative. Gene dosage methods based on PCR need to be quantitative (i.e., they should report molar quantities of starting material) or semi-quantitative (i.e., they should report gene dosage relative to an internal standard). Without some sort of quantitation, heterozygous deletions and duplications may be overlooked and therefore be under-ascertained. Gene dosage methods provide the additional benefit of reporting allele drop-out in the PCR. This could impact on SNP surveys, where large-scale genotyping may miss null alleles. Here we review recent developments in techniques for the detection of this type of mutation and compare their relative strengths and weaknesses. We emphasize that comprehensive mutation analysis should include scanning for large insertions and deletions and duplications. Copyright 2002 Wiley-Liss, Inc.

Analysis of mtDNT 4977bp deletion induced by ionizing radiation in human peripheral blood nucleated cells using real-time PCR

International Nuclear Information System (INIS)

Fan Tianli; Wang Ping; Han Lin; Liu Yulong; Liu Yumin

2010-01-01

To detect mitochondrial DNA(mtDNA) 4977bp deletion(triangle open mtDNA 4977 ) in human peripheral blood nucleated cells exposed to ionizing radiation in vitro by using real-time PCR, and explore possibility of the index as biodosimetry for estimating biological dose in radiation accident,six healthy individuals' peripheral blood was collected,and the blood samples were irradiated with 0,1,2,3,4 and 5 Gy 60 Co gamma-ray. The triangle open mtDNA 4977 and total mtDNA copy number(mtDNA total ) in the mtDNA samples were detected, and then the deletion rates were calculated. The results showed that the mtDNA total and triangle open mtDNA 4977 copy number, and the deletion rates of mtDNA 4977bp in the mtDNA samples from 6 healthy individuals' blood exposed to 1-5 Gy radiation were higher than that with the samples exposed to 0 Gy radiation(p 0.05). The results indicated that ionizing radiation can induce accumulation of the triangle open mtDNA 4977 and increase of mtDNA total copy number in human peripheral blood nucleated cells,but both the mtDNA 4977bp deletion and exposure dose(0-5 Gy) were not obviously correlated. (authors)

Mitochondrial DNA deletion and impairment of mitochondrial biogenesis are mediated by reactive oxygen species in ionizing radiation-induced premature senescence

Energy Technology Data Exchange (ETDEWEB)

Eom, Hyeon Soo; Jung, U Hee; Jo, Sung Kee [Radiation Biotechnology Research Division, Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of); Kim, Young Sang [College of Natural Sciences, Chungnam National University, Daejeon (Korea, Republic of)

2011-09-15

Mitochondrial DNA (mtDNA) deletion is a well-known marker for oxidative stress and aging, and contributes to harmful effects in cultured cells and animal tissues. mtDNA biogenesis genes (NRF-1, TFAM) are essential for the maintenance of mtDNA, as well as the transcription and replication of mitochondrial genomes. Considering that oxidative stress is known to affect mitochondrial biogenesis, we hypothesized that ionizing radiation (IR)-induced reactive oxygen species (ROS) causes mtDNA deletion by modulating the mitochondrial biogenesis, thereby leading to cellular senescence. Therefore, we examined the effects of IR on ROS levels, cellular senescence, mitochondrial biogenesis, and mtDNA deletion in IMR-90 human lung fibroblast cells. Young IMR-90 cells at population doubling (PD) 39 were irradiated at 4 or 8 Gy. Old cells at PD55, and H2O2-treated young cells at PD 39, were compared as a positive control. The IR increased the intracellular ROS level, senescence-associated {beta}-galactosidase (SA-{beta}-gal) activity, and mtDNA common deletion (4977 bp), and it decreased the mRNA expression of NRF-1 and TFAM in IMR-90 cells. Similar results were also observed in old cells (PD 55) and H{sub 2}O{sub 2}-treated young cells. To confirm that a increase in ROS level is essential for mtDNA deletion and changes of mitochondrial biogenesis in irradiated cells, the effects of N-acetylcysteine (NAC) were examined. In irradiated and H{sub 2}O{sub 2}-treated cells, 5 mM NAC significantly attenuated the increases of ROS, mtDNA deletion, and SA-{beta}-gal activity, and recovered from decreased expressions of NRF-1 and TFAM mRNA. These results suggest that ROS is a key cause of IR-induced mtDNA deletion, and the suppression of the mitochondrial biogenesis gene may mediate this process.

Mitochondrial DNA deletion and impairment of mitochondrial biogenesis are mediated by reactive oxygen species in ionizing radiation-induced premature senescence

International Nuclear Information System (INIS)

Eom, Hyeon Soo; Jung, U Hee; Jo, Sung Kee; Kim, Young Sang

2011-01-01

Mitochondrial DNA (mtDNA) deletion is a well-known marker for oxidative stress and aging, and contributes to harmful effects in cultured cells and animal tissues. mtDNA biogenesis genes (NRF-1, TFAM) are essential for the maintenance of mtDNA, as well as the transcription and replication of mitochondrial genomes. Considering that oxidative stress is known to affect mitochondrial biogenesis, we hypothesized that ionizing radiation (IR)-induced reactive oxygen species (ROS) causes mtDNA deletion by modulating the mitochondrial biogenesis, thereby leading to cellular senescence. Therefore, we examined the effects of IR on ROS levels, cellular senescence, mitochondrial biogenesis, and mtDNA deletion in IMR-90 human lung fibroblast cells. Young IMR-90 cells at population doubling (PD) 39 were irradiated at 4 or 8 Gy. Old cells at PD55, and H2O2-treated young cells at PD 39, were compared as a positive control. The IR increased the intracellular ROS level, senescence-associated β-galactosidase (SA-β-gal) activity, and mtDNA common deletion (4977 bp), and it decreased the mRNA expression of NRF-1 and TFAM in IMR-90 cells. Similar results were also observed in old cells (PD 55) and H 2 O 2 -treated young cells. To confirm that a increase in ROS level is essential for mtDNA deletion and changes of mitochondrial biogenesis in irradiated cells, the effects of N-acetylcysteine (NAC) were examined. In irradiated and H 2 O 2 -treated cells, 5 mM NAC significantly attenuated the increases of ROS, mtDNA deletion, and SA-β-gal activity, and recovered from decreased expressions of NRF-1 and TFAM mRNA. These results suggest that ROS is a key cause of IR-induced mtDNA deletion, and the suppression of the mitochondrial biogenesis gene may mediate this process.

Construction and confirmation of the plasmid of human mitochondrial DNA 4977 bp deletion induced by ionizing radiation

International Nuclear Information System (INIS)

Chen Xiaosui; Zhou Lijun; Wang Yuxiao; Qu Jia; Feng Jiangbing; Lu Xue; Chen Deqing; Liu Qingjie

2006-01-01

Objective: To construct a stable plasmid that spanning deleted human mitochondrial DNA (mtDNA) 4977 bp induced by ionizing radiation and another one for control DNA fragment, in order to use in the human mitochondrial genome study in the future. Methods: The peripheral blood, which had no mtDNA 4977 bp deletion found in previous study, was exposed to 10 Gy 60 Co γ-rays in vitro. The total cell DNA was extracted and PCR was carried out: a nest-PCR of three-round PCR was used for the mtDNA 4977 bp deletion and one- round regular PCR was used for the control ND1 gene. The PCR products were used for transfection by electroporation and the positive clones were obtained after screening. The plasmid DNA was isolated and sequenced after enzymatic digestion and purification. The sequence result was BLASTed with the human mitochondrial genome. Results: The sizes of PCR products for the flanked 4977 bp deletion and the ND1 gene were similar with those predicted according to GeneBank. The sequences for the positive clones were above 99 per cent homologous with the human mitochondrial genome after BLASTed. Conclusion: The plasmids for deleted human mtDNA 4977 bp and control DNA fragment have been constructed successfully, and they could be used in the quality and quantity studies on human mtDNA 4977 bp deletion. (authors)

Oocyte mitochondrial deletions and heteroplasmy in a bovine model of ageing and ovarian stimulation.

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Hammond, Elizabeth R; Green, Mark P; Shelling, Andrew N; Berg, Martin C; Peek, John C; Cree, Lynsey M

2016-04-01

Maternal ageing and ovarian stimulation result in the accumulation of mitochondrial DNA (mtDNA) deletions and heteroplasmy in individual oocytes from a novel bovine model for human assisted reproductive technology (ART). The levels of mtDNA deletions detected in oocytes increased with ovarian ageing. Low levels of mtDNA heteroplasmy were apparent across oocytes and no relationship was identified with respect to ovarian ageing or ovarian stimulation. Oocyte quality decreases with ovarian ageing and it is postulated that the mtDNA may have a role in this decline. The impact of ovarian stimulation on oocyte quality is poorly understood. Human studies investigating these effects are often limited by the use of low quality oocytes and embryos, variation in age and ovarian stimulation regimens within the patients studied, as well as genetic and environmental variability. Further, no study has investigated mtDNA heteroplasmy in individual oocytes using next-generation sequencing (NGS), and little is known about whether the oocyte accumulates heteroplasmic mtDNA mutations following ageing or ovarian stimulation. A novel bovine model for the effect of stimulation and age in human ART was undertaken using cows generated by somatic cell nuclear transfer (SCNT) from one founder, to produce a homogeneous population with reduced genetic and environmental variability. Oocytes and somatic tissues were collected from young (3 years of age; n = 4 females) and old (10 years of age; n = 5 females) cow clones following multiple natural ovarian cycles, as well as oocytes following multiple mild (FSH only) and standard (based on human a long GnRH agonist protocol) ovarian stimulation cycles. In addition, oocytes were recovered in a natural cycle from naturally conceived cows aged 4-13.5 years (n = 10) to provide a heterogeneous cohort for mtDNA deletion studies. The presence or absence of mtDNA deletions were investigated using long-range PCR in individual oocytes (n = 62). To determine

Radiosensitivity evaluation of Human tumor cell lines by detecting 4977bp deletion in mitochondrial DNA

International Nuclear Information System (INIS)

Zhang Yipei

2009-01-01

Objective: To explore the feasibility of determining radiosensitivity of human tumor cell lines in vitro using the assay of mtDNA4977bp deletion. Methods: Three human tumor cell lines were selected in this study, HepG 2 , EC-9706 and MCF-7. The surviving fraction(SF), the ratio of mtDNA4977bp deletion and DNA damage were detected by MTT assay and nested PCR technique respectively. Results: MTT assay: The SF of HepG 2 and EC-9706 after irradiated by 2, 4and 8Gy was lower significantly than that of MCF-7, which showed that the radiosensitivity of HepG 2 and EC-9706 was higher than that of MCF-7. But there was no statistical difference of SF between HepG 2 and EC-9706. PCR method:The differences on mtDNA 4977bp deletion in mitochondrial DNA among HepG 2 , EC-9706 and MCF-7 were not significant after 1Gy and 4Gy γ-ray irradiation. The ratio of 4977bp deletion in mitochondrial DNA of HepG 2 and EC-9706 increased while that of MCF-7 decreased after 8Gy irradiation. The ratio of mtDNA 4977bp deletion of HepG 2 and EC-9706 was higher significantly than that of MCF-7, which implies that the radiosensitivity of HepG 2 and EC-9706 was higher than that of MCF -7. Conclusion: As a new biological marker, mtDNA4977bp deletion may be hopeful to evaluate the radiosensitivity of tumor cells more objectively and exactly. (authors)

Detection of large scale 3′ deletions in the PMS2 gene amongst Colon-CFR participants – have we been missing anything?

Science.gov (United States)

Clendenning, Mark; Walsh, Michael D; Gelpi, Judith Balmana; Thibodeau, Stephen N.; Lindor, Noralane; Potter, John D.; Newcomb, Polly; LeMarchand, Loic; Haile, Robert; Gallinger, Steve; Hopper, John L.; Jenkins, Mark A.; Rosty, Christophe; Young, Joanne P.; Buchanan, Daniel D.

2013-01-01

Current screening practices have been able to identify PMS2 mutations in 78% of cases of colorectal cancer from the Colorectal Cancer Family Registry (Colon CFR) which showed solitary loss of the PMS2 protein. However the detection of large-scale deletions in the 3′ end of the PMS2 gene has not been possible due to technical difficulties associated with pseudogene sequences. Here, we utilised a recently described MLPA/long-range PCR-based approach to screen the remaining 22% (n = 16) of CRC-affected probands for mutations in the 3′ end of the PMS2 gene. No deletions encompassing any or all of exons 12 through 15 were identified; therefore, our results suggest that 3′ deletions in PMS2 are not a frequent occurrence in such families. PMID:23288611

A Novel 3670-Base Pair Mitochondrial DNA Deletion Resulting in Multi-systemic Manifestations in a Child

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Hsin-Ming Liu

2012-08-01

Full Text Available Mitochondrial DNA (mtDNA deletion is a rare occurrence that results in defects to oxidative phosphorylation. The common clinical presentations of mtDNA deletion vary but include mitochondrial myopathy, Pearson syndrome, Kearns-Sayre syndrome, and progressive external ophthalmoplegia. Here, we report the case of a 10-year-old boy who presented with progressive deterioration of his clinical status (which included hypoglycemia, short stature, sensorineural hearing loss, retinitis pigmentosa, and chronic gastrointestinal dysmotility that progressed to acute deterioration with pancreatitis, Fanconi syndrome, lactic acidosis, and acute encephalopathy. Following treatment, the patient was stabilized and his neurological condition improved. Through a combination of histological examinations and biochemical and molecular analyses, mitochondrial disease was confirmed. A novel 3670-base pair deletion (deletion of mtDNA nt 7,628-11,297 was identified in the muscle tissue. A direct repeat of CTACT at the breakpoints was also detected.

Accumulation of Mitochondrial DNA Common Deletion Since The Preataxic Stage of Machado-Joseph Disease.

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Raposo, Mafalda; Ramos, Amanda; Santos, Cristina; Kazachkova, Nadiya; Teixeira, Balbina; Bettencourt, Conceição; Lima, Manuela

2018-04-21

Molecular alterations reflecting pathophysiologic changes thought to occur many years before the clinical onset of Machado-Joseph disease (MJD)/spinocerebellar ataxia type 3 (SCA3), a late-onset polyglutamine disorder, remain unidentified. The absence of molecular biomarkers hampers clinical trials, which lack sensitive measures of disease progression, preventing the identification of events occurring prior to clinical onset. Our aim was to analyse the mtDNA content and the amount of the common deletion (m.8482_13460del4977) in a cohort of 16 preataxic MJD mutation carriers, 85 MJD patients and 101 apparently healthy age-matched controls. Relative expression levels of RPPH1, MT-ND1 and MT-ND4 genes were assessed by quantitative real-time PCR. The mtDNA content was calculated as the difference between the expression levels of a mitochondrial gene (MT-ND1) and a nuclear gene (RPPH1); the amount of mtDNA common deletion was calculated as the difference between expression levels of a deleted (MT-ND4) and an undeleted (MT-ND1) mitochondrial genes. mtDNA content in MJD carriers was similar to that of healthy age-matched controls, whereas the percentage of the common deletion was significantly increased in MJD subjects, and more pronounced in the preclinical stage (p < 0.05). The BCL2/BAX ratio was decreased in preataxic carriers compared to controls, suggesting that the mitochondrial-mediated apoptotic pathway is altered in MJD. Our findings demonstrate for the first time that accumulation of common deletion starts in the preclinical stage. Such early alterations provide support to the current understanding that any therapeutic intervention in MJD should start before the overt clinical phenotype.

MMS exposure promotes increased MtDNA mutagenesis in the presence of replication-defective disease-associated DNA polymerase γ variants.

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Stumpf, Jeffrey D; Copeland, William C

2014-10-01

Mitochondrial DNA (mtDNA) encodes proteins essential for ATP production. Mutant variants of the mtDNA polymerase cause mutagenesis that contributes to aging, genetic diseases, and sensitivity to environmental agents. We interrogated mtDNA replication in Saccharomyces cerevisiae strains with disease-associated mutations affecting conserved regions of the mtDNA polymerase, Mip1, in the presence of the wild type Mip1. Mutant frequency arising from mtDNA base substitutions that confer erythromycin resistance and deletions between 21-nucleotide direct repeats was determined. Previously, increased mutagenesis was observed in strains encoding mutant variants that were insufficient to maintain mtDNA and that were not expected to reduce polymerase fidelity or exonuclease proofreading. Increased mutagenesis could be explained by mutant variants stalling the replication fork, thereby predisposing the template DNA to irreparable damage that is bypassed with poor fidelity. This hypothesis suggests that the exogenous base-alkylating agent, methyl methanesulfonate (MMS), would further increase mtDNA mutagenesis. Mitochondrial mutagenesis associated with MMS exposure was increased up to 30-fold in mip1 mutants containing disease-associated alterations that affect polymerase activity. Disrupting exonuclease activity of mutant variants was not associated with increased spontaneous mutagenesis compared with exonuclease-proficient alleles, suggesting that most or all of the mtDNA was replicated by wild type Mip1. A novel subset of C to G transversions was responsible for about half of the mutants arising after MMS exposure implicating error-prone bypass of methylated cytosines as the predominant mutational mechanism. Exposure to MMS does not disrupt exonuclease activity that suppresses deletions between 21-nucleotide direct repeats, suggesting the MMS-induce mutagenesis is not explained by inactivated exonuclease activity. Further, trace amounts of CdCl2 inhibit mtDNA replication but

Parkinson's disease brain mitochondria have impaired respirasome assembly, age-related increases in distribution of oxidative damage to mtDNA and no differences in heteroplasmic mtDNA mutation abundance

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Keeney Paula M

2009-09-01

-related increases in distribution of oxidative mtDNA damage in sPD but not CTL brains is not clear, tracks with but does not determine the sPD phenotype, and may indicate a unique consequence of aging present in sPD that could contribute to mtDNA deletion generation in addition to mtDNA replication, transcription and sequencing errors. sPD frontal cortex experiences a generalized bioenergetic deficiency above and beyond aging that could contribute to mood disorders and cognitive impairments.

Identification of a Basic Helix-Loop-Helix-Type Transcription Regulator Gene in Aspergillus oryzae by Systematically Deleting Large Chromosomal Segments▿ †

OpenAIRE

Jin, Feng Jie; Takahashi, Tadashi; Machida, Masayuki; Koyama, Yasuji

2009-01-01

We previously developed two methods (loop-out and replacement-type recombination) for generating large-scale chromosomal deletions that can be applied to more effective chromosomal engineering in Aspergillus oryzae. In this study, the replacement-type method is used to systematically delete large chromosomal DNA segments to identify essential and nonessential regions in chromosome 7 (2.93 Mb), which is the smallest A. oryzae chromosome and contains a large number of nonsyntenic blocks. We con...

Ancient mtDNA genetic variants modulate mtDNA transcription and replication.

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Sarit Suissa

2009-05-01

Full Text Available Although the functional consequences of mitochondrial DNA (mtDNA genetic backgrounds (haplotypes, haplogroups have been demonstrated by both disease association studies and cell culture experiments, it is not clear which of the mutations within the haplogroup carry functional implications and which are "evolutionary silent hitchhikers". We set forth to study the functionality of haplogroup-defining mutations within the mtDNA transcription/replication regulatory region by in vitro transcription, hypothesizing that haplogroup-defining mutations occurring within regulatory motifs of mtDNA could affect these processes. We thus screened >2500 complete human mtDNAs representing all major populations worldwide for natural variation in experimentally established protein binding sites and regulatory regions comprising a total of 241 bp in each mtDNA. Our screen revealed 77/241 sites showing point mutations that could be divided into non-fixed (57/77, 74% and haplogroup/sub-haplogroup-defining changes (i.e., population fixed changes, 20/77, 26%. The variant defining Caucasian haplogroup J (C295T increased the binding of TFAM (Electro Mobility Shift Assay and the capacity of in vitro L-strand transcription, especially of a shorter transcript that maps immediately upstream of conserved sequence block 1 (CSB1, a region associated with RNA priming of mtDNA replication. Consistent with this finding, cybrids (i.e., cells sharing the same nuclear genetic background but differing in their mtDNA backgrounds harboring haplogroup J mtDNA had a >2 fold increase in mtDNA copy number, as compared to cybrids containing haplogroup H, with no apparent differences in steady state levels of mtDNA-encoded transcripts. Hence, a haplogroup J regulatory region mutation affects mtDNA replication or stability, which may partially account for the phenotypic impact of this haplogroup. Our analysis thus demonstrates, for the first time, the functional impact of particular mtDNA

Mechanism of Homologous Recombination and Implications for Aging-Related Deletions in Mitochondrial DNA

Science.gov (United States)

2013-01-01

SUMMARY Homologous recombination is a universal process, conserved from bacteriophage to human, which is important for the repair of double-strand DNA breaks. Recombination in mitochondrial DNA (mtDNA) was documented more than 4 decades ago, but the underlying molecular mechanism has remained elusive. Recent studies have revealed the presence of a Rad52-type recombination system of bacteriophage origin in mitochondria, which operates by a single-strand annealing mechanism independent of the canonical RecA/Rad51-type recombinases. Increasing evidence supports the notion that, like in bacteriophages, mtDNA inheritance is a coordinated interplay between recombination, repair, and replication. These findings could have profound implications for understanding the mechanism of mtDNA inheritance and the generation of mtDNA deletions in aging cells. PMID:24006472

Radiosensitivity evaluation of human tumor cell lines by detecting 4977 bp deletion in mitochondrial DNA and comet assay

International Nuclear Information System (INIS)

Chu Liping; Liu Qiang; Wang Qin; Li Jin; Yue Jingyin; Mu Chuanjie; Fan Feiyue

2008-01-01

Objective: To explore the feasibility of determining radiosensitivity of human tumor cell lines in vitro using the assay of mtDNA 4977 bp deletion and comet assay. Methods: Three human tumor cell lines were selected in this study, HepG 2 , EC-9706 and MCF-7. The surviving fraction(SF), the ratio of mtDNA 4977 bp deletion and DNA damage were detected by MTY assay, nested PCR technique and comet assay, respectively. Results: The results of MTT assay showed that the radiosensitivity of HepG 2 and EC-9706 was higher than that of MCF-7. The ratio of mtDNA 4977 bp deletion of HepG 2 and EC-9706 was higher significantly than that of MCF-7 (P 2 and EC-9706 was higher than that of MCF-7. The difference of radiosensitivity among these three tumor cell lines was significant after 8 Gy γ-ray irradiation. Conclusions: Combination of many biological parameter is helpful to evaluate the radiosensitivity of tumor cells more accurately. (authors)

Identification of a basic helix-loop-helix-type transcription regulator gene in Aspergillus oryzae by systematically deleting large chromosomal segments.

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Jin, Feng Jie; Takahashi, Tadashi; Machida, Masayuki; Koyama, Yasuji

2009-09-01

We previously developed two methods (loop-out and replacement-type recombination) for generating large-scale chromosomal deletions that can be applied to more effective chromosomal engineering in Aspergillus oryzae. In this study, the replacement-type method is used to systematically delete large chromosomal DNA segments to identify essential and nonessential regions in chromosome 7 (2.93 Mb), which is the smallest A. oryzae chromosome and contains a large number of nonsyntenic blocks. We constructed 12 mutants harboring deletions that spanned 16- to 150-kb segments of chromosome 7 and scored phenotypic changes in the resulting mutants. Among the deletion mutants, strains designated Delta5 and Delta7 displayed clear phenotypic changes involving growth and conidiation. In particular, the Delta5 mutant exhibited vigorous growth and conidiation, potentially beneficial characteristics for certain industrial applications. Further deletion analysis allowed identification of the AO090011000215 gene as the gene responsible for the Delta5 mutant phenotype. The AO090011000215 gene was predicted to encode a helix-loop-helix binding protein belonging to the bHLH family of transcription factors. These results illustrate the potential of the approach for identifying novel functional genes.

Delayed chromosomal instability caused by large deletion

International Nuclear Information System (INIS)

Ojima, M.; Suzuki, K.; Kodama, S.; Watanabe, M.

2003-01-01

Full text: There is accumulating evidence that genomic instability, manifested by the expression of delayed phenotypes, is induced by X-irradiation but not by ultraviolet (UV) light. It is well known that ionizing radiation, such as X-rays, induces DNA double strand breaks, but UV-light mainly causes base damage like pyrimidine dimers and (6-4) photoproducts. Although the mechanism of radiation-induced genomic instability has not been thoroughly explained, it is suggested that DNA double strand breaks contribute the induction of genomic instability. We examined here whether X-ray induced gene deletion at the hprt locus induces delayed instability in chromosome X. SV40-immortalized normal human fibroblasts, GM638, were irradiated with X-rays (3, 6 Gy), and the hprt mutants were isolated in the presence of 6-thioguanine (6-TG). A 2-fold and a 60-fold increase in mutation frequency were found by 3 Gy and 6 Gy irradiation, respectively. The molecular structure of the hprt mutations was determined by multiplex polymerase chain reaction of nine exons. Approximately 60% of 3 Gy mutants lost a part or the entire hprt gene, and the other mutants showed point mutations like spontaneous mutants. All 6 Gy mutants show total gene deletion. The chromosomes of the hprt mutants were analyzed by Whole Human Chromosome X Paint FISH or Xq telomere FISH. None of the point or partial gene deletion mutants showed aberrations of X-chromosome, however total gene deletion mutants induced translocations and dicentrics involving chromosome X. These results suggest that large deletion caused by DNA double strand breaks destabilizes chromosome structure, which may be involved in an induction of radiation-induced genomic instability

First description of a novel mitochondrial mutation in the MT-TI gene associated with multiple mitochondrial DNA deletion and depletion in family with severe dilated mitochondrial cardiomyopathy.

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Alila-Fersi, Olfa; Tabebi, Mouna; Maalej, Marwa; Belguith, Neila; Keskes, Leila; Mkaouar-Rebai, Emna; Fakhfakh, Faiza

2018-03-18

Mitochondria are essential for early cardiac development and impaired mitochondrial function was described associated with heart diseases such as hypertrophic or dilated mitochondrial cardiomyopathy. In this study, we report a family including two individuals with severe dilated mitochondrial cardiomyopathy. The whole mitochondrial genome screening showed the presence of several variations and a novel homoplasmic mutation m.4318-4322delC in the MT-TI gene shared by the two patients and their mother and leading to a disruption of the tRNA Ile secondary structure. In addition, a mitochondrial depletion was present in blood leucocyte of the two affected brother whereas a de novo heteroplasmic multiple deletion in the major arc of mtDNA was present in blood leucocyte and mucosa of only one of them. These deletions in the major arc of the mtDNA resulted to the loss of several protein-encoding genes and also some tRNA genes. The mtDNA deletion and depletion could result to an impairment of the oxidative phosphorylation and energy metabolism in the respiratory chain in the studied patients. Our report is the first description of a family with severe lethal dilated mitochondrial cardiomyopathy and presenting several mtDNA abnormalities including punctual mutation, deletion and depletion. Copyright © 2018 Elsevier Inc. All rights reserved.

Identification and characterization of large DNA deletions affecting oil quality traits in soybean seeds through transcriptome sequencing analysis.

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Goettel, Wolfgang; Ramirez, Martha; Upchurch, Robert G; An, Yong-Qiang Charles

2016-08-01

Identification and characterization of a 254-kb genomic deletion on a duplicated chromosome segment that resulted in a low level of palmitic acid in soybean seeds using transcriptome sequencing. A large number of soybean genotypes varying in seed oil composition and content have been identified. Understanding the molecular mechanisms underlying these variations is important for breeders to effectively utilize them as a genetic resource. Through design and application of a bioinformatics approach, we identified nine co-regulated gene clusters by comparing seed transcriptomes of nine soybean genotypes varying in oil composition and content. We demonstrated that four gene clusters in the genotypes M23, Jack and N0304-303-3 coincided with large-scale genome rearrangements. The co-regulated gene clusters in M23 and Jack mapped to a previously described 164-kb deletion and a copy number amplification of the Rhg1 locus, respectively. The coordinately down-regulated gene clusters in N0304-303-3 were caused by a 254-kb deletion containing 19 genes including a fatty acyl-ACP thioesterase B gene (FATB1a). This deletion was associated with reduced palmitic acid content in seeds and was the molecular cause of a previously reported nonfunctional FATB1a allele, fap nc . The M23 and N0304-304-3 deletions were located in duplicated genome segments retained from the Glycine-specific whole genome duplication that occurred 13 million years ago. The homoeologous genes in these duplicated regions shared a strong similarity in both their encoded protein sequences and transcript accumulation levels, suggesting that they may have conserved and important functions in seeds. The functional conservation of homoeologous genes may result in genetic redundancy and gene dosage effects for their associated seed traits, explaining why the large deletion did not cause lethal effects or completely eliminate palmitic acid in N0304-303-3.

mtDNA variation in the Yanomami: evidence for additional New World founding lineages.

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Easton, R D; Merriwether, D A; Crews, D E; Ferrell, R E

1996-07-01

Native Americans have been classified into four founding haplogroups with as many as seven founding lineages based on mtDNA RFLPs and DNA sequence data. mtDNA analysis was completed for 83 Yanomami from eight villages in the Surucucu and Catrimani Plateau regions of Roraima in northwestern Brazil. Samples were typed for 15 polymorphic mtDNA sites (14 RFLP sites and 1 deletion site), and a subset was sequenced for both hypervariable regions of the mitochondrial D-loop. Substantial mitochondrial diversity was detected among the Yanomami, five of seven accepted founding haplotypes and three others were observed. Of the 83 samples, 4 (4.8%) were lineage B1, 1 (1.2%) was lineage B2, 31 (37.4%) were lineage C1, 29 (34.9%) were lineage C2, 2 (2.4%) were lineage D1, 6 (7.2%) were lineage D2, 7 (8.4%) were a haplotype we designated "X6," and 3 (3.6%) were a haplotype we designated "X7." Sequence analysis found 43 haplotypes in 50 samples. B2, X6, and X7 are previously unrecognized mitochondrial founding lineage types of Native Americans. The widespread distribution of these haplotypes in the New World and Asia provides support for declaring these lineages to be New World founding types.

Detection the human mitochondrial DNA 4977 bp deletion induced by 60Co γ-rays in vitro by nest-PCR

International Nuclear Information System (INIS)

Feng Jiangbing; Lu Xue; Chen Deqing; Liu Qingjie; Chen Xiaosui

2004-01-01

Objective: To establish a method for detecting the mitochondrial DNA 4977 bp deletion (mtDNA 4977) induced by different doses of ionizing radiation. Methods: A nest-PCR method was established with 3 primer pairs for detecting the human peripheral mtDNA 4977. The final PCR products were sequenced after purified and the sequence was BLASTed with the standard genome information of human mitochondrion. The mtDNA 4977 level induced by 0-5 Gy 60 Co γ-rays of 5 healthy individuals was analyzed with the established nest-PCR. Results: The mtDNA 4977 could be detected by the established nest-PCR method. The mtDNA 4977 was observed on samples after exposed to 1-5 Gy 60 Co γ-rays, but it was not observed before (0 Gy) exposure. Conclusion: The nest-PCR method established in this study could be used to detect the mtDNA 4977 induced by ionizing radiation. (authors)

Mitochondrial mosaics in the liver of 3 infants with mtDNA defects

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Scalais Emmanuel

2009-06-01

Full Text Available Abstract Background In muscle cytochrome oxidase (COX negative fibers (mitochondrial mosaics have often been visualized. Methods COX activity staining of liver for light and electron microscopy, muscle stains, blue native gel electrophoresis and activity assays of respiratory chain proteins, their immunolocalisation, mitochondrial and nuclear DNA analysis. Results Three unrelated infants showed a mitochondrial mosaic in the liver after staining for COX activity, i.e. hepatocytes with strongly reactive mitochondria were found adjacent to cells with many negative, or barely reactive, mitochondria. Deficiency was most severe in the patient diagnosed with Pearson syndrome. Ragged-red fibers were absent in muscle biopsies of all patients. Enzyme biochemistry was not diagnostic in muscle, fibroblasts and lymphocytes. Blue native gel electrophoresis of liver tissue, but not of muscle, demonstrated a decreased activity of complex IV; in both muscle and liver subcomplexes of complex V were seen. Immunocytochemistry of complex IV confirmed the mosaic pattern in two livers, but not in fibroblasts. MRI of the brain revealed severe white matter cavitation in the Pearson case, but only slight cortical atrophy in the Alpers-Huttenlocher patient, and a normal image in the 3rd. MtDNA in leucocytes showed a common deletion in 50% of the mtDNA molecules of the Pearson patient. In the patient diagnosed with Alpers-Huttenlocher syndrome, mtDNA was depleted for 60% in muscle. In the 3rd patient muscular and hepatic mtDNA was depleted for more than 70%. Mutations in the nuclear encoded gene of POLG were subsequently found in both the 2nd and 3rd patients. Conclusion Histoenzymatic COX staining of a liver biopsy is fast and yields crucial data about the pathogenesis; it indicates whether mtDNA should be assayed. Each time a mitochondrial disorder is suspected and muscle data are non-diagnostic, a liver biopsy should be recommended. Mosaics are probably more frequent

Anti-replicative recombinant 5S rRNA molecules can modulate the mtDNA heteroplasmy in a glucose-dependent manner.

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Loutre, Romuald; Heckel, Anne-Marie; Jeandard, Damien; Tarassov, Ivan; Entelis, Nina

2018-01-01

Mutations in mitochondrial DNA are an important source of severe and incurable human diseases. The vast majority of these mutations are heteroplasmic, meaning that mutant and wild-type genomes are present simultaneously in the same cell. Only a very high proportion of mutant mitochondrial DNA (heteroplasmy level) leads to pathological consequences. We previously demonstrated that mitochondrial targeting of small RNAs designed to anneal with mutant mtDNA can decrease the heteroplasmy level by specific inhibition of mutant mtDNA replication, thus representing a potential therapy. We have also shown that 5S ribosomal RNA, partially imported into human mitochondria, can be used as a vector to deliver anti-replicative oligoribonucleotides into human mitochondria. So far, the efficiency of cellular expression of recombinant 5S rRNA molecules bearing therapeutic insertions remained very low. In the present study, we designed new versions of anti-replicative recombinant 5S rRNA targeting a large deletion in mitochondrial DNA which causes the KSS syndrome, analyzed their specific annealing to KSS mitochondrial DNA and demonstrated their import into mitochondria of cultured human cells. To obtain an increased level of the recombinant 5S rRNA stable expression, we created transmitochondrial cybrid cell line bearing a site for Flp-recombinase and used this system for the recombinase-mediated integration of genes coding for the anti-replicative recombinant 5S rRNAs into nuclear genome. We demonstrated that stable expression of anti-replicative 5S rRNA versions in human transmitochondrial cybrid cells can induce a shift in heteroplasmy level of KSS mutation in mtDNA. This shift was directly dependent on the level of the recombinant 5S rRNA expression and the sequence of the anti-replicative insertion. Quantification of mtDNA copy number in transfected cells revealed the absence of a non-specific effect on wild type mtDNA replication, indicating that the decreased proportion

Prenatal Diagnosis and Molecular Analysis of a Large Novel Deletion (- -JS) Causing α0-Thalassemia.

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Cao, Jinru; He, Shuzhen; Pu, Yudong; Liu, Jingjing; Liu, Fuping; Feng, Jun

α-Thalassemia (α-thal) is a very common single gene hereditary disease caused by large deletions or point mutations of the α-globin gene cluster in tropical and subtropical regions of the world. Here, we report for the first time, a novel large α-thal deletion in a Chinese family from Jiangsu Province, People's Republic of China (PRC), which removes almost the entire α2 and α1 genes from the α-globin gene cluster. Thus, it was named the Jiangsu deletion (- - JS ) on the α-globin gene cluster causing α 0 -thal. Heterozygotes for this deletion showed an α-thal trait phenotype with reduced mean corpuscular volume (MCV) and mean corpuscular hemoglobin (Hb) (MCH) levels. The sequencing results showed that a 2538 bp deletion (NG_000006.1: g.35801_38338) existed in this novel genotype on the basis of -α 4.2 (leftward), indicating a deletion of about 6.8 kb from the α-globin cluster. In addition, a 29 bp sequence was inserted into the deletion during the recombination events that led to this deletion. Through pedigree analysis, we knew that the proband inherited the novel allele from his mother.

Penetrance and clinical consequences of a gross SDHB deletion in a large family.

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Solis, D C; Burnichon, N; Timmers, H J L M; Raygada, M J; Kozupa, A; Merino, M J; Makey, D; Adams, K T; Venisse, A; Gimenez-Roqueplo, A-P; Pacak, K

2009-04-01

Mutations in the gene encoding subunit B of the mitochondrial enzyme succinate dehydrogenase (SDHB) are inherited in an autosomal dominant manner and are associated with hereditary paraganglioma (PGL) and pheochromocytoma. The phenotype of patients with SDHB point mutations has been previously described. However, the phenotype and penetrance of gross SDHB deletions have not been well characterized as they are rarely described. The objective was to describe the phenotype and estimate the penetrance of an exon 1 large SDHB deletion in one kindred. A retrospective and prospective study of 41 relatives across five generations was carried out. The main outcome measures were genetic testing, clinical presentations, plasma catecholamines and their O-methylated metabolites. Of the 41 mutation carriers identified, 11 were diagnosed with PGL, 12 were found to be healthy carriers after evaluation, and 18 were reportedly healthy based on family history accounts. The penetrance of PGL related to the exon 1 large SDHB deletion in this family was estimated to be 35% by age 40. Variable expressivity of the phenotype associated with a large exon 1 SDHB deletion was observed, including low penetrance, diverse primary PGL tumor locations, and malignant potential.

SVA retrotransposon insertion-associated deletion represents a novel mutational mechanism underlying large genomic copy number changes with non-recurrent breakpoints

Science.gov (United States)

2014-01-01

Background Genomic disorders are caused by copy number changes that may exhibit recurrent breakpoints processed by nonallelic homologous recombination. However, region-specific disease-associated copy number changes have also been observed which exhibit non-recurrent breakpoints. The mechanisms underlying these non-recurrent copy number changes have not yet been fully elucidated. Results We analyze large NF1 deletions with non-recurrent breakpoints as a model to investigate the full spectrum of causative mechanisms, and observe that they are mediated by various DNA double strand break repair mechanisms, as well as aberrant replication. Further, two of the 17 NF1 deletions with non-recurrent breakpoints, identified in unrelated patients, occur in association with the concomitant insertion of SINE/variable number of tandem repeats/Alu (SVA) retrotransposons at the deletion breakpoints. The respective breakpoints are refractory to analysis by standard breakpoint-spanning PCRs and are only identified by means of optimized PCR protocols designed to amplify across GC-rich sequences. The SVA elements are integrated within SUZ12P intron 8 in both patients, and were mediated by target-primed reverse transcription of SVA mRNA intermediates derived from retrotranspositionally active source elements. Both SVA insertions occurred during early postzygotic development and are uniquely associated with large deletions of 1 Mb and 867 kb, respectively, at the insertion sites. Conclusions Since active SVA elements are abundant in the human genome and the retrotranspositional activity of many SVA source elements is high, SVA insertion-associated large genomic deletions encompassing many hundreds of kilobases could constitute a novel and as yet under-appreciated mechanism underlying large-scale copy number changes in the human genome. PMID:24958239

MtDNA diversity among four Portuguese autochthonous dog breeds: a fine-scale characterisation

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Santa-Rita Pedro

2005-06-01

Full Text Available Abstract Background The picture of dog mtDNA diversity, as obtained from geographically wide samplings but from a small number of individuals per region or breed, has revealed weak geographic correlation and high degree of haplotype sharing between very distant breeds. We aimed at a more detailed picture through extensive sampling (n = 143 of four Portuguese autochthonous breeds – Castro Laboreiro Dog, Serra da Estrela Mountain Dog, Portuguese Sheepdog and Azores Cattle Dog-and comparatively reanalysing published worldwide data. Results Fifteen haplotypes belonging to four major haplogroups were found in these breeds, of which five are newly reported. The Castro Laboreiro Dog presented a 95% frequency of a new A haplotype, while all other breeds contained a diverse pool of existing lineages. The Serra da Estrela Mountain Dog, the most heterogeneous of the four Portuguese breeds, shared haplotypes with the other mainland breeds, while Azores Cattle Dog shared no haplotypes with the other Portuguese breeds. A review of mtDNA haplotypes in dogs across the world revealed that: (a breeds tend to display haplotypes belonging to different haplogroups; (b haplogroup A is present in all breeds, and even uncommon haplogroups are highly dispersed among breeds and continental areas; (c haplotype sharing between breeds of the same region is lower than between breeds of different regions and (d genetic distances between breeds do not correlate with geography. Conclusion MtDNA haplotype sharing occurred between Serra da Estrela Mountain dogs (with putative origin in the centre of Portugal and two breeds in the north and south of the country-with the Castro Laboreiro Dog (which behaves, at the mtDNA level, as a sub-sample of the Serra da Estrela Mountain Dog and the southern Portuguese Sheepdog. In contrast, the Azores Cattle Dog did not share any haplotypes with the other Portuguese breeds, but with dogs sampled in Northern Europe. This suggested that the

Limited phylogeographic signal in sex-linked and autosomal loci despite geographically, ecologically, and phenotypically concordant structure of mtDNA variation in the Holarctic avian genus Eremophila.

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Sergei V Drovetski

Full Text Available Phylogeographic studies of Holarctic birds are challenging because they involve vast geographic scale, complex glacial history, extensive phenotypic variation, and heterogeneous taxonomic treatment across countries, all of which require large sample sizes. Knowledge about the quality of phylogeographic information provided by different loci is crucial for study design. We use sequences of one mtDNA gene, one sex-linked intron, and one autosomal intron to elucidate large scale phylogeographic patterns in the Holarctic lark genus Eremophila. The mtDNA ND2 gene identified six geographically, ecologically, and phenotypically concordant clades in the Palearctic that diverged in the Early-Middle Pleistocene and suggested paraphyly of the horned lark (E. alpestris with respect to the Temminck's lark (E. bilopha. In the Nearctic, ND2 identified five subclades which diverged in the Late Pleistocene. They overlapped geographically and were not concordant phenotypically or ecologically. Nuclear alleles provided little information on geographic structuring of genetic variation in horned larks beyond supporting the monophyly of Eremophila and paraphyly of the horned lark. Multilocus species trees based on two nuclear or all three loci provided poor support for haplogroups identified by mtDNA. The node ages calculated using mtDNA were consistent with the available paleontological data, whereas individual nuclear loci and multilocus species trees appeared to underestimate node ages. We argue that mtDNA is capable of discovering independent evolutionary units within avian taxa and can provide a reasonable phylogeographic hypothesis when geographic scale, geologic history, and phenotypic variation in the study system are too complex for proposing reasonable a priori hypotheses required for multilocus methods. Finally, we suggest splitting the currently recognized horned lark into five Palearctic and one Nearctic species.

Techniques for Large-Scale Bacterial Genome Manipulation and Characterization of the Mutants with Respect to In Silico Metabolic Reconstructions.

Science.gov (United States)

diCenzo, George C; Finan, Turlough M

2018-01-01

The rate at which all genes within a bacterial genome can be identified far exceeds the ability to characterize these genes. To assist in associating genes with cellular functions, a large-scale bacterial genome deletion approach can be employed to rapidly screen tens to thousands of genes for desired phenotypes. Here, we provide a detailed protocol for the generation of deletions of large segments of bacterial genomes that relies on the activity of a site-specific recombinase. In this procedure, two recombinase recognition target sequences are introduced into known positions of a bacterial genome through single cross-over plasmid integration. Subsequent expression of the site-specific recombinase mediates recombination between the two target sequences, resulting in the excision of the intervening region and its loss from the genome. We further illustrate how this deletion system can be readily adapted to function as a large-scale in vivo cloning procedure, in which the region excised from the genome is captured as a replicative plasmid. We next provide a procedure for the metabolic analysis of bacterial large-scale genome deletion mutants using the Biolog Phenotype MicroArray™ system. Finally, a pipeline is described, and a sample Matlab script is provided, for the integration of the obtained data with a draft metabolic reconstruction for the refinement of the reactions and gene-protein-reaction relationships in a metabolic reconstruction.

Keeping mtDNA in shape between generations.

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James B Stewart

2014-10-01

Full Text Available Since the unexpected discovery that mitochondria contain their own distinct DNA molecules, studies of the mitochondrial DNA (mtDNA have yielded many surprises. In animals, transmission of the mtDNA genome is explicitly non-Mendelian, with a very high number of genome copies being inherited from the mother after a drastic bottleneck. Recent work has begun to uncover the molecular details of this unusual mode of transmission. Many surprising variations in animal mitochondrial biology are known; however, a series of recent studies have identified a core of evolutionarily conserved mechanisms relating to mtDNA inheritance, e.g., mtDNA bottlenecks during germ cell development, selection against specific mtDNA mutation types during maternal transmission, and targeted destruction of sperm mitochondria. In this review, we outline recent literature on the transmission of mtDNA in animals and highlight the implications for human health and ageing.

No evidence of Neandertal mtDNA contribution to early modern humans.

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David Serre

2004-03-01

Full Text Available The retrieval of mitochondrial DNA (mtDNA sequences from four Neandertal fossils from Germany, Russia, and Croatia has demonstrated that these individuals carried closely related mtDNAs that are not found among current humans. However, these results do not definitively resolve the question of a possible Neandertal contribution to the gene pool of modern humans since such a contribution might have been erased by genetic drift or by the continuous influx of modern human DNA into the Neandertal gene pool. A further concern is that if some Neandertals carried mtDNA sequences similar to contemporaneous humans, such sequences may be erroneously regarded as modern contaminations when retrieved from fossils. Here we address these issues by the analysis of 24 Neandertal and 40 early modern human remains. The biomolecular preservation of four Neandertals and of five early modern humans was good enough to suggest the preservation of DNA. All four Neandertals yielded mtDNA sequences similar to those previously determined from Neandertal individuals, whereas none of the five early modern humans contained such mtDNA sequences. In combination with current mtDNA data, this excludes any large genetic contribution by Neandertals to early modern humans, but does not rule out the possibility of a smaller contribution.

ReacKnock: identifying reaction deletion strategies for microbial strain optimization based on genome-scale metabolic network.

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Zixiang Xu

Full Text Available Gene knockout has been used as a common strategy to improve microbial strains for producing chemicals. Several algorithms are available to predict the target reactions to be deleted. Most of them apply mixed integer bi-level linear programming (MIBLP based on metabolic networks, and use duality theory to transform bi-level optimization problem of large-scale MIBLP to single-level programming. However, the validity of the transformation was not proved. Solution of MIBLP depends on the structure of inner problem. If the inner problem is continuous, Karush-Kuhn-Tucker (KKT method can be used to reformulate the MIBLP to a single-level one. We adopt KKT technique in our algorithm ReacKnock to attack the intractable problem of the solution of MIBLP, demonstrated with the genome-scale metabolic network model of E. coli for producing various chemicals such as succinate, ethanol, threonine and etc. Compared to the previous methods, our algorithm is fast, stable and reliable to find the optimal solutions for all the chemical products tested, and able to provide all the alternative deletion strategies which lead to the same industrial objective.

Large Genomic Deletions in CACNA1A Cause Episodic Ataxia Type 2

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Jijun eWan

2011-09-01

Full Text Available Episodic ataxia (EA syndromes are heritable diseases characterized by dramatic episodes of imbalance and incoordination. Episodic ataxia type 2 (EA2, the most common and the best characterized subtype, is caused by mostly nonsense, splice site, small indel and sometimes missense mutations in CACNA1A. Direct sequencing of CACNA1A fails to identify mutations in some patients with EA2-like features, possibly due to incomplete interrogation of CACNA1A or defects in other EA genes not yet defined. Previous reports described genomic deletions between 4-40kb in EA2. In 47 subjects with EA (26 with EA2-like features who tested negative for mutations in the known EA genes, we used Multiplex Ligation-dependent Probe Amplification (MLPA to analyze CACNA1A for exonic copy number variations. Breakpoints were further defined by long-range PCR. We identified distinct multi-exonic deletions in three probands with classic EA2-like features: episodes of prolonged vertigo and ataxia triggered by stress and fatigue, interictal nystagmus, with onset during infancy or early childhood. The breakpoints in all three probands are located in Alu sequences, indicating errors in homologous recombination of Alu sequences as the underlying mechanism. The smallest deletion spanned exons 39 and 40, while the largest deletion spanned 200kb, missing all but the first three exons. One deletion involving exons 39 through 47 arose spontaneously. The search for mutations in CACNA1A appears most fruitful in EA patients with interictal nystagmus and onset early in life. The finding of large heterozygous deletions suggests haploinsufficiency as a possible pathomechanism of EA2.

A novel large deletion of the ICR1 region including H19 and putative enhancer elements.

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Fryssira, Helen; Amenta, Stella; Kanber, Deniz; Sofocleous, Christalena; Lykopoulou, Evangelia; Kanaka-Gantenbein, Christina; Cerrato, Flavia; Lüdecke, Hermann-Josef; Bens, Susanne; Riccio, Andrea; Buiting, Karin

2015-05-06

Beckwith-Wiedemann syndrome (BWS) is a rare pediatric overgrowth disorder with a variable clinical phenotype caused by deregulation affecting imprinted genes in the chromosomal region 11p15. Alterations of the imprinting control region 1 (ICR1) at the IGF2/H19 locus resulting in biallelic expression of IGF2 and biallelic silencing of H19 account for approximately 10% of patients with BWS. The majority of these patients have epimutations of the ICR1 without detectable DNA sequence changes. Only a few patients were found to have deletions. Most of these deletions are small affecting different parts of the ICR1 differentially methylated region (ICR1-DMR) removing target sequences for CTCF. Only a very few deletions reported so far include the H19 gene in addition to the CTCF binding sites. None of these deletions include IGF2. A male patient was born with hypotonia, facial dysmorphisms and hypoglycemia suggestive of Beckwith-Wiedemann syndrome. Using methylation-specific (MS)-MLPA (Multiplex ligation-dependent probe amplification) we have identified a maternally inherited large deletion of the ICR1 region in a patient and his mother. The deletion results in a variable clinical expression with a classical BWS in the mother and a more severe presentation of BWS in her son. By genome-wide SNP array analysis the deletion was found to span ~100 kb genomic DNA including the ICR1DMR, H19, two adjacent non-imprinted genes and two of three predicted enhancer elements downstream to H19. Methylation analysis by deep bisulfite next generation sequencing revealed hypermethylation of the maternal allele at the IGF2 locus in both, mother and child, although IGF2 is not affected by the deletion. We here report on a novel large familial deletion of the ICR1 region in a BWS family. Due to the deletion of the ICR1-DMR CTCF binding cannot take place and the residual enhancer elements have access to the IGF2 promoters. The aberrant methylation (hypermethylation) of the maternal IGF2

Decreased Circulating mtDNA Levels in Professional Male Volleyball Players.

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Nasi, Milena; Cristani, Alessandro; Pinti, Marcello; Lamberti, Igor; Gibellini, Lara; De Biasi, Sara; Guazzaloca, Alessandro; Trenti, Tommaso; Cossarizza, Andrea

2016-01-01

Exercise exerts various effects on the immune system, and evidence is emerging on its anti-inflammatory effects; the mechanisms on the basis of these modifications are poorly understood. Mitochondrial DNA (mtDNA) released from damaged cells acts as a molecule containing the so-called damage-associated molecular patterns and can trigger sterile inflammation. Indeed, high plasma levels of mtDNA are associated to several inflammatory conditions and physiological aging and longevity. The authors evaluated plasma mtDNA in professional male volleyball players during seasonal training and the possible correlation between mtDNA levels and clinical parameters, body composition, and physical performance. Plasma mtDNA was quantified by real-time PCR every 2 mo in 12 professional volleyball players (PVPs) during 2 consecutive seasons. As comparison, 20 healthy nonathlete male volunteers (NAs) were analyzed. The authors found lower levels of mtDNA in plasma of PVPs than in NAs. However, PVPs showed a decrease of circulating mtDNA only in the first season, while no appreciable variations were observed during the second season. No correlation was observed among mtDNA, hematochemical, and anthropometric parameters. Regular physical activity appeared associated with lower levels of circulating mtDNA, further confirming the protective, anti-inflammatory effect of exercise.

mtDNA mutation C1494T, haplogroup A, and hearing loss in Chinese

International Nuclear Information System (INIS)

Wang Chengye; Kong Qingpeng; Yao Yonggang; Zhang Yaping

2006-01-01

Mutation C1494T in mitochondrial 12S rRNA gene was recently reported in two large Chinese families with aminoglycoside-induced and nonsyndromic hearing loss (AINHL) and was claimed to be pathogenic. This mutation, however, was first reported in a sample from central China in our previous study that was aimed to reconstruct East Asian mtDNA phylogeny. All these three mtDNAs formed a subclade defined by mutation C1494T in mtDNA haplogroup A. It thus seems that mutation C1494T is a haplogroup A-associated mutation and this matrilineal background may contribute a high risk for the penetrance of mutation C1494T in Chinese with AINHL. To test this hypothesis, we first genotyped mutation C1494T in 553 unrelated individuals from three regional Chinese populations and performed an extensive search for published complete or near-complete mtDNA data sets (>3000 mtDNAs), we then screened the C1494T mutation in 111 mtDNAs with haplogroup A status that were identified from 1823 subjects across China. The search for published mtDNA data sets revealed no other mtDNA besides the above-mentioned three carrying mutation C1494T. None of the 553 randomly selected individuals and the 111 haplogroup A mtDNAs was found to bear this mutation. Therefore, our results suggest that C1494T is a very rare event. The mtDNA haplogroup A background in general is unlikely to play an active role in the penetrance of mutation C1494T in AINHL

Large scale electrolysers

International Nuclear Information System (INIS)

B Bello; M Junker

2006-01-01

Hydrogen production by water electrolysis represents nearly 4 % of the world hydrogen production. Future development of hydrogen vehicles will require large quantities of hydrogen. Installation of large scale hydrogen production plants will be needed. In this context, development of low cost large scale electrolysers that could use 'clean power' seems necessary. ALPHEA HYDROGEN, an European network and center of expertise on hydrogen and fuel cells, has performed for its members a study in 2005 to evaluate the potential of large scale electrolysers to produce hydrogen in the future. The different electrolysis technologies were compared. Then, a state of art of the electrolysis modules currently available was made. A review of the large scale electrolysis plants that have been installed in the world was also realized. The main projects related to large scale electrolysis were also listed. Economy of large scale electrolysers has been discussed. The influence of energy prices on the hydrogen production cost by large scale electrolysis was evaluated. (authors)

Data on haplotype diversity in the hypervariable region I, II and III of mtDNA amongst the Brahmin population of Haryana

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Kapil Verma

2018-04-01

Full Text Available Human mitochondrial DNA (mtDNA is routinely analysed for pathogenic mutations, evolutionary studies, estimation of time of divergence within or between species, phylogenetic studies and identification of degraded remains. The data on various regions of human mtDNA has added enormously to the knowledge pool of population genetics as well as forensic genetics. The displacement-loop (D-loop in the control region of mtDNA is rated as the most rapidly evolving part, due to the presence of variations in this region. The control region consists of three hypervariable regions. These hypervariable regions (HVI, HVII and HVIII tend to mutate 5–10 times faster than nuclear DNA. The high mutation rate of these hypervariable regions is used in population genetic studies and human identity testing. In the present data, potentially informative hypervariable regions of mitochondrial DNA (mtDNA i.e. HVI (np 16024–16365, HVII (np 73–340 and HVIII (np 438–576 were estimated to understand the genetic diversity amongst Brahmin population of Haryana. Blood samples had been collected from maternally unrelated individuals from the different districts of Haryana. An array of parameters comprising of polymorphic sites, transitions, transversions, deletions, gene diversity, nucleotide diversity, pairwise differences, Tajima's D test, Fu's Fs test, mismatch observed variance and expected heterozygosity were estimated. The observed polymorphisms with their respective haplogroups in comparison to rCRS were assigned. Keywords: Mitochondrial DNA, D-loop, Hypervariable regions, Forensic genetics

Increased mitochondrial DNA deletions and copy number in transfusion-dependent thalassemia

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Calloway, Cassandra

2016-01-01

BACKGROUND. Iron overload is the primary cause of morbidity in transfusion-dependent thalassemia. Increase in iron causes mitochondrial dysfunction under experimental conditions, but the occurrence and significance of mitochondrial damage is not understood in patients with thalassemia. METHODS. Mitochondrial DNA (mtDNA) to nuclear DNA copy number (Mt/N) and frequency of the common 4977-bp mitochondrial deletion (ΔmtDNA4977) were quantified using a quantitative PCR assay on whole blood samples from 38 subjects with thalassemia who were receiving regular transfusions. RESULTS. Compared with healthy controls, Mt/N and ΔmtDNA4977 frequency were elevated in thalassemia (P = 0.038 and P 15 mg/g dry-weight or splenectomy, with the highest levels observed in subjects who had both risk factors (P = 0.003). Myocardial iron (MRI T2* 40/1 × 107 mtDNA, respectively (P = 0.025). Subjects with Mt/N values below the group median had significantly lower Matsuda insulin sensitivity index (5.76 ± 0.53) compared with the high Mt/N group (9.11 ± 0.95, P = 0.008). CONCLUSION. Individuals with transfusion-dependent thalassemia demonstrate age-related increase in mtDNA damage in leukocytes. These changes are markedly amplified by splenectomy and are associated with extrahepatic iron deposition. Elevated mtDNA damage in blood cells may predict the risk of iron-associated organ damage in thalassemia. FUNDING. This project was supported by Children’s Hospital & Research Center Oakland Institutional Research Award and by the National Center for Advancing Translational Sciences, NIH, through UCSF-CTSI grant UL1 TR000004. PMID:27583305

MELAS syndrome associated with both A3243G-tRNALeu mutation and multiple mitochondrial DNA deletions.

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Aharoni, Sharon; Traves, Teres A; Melamed, Eldad; Cohen, Sarit; Silver, Esther Leshinsky

2010-09-15

The syndrome of mitochondrial encephalopathy, lactic acidosis, and stroke-like episode (MELAS) is characterized clinically by recurrent focal neurological deficits, epilepsy, and short stature. The phenotypic spectrum is extremely diverse, with multisystemic organ involvement leading to isolated diabetes, deafness, renal tubulopathy, hypertrophic cardiomyopathy, and retinitis pigmentosa. In 80% of cases, the syndrome is associated with an AG transmission mutation (A3243G) in the tRNALeu gene of the mitochondrial DNA (mtDNA). We describe a woman with a unique combination of the MELAS A3243G mutation and multiple mtDNA deletions with normal POLG sequence. The patient presented with diabetes mellitus, sensorineural deafness, short stature, and mental disorientation. All her three children died in early adolescence. 2010 Elsevier B.V. All rights reserved.

Changes in the human mitochondrial genome after treatment of malignant disease

International Nuclear Information System (INIS)

Wardell, Theresa M.; Ferguson, Elaine; Chinnery, Patrick F.; Borthwick, Gillian M.; Taylor, Robert W.; Jackson, Graham; Craft, Alan; Lightowlers, Robert N.; Howell, Neil; Turnbull, Douglass M.

2003-01-01

Mitochondrial DNA (mtDNA) is the only extrachromosomal DNA in human cells. The mitochondrial genome encodes essential information for the synthesis of the mitochondrial respiratory chain. Inherited defects of this genome are an important cause of human disease. In addition, the mitochondrial genome seems to be particularly prone to DNA damage and acquired mutations may have a role in ageing, cancer and neurodegeneration. We wished to determine if radiotherapy and chemotherapy used in the treatment of cancer could induce changes in the mitochondrial genome. Such changes would be an important genetic marker of DNA damage and may explain some of the adverse effects of treatment. We studied samples from patients who had received radiotherapy and chemotherapy for point mutations within the mtDNA control region, and for large-scale deletions. In blood samples from patients, we found a significantly increased number of point mutations compared to the control subjects. In muscle biopsies from 7 of 8 patients whom had received whole body irradiation as well as chemotherapy, the level of a specific mtDNA deletion was significantly greater than in control subjects. Our studies have shown that in patients who have been treated for cancer there is an increased level of mtDNA damage

Contribution of Large Genomic Rearrangements in Italian Lynch Syndrome Patients: Characterization of a Novel Alu-Mediated Deletion

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Francesca Duraturo

2013-01-01

Full Text Available Lynch syndrome is associated with germ-line mutations in the DNA mismatch repair (MMR genes, mainly MLH1 and MSH2. Most of the mutations reported in these genes to date are point mutations, small deletions, and insertions. Large genomic rearrangements in the MMR genes predisposing to Lynch syndrome also occur, but the frequency varies depending on the population studied on average from 5 to 20%. The aim of this study was to examine the contribution of large rearrangements in the MLH1 and MSH2 genes in a well-characterised series of 63 unrelated Southern Italian Lynch syndrome patients who were negative for pathogenic point mutations in the MLH1, MSH2, and MSH6 genes. We identified a large novel deletion in the MSH2 gene, including exon 6 in one of the patients analysed (1.6% frequency. This deletion was confirmed and localised by long-range PCR. The breakpoints of this rearrangement were characterised by sequencing. Further analysis of the breakpoints revealed that this rearrangement was a product of Alu-mediated recombination. Our findings identified a novel Alu-mediated rearrangement within MSH2 gene and showed that large deletions or duplications in MLH1 and MSH2 genes are low-frequency mutational events in Southern Italian patients with an inherited predisposition to colon cancer.

Large deletions play a minor but essential role in congenital coagulation factor VII and X deficiencies.

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Rath, M; Najm, J; Sirb, H; Kentouche, K; Dufke, A; Pauli, S; Hackmann, K; Liehr, T; Hübner, C A; Felbor, U

2015-01-01

Congenital factor VII (FVII) and factor X (FX) deficiencies belong to the group of rare bleeding disorders which may occur in separate or combined forms since both the F7 and F10 genes are located in close proximity on the distal long arm of chromosome 13 (13q34). We here present data of 192 consecutive index cases with FVII and/or FX deficiency. 10 novel and 53 recurrent sequence alterations were identified in the F7 gene and 5 novel as well as 11 recurrent in the F10 gene including one homozygous 4.35 kb deletion within F7 (c.64+430_131-6delinsTCGTAA) and three large heterozygous deletions involving both the F7 and F10 genes. One of the latter proved to be cytogenetically visible as a chromosome 13q34 deletion and associated with agenesis of the corpus callosum and psychomotor retardation. Large deletions play a minor but essential role in the mutational spectrum of the F7 and F10 genes. Copy number analyses (e. g. MLPA) should be considered if sequencing cannot clarify the underlying reason of an observed coagulopathy. Of note, in cases of combined FVII/FX deficiency, a deletion of the two contiguous genes might be part of a larger chromosomal rearrangement.

Metabolic rescue in pluripotent cells from patients with mtDNA disease.

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Ma, Hong; Folmes, Clifford D L; Wu, Jun; Morey, Robert; Mora-Castilla, Sergio; Ocampo, Alejandro; Ma, Li; Poulton, Joanna; Wang, Xinjian; Ahmed, Riffat; Kang, Eunju; Lee, Yeonmi; Hayama, Tomonari; Li, Ying; Van Dyken, Crystal; Gutierrez, Nuria Marti; Tippner-Hedges, Rebecca; Koski, Amy; Mitalipov, Nargiz; Amato, Paula; Wolf, Don P; Huang, Taosheng; Terzic, Andre; Laurent, Louise C; Izpisua Belmonte, Juan Carlos; Mitalipov, Shoukhrat

2015-08-13

Mitochondria have a major role in energy production via oxidative phosphorylation, which is dependent on the expression of critical genes encoded by mitochondrial (mt)DNA. Mutations in mtDNA can cause fatal or severely debilitating disorders with limited treatment options. Clinical manifestations vary based on mutation type and heteroplasmy (that is, the relative levels of mutant and wild-type mtDNA within each cell). Here we generated genetically corrected pluripotent stem cells (PSCs) from patients with mtDNA disease. Multiple induced pluripotent stem (iPS) cell lines were derived from patients with common heteroplasmic mutations including 3243A>G, causing mitochondrial encephalomyopathy and stroke-like episodes (MELAS), and 8993T>G and 13513G>A, implicated in Leigh syndrome. Isogenic MELAS and Leigh syndrome iPS cell lines were generated containing exclusively wild-type or mutant mtDNA through spontaneous segregation of heteroplasmic mtDNA in proliferating fibroblasts. Furthermore, somatic cell nuclear transfer (SCNT) enabled replacement of mutant mtDNA from homoplasmic 8993T>G fibroblasts to generate corrected Leigh-NT1 PSCs. Although Leigh-NT1 PSCs contained donor oocyte wild-type mtDNA (human haplotype D4a) that differed from Leigh syndrome patient haplotype (F1a) at a total of 47 nucleotide sites, Leigh-NT1 cells displayed transcriptomic profiles similar to those in embryo-derived PSCs carrying wild-type mtDNA, indicative of normal nuclear-to-mitochondrial interactions. Moreover, genetically rescued patient PSCs displayed normal metabolic function compared to impaired oxygen consumption and ATP production observed in mutant cells. We conclude that both reprogramming approaches offer complementary strategies for derivation of PSCs containing exclusively wild-type mtDNA, through spontaneous segregation of heteroplasmic mtDNA in individual iPS cell lines or mitochondrial replacement by SCNT in homoplasmic mtDNA-based disease.

Nuclear DNA but not mtDNA controls tumor phenotypes in mouse cells

International Nuclear Information System (INIS)

Akimoto, Miho; Niikura, Mamoru; Ichikawa, Masami; Yonekawa, Hiromichi; Nakada, Kazuto; Honma, Yoshio; Hayashi, Jun-Ichi

2005-01-01

Recent studies showed high frequencies of homoplasmic mtDNA mutations in various human tumor types, suggesting that the mutated mtDNA haplotypes somehow contribute to expression of tumor phenotypes. We directly addressed this issue by isolating mouse mtDNA-less (ρ 0 ) cells for complete mtDNA replacement between normal cells and their carcinogen-induced transformants, and examined the effect of the mtDNA replacement on expression of tumorigenicity, a phenotype forming tumors in nude mice. The results showed that genome chimera cells carrying nuclear DNA from tumor cells and mtDNA from normal cells expressed tumorigenicity, whereas those carrying nuclear DNA from normal cells and mtDNA from tumor cells did not. These observations provided direct evidence that nuclear DNA, but not mtDNA, is responsible for carcinogen-induced malignant transformation, although it remains possible that mtDNA mutations and resultant respiration defects may influence the degree of malignancy, such as invasive or metastatic properties

Alu-mediated large deletion of the CDSN gene as a cause of peeling skin disease.

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Wada, T; Matsuda, Y; Muraoka, M; Toma, T; Takehara, K; Fujimoto, M; Yachie, A

2014-10-01

Peeling skin disease (PSD) is an autosomal recessive skin disorder caused by mutations in CDSN and is characterized by superficial peeling of the upper epidermis. Corneodesmosin (CDSN) is a major component of corneodesmosomes that plays an important role in maintaining epidermis integrity. Herein, we report a patient with PSD caused by a novel homozygous large deletion in the 6p21.3 region encompassing the CDSN gene, which abrogates CDSN expression. Several genes including C6orf15, PSORS1C1, PSORS1C2, CCHCR1, and TCF19 were also deleted, however, the patient showed only clinical features typical of PSD. The deletion size was 59.1 kb. Analysis of the sequence surrounding the breakpoint showed that both telomeric and centromeric breakpoints existed within Alu-S sequences that were oriented in opposite directions. These results suggest an Alu-mediated recombination event as the mechanism underlying the deletion in our patient. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Land, language, and loci: mtDNA in Native Americans and the genetic history of Peru.

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Lewis, Cecil M; Tito, Raúl Y; Lizárraga, Beatriz; Stone, Anne C

2005-07-01

Despite a long history of complex societies and despite extensive present-day linguistic and ethnic diversity, relatively few populations in Peru have been sampled for population genetic investigations. In order to address questions about the relationships between South American populations and about the extent of correlation between genetic distance, language, and geography in the region, mitochondrial DNA (mtDNA) hypervariable region I sequences and mtDNA haplogroup markers were examined in 33 individuals from the state of Ancash, Peru. These sequences were compared to those from 19 American Indian populations using diversity estimates, AMOVA tests, mismatch distributions, a multidimensional scaling plot, and regressions. The results show correlations between genetics, linguistics, and geographical affinities, with stronger correlations between genetics and language. Additionally, the results suggest a pattern of differential gene flow and drift in western vs. eastern South America, supporting previous mtDNA and Y chromosome investigations. (c) 2004 Wiley-Liss, Inc

Ultra-deep sequencing of mouse mitochondrial DNA: mutational patterns and their origins.

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Adam Ameur

2011-03-01

Full Text Available Somatic mutations of mtDNA are implicated in the aging process, but there is no universally accepted method for their accurate quantification. We have used ultra-deep sequencing to study genome-wide mtDNA mutation load in the liver of normally- and prematurely-aging mice. Mice that are homozygous for an allele expressing a proof-reading-deficient mtDNA polymerase (mtDNA mutator mice have 10-times-higher point mutation loads than their wildtype siblings. In addition, the mtDNA mutator mice have increased levels of a truncated linear mtDNA molecule, resulting in decreased sequence coverage in the deleted region. In contrast, circular mtDNA molecules with large deletions occur at extremely low frequencies in mtDNA mutator mice and can therefore not drive the premature aging phenotype. Sequence analysis shows that the main proportion of the mutation load in heterozygous mtDNA mutator mice and their wildtype siblings is inherited from their heterozygous mothers consistent with germline transmission. We found no increase in levels of point mutations or deletions in wildtype C57Bl/6N mice with increasing age, thus questioning the causative role of these changes in aging. In addition, there was no increased frequency of transversion mutations with time in any of the studied genotypes, arguing against oxidative damage as a major cause of mtDNA mutations. Our results from studies of mice thus indicate that most somatic mtDNA mutations occur as replication errors during development and do not result from damage accumulation in adult life.

Cells Lacking mtDNA Display Increased dNTP Pools upon DNA Damage

DEFF Research Database (Denmark)

Skovgaard, Tine; Rasmussen, Lene Juel; Munch-Petersen, Birgitte

Imbalanced dNTP pools are highly mutagenic due to a deleterious effect on DNA polymerase fidelity. Mitochondrial DNA defects, including mutations and deletions, are commonly found in a wide variety of different cancer types. In order to further study the interconnection between dNTP pools...... and mitochondrial function we have examined the effect of DNA damage on dNTP pools in cells deficient of mtDNA. We show that DNA damage induced by UV irradiation, in a dose corresponding to LD50, induces an S phase delay in different human osteosarcoma cell lines. The UV pulse also has a destabilizing effect...... shows that normal mitochondrial function is prerequisite for retaining stable dNTP pools upon DNA damage. Therefore it is likely that mitochondrial deficiency defects may cause an increase in DNA mutations by disrupting dNTP pool balance....

Mitochondrial nucleoid clusters protect newly synthesized mtDNA during Doxorubicin- and Ethidium Bromide-induced mitochondrial stress

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Alán, Lukáš, E-mail: lukas.alan@fgu.cas.cz; Špaček, Tomáš; Pajuelo Reguera, David; Jabůrek, Martin; Ježek, Petr

2016-07-01

Mitochondrial DNA (mtDNA) is compacted in ribonucleoprotein complexes called nucleoids, which can divide or move within the mitochondrial network. Mitochondrial nucleoids are able to aggregate into clusters upon reaction with intercalators such as the mtDNA depletion agent Ethidium Bromide (EB) or anticancer drug Doxorobicin (DXR). However, the exact mechanism of nucleoid clusters formation remains unknown. Resolving these processes may help to elucidate the mechanisms of DXR-induced cardiotoxicity. Therefore, we addressed the role of two key nucleoid proteins; mitochondrial transcription factor A (TFAM) and mitochondrial single-stranded binding protein (mtSSB); in the formation of mitochondrial nucleoid clusters during the action of intercalators. We found that both intercalators cause numerous aberrations due to perturbing their native status. By blocking mtDNA replication, both agents also prevented mtDNA association with TFAM, consequently causing nucleoid aggregation into large nucleoid clusters enriched with TFAM, co-existing with the normal nucleoid population. In the later stages of intercalation (> 48 h), TFAM levels were reduced to 25%. In contrast, mtSSB was released from mtDNA and freely distributed within the mitochondrial network. Nucleoid clusters mostly contained nucleoids with newly replicated mtDNA, however the nucleoid population which was not in replication mode remained outside the clusters. Moreover, the nucleoid clusters were enriched with p53, an anti-oncogenic gatekeeper. We suggest that mitochondrial nucleoid clustering is a mechanism for protecting nucleoids with newly replicated DNA against intercalators mediating genotoxic stress. These results provide new insight into the common mitochondrial response to mtDNA stress and can be implied also on DXR-induced mitochondrial cytotoxicity. - Highlights: • The mechanism for mitochondrial nucleoid clustering is proposed. • DNA intercalators (Doxorubicin or Ethidium Bromide) prevent TFAM

mtDNA, Metastasis, and the Mitochondrial Unfolded Protein Response (UPRmt).

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Kenny, Timothy C; Germain, Doris

2017-01-01

While several studies have confirmed a link between mitochondrial DNA (mtDNA) mutations and cancer cell metastasis, much debate remains regarding the nature of the alternations in mtDNA leading to this effect. Meanwhile, the mitochondrial unfolded protein response (UPR mt ) has gained much attention in recent years, with most studies of this pathway focusing on its role in aging. However, the UPR mt has also been studied in the context of cancer. More recent work suggests that rather than a single mutation or alternation, specific combinatorial mtDNA landscapes able to activate the UPR mt may be those that are selected by metastatic cells, while mtDNA landscapes unable to activate the UPR mt do not. This review aims at offering an overview of the confusing literature on mtDNA mutations and metastasis and the more recent work on the UPR mt in this setting.

Optimized mtDNA Control Region Primer Extension Capture Analysis for Forensically Relevant Samples and Highly Compromised mtDNA of Different Age and Origin

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Mayra Eduardoff

2017-09-01

Full Text Available The analysis of mitochondrial DNA (mtDNA has proven useful in forensic genetics and ancient DNA (aDNA studies, where specimens are often highly compromised and DNA quality and quantity are low. In forensic genetics, the mtDNA control region (CR is commonly sequenced using established Sanger-type Sequencing (STS protocols involving fragment sizes down to approximately 150 base pairs (bp. Recent developments include Massively Parallel Sequencing (MPS of (multiplex PCR-generated libraries using the same amplicon sizes. Molecular genetic studies on archaeological remains that harbor more degraded aDNA have pioneered alternative approaches to target mtDNA, such as capture hybridization and primer extension capture (PEC methods followed by MPS. These assays target smaller mtDNA fragment sizes (down to 50 bp or less, and have proven to be substantially more successful in obtaining useful mtDNA sequences from these samples compared to electrophoretic methods. Here, we present the modification and optimization of a PEC method, earlier developed for sequencing the Neanderthal mitochondrial genome, with forensic applications in mind. Our approach was designed for a more sensitive enrichment of the mtDNA CR in a single tube assay and short laboratory turnaround times, thus complying with forensic practices. We characterized the method using sheared, high quantity mtDNA (six samples, and tested challenging forensic samples (n = 2 as well as compromised solid tissue samples (n = 15 up to 8 kyrs of age. The PEC MPS method produced reliable and plausible mtDNA haplotypes that were useful in the forensic context. It yielded plausible data in samples that did not provide results with STS and other MPS techniques. We addressed the issue of contamination by including four generations of negative controls, and discuss the results in the forensic context. We finally offer perspectives for future research to enable the validation and accreditation of the PEC MPS

Quantitative PCR analysis reveals a high incidence of large intragenic deletions in the FANCA gene in Spanish Fanconi anemia patients.

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Callén, E; Tischkowitz, M D; Creus, A; Marcos, R; Bueren, J A; Casado, J A; Mathew, C G; Surrallés, J

2004-01-01

Fanconi anaemia is an autosomal recessive disease characterized by chromosome fragility, multiple congenital abnormalities, progressive bone marrow failure and a high predisposition to develop malignancies. Most of the Fanconi anaemia patients belong to complementation group FA-A due to mutations in the FANCA gene. This gene contains 43 exons along a 4.3-kb coding sequence with a very heterogeneous mutational spectrum that makes the mutation screening of FANCA a difficult task. In addition, as the FANCA gene is rich in Alu sequences, it was reported that Alu-mediated recombination led to large intragenic deletions that cannot be detected in heterozygous state by conventional PCR, SSCP analysis, or DNA sequencing. To overcome this problem, a method based on quantitative fluorescent multiplex PCR was proposed to detect intragenic deletions in FANCA involving the most frequently deleted exons (exons 5, 11, 17, 21 and 31). Here we apply the proposed method to detect intragenic deletions in 25 Spanish FA-A patients previously assigned to complementation group FA-A by FANCA cDNA retroviral transduction. A total of eight heterozygous deletions involving from one to more than 26 exons were detected. Thus, one third of the patients carried a large intragenic deletion that would have not been detected by conventional methods. These results are in agreement with previously published data and indicate that large intragenic deletions are one of the most frequent mutations leading to Fanconi anaemia. Consequently, this technology should be applied in future studies on FANCA to improve the mutation detection rate. Copyright 2003 S. Karger AG, Basel

Common Deletion (CD) in mitochondrial DNA of irradiated rat heart

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Siqueira, Raquel Gomes; Ferreira-Machado, Samara C.; Almeida, Carlos E.V. de, E-mail: raquelgsiqueira@gmail.com [Universidade do Estado do Rio de Janeiro (UERJ), RJ (Brazil). Instituto de Biologia Roberto Alcanatara Gomes. Lab. de Ciencias Radiologicas; Silva, Dayse A. da; Carvalho, Elizeu F. de [Universidade do Estado do Rio de Janeiro (UERJ), RJ (Brazil). Instituto de Biologia Roberto Alcanatara Gomes. Lab. de Diagnosticos por DNA; Melo, Luiz D.B. de [Universidade do Estado do Rio de Janeiro (UERJ), RJ (Brazil). Instituto de Biofisica Carlos Chagas Filho. Lab. de Parasitologia Molecular

2014-05-15

The purpose of this study was to map the common deletion (CD) area in mtDNA and investigate the levels of this deletion in irradiated heart. The assays were developed in male Wistar rats that were irradiated with three different single doses (5, 10 or 15 Gy) delivered directly to the heart and the analyses were performed at various times post-irradiation (3, 15 or 120 days). The CDs area were sequenced and the CD quantified by real-time PCR. Our study demonstrated that the CD levels progressively decreased from the 3rd until the 15th day after irradiation, and then increased thereafter. Additionally, it was observed that the levels of CD are modulated differently according to the different categories of doses (moderate and high). This study demonstrated an immediate response to ionizing radiation, measured by the presence of mutations in the CD area and a decrease in the CD levels. (author)

Mapping the end points of large deletions affecting the hprt locus in human peripheral blood cells and cell lines

International Nuclear Information System (INIS)

Nelson, S.L.; Grosovsky, A.J.; Jones, I.M.; Burkhart-Schultz, K.; Fuscoe, J.C.

1995-01-01

We have examined the extent of of HPRT - total gene deletions in three mutant collections: spontaneous and X-ray-induced deletions in TK6 human B lymphoblasts, and HPRT - deletions arising in vivo in T cells. A set of 13 Xq26 STS markers surrounding hprt and spanning approximately 3.3 Mb was used. Each marker used was observed to be missing in at least one of the hprt deletion mutants analyzed. The largest deletion observed encompassed at least 3 Mb. Nine deletions extended outside of the mapped region in the centromeric direction (>1.7 Mb). In contrast, only two telomeric deletions extended to marker 342R (1.26 Mb), and both exhibited slowed or limited cell growth. These data suggest the existence of a gene, within the vicinity of 342R, which establishes the telomeric limit of recoverable deletions. Most (25/41) X-ray-induced total gene deletion mutants exhibited marker loss, but only 1/8 of the spontaneous deletions encompassed any Xq26 markers (P = 0.0187). Furthermore, nearly half (3/8) of the spontaneous 3' total deletion breakpoints were within 14 kb of the hprt coding sequence. In contrast, 40/41 X-ray-induced HPRT - total deletions extended beyond this point (P = 0.011). Although the overall representation of total gene deletions in the in vivo spectrum is low, 4/5 encompass Xq26 markers flanking hprt. This pattern differs significantly from spontaneous HPRT - large deletions occurring in vitro (P = 0.032) but resembles the spectrum of X-ray-induced deletions. 24 refs., 6 figs., 1 tab

Melanesian mtDNA complexity.

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Jonathan S Friedlaender

Full Text Available Melanesian populations are known for their diversity, but it has been hard to grasp the pattern of the variation or its underlying dynamic. Using 1,223 mitochondrial DNA (mtDNA sequences from hypervariable regions 1 and 2 (HVR1 and HVR2 from 32 populations, we found the among-group variation is structured by island, island size, and also by language affiliation. The more isolated inland Papuan-speaking groups on the largest islands have the greatest distinctions, while shore dwelling populations are considerably less diverse (at the same time, within-group haplotype diversity is less in the most isolated groups. Persistent differences between shore and inland groups in effective population sizes and marital migration rates probably cause these differences. We also add 16 whole sequences to the Melanesian mtDNA phylogenies. We identify the likely origins of a number of the haplogroups and ancient branches in specific islands, point to some ancient mtDNA connections between Near Oceania and Australia, and show additional Holocene connections between Island Southeast Asia/Taiwan and Island Melanesia with branches of haplogroup E. Coalescence estimates based on synonymous transitions in the coding region suggest an initial settlement and expansion in the region at approximately 30-50,000 years before present (YBP, and a second important expansion from Island Southeast Asia/Taiwan during the interval approximately 3,500-8,000 YBP. However, there are some important variance components in molecular dating that have been overlooked, and the specific nature of ancestral (maternal Austronesian influence in this region remains unresolved.

High incidence of large deletions in the PMS2 gene in Spanish Lynch syndrome families.

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Brea-Fernández, A J; Cameselle-Teijeiro, J M; Alenda, C; Fernández-Rozadilla, C; Cubiella, J; Clofent, J; Reñé, J M; Anido, U; Milá, M; Balaguer, F; Castells, A; Castellvi-Bel, S; Jover, R; Carracedo, A; Ruiz-Ponte, C

2014-06-01

Lynch syndrome (LS) is caused by germline mutations in one of the four mismatch repair (MMR) genes. Defects in this pathway lead to microsatellite instability (MSI) in DNA tumors, which constitutes the molecular hallmark of this disease. Selection of patients for genetic testing in LS is usually based on fulfillment of diagnostic clinical criteria (i.e. Amsterdam criteria or the revised Bethesda guidelines). However, following these criteria PMS2 mutations have probably been underestimated as their penetrances appear to be lower than those of the other MMR genes. The use of universal MMR study-based strategies, using MSI testing and immunohistochemical (IHC) staining, is being one proposed alternative. Besides, germline mutation detection in PMS2 is complicated by the presence of highly homologous pseudogenes. Nevertheless, specific amplification of PMS2 by long-range polymerase chain reaction (PCR) and the improvement of the analysis of large deletions/duplications by multiplex ligation-dependent probe amplification (MLPA) overcome this difficulty. By using both approaches, we analyzed 19 PMS2-suspected carriers who have been selected by clinical or universal strategies and found five large deletions and one frameshift mutation in PMS2 in six patients (31%). Owing to the high incidence of large deletions found in our cohort, we recommend MLPA analysis as the first-line method for searching germline mutations in PMS2. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Myopathic mtDNA Depletion Syndrome Due to Mutation in TK2 Gene.

Science.gov (United States)

Martín-Hernández, Elena; García-Silva, María Teresa; Quijada-Fraile, Pilar; Rodríguez-García, María Elena; Rivera, Henry; Hernández-Laín, Aurelio; Coca-Robinot, David; Fernández-Toral, Joaquín; Arenas, Joaquín; Martín, Miguel A; Martínez-Azorín, Francisco

2017-01-01

Whole-exome sequencing was used to identify the disease gene(s) in a Spanish girl with failure to thrive, muscle weakness, mild facial weakness, elevated creatine kinase, deficiency of mitochondrial complex III and depletion of mtDNA. With whole-exome sequencing data, it was possible to get the whole mtDNA sequencing and discard any pathogenic variant in this genome. The analysis of whole exome uncovered a homozygous pathogenic mutation in thymidine kinase 2 gene ( TK2; NM_004614.4:c.323 C>T, p.T108M). TK2 mutations have been identified mainly in patients with the myopathic form of mtDNA depletion syndromes. This patient presents an atypical TK2-related myopathic form of mtDNA depletion syndromes, because despite having a very low content of mtDNA (TK2 gene in mtDNA depletion syndromes and expanded the phenotypic spectrum.

The influence of large deletions on the mutation frequency induced by tritiated water and X-radiation in male Drosophila melanogaster post-meiotic germ cells

International Nuclear Information System (INIS)

Fossett, N.G.; Byrne, B.J.; Kelley, S.J.; Tucker, A.B.; Arbour-Reily, P.; Lee, W.R.

1994-01-01

Tritium beta radiation ( 3 H β-radiation) in the form of tritiated water was used to induce mutations at the alcohol dehydrogenase (Adh) locus in male Drosophila melanogaster post-meiotic germ cells. All 23 Adh null mutations were large deletions (>20 kb), determined by genetic complementation and Southern blot analyses. 27 Adh null mutations have been induced by 100-kVp X-rays and have been genetically and molecularly characterized. In contrast to 3 H β-radiation, 100-kVp X-rays induced a bimodal distribution of Adh null mutations, intragenic mutations, ≤250 bp, and large deletions, >100 kb. A statistically significant difference was observed between the frequency of large deletions (23/23 or 1.0) induced by 3 H β-radiation and the frequency of large deletions (19/27 or 0.7) induced by 100-kVp X-rays. However, a statistical difference was not observed between the size distribution of the large deletions induced by 3 H β-radiation and X-rays. The relative deletion frequency (RDF) induced by 3 H β-radiation and 100-kVp X-rays was (1.0/0.7=1.4). The relative biological effectiveness (RBE) of these two radiation sources was 1.4, determined from the ratio of the regression coefficients of the respective 3 H β-radiation and X-ray sex-linked recessive lethal (SLRL) dose-response data. The large difference in size between the two classes of X-ray-induced Adh null mutations and the increase in mutation frequency and deletion frequency for 3 H β-radiation with respect to X-rays may indicate that the relative deletion frequency (RDF) is the molecular biological basis for the increase in the RBE for radiation sources with a mean LET value ≤10 keV/μm

VARIAN NON-DELESI 9 PASANG BASA DNA MITOKONDRIA MANUSIA SAMPEL FORENSIK BALI

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Gun Gun Gumilar

2005-06-01

Full Text Available One of human mitochondrial DNA (mtDNA variant is a 9 base pairs (bp deletion in the COII/tRNALys intergenic region. In construction mtDNA nomenclature, 9-bp deletion database consist of primary and secondary data is needed, including Bali bombing forensic samples. Here we report a 9-bp non- deletion mtDNA variant from Bali bombing forensic samples to complete primary data. Polymerase Chain Reaction (PCR technique with 2 set primer was used to detect 9-bp deletion. The PCR result was detected by agarose gel electrophoresis, which showed two bands (0.1 and 0.4 kb for non-deletion variant control, and one band (0.4 kb for deletion variant control. If the sample has 9-bp deletion, only one of the primer pairs could amplify a fragment of 0.4 kb. If the sample does not have 9-bp deletion, the other primer pair will amplify a 0.1 kb product. The result showed that none of the 24 samples has 9-bp deletion. These results are contributed to the human mtDNA database and nomenclature construction. Keywords: mtDNA, 9-bp deletion, PCR

Mitochondrial DNA copy number threshold in mtDNA depletion myopathy.

Science.gov (United States)

Durham, S E; Bonilla, E; Samuels, D C; DiMauro, S; Chinnery, P F

2005-08-09

The authors measured the absolute amount of mitochondrial DNA (mtDNA) within single muscle fibers from two patients with thymidine kinase 2 (TK2) deficiency and two healthy controls. TK2 deficient fibers containing more than 0.01 mtDNA/microm3 had residual cytochrome c oxidase (COX) activity. This defines the minimum amount of wild-type mtDNA molecules required to maintain COX activity in skeletal muscle and provides an explanation for the mosaic histochemical pattern seen in patients with mtDNA depletion syndrome.

Molecular evidence for the induction of large interstitial deletions on mouse chromosome 8 by ionizing radiation

International Nuclear Information System (INIS)

Turker, Mitchell S.; Pieretti, Maura; Kumar, Sudha

1997-01-01

The P19H22 mouse embryonal carcinoma cell line is characterized by a hemizygous deficiency for the chromosome 8 encoded aprt (adenine phosphoribosyltransferase) gene and heterozygosity for many chromosome 8 loci. We have previously demonstrated that this cell line is suitable for mutational studies because it is permissive of events ranging in size from base-pair substitutions at the aprt locus to apparent loss of chromosome 8. Large mutational events, defined by loss of the remaining aprt allele, were found to predominate in spontaneous mutants and those induced by ionizing radiation. In this study we have used a PCR based assay to screen for loss of heterozygosity at microsatellite loci both proximal and distal to aprt in 137 Cs-induced and spontaneous aprt mutants. This approach allowed us to distinguish apparent interstitial deletional events from apparent recombinational events. Significantly, 32.5% (26 of 80) of the mutational events induced by 137 Cs appeared to be interstitial deletions as compared with 7.7% (6 of 78) in the spontaneous group. This difference was statistically significant (p 137 Cs caused a significant number of deletion mutations. Most 137 Cs-induced interstitial deletions were larger than 6 cM, whereas none of the spontaneous deletions were larger than 6 cM. These results provide further support for the notion that ionizing radiation induces deletion mutations and validate the use of the P19H22 cell line for the study of events induced by ionizing radiation

Hypervariable region polymorphism of mtDNA of recurrent oral ulceration in Chinese.

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Mao Sun

Full Text Available BACKGROUND: MtDNA haplogroups could have important implication for understanding of the relationship between the mutations of the mitochondrial genome and diseases. Distribution of a variety of diseases among these haplogroups showed that some of the mitochondrial haplogroups are predisposed to disease. To examine the susceptibility of mtDNA haplogroups to ROU, we sequenced the mtDNA HV1, HV2 and HV3 in Chinese ROU. METHODOLOGY/PRINCIPAL FINDINGS: MtDNA haplogroups were analyzed in the 249 cases of ROU patients and the 237 cases of healthy controls respectively by means of primer extension analysis and DNA sequencing. Haplogroups G1 and H were found significantly more abundant in ROU patients than in healthy persons, while haplogroups D5 and R showed a trend toward a higher frequency in control as compared to those in patients. The distribution of C-stretch sequences polymorphism in mtDNA HV1, HV2 and HV3 regions was found in diversity. CONCLUSIONS/SIGNIFICANCE: For the first time, the relationship of mtDNA haplogroups and ROU in Chinese was investigated. Our results indicated that mtDNA haplogroups G1 and H might constitute a risk factor for ROU, which possibly increasing the susceptibility of ROU. Meanwhile, haplogroups D5 and R were indicated as protective factors for ROU. The polymorphisms of C-stretch sequences might being unstable and influence the mtDNA replication fidelity.

Automatic Generation of Connectivity for Large-Scale Neuronal Network Models through Structural Plasticity.

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Diaz-Pier, Sandra; Naveau, Mikaël; Butz-Ostendorf, Markus; Morrison, Abigail

2016-01-01

With the emergence of new high performance computation technology in the last decade, the simulation of large scale neural networks which are able to reproduce the behavior and structure of the brain has finally become an achievable target of neuroscience. Due to the number of synaptic connections between neurons and the complexity of biological networks, most contemporary models have manually defined or static connectivity. However, it is expected that modeling the dynamic generation and deletion of the links among neurons, locally and between different regions of the brain, is crucial to unravel important mechanisms associated with learning, memory and healing. Moreover, for many neural circuits that could potentially be modeled, activity data is more readily and reliably available than connectivity data. Thus, a framework that enables networks to wire themselves on the basis of specified activity targets can be of great value in specifying network models where connectivity data is incomplete or has large error margins. To address these issues, in the present work we present an implementation of a model of structural plasticity in the neural network simulator NEST. In this model, synapses consist of two parts, a pre- and a post-synaptic element. Synapses are created and deleted during the execution of the simulation following local homeostatic rules until a mean level of electrical activity is reached in the network. We assess the scalability of the implementation in order to evaluate its potential usage in the self generation of connectivity of large scale networks. We show and discuss the results of simulations on simple two population networks and more complex models of the cortical microcircuit involving 8 populations and 4 layers using the new framework.

Increasing on-target cleavage efficiency for CRISPR/Cas9-induced large fragment deletion in Myxococcus xanthus.

Science.gov (United States)

Yang, Ying-Jie; Wang, Ye; Li, Zhi-Feng; Gong, Ya; Zhang, Peng; Hu, Wen-Chao; Sheng, Duo-Hong; Li, Yue-Zhong

2017-08-16

The CRISPR/Cas9 system is a powerful tool for genome editing, in which the sgRNA binds and guides the Cas9 protein for the sequence-specific cleavage. The protocol is employable in different organisms, but is often limited by cell damage due to the endonuclease activity of the introduced Cas9 and the potential off-target DNA cleavage from incorrect guide by the 20 nt spacer. In this study, after resolving some critical limits, we have established an efficient CRISPR/Cas9 system for the deletion of large genome fragments related to the biosynthesis of secondary metabolites in Myxococcus xanthus cells. We revealed that the high expression of a codon-optimized cas9 gene in M. xanthus was cytotoxic, and developed a temporally high expression strategy to reduce the cell damage from high expressions of Cas9. We optimized the deletion protocol by using the tRNA-sgRNA-tRNA chimeric structure to ensure correct sgRNA sequence. We found that, in addition to the position-dependent nucleotide preference, the free energy of a 20 nt spacer was a key factor for the deletion efficiency. By using the developed protocol, we achieved the CRISPR/Cas9-induced deletion of large biosynthetic gene clusters for secondary metabolites in M. xanthus DK1622 and its epothilone-producing mutant. The findings and the proposals described in this paper were suggested to be workable in other organisms, for example, other Gram negative bacteria with high GC content.

Oxidants and not alkylating agents induce rapid mtDNA loss and mitochondrial dysfunction

Science.gov (United States)

Furda, Amy M.; Marrangoni, Adele M.; Lokshin, Anna; Van Houten, Bennett

2013-01-01

Mitochondrial DNA (mtDNA) is essential for proper mitochondrial function and encodes 22 tRNAs, 2 rRNAs and 13 polypeptides that make up subunits of complex I, III, IV, in the electron transport chain and complex V, the ATP synthase. Although mitochondrial dysfunction has been implicated in processes such as premature aging, neurodegeneration, and cancer, it has not been shown whether persistent mtDNA damage causes a loss of oxidative phosphorylation. We addressed this question by treating mouse embryonic fibroblasts with either hydrogen peroxide (H2O2) or the alkylating agent methyl methanesulfonate (MMS) and measuring several endpoints, including mtDNA damage and repair rates using QPCR, levels of mitochondrial- and nuclear-encoded proteins using antibody analysis, and a pharmacologic profile of mitochondria using the Seahorse Extracellular Flux Analyzer. We show that a 60 min treatment with H2O2 causes persistent mtDNA lesions, mtDNA loss, decreased levels of a nuclear-encoded mitochondrial subunit, a loss of ATP-linked oxidative phosphorylation and a loss of total reserve capacity. Conversely, a 60 min treatment with 2 mM MMS causes persistent mtDNA lesions but no mtDNA loss, no decrease in levels of a nuclear-encoded mitochondrial subunit, and no mitochondrial dysfunction. These results suggest that persistent mtDNA damage is not sufficient to cause mitochondrial dysfunction. PMID:22766155

Large-scale solar purchasing

International Nuclear Information System (INIS)

1999-01-01

The principal objective of the project was to participate in the definition of a new IEA task concerning solar procurement (''the Task'') and to assess whether involvement in the task would be in the interest of the UK active solar heating industry. The project also aimed to assess the importance of large scale solar purchasing to UK active solar heating market development and to evaluate the level of interest in large scale solar purchasing amongst potential large scale purchasers (in particular housing associations and housing developers). A further aim of the project was to consider means of stimulating large scale active solar heating purchasing activity within the UK. (author)

mtDNA sequence diversity of Hazara ethnic group from Pakistan.

Science.gov (United States)

Rakha, Allah; Fatima; Peng, Min-Sheng; Adan, Atif; Bi, Rui; Yasmin, Memona; Yao, Yong-Gang

2017-09-01

The present study was undertaken to investigate mitochondrial DNA (mtDNA) control region sequences of Hazaras from Pakistan, so as to generate mtDNA reference database for forensic casework in Pakistan and to analyze phylogenetic relationship of this particular ethnic group with geographically proximal populations. Complete mtDNA control region (nt 16024-576) sequences were generated through Sanger Sequencing for 319 Hazara individuals from Quetta, Baluchistan. The population sample set showed a total of 189 distinct haplotypes, belonging mainly to West Eurasian (51.72%), East & Southeast Asian (29.78%) and South Asian (18.50%) haplogroups. Compared with other populations from Pakistan, the Hazara population had a relatively high haplotype diversity (0.9945) and a lower random match probability (0.0085). The dataset has been incorporated into EMPOP database under accession number EMP00680. The data herein comprises the largest, and likely most thoroughly examined, control region mtDNA dataset from Hazaras of Pakistan. Copyright © 2017 Elsevier B.V. All rights reserved.

The generation of chromosomal deletions to provide extensive coverage and subdivision of the Drosophila melanogaster genome.

Science.gov (United States)

Cook, R Kimberley; Christensen, Stacey J; Deal, Jennifer A; Coburn, Rachel A; Deal, Megan E; Gresens, Jill M; Kaufman, Thomas C; Cook, Kevin R

2012-01-01

Chromosomal deletions are used extensively in Drosophila melanogaster genetics research. Deletion mapping is the primary method used for fine-scale gene localization. Effective and efficient deletion mapping requires both extensive genomic coverage and a high density of molecularly defined breakpoints across the genome. A large-scale resource development project at the Bloomington Drosophila Stock Center has improved the choice of deletions beyond that provided by previous projects. FLP-mediated recombination between FRT-bearing transposon insertions was used to generate deletions, because it is efficient and provides single-nucleotide resolution in planning deletion screens. The 793 deletions generated pushed coverage of the euchromatic genome to 98.4%. Gaps in coverage contain haplolethal and haplosterile genes, but the sizes of these gaps were minimized by flanking these genes as closely as possible with deletions. In improving coverage, a complete inventory of haplolethal and haplosterile genes was generated and extensive information on other haploinsufficient genes was compiled. To aid mapping experiments, a subset of deletions was organized into a Deficiency Kit to provide maximal coverage efficiently. To improve the resolution of deletion mapping, screens were planned to distribute deletion breakpoints evenly across the genome. The median chromosomal interval between breakpoints now contains only nine genes and 377 intervals contain only single genes. Drosophila melanogaster now has the most extensive genomic deletion coverage and breakpoint subdivision as well as the most comprehensive inventory of haploinsufficient genes of any multicellular organism. The improved selection of chromosomal deletion strains will be useful to nearly all Drosophila researchers.

Random mtDNA mutations modulate proliferation capacity in mouse embryonic fibroblasts

International Nuclear Information System (INIS)

Kukat, Alexandra; Edgar, Daniel; Bratic, Ivana; Maiti, Priyanka; Trifunovic, Aleksandra

2011-01-01

Highlights: → Increased mtDNA mutations in MEFs lead to high level of spontaneous immortalization. → This process is independent of endogenous ROS production. → Aerobic glycolysis significantly contributes to spontaneous immortalization of MEFs. -- Abstract: An increase in mtDNA mutation load leads to a loss of critical cells in different tissues thereby contributing to the physiological process of organismal ageing. Additionally, the accumulation of senescent cells that display changes in metabolic function might act in an active way to further disrupt the normal tissue function. We believe that this could be the important link missing in our understanding of the molecular mechanisms of premature ageing in the mtDNA mutator mice. We tested proliferation capacity of mtDNA mutator cells in vitro. When cultured in physiological levels of oxygen (3%) their proliferation capacity is somewhat lower than wild-type cells. Surprisingly, in conditions of increased oxidative stress (20% O 2 ) mtDNA mutator mouse embryonic fibroblasts exhibit continuous proliferation due to spontaneous immortalization, whereas the same conditions promote senescence in wild-type cells. We believe that an increase in aerobic glycolysis observed in mtDNA mutator mice is a major mechanism behind this process. We propose that glycolysis promotes proliferation and allows a fast turnover of metabolites, but also leads to energy crisis due to lower ATP production rate. This could lead to compromised replication and/or repair and therefore, in rare cases, might lead to mutations in tumor suppressor genes and spontaneous immortalization.

Mitochondrial depolarization in yeast zygotes inhibits clonal expansion of selfish mtDNA.

Science.gov (United States)

Karavaeva, Iuliia E; Golyshev, Sergey A; Smirnova, Ekaterina A; Sokolov, Svyatoslav S; Severin, Fedor F; Knorre, Dmitry A

2017-04-01

Non-identical copies of mitochondrial DNA (mtDNA) compete with each other within a cell and the ultimate variant of mtDNA present depends on their relative replication rates. Using yeast Saccharomyces cerevisiae cells as a model, we studied the effects of mitochondrial inhibitors on the competition between wild-type mtDNA and mutant selfish mtDNA in heteroplasmic zygotes. We found that decreasing mitochondrial transmembrane potential by adding uncouplers or valinomycin changes the competition outcomes in favor of the wild-type mtDNA. This effect was significantly lower in cells with disrupted mitochondria fission or repression of the autophagy-related genes ATG8 , ATG32 or ATG33 , implying that heteroplasmic zygotes activate mitochondrial degradation in response to the depolarization. Moreover, the rate of mitochondrially targeted GFP turnover was higher in zygotes treated with uncoupler than in haploid cells or untreated zygotes. Finally, we showed that vacuoles of zygotes with uncoupler-activated autophagy contained DNA. Taken together, our data demonstrate that mitochondrial depolarization inhibits clonal expansion of selfish mtDNA and this effect depends on mitochondrial fission and autophagy. These observations suggest an activation of mitochondria quality control mechanisms in heteroplasmic yeast zygotes. © 2017. Published by The Company of Biologists Ltd.

Fast detection of deletion breakpoints using quantitative PCR

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Gulshara Abildinova

2016-01-01

Full Text Available Abstract The routine detection of large and medium copy number variants (CNVs is well established. Hemizygotic deletions or duplications in the large Duchenne muscular dystrophy DMD gene responsible for Duchenne and Becker muscular dystrophies are routinely identified using multiple ligation probe amplification and array-based comparative genomic hybridization. These methods only map deleted or duplicated exons, without providing the exact location of breakpoints. Commonly used methods for the detection of CNV breakpoints include long-range PCR and primer walking, their success being limited by the deletion size, GC content and presence of DNA repeats. Here, we present a strategy for detecting the breakpoints of medium and large CNVs regardless of their size. The hemizygous deletion of exons 45-50 in the DMD gene and the large autosomal heterozygous PARK2 deletion were used to demonstrate the workflow that relies on real-time quantitative PCR to narrow down the deletion region and Sanger sequencing for breakpoint confirmation. The strategy is fast, reliable and cost-efficient, making it amenable to widespread use in genetic laboratories.

Schizophrenia Spectrum Disorders in a Danish 22q11.2 Deletion Syndrome Cohort Compared to the Total Danish Population-A Nationwide Register Study

DEFF Research Database (Denmark)

Vangkilde, Anders; Olsen, Line; Hoeffding, Louise K

2016-01-01

OBJECTIVE: Cross-sectional studies have shown associations between 22q11.2 deletion syndrome and schizophrenia. However, large-scale prospective studies have been lacking. We, therefore, conducted the first large-scale population based study on the risk of being diagnosed with schizophrenia...... in persons identified with 22q11.2 deletion syndrome. METHODS: Danish nationwide registers were linked to establish a cohort consisting of all Danish citizens born during 1955-2004 and the cohort was followed from January 1, 1994 until December 31, 2013. Data were analyzed using survival analyses...... and adjusted for calendar year, age, sex, and parental mental health history. RESULTS: A total of 156 individuals with 22q11.2 deletion syndrome were identified, out of which 6 individuals were diagnosed with schizophrenia spectrum disorders following identification with 22q11 deletion syndrome. Identified...

Evidence of animal mtDNA recombination between divergent populations of the potato cyst nematode Globodera pallida.

Science.gov (United States)

Hoolahan, Angelique H; Blok, Vivian C; Gibson, Tracey; Dowton, Mark

2012-03-01

Recombination is typically assumed to be absent in animal mitochondrial genomes (mtDNA). However, the maternal mode of inheritance means that recombinant products are indistinguishable from their progenitor molecules. The majority of studies of mtDNA recombination assess past recombination events, where patterns of recombination are inferred by comparing the mtDNA of different individuals. Few studies assess contemporary mtDNA recombination, where recombinant molecules are observed as direct mosaics of known progenitor molecules. Here we use the potato cyst nematode, Globodera pallida, to investigate past and contemporary recombination. Past recombination was assessed within and between populations of G. pallida, and contemporary recombination was assessed in the progeny of experimental crosses of these populations. Breeding of genetically divergent organisms may cause paternal mtDNA leakage, resulting in heteroplasmy and facilitating the detection of recombination. To assess contemporary recombination we looked for evidence of recombination between the mtDNA of the parental populations within the mtDNA of progeny. Past recombination was detected between a South American population and several UK populations of G. pallida, as well as between two South American populations. This suggests that these populations may have interbred, paternal mtDNA leakage occurred, and the mtDNA of these populations subsequently recombined. This evidence challenges two dogmas of animal mtDNA evolution; no recombination and maternal inheritance. No contemporary recombination between the parental populations was detected in the progeny of the experimental crosses. This supports current arguments that mtDNA recombination events are rare. More sensitive detection methods may be required to adequately assess contemporary mtDNA recombination in animals.

Minding the gap: Frequency of indels in mtDNA control region sequence data and influence on population genetic analyses

Science.gov (United States)

Pearce, J.M.

2006-01-01

Insertions and deletions (indels) result in sequences of various lengths when homologous gene regions are compared among individuals or species. Although indels are typically phylogenetically informative, occurrence and incorporation of these characters as gaps in intraspecific population genetic data sets are rarely discussed. Moreover, the impact of gaps on estimates of fixation indices, such as FST, has not been reviewed. Here, I summarize the occurrence and population genetic signal of indels among 60 published studies that involved alignments of multiple sequences from the mitochondrial DNA (mtDNA) control region of vertebrate taxa. Among 30 studies observing indels, an average of 12% of both variable and parsimony-informative sites were composed of these sites. There was no consistent trend between levels of population differentiation and the number of gap characters in a data block. Across all studies, the average influence on estimates of ??ST was small, explaining only an additional 1.8% of among population variance (range 0.0-8.0%). Studies most likely to observe an increase in ??ST with the inclusion of gap characters were those with control region DNA appears small, dependent upon total number of variable sites in the data block, and related to species-specific characteristics and the spatial distribution of mtDNA lineages that contain indels. ?? 2006 Blackwell Publishing Ltd.

Partial deletion 11q

DEFF Research Database (Denmark)

Hertz, Jens Michael; Tommerup, N; Sørensen, F B

1995-01-01

We describe the cytogenetic findings and the dysmorphic features in a stillborn girl with a large de novo terminal deletion of the long arm of chromosome 11. The karyotype was 46,XX,del(11)(q21qter). By reviewing previous reports of deletion 11q, we found that cleft lip and palate are most...

The mitochondrial outer membrane protein MDI promotes local protein synthesis and mtDNA replication.

Science.gov (United States)

Zhang, Yi; Chen, Yong; Gucek, Marjan; Xu, Hong

2016-05-17

Early embryonic development features rapid nuclear DNA replication cycles, but lacks mtDNA replication. To meet the high-energy demands of embryogenesis, mature oocytes are furnished with vast amounts of mitochondria and mtDNA However, the cellular machinery driving massive mtDNA replication in ovaries remains unknown. Here, we describe a Drosophila AKAP protein, MDI that recruits a translation stimulator, La-related protein (Larp), to the mitochondrial outer membrane in ovaries. The MDI-Larp complex promotes the synthesis of a subset of nuclear-encoded mitochondrial proteins by cytosolic ribosomes on the mitochondrial surface. MDI-Larp's targets include mtDNA replication factors, mitochondrial ribosomal proteins, and electron-transport chain subunits. Lack of MDI abolishes mtDNA replication in ovaries, which leads to mtDNA deficiency in mature eggs. Targeting Larp to the mitochondrial outer membrane independently of MDI restores local protein synthesis and rescues the phenotypes of mdi mutant flies. Our work suggests that a selective translational boost by the MDI-Larp complex on the outer mitochondrial membrane might be essential for mtDNA replication and mitochondrial biogenesis during oogenesis. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

The amount and integrity of mtDNA in maize decline with development.

Science.gov (United States)

Oldenburg, Delene J; Kumar, Rachana A; Bendich, Arnold J

2013-02-01

In maize and other grasses there is a developmental gradient from the meristematic cells at the base of the stalk to the differentiated cells at the leaf tip. This gradient presents an opportunity to investigate changes in mitochondrial DNA (mtDNA) that accompany growth under light and dark conditions, as done previously for plastid DNA. Maize mtDNA was analyzed by DAPI-DNA staining of individual mitochondria, gel electrophoresis/blot hybridization, and real-time qPCR. Both the amount and integrity of the mtDNA were found to decline with development. There was a 20-fold decline in mtDNA copy number per cell from the embryo to the light-grown leaf blade. The amount of DNA per mitochondrial particle was greater in dark-grown leaf blade (24 copies, on average) than in the light (2 copies), with some mitochondria lacking any detectable DNA. Three factors that influence the demise of mtDNA during development are considered: (1) the decision to either repair or degrade mtDNA molecules that are damaged by the reactive oxygen species produced as byproducts of respiration; (2) the generation of ATP by photophosphorylation in chloroplasts, reducing the need for respiratory-competent mitochondria; and (3) the shift in mitochondrial function from energy-generating respiration to photorespiration during the transition from non-green to green tissue.

Screening for large genomic rearrangements in the FANCA gene reveals extensive deletion in a Finnish breast cancer family.

Science.gov (United States)

Solyom, Szilvia; Winqvist, Robert; Nikkilä, Jenni; Rapakko, Katrin; Hirvikoski, Pasi; Kokkonen, Hannaleena; Pylkäs, Katri

2011-03-28

A portion of familial breast cancer cases are caused by mutations in the same genes that are inactivated in the downstream part of Fanconi anemia (FA) signaling pathway. Here we have assessed the FANCA gene for breast cancer susceptibility by examining blood DNA for aberrations from 100 Northern Finnish breast cancer families using the MLPA method. We identified a novel heterozygous deletion, removing the promoter and 12 exons of the gene in one family. This allele was absent from 124 controls. We conclude that FANCA deletions might contribute to breast cancer susceptibility, potentially in combination with other germline mutations. To our knowledge, this is the first study reporting a large deletion in an upstream FA gene in familial breast cancer. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Mitochondrial DNA deletion in a patient with combined features of Leigh and Pearson syndromes

Energy Technology Data Exchange (ETDEWEB)

Blok, R.B.; Thorburn, D.R.; Danks, D.M. [Royal Children`s Hospital, Melbourne (Australia)] [and others

1994-09-01

We describe a heteroplasmic 4237 bp mitochondrial DNA (mtDNA) deletion in an 11 year old girl who has suffered from progressive illness since birth. She has some features of Leigh syndrome (global developmental delay with regression, brainstem dysfunction and lactic acidosis), together with other features suggestive of Pearson syndrome (history of pancytopenia and failure to thrive). The deletion was present at a level greater than 50% in skeletal muscle, but barely detectable in skin fibroblasts following Southern blot analysis, and only observed in blood following PCR analysis. The deletion spanned nt 9498 to nt 13734, and was flanked by a 12 bp direct repeat. Genes for cytochrome c oxidase subunit III, NADH dehydrogenase subunits 3, 4L, 4 and 5, and tRNAs for glycine, arginine, histidine, serine({sup AGY}) and leucine({sup CUN}) were deleted. Southern blotting also revealed an altered Apa I restriction site which was shown by sequence analysis to be caused by G{r_arrow}A nucleotide substitution at nt 1462 in the 12S rRNA gene. This was presumed to be a polymorphism. No abnormalities of mitochondrial ultrastructure, distribution or of respiratory chain enzyme complexes I-IV in skeletal muscle were observed. Mitochondrial disorders with clinical features overlapping more than one syndrome have been reported previously. This case further demonstrates the difficulty in correlating observed clinical features with a specific mitochondrial DNA mutation.

Energy transfers in large-scale and small-scale dynamos

Science.gov (United States)

Samtaney, Ravi; Kumar, Rohit; Verma, Mahendra

2015-11-01

We present the energy transfers, mainly energy fluxes and shell-to-shell energy transfers in small-scale dynamo (SSD) and large-scale dynamo (LSD) using numerical simulations of MHD turbulence for Pm = 20 (SSD) and for Pm = 0.2 on 10243 grid. For SSD, we demonstrate that the magnetic energy growth is caused by nonlocal energy transfers from the large-scale or forcing-scale velocity field to small-scale magnetic field. The peak of these energy transfers move towards lower wavenumbers as dynamo evolves, which is the reason for the growth of the magnetic fields at the large scales. The energy transfers U2U (velocity to velocity) and B2B (magnetic to magnetic) are forward and local. For LSD, we show that the magnetic energy growth takes place via energy transfers from large-scale velocity field to large-scale magnetic field. We observe forward U2U and B2B energy flux, similar to SSD.

Analysis of large deletions in BRCA1, BRCA2 and PALB2 genes in Finnish breast and ovarian cancer families

International Nuclear Information System (INIS)

Pylkäs, Katri; Erkko, Hannele; Nikkilä, Jenni; Sólyom, Szilvia; Winqvist, Robert

2008-01-01

BRCA1 and BRCA2 are the two most important genes associated with familial breast and ovarian cancer susceptibility. In addition, PALB2 has recently been identified as a breast cancer susceptibility gene in several populations. Here we have evaluated whether large genomic rearrangement in these genes could explain some of Finnish breast and/or ovarian cancer families. Altogether 61 index patients of Northern Finnish breast and/or ovarian cancer families were analyzed by Multiplex ligation-dependent probe amplification (MLPA) method in order to identify exon deletions and duplications in BRCA1, BRCA2 and PALB2. The families have been comprehensively screened for germline mutation in these genes by conventional methods of mutation analysis and were found negative. We identified one large deletion in BRCA1, deleting the most part of the gene (exon 1A-13) in one family with family history of ovarian cancer. No large genomic rearrangements were identified in either BRCA2 or PALB2. In Finland, women eligible for BRCA1 or BRCA2 mutation screening, when found negative, could benefit from screening for large genomic rearrangements at least in BRCA1. On the contrary, the genomic rearrangements in PALB2 seem not to contribute to the hereditary breast cancer susceptibility

Characterization of Hb Bart's Hydrops Fetalis Caused by - -SEA and a Large Novel α0-Thalassemia Deletion.

Science.gov (United States)

He, Sheng; Li, Jihui; Huang, Peng; Zhang, Shujie; Lin, Li; Zuo, Yangjin; Tian, Xiaoxian; Zheng, Chenguang; Qiu, Xiaoxia; Chen, Biyan

2018-01-01

Hb Bart's hydrops fetalis is the most severe and generally fatal clinical phenotype of α-thalassemia (α-thal), which is due to the deletion of all four functional α-globin genes of hemoglobin (Hb), resulting in no α-globin chain production (- -/- -). Homozygosity for the - - SEA (Southeast Asian) α-globin gene deletion is the main cause of the Hb Bart's hydrops fetalis in Asia, especially South China. Occasionally, other α 0 -thal deletions can also be found. In this study, we report a case with an atypical form of Hb Bart's hydrops fetalis that was caused by - - SEA and a large novel α 0 -thal deletion (- - GX ) (Guangxi). The fetus with Hb Bart's in our study presented fetal hydrops features in early gestation which was different from that of traditional Hb Bart's hydrops fetalis with a homozygous - - SEA deletion. The early onset of fetal hydrops is attributed to the decreased formation of embryonic Hb Portland (ζ2γ2), which is proposed as a candidate for reactivation in cases of severe α-thal. Our findings indicated that it was important to characterize new or rare mutations, and highlighted the significance of using ultrasonography to identify signs of Hb Bart's hydrops fetalis.

[Whole Genome Sequencing of Human mtDNA Based on Ion Torrent PGM™ Platform].

Science.gov (United States)

Cao, Y; Zou, K N; Huang, J P; Ma, K; Ping, Y

2017-08-01

To analyze and detect the whole genome sequence of human mitochondrial DNA （mtDNA） by Ion Torrent PGM™ platform and to study the differences of mtDNA sequence in different tissues. Samples were collected from 6 unrelated individuals by forensic postmortem examination, including chest blood, hair, costicartilage, nail, skeletal muscle and oral epithelium. Amplification of whole genome sequence of mtDNA was performed by 4 pairs of primer. Libraries were constructed with Ion Shear™ Plus Reagents kit and Ion Plus Fragment Library kit. Whole genome sequencing of mtDNA was performed using Ion Torrent PGM™ platform. Sanger sequencing was used to determine the heteroplasmy positions and the mutation positions on HVⅠ region. The whole genome sequence of mtDNA from all samples were amplified successfully. Six unrelated individuals belonged to 6 different haplotypes. Different tissues in one individual had heteroplasmy difference. The heteroplasmy positions and the mutation positions on HVⅠ region were verified by Sanger sequencing. After a consistency check by the Kappa method, it was found that the results of mtDNA sequence had a high consistency in different tissues. The testing method used in present study for sequencing the whole genome sequence of human mtDNA can detect the heteroplasmy difference in different tissues, which have good consistency. The results provide guidance for the further applications of mtDNA in forensic science. Copyright© by the Editorial Department of Journal of Forensic Medicine

Estimates of Continental Ancestry Vary Widely among Individuals with the Same mtDNA Haplogroup

Science.gov (United States)

Emery, Leslie S.; Magnaye, Kevin M.; Bigham, Abigail W.; Akey, Joshua M.; Bamshad, Michael J.

2015-01-01

The association between a geographical region and an mtDNA haplogroup(s) has provided the basis for using mtDNA haplogroups to infer an individual’s place of origin and genetic ancestry. Although it is well known that ancestry inferences using mtDNA haplogroups and those using genome-wide markers are frequently discrepant, little empirical information exists on the magnitude and scope of such discrepancies between multiple mtDNA haplogroups and worldwide populations. We compared genetic-ancestry inferences made by mtDNA-haplogroup membership to those made by autosomal SNPs in ∼940 samples of the Human Genome Diversity Panel and recently admixed populations from the 1000 Genomes Project. Continental-ancestry proportions often varied widely among individuals sharing the same mtDNA haplogroup. For only half of mtDNA haplogroups did the highest average continental-ancestry proportion match the highest continental-ancestry proportion of a majority of individuals with that haplogroup. Prediction of an individual’s mtDNA haplogroup from his or her continental-ancestry proportions was often incorrect. Collectively, these results indicate that for most individuals in the worldwide populations sampled, mtDNA-haplogroup membership provides limited information about either continental ancestry or continental region of origin. PMID:25620206

PCR detection of retinoblastoma gene deletions in radiation-induced mouse lung adenocarcinomas

International Nuclear Information System (INIS)

Churchill, M.E.; Gemmell, M.A.; Woloschak, G.E.

1994-01-01

From 1971--1986, Argonne National Laboratory conducted a series of large-scale studies of tumor incidence in 40,000 BCF 1 mice irradiated with 60 Co γ-rays or JANUS fission-spectrum neutrons. Polymerase chain reaction (PCR) technique was used to detect deletions in the mouse retinoblastoma (mRb) gene. Six mRb gene exon fragments were amplified in a 40-cycle, 3-temperature PCR protocol. Absence of any of these fragments on a Southern blot indicated a deletion of that portion of the mRb gene. Tumors chosen for analysis were lung adenocarcinomas that were judged to be the cause of death in post-mortem analyses. Spontaneous tumors as well as those from irradiated mice were analyzed for mRb deletions. In all normal mouse tissues studies all six mRb exon fragments were present on Southern blots. Tumors in six neutron-irradiated mice also had no mRb deletions. However, 1 of 6 tumors from γ-irradiated mice and 6 of 18 spontaneous tumors from unirradiated mice showed a deletion in one or both mRb alleles. All deletions detected were in the 5' region of the mRb gene

Quantum deletion: Beyond the no-deletion principle

International Nuclear Information System (INIS)

Adhikari, Satyabrata

2005-01-01

Suppose we are given two identical copies of an unknown quantum state and we wish to delete one copy from among the given two copies. The quantum no-deletion principle restricts us from perfectly deleting a copy but it does not prohibit us from deleting a copy approximately. Here we construct two types of a 'universal quantum deletion machine' which approximately deletes a copy such that the fidelity of deletion does not depend on the input state. The two types of universal quantum deletion machines are (1) a conventional deletion machine described by one unitary operator and (2) a modified deletion machine described by two unitary operators. Here it is shown that the modified deletion machine deletes a qubit with fidelity 3/4, which is the maximum limit for deleting an unknown quantum state. In addition to this we also show that the modified deletion machine retains the qubit in the first mode with average fidelity 0.77 (approx.) which is slightly greater than the fidelity of measurement for two given identical states, showing how precisely one can determine its state [S. Massar and S. Popescu, Phys. Rev. Lett. 74, 1259 (1995)]. We also show that the deletion machine itself is input state independent, i.e., the information is not hidden in the deleting machine, and hence we can delete the information completely from the deletion machine

No variation and low synonymous substitution rates in coral mtDNA despite high nuclear variation

Directory of Open Access Journals (Sweden)

Hellberg Michael E

2006-03-01

Full Text Available Abstract Background The mitochondrial DNA (mtDNA of most animals evolves more rapidly than nuclear DNA, and often shows higher levels of intraspecific polymorphism and population subdivision. The mtDNA of anthozoans (corals, sea fans, and their kin, by contrast, appears to evolve slowly. Slow mtDNA evolution has been reported for several anthozoans, however this slow pace has been difficult to put in phylogenetic context without parallel surveys of nuclear variation or calibrated rates of synonymous substitution that could permit quantitative rate comparisons across taxa. Here, I survey variation in the coding region of a mitochondrial gene from a coral species (Balanophyllia elegans known to possess high levels of nuclear gene variation, and estimate synonymous rates of mtDNA substitution by comparison to another coral (Tubastrea coccinea. Results The mtDNA surveyed (630 bp of cytochrome oxidase subunit I was invariant among individuals sampled from 18 populations spanning 3000 km of the range of B. elegans, despite high levels of variation and population subdivision for allozymes over these same populations. The synonymous substitution rate between B. elegans and T. coccinea (0.05%/site/106 years is similar to that in most plants, but 50–100 times lower than rates typical for most animals. In addition, while substitutions to mtDNA in most animals exhibit a strong bias toward transitions, mtDNA from these corals does not. Conclusion Slow rates of mitochondrial nucleotide substitution result in low levels of intraspecific mtDNA variation in corals, even when nuclear loci vary. Slow mtDNA evolution appears to be the basal condition among eukaryotes. mtDNA substitution rates switch from slow to fast abruptly and unidirectionally. This switch may stem from the loss of just one or a few mitochondrion-specific DNA repair or replication genes.

Large-scale data analytics

CERN Document Server

Gkoulalas-Divanis, Aris

2014-01-01

Provides cutting-edge research in large-scale data analytics from diverse scientific areas Surveys varied subject areas and reports on individual results of research in the field Shares many tips and insights into large-scale data analytics from authors and editors with long-term experience and specialization in the field

The mtDNA haplogroup P of modern Asian cattle: A genetic legacy of Asian aurochs?

Science.gov (United States)

Noda, Aoi; Yonesaka, Riku; Sasazaki, Shinji

2018-01-01

Background Aurochs (Bos primigenius) were distributed throughout large parts of Eurasia and Northern Africa during the late Pleistocene and the early Holocene, and all modern cattle are derived from the aurochs. Although the mtDNA haplogroups of most modern cattle belong to haplogroups T and I, several additional haplogroups (P, Q, R, C and E) have been identified in modern cattle and aurochs. Haplogroup P was the most common haplogroup in European aurochs, but so far, it has been identified in only three of >3,000 submitted haplotypes of modern Asian cattle. Methodology We sequenced the complete mtDNA D-loop region of 181 Japanese Shorthorn cattle and analyzed these together with representative bovine mtDNA sequences. The haplotype P of Japanese Shorthorn cattle was analyzed along with that of 36 previously published European aurochs and three modern Asian cattle sequences using the hypervariable 410 bp of the D-loop region. Conclusions We detected the mtDNA haplogroup P in Japanese Shorthorn cattle with an extremely high frequency (83/181). Phylogenetic networks revealed two main clusters, designated as Pa for haplogroup P in European aurochs and Pc in modern Asian cattle. We also report the genetic diversity of haplogroup P compared with the sequences of extinct aurochs. No shared haplotypes are observed between the European aurochs and the modern Asian cattle. This finding suggests the possibility of local and secondary introgression events of haplogroup P in northeast Asian cattle, and will contribute to a better understanding of its origin and genetic diversity. PMID:29304129

The mtDNA haplogroup P of modern Asian cattle: A genetic legacy of Asian aurochs?

Science.gov (United States)

Noda, Aoi; Yonesaka, Riku; Sasazaki, Shinji; Mannen, Hideyuki

2018-01-01

Aurochs (Bos primigenius) were distributed throughout large parts of Eurasia and Northern Africa during the late Pleistocene and the early Holocene, and all modern cattle are derived from the aurochs. Although the mtDNA haplogroups of most modern cattle belong to haplogroups T and I, several additional haplogroups (P, Q, R, C and E) have been identified in modern cattle and aurochs. Haplogroup P was the most common haplogroup in European aurochs, but so far, it has been identified in only three of >3,000 submitted haplotypes of modern Asian cattle. We sequenced the complete mtDNA D-loop region of 181 Japanese Shorthorn cattle and analyzed these together with representative bovine mtDNA sequences. The haplotype P of Japanese Shorthorn cattle was analyzed along with that of 36 previously published European aurochs and three modern Asian cattle sequences using the hypervariable 410 bp of the D-loop region. We detected the mtDNA haplogroup P in Japanese Shorthorn cattle with an extremely high frequency (83/181). Phylogenetic networks revealed two main clusters, designated as Pa for haplogroup P in European aurochs and Pc in modern Asian cattle. We also report the genetic diversity of haplogroup P compared with the sequences of extinct aurochs. No shared haplotypes are observed between the European aurochs and the modern Asian cattle. This finding suggests the possibility of local and secondary introgression events of haplogroup P in northeast Asian cattle, and will contribute to a better understanding of its origin and genetic diversity.

Characterization of a large deletion in the {beta}-globin gene cluster in a newborn with hemoglobin FE

Energy Technology Data Exchange (ETDEWEB)

Louie, E.; Dietz, L.; Shafer, F. [Children`s Hosptial, Oakland, CA (United States)] [and others

1994-09-01

A sample on a newborn with hemoglobin FE screen results was obtained to investigate whether E/E or B/{beta}{degrees} thalassemia was present using polymerase chain reaction (PCR) methodology. The newborn appeared homozygous for the hemoglobin E mutation in our initial study, but the parents` genotypes did not support this diagnosis. The father is homozygous for the absence of the hemoglobin E mutation (non E/non E) and the mother is heterozygous (E/non E) for this mutation. The limitation of PCR analysis is an assumption that the amplification of the two {beta}-globin alleles is equivalent. A large deletion on one {beta}-globin gene, which would produce E/{beta}{degrees} thalassemia, would be missed if it included part or the entire region subjected to amplification. The family results were consistent with either non-paternity, sample mix-up or such a deletion of the {beta}-globin gene in the father and child. To rule out the possibility of non-paternity, two polymorphic loci (HLA on chromosome 6 and a VNTR system of chromosome 17) that are outside of the {beta}-globin gene were analyzed and show that inheritance is consistent and the likelihood of a sample mix-up is then reduced. We therefore believe there is a gene deletion in this family. At the present time, analyses of the RFLPs that are 5{prime} of the {beta}-globin gene cluster show that the polymorphisms most distal from the 5{prime} {beta}-globin gene are not being inherited as expected. These results support our interpretation that a deletion exists in the father and was inherited by the child. The father`s clinical picture of possible HPFH (the father has 12% hemoglobin F) also supports the interpretation of a deletion in this family. Deletions of the {beta}-globin gene within this ethnic group are rare. Currently, Southern blots on the family are being probed to determine the extent of the putative deletion.

A Large PROP1 Gene Deletion in a Turkish Pedigree

Directory of Open Access Journals (Sweden)

Suheyla Gorar

2018-01-01

Full Text Available Pituitary-specific paired-like homeodomain transcription factor, PROP1, is associated with multiple pituitary hormone deficiency. Alteration of the gene encoding the PROP1 may affect somatotropes, thyrotropes, and lactotropes, as well as gonadotropes and corticotropes. We performed genetic analysis of PROP1 gene in a Turkish pedigree with three siblings who presented with short stature. Parents were first degree cousins. Index case, a boy, had somatotrope, gonadotrope, thyrotrope, and corticotrope deficiency. However, two elder sisters had somatotroph, gonadotroph, and thyrotroph deficiency and no corticotroph deficiency. On pituitary magnetic resonance, partial empty sella was detected with normal bright spot in all siblings. In genetic analysis, we found a gross deletion involving PROP1 coding region. In conclusion, we report three Turkish siblings with a gross deletion in PROP1 gene. Interestingly, although little boy with combined pituitary hormone deficiency has adrenocorticotropic hormone (ACTH deficiency, his elder sisters with the same gross PROP1 deletion have no ACTH deficiency. This finding is in line with the fact that patients with PROP1 mutations may have different phenotype/genotype correlation.

Large-scale grid management

International Nuclear Information System (INIS)

Langdal, Bjoern Inge; Eggen, Arnt Ove

2003-01-01

The network companies in the Norwegian electricity industry now have to establish a large-scale network management, a concept essentially characterized by (1) broader focus (Broad Band, Multi Utility,...) and (2) bigger units with large networks and more customers. Research done by SINTEF Energy Research shows so far that the approaches within large-scale network management may be structured according to three main challenges: centralization, decentralization and out sourcing. The article is part of a planned series

Defining mtDNA origins and population stratification in Rio de Janeiro.

Science.gov (United States)

Simão, Filipa; Ferreira, Ana Paula; de Carvalho, Elizeu Fagundes; Parson, Walther; Gusmão, Leonor

2018-05-01

The genetic composition of the Brazilian population was shaped by interethnic admixture between autochthonous Native Americans, Europeans settlers and African slaves. This structure, characteristic of most American populations, implies the need for large population forensic databases to capture the high diversity that is usually associated with admixed populations. In the present work, we sequenced the control region of mitochondrial DNA from 205 non-related individuals living in the Rio de Janeiro metropolitan region. Overall high haplotype diversity (0.9994 ± 0.0006) was observed, and pairwise comparisons showed a high proportion of haplotype pairs with more than one-point differences. When ignoring homopolymeric tracts, pairwise comparisons showed no differences 0.18% of the time, and differences in a single position were found with a frequency of 0.32%. A high percentage of African mtDNA was found (42%), with lineages showing a major South West origin. For the West Eurasian and Native American haplogroups (representing 32% and 26%, respectively) it was not possible to evaluate a clear geographic or linguistic affiliation. When grouping the mtDNA lineages according to their continental origin (Native American, European and African), differences were observed for the ancestry proportions estimated with autosomal ancestry-informative markers, suggesting some level of genetic substructure. The results from this study are in accordance with historical data where admixture processes are confirmed with a strong maternal contribution of African maternal ancestry and a relevant contribution of Native American maternal ancestry. Moreover, the evidence for some degree of association between mtDNA and autosomal information should be considered when combining these types of markers in forensic analysis. Copyright © 2018 Elsevier B.V. All rights reserved.

Restricted gene flow at the micro- and macro-geographical scale in marble trout based on mtDNA and microsatellite polymorphism

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Patarnello Tomaso

2011-04-01

Full Text Available Abstract Background The genetic structure of the marble trout Salmo trutta marmoratus, an endemic salmonid of northern Italy and the Balkan peninsula, was explored at the macro- and micro-scale level using a combination of mitochondrial DNA (mtDNA and microsatellite data. Results Sequence variation in the mitochondrial control region showed the presence of nonindigenous haplotypes indicative of introgression from brown trout into marble trout. This was confirmed using microsatellite markers, which showed a higher introgression at nuclear level. Microsatellite loci revealed a strong genetic differentiation across the geographical range of marble trout, which suggests restricted gene flow both at the micro-geographic (within rivers and macro-geographic (among river systems scale. A pattern of Isolation-by-Distance was found, in which genetic samples were correlated with hydrographic distances. A general West-to-East partition of the microsatellite polymorphism was observed, which was supported by the geographic distribution of mitochondrial haplotypes. Conclusion While introgression at both mitochondrial and nuclear level is unlikely to result from natural migration and might be the consequence of current restocking practices, the pattern of genetic substructuring found at microsatellites has been likely shaped by historical colonization patterns determined by the geological evolution of the hydrographic networks.

Ethics of large-scale change

OpenAIRE

Arler, Finn

2006-01-01

  The subject of this paper is long-term large-scale changes in human society. Some very significant examples of large-scale change are presented: human population growth, human appropriation of land and primary production, the human use of fossil fuels, and climate change. The question is posed, which kind of attitude is appropriate when dealing with large-scale changes like these from an ethical point of view. Three kinds of approaches are discussed: Aldo Leopold's mountain thinking, th...

Reduced Mtdna Diversity in the Ngobe Amerinds of Panama

Science.gov (United States)

Kolman, C. J.; Bermingham, E.; Cooke, R.; Ward, R. H.; Arias, T. D.; Guionneau-Sinclair, F.

1995-01-01

Mitochondrial DNA (mtDNA) haplotype diversity was determined for 46 Ngobe Amerinds sampled widely across their geographic range in western Panama. The Ngobe data were compared with mtDNA control region I sequences from two additional Amerind groups located at the northern and southern extremes of Amerind distribution, the Nuu-Chah-Nulth of the Pacific Northwest and the Chilean Mapuche and from one Na-Dene group, the Haida of the Pacific Northwest. The Ngobe exhibit the lowest mtDNA control region sequence diversity yet reported for an Amerind group. Moreover, they carry only two of the four Amerind founding lineages first described by Wallace and coworkers. We posit that the Ngobe passed through a population bottleneck caused by ethnogenesis from a small founding population and/or European conquest and colonization. Dating of the Ngobe population expansion using the HARPENDING et al. approach to the analysis of pairwise genetic differences indicates a Ngobe expansion at roughly 6800 years before present (range: 1850-14,000 years before present), a date more consistent with a bottleneck at Chibcha ethnogenesis than a conquest-based event. PMID:7635293

Characterization of mtDNA haplogroups in 14 Mexican indigenous populations.

Science.gov (United States)

Peñaloza-Espinosa, Rosenda I; Arenas-Aranda, Diego; Cerda-Flores, Ricardo M; Buentello-Malo, Leonor; González-Valencia, Gerardo; Torres, Javier; Alvarez, Berenice; Mendoza, Irma; Flores, Mario; Sandoval, Lucila; Loeza, Francisco; Ramos, Irma; Muñoz, Leopoldo; Salamanca, Fabio

2007-06-01

In this descriptive study we investigated the genetic structure of 513 Mexican indigenous subjects grouped in 14 populations (Mixteca-Alta, Mixteca-Baja, Otomi, Purépecha, Tzeltal, Tarahumara, Huichol, Nahua-Atocpan, Nahua-Xochimilco, Nahua-Zitlala, Nahua-Chilacachapa, Nahua-Ixhuatlancillo, Nahua-Necoxtla, and Nahua-Coyolillo) based on mtDNA haplogroups. These communities are geographically and culturally isolated; parents and grandparents were born in the community. Our data show that 98.6% of the mtDNA was distributed in haplogroups A1, A2, B1, B2, C1, C2, D1, and D2. Haplotype X6 was present in the Tarahumara (1/53) and Huichol (3/15), and haplotype L was present in the Nahua-Coyolillo (3/38). The first two principal components accounted for 95.9% of the total variation in the sample. The mtDNA haplogroup frequencies in the Purépecha and Zitlala were intermediate to cluster 1 (Otomi, Nahua-Ixhuatlancillo, Nahua-Xochimilco, Mixteca-Baja, and Tzeltal) and cluster 2 (Nahua-Necoxtla, Nahua-Atocpan, and Nahua-Chilacachapa). The Huichol, Tarahumara, Mixteca-Alta, and Nahua-Coyolillo were separated from the rest of the populations. According to these findings, the distribution of mtDNA haplogroups found in Mexican indigenous groups is similar to other Amerindian haplogroups, except for the African haplogroup found in one population.

DNA methyltransferase 1 mutations and mitochondrial pathology: is mtDNA methylated?

Directory of Open Access Journals (Sweden)

Alessandra eMaresca

2015-03-01

Full Text Available Autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN and Hereditary sensory neuropathy with dementia and hearing loss (HSN1E are two rare, overlapping neurodegenerative syndromes that have been recently linked to allelic dominant pathogenic mutations in the DNMT1 gene, coding for DNA (cytosine-5-methyltransferase 1. DNMT1 is the enzyme responsible for maintaining the nuclear genome methylation patterns during the DNA replication and repair, thus regulating gene expression. The mutations responsible for ADCA-DN and HSN1E affect the replication foci targeting sequence domain, which regulates DNMT1 binding to chromatin. DNMT1 dysfunction is anticipated to lead to a global alteration of the DNA methylation pattern with predictable downstream consequences on gene expression. Interestingly, ADCA-DN and HSN1E phenotypes share some clinical features typical of mitochondrial diseases, such as optic atrophy, peripheral neuropathy and deafness, and some biochemical evidence of mitochondrial dysfunction. The recent discovery of a mitochondrial isoform of DNMT1 and its proposed role in methylating mitochondrial DNA (mtDNA suggests that DNMT1 mutations may directly affect mtDNA and mitochondrial physiology. On the basis of this latter finding the link between DNMT1 abnormal activity and mitochondrial dysfunction in ADCA-DN and HSN1E appears intuitive, however mtDNA methylation remains highly debated. In the last years several groups demonstrated the presence of 5-methylcytosine in mtDNA by different approaches, but, on the other end, the opposite evidence that mtDNA is not methylated has also been published. Since over 1500 mitochondrial proteins are encoded by the nuclear genome, the altered methylation of these genes may well have a critical role in leading to the mitochondrial impairment observed in ADCA-DN and HSN1E. Thus, many open questions still remain unanswered, such as why mtDNA should be methylated, and how this process is

Novel 12S mtDNA findings in sloths (Pilosa, Folivora) and anteaters (Pilosa, Vermilingua) suggest a true case of long branch attraction

OpenAIRE

Barros, Maria Claudene; Sampaio, Iracilda; Schneider, Horacio

2008-01-01

We sequenced 12S RNA mtDNA for the majority of the extant species of sloths and anteaters and compared our results with previous data obtained by our group using 16S RNA mtDNA in the same specimens and to GenBank sequences of the extinct giant sloth Mylodon. Our results suggest that pigmy-anteaters may be a case of the long-branch attraction phenomenon and also show the large genetic difference between the Amazonian and Atlantic forest three-toed sloths, contrasting with the small differences...

Identification of a novel large intragenic deletion in a family with Fanconi anemia: first molecular report from India and review of literature.

Science.gov (United States)

Shukla, Pallavi; Rao, Anita; Ghosh, Kanjaksha; Vundinti, Babu Rao

2013-04-15

We report here an Indian case with Fanconi anemia (FA) presented with fever, pallor, short stature, hyperpigmentation and upper limb anomaly. Chromosome breakage analysis together with FANCD2 Western blot monoubiquitination assay confirmed the diagnosis as FA. Multiplex ligation-dependent probe amplification (MLPA) revealed a novel homozygous large intragenic deletion (exons 8-27 del) in the FANCA gene in the proband. His sib and parents were also analyzed and found to be heterozygous for the same mutation. We also reviewed the literature of FANCA large intragenic deletions found in FA patients from different countries and the mechanism involved in the formation of these deletions. To the best of our knowledge, this is the first molecular report from India on FA. The finding expands the mutation spectrum of the FANCA gene. Identification of the mutation confirms the diagnosis of FA at DNA level and helps in providing proper genetic counseling to the family. Copyright © 2013 Elsevier B.V. All rights reserved.

Political consultation and large-scale research

International Nuclear Information System (INIS)

Bechmann, G.; Folkers, H.

1977-01-01

Large-scale research and policy consulting have an intermediary position between sociological sub-systems. While large-scale research coordinates science, policy, and production, policy consulting coordinates science, policy and political spheres. In this very position, large-scale research and policy consulting lack of institutional guarantees and rational back-ground guarantee which are characteristic for their sociological environment. This large-scale research can neither deal with the production of innovative goods under consideration of rentability, nor can it hope for full recognition by the basis-oriented scientific community. Policy consulting knows neither the competence assignment of the political system to make decisions nor can it judge succesfully by the critical standards of the established social science, at least as far as the present situation is concerned. This intermediary position of large-scale research and policy consulting has, in three points, a consequence supporting the thesis which states that this is a new form of institutionalization of science: These are: 1) external control, 2) the organization form, 3) the theoretical conception of large-scale research and policy consulting. (orig.) [de

Large-scale multimedia modeling applications

International Nuclear Information System (INIS)

Droppo, J.G. Jr.; Buck, J.W.; Whelan, G.; Strenge, D.L.; Castleton, K.J.; Gelston, G.M.

1995-08-01

Over the past decade, the US Department of Energy (DOE) and other agencies have faced increasing scrutiny for a wide range of environmental issues related to past and current practices. A number of large-scale applications have been undertaken that required analysis of large numbers of potential environmental issues over a wide range of environmental conditions and contaminants. Several of these applications, referred to here as large-scale applications, have addressed long-term public health risks using a holistic approach for assessing impacts from potential waterborne and airborne transport pathways. Multimedia models such as the Multimedia Environmental Pollutant Assessment System (MEPAS) were designed for use in such applications. MEPAS integrates radioactive and hazardous contaminants impact computations for major exposure routes via air, surface water, ground water, and overland flow transport. A number of large-scale applications of MEPAS have been conducted to assess various endpoints for environmental and human health impacts. These applications are described in terms of lessons learned in the development of an effective approach for large-scale applications

Quantification of the mitochondrial DNA common deletion in presbycusis.

Science.gov (United States)

Markaryan, Adam; Nelson, Erik G; Hinojosa, Raul

2009-06-01

This study was conducted to evaluate the association between the mitochondrial DNA (mtDNA) common deletion (CD) level in cochlear tissue and the severity of hearing loss in individuals with presbycusis. Nineteen individuals with presbycusis, ranging from 60 to 87 years of age, who met strict audiometric criteria were compared with four age frequency-matched normal hearing controls ranging from 51 to 76 years of age. Five additional normal hearing individuals, ranging from 9 to 50 years of age, were also studied. A duplex real time polymerase chain reaction assay was used to quantify the mtDNA in archival cochlear tissue samples. Linear regression models were used for comparison of the CD level between groups. The presbycusis group had a mean CD level of 32% with a standard deviation of 14%, and the normal hearing age matched control group had a mean CD level of 12% with a standard deviation of 2%. This difference in CD levels reached statistical significance (P = .011) and remained significant after adjusting for any differences in age between the two groups (age-adjusted P = .007). Furthermore, there was evidence for a significant association between the CD level and the severity of hearing loss based on audiometric thresholds at 8 kHz (r = 0.44, P = .034; age-adjusted partial correlation = 0.55, P = .007). For the first time, to our knowledge, these results demonstrate a relationship between quantitatively measured levels of the CD in human cochlear tissue and the severity of hearing loss in individuals with presbycusis. Laryngoscope, 2009.

Alterations in mtDNA, gastric carcinogenesis and early diagnosis.

Science.gov (United States)

Rodrigues-Antunes, S; Borges, B N

2018-05-26

Gastric cancer remains one of the most prevalent cancers in the world. Due to this, efforts are being made to improve the diagnosis of this neoplasm and the search for molecular markers that may be involved in its genesis. Within this perspective, the mitochondrial DNA is considered as a potential candidate, since it has several well documented changes and is readily accessible. However, numerous alterations have been reported in mtDNA, not facilitating the visualization of which alterations and molecular markers are truly involved with gastric carcinogenesis. This review presents a compilation of the main known changes relating mtDNA to gastric cancer and their clinical significance.

Mitochondrial DNA mutations in mutator mice confer respiration defects and B-cell lymphoma development.

Directory of Open Access Journals (Sweden)

Takayuki Mito

Full Text Available Mitochondrial DNA (mtDNA mutator mice are proposed to express premature aging phenotypes including kyphosis and hair loss (alopecia due to their carrying a nuclear-encoded mtDNA polymerase with a defective proofreading function, which causes accelerated accumulation of random mutations in mtDNA, resulting in expression of respiration defects. On the contrary, transmitochondrial mito-miceΔ carrying mtDNA with a large-scale deletion mutation (ΔmtDNA also express respiration defects, but not express premature aging phenotypes. Here, we resolved this discrepancy by generating mtDNA mutator mice sharing the same C57BL/6J (B6J nuclear background with that of mito-miceΔ. Expression patterns of premature aging phenotypes are very close, when we compared between homozygous mtDNA mutator mice carrying a B6J nuclear background and selected mito-miceΔ only carrying predominant amounts of ΔmtDNA, in their expression of significant respiration defects, kyphosis, and a short lifespan, but not the alopecia. Therefore, the apparent discrepancy in the presence and absence of premature aging phenotypes in mtDNA mutator mice and mito-miceΔ, respectively, is partly the result of differences in the nuclear background of mtDNA mutator mice and of the broad range of ΔmtDNA proportions of mito-miceΔ used in previous studies. We also provided direct evidence that mtDNA abnormalities in homozygous mtDNA mutator mice are responsible for respiration defects by demonstrating the co-transfer of mtDNA and respiration defects from mtDNA mutator mice into mtDNA-less (ρ(0 mouse cells. Moreover, heterozygous mtDNA mutator mice had a normal lifespan, but frequently developed B-cell lymphoma, suggesting that the mtDNA abnormalities in heterozygous mutator mice are not sufficient to induce a short lifespan and aging phenotypes, but are able to contribute to the B-cell lymphoma development during their prolonged lifespan.

Decentralized Large-Scale Power Balancing

DEFF Research Database (Denmark)

Halvgaard, Rasmus; Jørgensen, John Bagterp; Poulsen, Niels Kjølstad

2013-01-01

problem is formulated as a centralized large-scale optimization problem but is then decomposed into smaller subproblems that are solved locally by each unit connected to an aggregator. For large-scale systems the method is faster than solving the full problem and can be distributed to include an arbitrary...

Automating large-scale reactor systems

International Nuclear Information System (INIS)

Kisner, R.A.

1985-01-01

This paper conveys a philosophy for developing automated large-scale control systems that behave in an integrated, intelligent, flexible manner. Methods for operating large-scale systems under varying degrees of equipment degradation are discussed, and a design approach that separates the effort into phases is suggested. 5 refs., 1 fig

Data from complete mtDNA sequencing of Tunisian centenarians: testing haplogroup association and the "golden mean" to longevity.

Science.gov (United States)

Costa, Marta D; Cherni, Lotfi; Fernandes, Verónica; Freitas, Fernando; Ammar El Gaaied, Amel Ben; Pereira, Luísa

2009-04-01

Since the mitochondrial theory of ageing was proposed, mitochondrial DNA (mtDNA) diversity has been largely studied in old people, however complete genomes are still rare, being limited to Japanese and UK/US samples. In this work, we evaluated possible longevity associated polymorphisms/haplogroups in an African population, from Tunisia, by performing complete mtDNA sequencing. This population has a mixed Eurasian/sub-Saharan mtDNA gene pool, which could potentially facilitate the evaluation of association for sub-Saharan lineages. Sub-Saharan haplogroups were shown to be significantly less represented in centenarians (9.5%) than in controls (54.5%), but it is not possible to rule out an influence of population structure, which is high in these populations. No recurrent polymorphism were more frequent in centenarians than in controls, and although the Tunisian centenarians presented less synonymous and replacement polymorphisms than controls, this difference was not statistically significant. So far, it does not seem that centenarians have significantly less mildly deleterious substitutions, not only in Tunisia but also in Japanese and UK/US samples, as tested here, not favouring a "golden mean" to longevity.

mtDNA point and length heteroplasmy in high- and low radiation areas of Kerala

International Nuclear Information System (INIS)

Forster, L.; Forster, P.; Gurney, S.M.; Spencer, M.; Huang, C.; Röhl, A.; Brinkmann, B.

2010-01-01

A coastal peninsula in Kerala (India) contains the world's highest level of natural radioactivity in a densely populated area, offering an opportunity to characterize radiation-associated DNA mutations. Here, we focus on mitochondrial DNA (mtDNA) mutations, which are passed exclusively from the mother to her children. To analyse point mutations, we sampled 248 pedigrees (988 individuals) in the high-radiation peninsula and in nearby low-radiation islands as a control population. Then, in an extended sample of 1,172 mtDNA sequences (containing some non-Indians for comparison), we also analysed length mutations, which in mtDNA can lead to the phenomenon of length heteroplasmy, i.e. the existence of different DNA types in the same cell. We wished to find out how fast mtDNA mutates between generations, and whether the mutation rate is increased in radioactive conditions compared to the low-irradiation sample

Mitochondrial DNA (mtDNA haplogroups in 1526 unrelated individuals from 11 Departments of Colombia

Directory of Open Access Journals (Sweden)

Juan J. Yunis

2013-01-01

Full Text Available The frequencies of four mitochondrial Native American DNA haplogroups were determined in 1526 unrelated individuals from 11 Departments of Colombia and compared to the frequencies previously obtained for Amerindian and Afro-Colombian populations. Amerindian mtDNA haplogroups ranged from 74% to 97%. The lowest frequencies were found in Departments on the Caribbean coast and in the Pacific region, where the frequency of Afro-Colombians is higher, while the highest mtDNA Amerindian haplogroup frequencies were found in Departments that historically have a strong Amerindian heritage. Interestingly, all four mtDNA haplogroups were found in all Departments, in contrast to the complete absence of haplogroup D and high frequencies of haplogroup A in Amerindian populations in the Caribbean region of Colombia. Our results indicate that all four Native American mtDNA haplogroups were widely distributed in Colombia at the time of the Spanish conquest.

A novel KCNQ4 one-base deletion in a large pedigree with hearing loss: implication for the genotype-phenotype correlation.

Science.gov (United States)

Kamada, Fumiaki; Kure, Shigeo; Kudo, Takayuki; Suzuki, Yoichi; Oshima, Takeshi; Ichinohe, Akiko; Kojima, Kanako; Niihori, Tetsuya; Kanno, Junko; Narumi, Yoko; Narisawa, Ayumi; Kato, Kumi; Aoki, Yoko; Ikeda, Katsuhisa; Kobayashi, Toshimitsu; Matsubara, Yoichi

2006-01-01

Autosomal-dominant, nonsyndromic hearing impairment is clinically and genetically heterogeneous. We encountered a large Japanese pedigree in which nonsyndromic hearing loss was inherited in an autosomal-dominant fashion. A genome-wide linkage study indicated linkage to the DFNA2 locus on chromosome 1p34. Mutational analysis of KCNQ4 encoding a potassium channel revealed a novel one-base deletion in exon 1, c.211delC, which generated a profoundly truncated protein without transmembrane domains (p.Q71fsX138). Previously, six missense mutations and one 13-base deletion, c.211_223del, had been reported in KCNQ4. Patients with the KCNQ4 missense mutations had younger-onset and more profound hearing loss than patients with the 211_223del mutation. In our current study, 12 individuals with the c.211delC mutation manifested late-onset and pure high-frequency hearing loss. Our results support the genotype-phenotype correlation that the KCNQ4 deletions are associated with later-onset and milder hearing impairment than the missense mutations. The phenotypic difference may be caused by the difference in pathogenic mechanisms: haploinsufficiency in deletions and dominant-negative effect in missense mutations.

Hybrid male sterility is caused by mitochondrial DNA deletion.

Science.gov (United States)

Hayashida, Kenji; Kohno, Shigeru

2009-07-01

Although it is known that the hybrid male mouse is sterile just like any other animal's heterogametic sex, the reason why only the male germ cells are impaired has yet to be discovered. TdT-mediated dUTP nick end labeling assay using a confocal fluorescence microscope and DNA fragmentation assay of hybrid testis indicated destruction of the mitochondrial DNA (mtDNA) rather than the nuclear DNA. Previously we reported that maternal mtDNA inheritance is through selective sperm mtDNA elimination based on the sperm factor and two egg factors, and expression of these three factors was recognized in the hybrid testis. It was thereby assumed that mtDNA destruction caused by the expression of maternal mtDNA inheritance system in male germ cells is implicated in the hybrid male sterility of mice.

The Software Reliability of Large Scale Integration Circuit and Very Large Scale Integration Circuit

OpenAIRE

Artem Ganiyev; Jan Vitasek

2010-01-01

This article describes evaluation method of faultless function of large scale integration circuits (LSI) and very large scale integration circuits (VLSI). In the article there is a comparative analysis of factors which determine faultless of integrated circuits, analysis of already existing methods and model of faultless function evaluation of LSI and VLSI. The main part describes a proposed algorithm and program for analysis of fault rate in LSI and VLSI circuits.

Identification of the first large deletion in the CLDN16 gene in a patient with FHHNC and late-onset of chronic kidney disease: case report.

Science.gov (United States)

Yamaguti, Paulo Marcio; dos Santos, Pollyanna Almeida Costa; Leal, Bruno Sakamoto; Santana, Viviane Brandão Bandeira de Mello; Mazzeu, Juliana Forte; Acevedo, Ana Carolina; Neves, Francisco de Assis Rocha

2015-07-02

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is a rare autosomal recessive renal disease characterized by tubular disorders at the thick ascending limb of Henle's loop. It is caused by mutations in the tight junction structural proteins claudin-16 or claudin-19, which are encoded by the CLDN16 and CLDN19 genes, respectively. Patients exhibit excessive wasting of calcium and magnesium, nephrocalcinosis, chronic kidney disease, and early progression to end-stage renal failure during infancy. We here report the phenotype and molecular analysis of a female Brazilian patient with a novel large homozygous deletion in the CLDN16 gene. The proband, born from consanguineous parents, presented the first symptoms at age 20. Clinical examination revealed hypocalcemia, hypomagnesemia, nephrocalcinosis, mild myopia, high serum levels of uric acid and intact parathyroid hormone, and moderate chronic kidney disease (stage 3). She and her mother were subjected to CLDN16 and CLDN19 mutational analysis. In addition, the multiplex ligation-dependent probe amplification method was used to confirm a CLDN16 multi-exon deletion. Direct sequencing revealed a normal CLDN19 sequence and suggested a large deletion in the CLDN16 gene. Multiplex ligation-dependent probe amplification showed a homozygous CLDN16 multi-exon deletion (E2_E5del). The patient initiated conventional treatment for familial hypomagnesemia with hypercalciuria and nephrocalcinosis and progressed to end-stage kidney disease after five years. This study provides the first report of a large homozygous deletion in the CLDN16 gene causing familial hypomagnesemia with hypercalciuria and nephrocalcinosis with late onset of the first symptoms. This description expands the phenotypic and genotypic characterization of the disease. The late-onset chronic kidney disease in the presence of a homozygous deletion in the CLDN16 gene reinforces the great variability of genotype-phenotype manifestation in patients with

Fluorescence in situ hybridization evaluation of chromosome deletion patterns in prostate cancer.

Science.gov (United States)

Huang, S F; Xiao, S; Renshaw, A A; Loughlin, K R; Hudson, T J; Fletcher, J A

1996-11-01

Various nonrandom chromosomal aberrations have been identified in prostate carcinoma. These aberrations include deletions of several chromosome regions, particularly the chromosome 8 short arm. Large-scale numerical aberrations, reflected in aberrant DNA ploidy, are also found in a minority of cases. However, it is unclear whether prostate carcinomas contain aberrations of certain chromosome regions that are deleted frequently in other common types of cancer. In this study, we performed dual-color fluorescence in situ hybridization on intact nuclei from touch preparations of 16 prostate cancers. Chromosome copy number was determined using pericentromeric probes, whereas potential chromosome arm deletions were evaluated using yeast artificial chromosome (YAC) and P1 probes. Two YAC probes targeted chromosome 8 short arm regions known to be deleted frequently in prostate cancer. Other YACs and P1s were for chromosome regions, including 1p22, 3p14, 6q21, 9p21, and 22q12, that are deletion targets in a variety of cancers although not extensively studied in prostate cancer. Hybridization efficiencies and signal intensities were excellent for both repeat sequence (alpha-satellite) and single, copy (YAC and P1) fluorescence in situ hybridization probes. Of 16 prostate cancers, 11 had clonal aberrations of 1 or more of the 13 chromosome regions evaluated, and 10 cases (62.5%) had 8p deletions, including 4 cases with 8p deletion in virtually all cells and aneuploidy in only a subset of those deleted cells. Deletions at 3p14, 6q21, and 22q12 were identified in 2, 1, and 1 case, respectively, and each of those cases had a similarly sized cell population with 8p deletion. These studies confirm 8p deletion in the majority of prostate carcinomas. 8p deletions appear to be early events in prostate tumorigenesis, often antedating aneuploidy. Fluorescence in situ hybridization strategies incorporating pericentromeric and single-copy regional chromosome probes offer a powerful and

Myeloablation-associated deletion of ORF4 in a human coronavirus 229E infection.

Science.gov (United States)

Greninger, Alexander L; Pepper, Gregory; Shean, Ryan C; Cent, Anne; Palileo, Isabel; Kuypers, Jane M; Schiffer, Joshua T; Jerome, Keith R

2017-01-01

We describe metagenomic next-generation sequencing (mNGS) of a human coronavirus 229E from a patient with AML and persistent upper respiratory symptoms, who underwent hematopoietic cell transplantation (HCT). mNGS revealed a 548-nucleotide deletion, which comprised the near entirety of the ORF4 gene, and no minor allele variants were detected to suggest a mixed infection. As part of her pre-HCT conditioning regimen, the patient received myeloablative treatment with cyclophosphamide and 12 Gy total body irradiation. Iterative sequencing and RT-PCR confirmation of four respiratory samples over the 4-week peritransplant period revealed that the pre-conditioning strain contained an intact ORF4 gene, while the deletion strain appeared just after conditioning and persisted over a 2.5-week period. This sequence represents one of the largest genomic deletions detected in a human RNA virus and describes large-scale viral mutation associated with myeloablation for HCT.

Detection of large deletion in human BRCA1 gene in human breast carcinoma MCF-7 cells by using DNA-Silver Nanoclusters

Science.gov (United States)

Borghei, Yasaman-Sadat; Hosseini, Morteza; Ganjali, Mohammad Reza

2018-01-01

Here we describe a label-free detection strategy for large deletion mutation in breast cancer (BC) related gene BRCA1 based on a DNA-silver nanocluster (NC) fluorescence upon recognition-induced hybridization. The specific hybridization of DNA templated silver NCs fluorescent probe to target DNAs can act as effective templates for enhancement of AgNCs fluorescence, which can be used to distinguish the deletion of BRCA1 due to different fluorescence intensities. Under the optimal conditions, the fluorescence intensity of the DNA-AgNCs at emission peaks around 440 nm (upon excitation at 350 nm) increased with the increasing deletion type within a dynamic range from 1.0 × 10-10 to 2.4 × 10-6 M with a detection limit (LOD) of 6.4 × 10-11 M. In this sensing system, the normal type shows no significant fluorescence; on the other hand, the deletion type emits higher fluorescence than normal type. Using this nanobiosensor, we successfully determined mutation using the non-amplified genomic DNAs that were isolated from the BC cell line.

A test of the transcription model for biased inheritance of yeast mitochondrial DNA.

Science.gov (United States)

Lorimer, H E; Brewer, B J; Fangman, W L

1995-09-01

Two strand-specific origins of replication appear to be required for mammalian mitochondrial DNA (mtDNA) replication. Structural equivalents of these origins are found in the rep sequences of Saccharomyces cerevisiae mtDNA. These striking similarities have contributed to a universal model for the initiation of mtDNA replication in which a primer is created by cleavage of an origin region transcript. Consistent with this model are the properties of deletion mutants of yeast mtDNA ([rho-]) with a high density of reps (HS [rho-]). These mutant mtDNAs are preferentially inherited by the progeny resulting from the mating of HS [rho-] cells with cells containing wild-type mtDNA ([rho+]). This bias is presumed to result from a replication advantage conferred on HS [rho-] mtDNA by the high density of rep sequences acting as origins. To test whether transcription is indeed required for the preferential inheritance of HS [rho-] mtDNA, we deleted the nuclear gene (RPO41) for the mitochondrial RNA polymerase, reducing transcripts by at least 1000-fold. Since [rho-] genomes, but not [rho+] genomes, are stable when RPO41 is deleted, we examined matings between HS [rho-] and neutral [rho-] cells. Neutral [rho-] mtDNAs lack rep sequences and are not preferentially inherited in [rho-] x [rho+] crosses. In HS [rho-] x neutral [rho-] matings, the HS [rho-] mtDNA was preferentially inherited whether both parents were wild type or both were deleted for RPO41. Thus, transcription from the rep promoter does not appear to be necessary for biased inheritance. Our results, and analysis of the literature, suggest that priming by transcription is not a universal mechanism for mtDNA replication initiation.

A defect in the thymidine kinase 2 gene causing isolated mitochondrial myopathy without mtDNA depletion.

Science.gov (United States)

Leshinsky-Silver, E; Michelson, M; Cohen, S; Ginsberg, M; Sadeh, M; Barash, V; Lerman-Sagie, T; Lev, D

2008-07-01

Isolated mitochondrial myopathies (IMM) are either due to primary defects in mtDNA, in nuclear genes that control mtDNA abundance and structure such as thymidine kinase 2 (TK2), or due to CoQ deficiency. Defects in the TK2 gene have been found to be associated with mtDNA depletion attributed to a depleted mitochondrial dNTP pool in non-dividing cells. We report an unusual case of IMM, homozygous for the H90N mutation in the TK2 gene but unlike other cases with the same mutation, does not demonstrate mtDNA depletion. The patient's clinical course is relatively mild and a muscle biopsy showed ragged red muscle fibers with a mild decrease in complexes I and an increase in complexes IV and II activities. This report extends the phenotypic expression of TK2 defects and suggests that all patients who present with an IMM even with normal quantities of mtDNA should be screened for TK2 mutations.

A Phenotype-Driven Approach to Generate Mouse Models with Pathogenic mtDNA Mutations Causing Mitochondrial Disease

Directory of Open Access Journals (Sweden)

Johanna H.K. Kauppila

2016-09-01

Full Text Available Mutations of mtDNA are an important cause of human disease, but few animal models exist. Because mammalian mitochondria cannot be transfected, the development of mice with pathogenic mtDNA mutations has been challenging, and the main strategy has therefore been to introduce mutations found in cell lines into mouse embryos. Here, we describe a phenotype-driven strategy that is based on detecting clonal expansion of pathogenic mtDNA mutations in colonic crypts of founder mice derived from heterozygous mtDNA mutator mice. As proof of concept, we report the generation of a mouse line transmitting a heteroplasmic pathogenic mutation in the alanine tRNA gene of mtDNA displaying typical characteristics of classic mitochondrial disease. In summary, we describe a straightforward and technically simple strategy based on mouse breeding and histology to generate animal models of mtDNA-mutation disease, which will be of great importance for studies of disease pathophysiology and preclinical treatment trials.

MtDNA variation in the Altai-Kizhi population of southern Siberia: a synthesis of genetic variation.

Science.gov (United States)

Phillips-Krawczak, Christine; Devor, Eric; Zlojutro, Mark; Moffat-Wilson, Kristin; Crawford, Michael H

2006-08-01

The native peoples of Gorno Altai in southern Siberia represent a genetically diverse population and have been of great interest to anthropological genetics. In particular, the southern Altaian population is argued to be the best candidate for the New World ancestral population. In this study we sampled Altai-Kizhi from the southern Altaian village of Mendur-Sokkon, analyzed mtDNA RFLP markers and HVS-I sequences, and compared the results to other published mtDNA data from Derenko et al. (2003) and Shields et al. (1993) encompassing the same region. Because each independent study uses different sampling techniques in characterizing gene pools, in this paper we explore the accuracy and reliability of evolutionary studies on human populations. All the major Native American haplogroups (A, B, C, and D) were identified in the Mendur-Sokkon sample, including a single individual belonging to haplogroup X. The most common mtDNA lineages are C (35.7%) and D (13.3%), which is consistent with the haplogroup profiles of neighboring Siberian groups. The Mendur-Sokkon sample exhibits depressed HVS-I diversity values and neutrality test scores, which starkly differs from the Derenko et al. (2003) data set and more closely resembles the results for neighboring south Siberian groups. Furthermore, the multidimensional scaling plot of DA genetic distances does not cluster the Altai samples, showing different genetic affinities with various Asian groups. The findings underscore the importance of sampling strategy in the reconstruction of evolutionary history at the population level.

Phylogenetic distribution of large-scale genome patchiness

Directory of Open Access Journals (Sweden)

Hackenberg Michael

2008-04-01

Full Text Available Abstract Background The phylogenetic distribution of large-scale genome structure (i.e. mosaic compositional patchiness has been explored mainly by analytical ultracentrifugation of bulk DNA. However, with the availability of large, good-quality chromosome sequences, and the recently developed computational methods to directly analyze patchiness on the genome sequence, an evolutionary comparative analysis can be carried out at the sequence level. Results The local variations in the scaling exponent of the Detrended Fluctuation Analysis are used here to analyze large-scale genome structure and directly uncover the characteristic scales present in genome sequences. Furthermore, through shuffling experiments of selected genome regions, computationally-identified, isochore-like regions were identified as the biological source for the uncovered large-scale genome structure. The phylogenetic distribution of short- and large-scale patchiness was determined in the best-sequenced genome assemblies from eleven eukaryotic genomes: mammals (Homo sapiens, Pan troglodytes, Mus musculus, Rattus norvegicus, and Canis familiaris, birds (Gallus gallus, fishes (Danio rerio, invertebrates (Drosophila melanogaster and Caenorhabditis elegans, plants (Arabidopsis thaliana and yeasts (Saccharomyces cerevisiae. We found large-scale patchiness of genome structure, associated with in silico determined, isochore-like regions, throughout this wide phylogenetic range. Conclusion Large-scale genome structure is detected by directly analyzing DNA sequences in a wide range of eukaryotic chromosome sequences, from human to yeast. In all these genomes, large-scale patchiness can be associated with the isochore-like regions, as directly detected in silico at the sequence level.

Managing large-scale models: DBS

International Nuclear Information System (INIS)

1981-05-01

A set of fundamental management tools for developing and operating a large scale model and data base system is presented. Based on experience in operating and developing a large scale computerized system, the only reasonable way to gain strong management control of such a system is to implement appropriate controls and procedures. Chapter I discusses the purpose of the book. Chapter II classifies a broad range of generic management problems into three groups: documentation, operations, and maintenance. First, system problems are identified then solutions for gaining management control are disucssed. Chapters III, IV, and V present practical methods for dealing with these problems. These methods were developed for managing SEAS but have general application for large scale models and data bases

Large Scale Self-Organizing Information Distribution System

National Research Council Canada - National Science Library

Low, Steven

2005-01-01

This project investigates issues in "large-scale" networks. Here "large-scale" refers to networks with large number of high capacity nodes and transmission links, and shared by a large number of users...

Large scale structure and baryogenesis

International Nuclear Information System (INIS)

Kirilova, D.P.; Chizhov, M.V.

2001-08-01

We discuss a possible connection between the large scale structure formation and the baryogenesis in the universe. An update review of the observational indications for the presence of a very large scale 120h -1 Mpc in the distribution of the visible matter of the universe is provided. The possibility to generate a periodic distribution with the characteristic scale 120h -1 Mpc through a mechanism producing quasi-periodic baryon density perturbations during inflationary stage, is discussed. The evolution of the baryon charge density distribution is explored in the framework of a low temperature boson condensate baryogenesis scenario. Both the observed very large scale of a the visible matter distribution in the universe and the observed baryon asymmetry value could naturally appear as a result of the evolution of a complex scalar field condensate, formed at the inflationary stage. Moreover, for some model's parameters a natural separation of matter superclusters from antimatter ones can be achieved. (author)

Automatic management software for large-scale cluster system

International Nuclear Information System (INIS)

Weng Yunjian; Chinese Academy of Sciences, Beijing; Sun Gongxing

2007-01-01

At present, the large-scale cluster system faces to the difficult management. For example the manager has large work load. It needs to cost much time on the management and the maintenance of large-scale cluster system. The nodes in large-scale cluster system are very easy to be chaotic. Thousands of nodes are put in big rooms so that some managers are very easy to make the confusion with machines. How do effectively carry on accurate management under the large-scale cluster system? The article introduces ELFms in the large-scale cluster system. Furthermore, it is proposed to realize the large-scale cluster system automatic management. (authors)

Properties of the simian virus 40 (SV40) large T antigens encoded by SV40 mutants with deletions in gene A.

Science.gov (United States)

Cole, C N; Tornow, J; Clark, R; Tjian, R

1986-01-01

The biochemical properties of the large T antigens encoded by simian virus 40 (SV40) mutants with deletions at DdeI sites in the SV40 A gene were determined. Mutant large T antigens containing only the first 138 to 140 amino acids were unable to bind to the SV40 origin of DNA replication as were large T antigens containing at their COOH termini 96 or 97 amino acids encoded by the long open reading frame located between 0.22 and 0.165 map units (m.u.). All other mutant large T antigens were able to bind to the SV40 origin of replication. Mutants with in-phase deletions at 0.288 and 0.243 m.u. lacked ATPase activity, but ATPase activity was normal in mutants lacking origin-binding activity. The 627-amino acid large T antigen encoded by dlA2465, with a deletion at 0.219 m.u., was the smallest large T antigen displaying ATPase activity. Mutant large T antigens with the alternate 96- or 97-amino acid COOH terminus also lacked ATPase activity. All mutant large T antigens were found in the nuclei of infected cells; a small amount of large T with the alternate COOH terminus was also located in the cytoplasm. Mutant dlA2465 belonged to the same class of mutants as dlA2459. It was unable to form plaques on CV-1p cells at 37 or 32 degrees C but could form plaques on BSC-1 monolayers at 37 degrees C but not at 32 degrees C. It was positive for viral DNA replication and showed intracistronic complementation with any group A mutant whose large T antigen contained a normal carboxyl terminus. These findings and those of others suggest that both DNA binding and ATPase activity are required for the viral DNA replication function of large T antigen, that these two activities must be located on the same T antigen monomer, and that these two activities are performed by distinct domains of the polypeptide. These domains are distinct and separable from the domain affected by the mutation of dlA2465 and indicate that SV40 large T antigen is made up of at least three separate functional

A case of an atypically large proximal 15q deletion as cause for Prader-Willi syndrome arising from a de novo unbalanced translocation.

Science.gov (United States)

Hickey, Scott E; Thrush, Devon Lamb; Walters-Sen, Lauren; Reshmi, Shalini C; Astbury, Caroline; Gastier-Foster, Julie M; Atkin, Joan

2013-09-01

We describe an 11 month old female with Prader-Willi syndrome (PWS) resulting from an atypically large deletion of proximal 15q due to a de novo 3;15 unbalanced translocation. The 10.6 Mb deletion extends from the chromosome 15 short arm and is not situated in a region previously reported as a common distal breakpoint for unbalanced translocations. There was no deletion of the reciprocal chromosome 3q subtelomeric region detected by either chromosomal microarray or FISH. The patient has hypotonia, failure to thrive, and typical dysmorphic facial features for PWS. The patient also has profound global developmental delay consistent with an expanded, more severe, phenotype. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Infantile presentation of the mtDNA A3243G tRNA(Leu (UUR)) mutation.

NARCIS (Netherlands)

Okhuijsen-Kroes, E.J.; Trijbels, J.M.F.; Sengers, R.C.A.; Mariman, E.C.M.; Heuvel, L.P.W.J. van den; Wendel, U.A.H.; Koch, G.; Smeitink, J.A.M.

2001-01-01

Mitochondrial DNA (mtDNA) disorders are clinically very heterogeneous, ranging from single organ involvement to severe multisystem disease. One of the most frequently observed mtDNA mutations is the A-to-G transition at position 3243 of the tRNA(Leu (UUR)) gene. This mutation is often related to

High proportion of large genomic deletions and a genotype phenotype update in 80 unrelated families with juvenile polyposis syndrome

DEFF Research Database (Denmark)

Aretz, S; Stienen, D; Uhlhaas, S

2007-01-01

BACKGROUND: In patients with juvenile polyposis syndrome (JPS) the frequency of large genomic deletions in the SMAD4 and BMPR1A genes was unknown. METHODS: Mutation and phenotype analysis was used in 80 unrelated patients of whom 65 met the clinical criteria for JPS (typical JPS) and 15 were susp...

Thymidine kinase 2 deficiency-induced mtDNA depletion in mouse liver leads to defect β-oxidation.

Directory of Open Access Journals (Sweden)

Xiaoshan Zhou

Full Text Available Thymidine kinase 2 (TK2 deficiency in humans causes mitochondrial DNA (mtDNA depletion syndrome. To study the molecular mechanisms underlying the disease and search for treatment options, we previously generated and described a TK2 deficient mouse strain (TK2(-/- that progressively loses its mtDNA. The TK2(-/- mouse model displays symptoms similar to humans harboring TK2 deficient infantile fatal encephalomyopathy. Here, we have studied the TK2(-/- mouse model to clarify the pathological role of progressive mtDNA depletion in liver for the severe outcome of TK2 deficiency. We observed that a gradual depletion of mtDNA in the liver of the TK2(-/- mice was accompanied by increasingly hypertrophic mitochondria and accumulation of fat vesicles in the liver cells. The levels of cholesterol and nonesterified fatty acids were elevated and there was accumulation of long chain acylcarnitines in plasma of the TK2(-/- mice. In mice with hepatic mtDNA levels below 20%, the blood sugar and the ketone levels dropped. These mice also exhibited reduced mitochondrial β-oxidation due to decreased transport of long chain acylcarnitines into the mitochondria. The gradual loss of mtDNA in the liver of the TK2(-/- mice causes impaired mitochondrial function that leads to defect β-oxidation and, as a result, insufficient production of ketone bodies and glucose. This study provides insight into the mechanism of encephalomyopathy caused by TK2 deficiency-induced mtDNA depletion that may be used to explore novel therapeutic strategies.

Thymidine kinase 2 deficiency-induced mtDNA depletion in mouse liver leads to defect β-oxidation.

Science.gov (United States)

Zhou, Xiaoshan; Kannisto, Kristina; Curbo, Sophie; von Döbeln, Ulrika; Hultenby, Kjell; Isetun, Sindra; Gåfvels, Mats; Karlsson, Anna

2013-01-01

Thymidine kinase 2 (TK2) deficiency in humans causes mitochondrial DNA (mtDNA) depletion syndrome. To study the molecular mechanisms underlying the disease and search for treatment options, we previously generated and described a TK2 deficient mouse strain (TK2(-/-)) that progressively loses its mtDNA. The TK2(-/-) mouse model displays symptoms similar to humans harboring TK2 deficient infantile fatal encephalomyopathy. Here, we have studied the TK2(-/-) mouse model to clarify the pathological role of progressive mtDNA depletion in liver for the severe outcome of TK2 deficiency. We observed that a gradual depletion of mtDNA in the liver of the TK2(-/-) mice was accompanied by increasingly hypertrophic mitochondria and accumulation of fat vesicles in the liver cells. The levels of cholesterol and nonesterified fatty acids were elevated and there was accumulation of long chain acylcarnitines in plasma of the TK2(-/-) mice. In mice with hepatic mtDNA levels below 20%, the blood sugar and the ketone levels dropped. These mice also exhibited reduced mitochondrial β-oxidation due to decreased transport of long chain acylcarnitines into the mitochondria. The gradual loss of mtDNA in the liver of the TK2(-/-) mice causes impaired mitochondrial function that leads to defect β-oxidation and, as a result, insufficient production of ketone bodies and glucose. This study provides insight into the mechanism of encephalomyopathy caused by TK2 deficiency-induced mtDNA depletion that may be used to explore novel therapeutic strategies.

Comprehensive analysis of pathogenic deletion variants in Fanconi anemia genes.

Science.gov (United States)

Flynn, Elizabeth K; Kamat, Aparna; Lach, Francis P; Donovan, Frank X; Kimble, Danielle C; Narisu, Narisu; Sanborn, Erica; Boulad, Farid; Davies, Stella M; Gillio, Alfred P; Harris, Richard E; MacMillan, Margaret L; Wagner, John E; Smogorzewska, Agata; Auerbach, Arleen D; Ostrander, Elaine A; Chandrasekharappa, Settara C

2014-11-01

Fanconi anemia (FA) is a rare recessive disease resulting from mutations in one of at least 16 different genes. Mutation types and phenotypic manifestations of FA are highly heterogeneous and influence the clinical management of the disease. We analyzed 202 FA families for large deletions, using high-resolution comparative genome hybridization arrays, single-nucleotide polymorphism arrays, and DNA sequencing. We found pathogenic deletions in 88 FANCA, seven FANCC, two FANCD2, and one FANCB families. We find 35% of FA families carry large deletions, accounting for 18% of all FA pathogenic variants. Cloning and sequencing across the deletion breakpoints revealed that 52 FANCA deletion ends, and one FANCC deletion end extended beyond the gene boundaries, potentially affecting neighboring genes with phenotypic consequences. Seventy-five percent of the FANCA deletions are Alu-Alu mediated, predominantly by AluY elements, and appear to be caused by nonallelic homologous recombination. Individual Alu hotspots were identified. Defining the haplotypes of four FANCA deletions shared by multiple families revealed that three share a common ancestry. Knowing the exact molecular changes that lead to the disease may be critical for a better understanding of the FA phenotype, and to gain insight into the mechanisms driving these pathogenic deletion variants. © 2014 WILEY PERIODICALS, INC.

Most of the extant mtDNA boundaries in South and Southwest Asia were likely shaped during the initial settlement of Eurasia by anatomically modern humans

Directory of Open Access Journals (Sweden)

Mastana Sarabjit

2004-08-01

Full Text Available Abstract Background Recent advances in the understanding of the maternal and paternal heritage of south and southwest Asian populations have highlighted their role in the colonization of Eurasia by anatomically modern humans. Further understanding requires a deeper insight into the topology of the branches of the Indian mtDNA phylogenetic tree, which should be contextualized within the phylogeography of the neighboring regional mtDNA variation. Accordingly, we have analyzed mtDNA control and coding region variation in 796 Indian (including both tribal and caste populations from different parts of India and 436 Iranian mtDNAs. The results were integrated and analyzed together with published data from South, Southeast Asia and West Eurasia. Results Four new Indian-specific haplogroup M sub-clades were defined. These, in combination with two previously described haplogroups, encompass approximately one third of the haplogroup M mtDNAs in India. Their phylogeography and spread among different linguistic phyla and social strata was investigated in detail. Furthermore, the analysis of the Iranian mtDNA pool revealed patterns of limited reciprocal gene flow between Iran and the Indian sub-continent and allowed the identification of different assemblies of shared mtDNA sub-clades. Conclusions Since the initial peopling of South and West Asia by anatomically modern humans, when this region may well have provided the initial settlers who colonized much of the rest of Eurasia, the gene flow in and out of India of the maternally transmitted mtDNA has been surprisingly limited. Specifically, our analysis of the mtDNA haplogroups, which are shared between Indian and Iranian populations and exhibit coalescence ages corresponding to around the early Upper Paleolithic, indicates that they are present in India largely as Indian-specific sub-lineages. In contrast, other ancient Indian-specific variants of M and R are very rare outside the sub-continent.

Parameters affecting the resilience of scale-free networks to random failures.

Energy Technology Data Exchange (ETDEWEB)

Link, Hamilton E.; LaViolette, Randall A.; Lane, Terran (University of New Mexico, Albuquerque, NM); Saia, Jared (University of New Mexico, Albuquerque, NM)

2005-09-01

It is commonly believed that scale-free networks are robust to massive numbers of random node deletions. For example, Cohen et al. in (1) study scale-free networks including some which approximate the measured degree distribution of the Internet. Their results suggest that if each node in this network failed independently with probability 0.99, most of the remaining nodes would still be connected in a giant component. In this paper, we show that a large and important subclass of scale-free networks are not robust to massive numbers of random node deletions. In particular, we study scale-free networks which have minimum node degree of 1 and a power-law degree distribution beginning with nodes of degree 1 (power-law networks). We show that, in a power-law network approximating the Internet's reported distribution, when the probability of deletion of each node is 0.5 only about 25% of the surviving nodes in the network remain connected in a giant component, and the giant component does not persist beyond a critical failure rate of 0.9. The new result is partially due to improved analytical accommodation of the large number of degree-0 nodes that result after node deletions. Our results apply to power-law networks with a wide range of power-law exponents, including Internet-like networks. We give both analytical and empirical evidence that such networks are not generally robust to massive random node deletions.

Large scale network-centric distributed systems

CERN Document Server

Sarbazi-Azad, Hamid

2014-01-01

A highly accessible reference offering a broad range of topics and insights on large scale network-centric distributed systems Evolving from the fields of high-performance computing and networking, large scale network-centric distributed systems continues to grow as one of the most important topics in computing and communication and many interdisciplinary areas. Dealing with both wired and wireless networks, this book focuses on the design and performance issues of such systems. Large Scale Network-Centric Distributed Systems provides in-depth coverage ranging from ground-level hardware issu

Large-Scale Outflows in Seyfert Galaxies

Science.gov (United States)

Colbert, E. J. M.; Baum, S. A.

1995-12-01

\\catcode`\\@=11 \\ialign{m @th#1hfil ##hfil \\crcr#2\\crcr\\sim\\crcr}}} \\catcode`\\@=12 Highly collimated outflows extend out to Mpc scales in many radio-loud active galaxies. In Seyfert galaxies, which are radio-quiet, the outflows extend out to kpc scales and do not appear to be as highly collimated. In order to study the nature of large-scale (>~1 kpc) outflows in Seyferts, we have conducted optical, radio and X-ray surveys of a distance-limited sample of 22 edge-on Seyfert galaxies. Results of the optical emission-line imaging and spectroscopic survey imply that large-scale outflows are present in >~{{1} /{4}} of all Seyferts. The radio (VLA) and X-ray (ROSAT) surveys show that large-scale radio and X-ray emission is present at about the same frequency. Kinetic luminosities of the outflows in Seyferts are comparable to those in starburst-driven superwinds. Large-scale radio sources in Seyferts appear diffuse, but do not resemble radio halos found in some edge-on starburst galaxies (e.g. M82). We discuss the feasibility of the outflows being powered by the active nucleus (e.g. a jet) or a circumnuclear starburst.

Deletion at the GCNT2 Locus Causes Autosomal Recessive Congenital Cataracts.

Science.gov (United States)

Irum, Bushra; Khan, Shahid Y; Ali, Muhammad; Daud, Muhammad; Kabir, Firoz; Rauf, Bushra; Fatima, Fareeha; Iqbal, Hira; Khan, Arif O; Al Obaisi, Saif; Naeem, Muhammad Asif; Nasir, Idrees A; Khan, Shaheen N; Husnain, Tayyab; Riazuddin, Sheikh; Akram, Javed; Eghrari, Allen O; Riazuddin, S Amer

2016-01-01

The aim of this study is to identify the molecular basis of autosomal recessive congenital cataracts (arCC) in a large consanguineous pedigree. All participating individuals underwent a detailed ophthalmic examination. Each patient's medical history, particularly of cataracts and other ocular abnormalities, was compiled from available medical records and interviews with family elders. Blood samples were donated by all participating family members and used to extract genomic DNA. Genetic analysis was performed to rule out linkage to known arCC loci and genes. Whole-exome sequencing libraries were prepared and paired-end sequenced. A large deletion was found that segregated with arCC in the family, and chromosome walking was conducted to estimate the proximal and distal boundaries of the deletion mutation. Exclusion and linkage analysis suggested linkage to a region of chromosome 6p24 harboring GCNT2 (glucosaminyl (N-acetyl) transferase 2) with a two-point logarithm of odds score of 5.78. PCR amplifications of the coding exons of GCNT2 failed in individuals with arCC, and whole-exome data analysis revealed a large deletion on chromosome 6p in the region harboring GCNT2. Chromosomal walking using multiple primer pairs delineated the extent of the deletion to approximately 190 kb. Interestingly, a failure to amplify a junctional fragment of the deletion break strongly suggests an insertion in addition to the large deletion. Here, we report a novel insertion/deletion mutation at the GCNT2 locus that is responsible for congenital cataracts in a large consanguineous family.

Ultraviolet B, melanin and mitochondrial DNA: Photo-damage in human epidermal keratinocytes and melanocytes modulated by alpha-melanocyte-stimulating hormone [version 1; referees: 2 approved

Directory of Open Access Journals (Sweden)

Markus Böhm

2016-05-01

Full Text Available Alpha-melanocyte-stimulating hormone (alpha-MSH increases melanogenesis and protects from UV-induced DNA damage. However, its effect on mitochondrial DNA (mtDNA damage is unknown. We have addressed this issue in a pilot study using human epidermal keratinocytes and melanocytes incubated with alpha-MSH and irradiated with UVB. Real-time touchdown PCR was used to quantify total and deleted mtDNA. The deletion detected encompassed the common deletion but was more sensitive to detection. There were 4.4 times more mtDNA copies in keratinocytes than in melanocytes. Irradiation alone did not affect copy numbers. Alpha-MSH slightly increased copy numbers in both cell types in the absence of UVB and caused a similar small decrease in copy number with dose in both cell types. Deleted copies were nearly twice as frequent in keratinocytes as in melanocytes. Alpha-MSH reduced the frequency of deleted copies by half in keratinocytes but not in melanocytes. UVB dose dependently led to an increase in the deleted copy number in alpha-MSH-treated melanocytes. UVB irradiation had little effect on deleted copy number in alpha-MSH-treated keratinocytes. In summary, alpha-MSH enhances mtDNA damage in melanocytes presumably by increased melanogenesis, while α-MSH is protective in keratinocytes, the more so in the absence of irradiation.

Large intragenic deletion of CDC73 (exons 4-10) in a three-generation hyperparathyroidism-jaw tumor (HPT-JT) syndrome family.

Science.gov (United States)

Guarnieri, Vito; Seaberg, Raewyn M; Kelly, Catherine; Jean Davidson, M; Raphael, Simon; Shuen, Andrew Y; Baorda, Filomena; Palumbo, Orazio; Scillitani, Alfredo; Hendy, Geoffrey N; Cole, David E C

2017-08-03

Inactivating mutations of CDC73 cause Hyperparathyroidism-Jaw Tumour syndrome (HPT-JT), Familial Isolated Hyperparathyroidism (FIHP) and sporadic parathyroid carcinoma. We conducted CDC73 mutation analysis in an HPT-JT family and confirm carrier status of the proband's daughter. The proband had primary hyperparathyroidism (parathyroid carcinoma) and uterine leiomyomata. Her father and daughter had hyperparathyroidism (parathyroid adenoma) but no other manifestations of HPT-JT. CDC73 mutation analysis (sequencing of all 17 exons) and whole-genome copy number variation (CNV) analysis was done on leukocyte DNA of the three affecteds as well as the proband's unaffected sister. A novel deletion of exons 4 to 10 of CDC73 was detected by CNV analysis in the three affecteds. A novel insertion in the 5'UTR (c.-4_-11insG) that co-segregated with the deletion was identified. By in vitro assay the 5'UTR insertion was shown to significantly impair the expression of the parafibromin protein. Screening for the mutated CDC73 confirmed carrier status in the proband's daughter and the biochemistry and ultrasonography led to pre-emptive surgery and resolution of the hyperparathyroidism. A novel gross deletion mutation in CDC73 was identified in a three-generation HPT-JT family emphasizing the importance of including screening for large deletions in the molecular diagnostic protocol.

Inspecting close maternal relatedness: Towards better mtDNA population samples in forensic databases.

Science.gov (United States)

Bodner, Martin; Irwin, Jodi A; Coble, Michael D; Parson, Walther

2011-03-01

Reliable data are crucial for all research fields applying mitochondrial DNA (mtDNA) as a genetic marker. Quality control measures have been introduced to ensure the highest standards in sequence data generation, validation and a posteriori inspection. A phylogenetic alignment strategy has been widely accepted as a prerequisite for data comparability and database searches, for forensic applications, for reconstructions of human migrations and for correct interpretation of mtDNA mutations in medical genetics. There is continuing effort to enhance the number of worldwide population samples in order to contribute to a better understanding of human mtDNA variation. This has often lead to the analysis of convenience samples collected for other purposes, which might not meet the quality requirement of random sampling for mtDNA data sets. Here, we introduce an additional quality control means that deals with one aspect of this limitation: by combining autosomal short tandem repeat (STR) marker with mtDNA information, it helps to avoid the bias introduced by related individuals included in the same (small) sample. By STR analysis of individuals sharing their mitochondrial haplotype, pedigree construction and subsequent software-assisted calculation of likelihood ratios based on the allele frequencies found in the population, closely maternally related individuals can be identified and excluded. We also discuss scenarios that allow related individuals in the same set. An ideal population sample would be representative for its population: this new approach represents another contribution towards this goal. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

SCALE INTERACTION IN A MIXING LAYER. THE ROLE OF THE LARGE-SCALE GRADIENTS

KAUST Repository

Fiscaletti, Daniele

2015-08-23

The interaction between scales is investigated in a turbulent mixing layer. The large-scale amplitude modulation of the small scales already observed in other works depends on the crosswise location. Large-scale positive fluctuations correlate with a stronger activity of the small scales on the low speed-side of the mixing layer, and a reduced activity on the high speed-side. However, from physical considerations we would expect the scales to interact in a qualitatively similar way within the flow and across different turbulent flows. Therefore, instead of the large-scale fluctuations, the large-scale gradients modulation of the small scales has been additionally investigated.

Lack of sex-biased dispersal promotes fine-scale genetic structure in alpine ungulates

Science.gov (United States)

Roffler, Gretchen H.; Talbot, Sandra L.; Luikart, Gordon; Sage, George K.; Pilgrim, Kristy L.; Adams, Layne G.; Schwartz, Michael K.

2014-01-01

Identifying patterns of fine-scale genetic structure in natural populations can advance understanding of critical ecological processes such as dispersal and gene flow across heterogeneous landscapes. Alpine ungulates generally exhibit high levels of genetic structure due to female philopatry and patchy configuration of mountain habitats. We assessed the spatial scale of genetic structure and the amount of gene flow in 301 Dall’s sheep (Ovis dalli dalli) at the landscape level using 15 nuclear microsatellites and 473 base pairs of the mitochondrial (mtDNA) control region. Dall’s sheep exhibited significant genetic structure within contiguous mountain ranges, but mtDNA structure occurred at a broader geographic scale than nuclear DNA within the study area, and mtDNA structure for other North American mountain sheep populations. No evidence of male-mediated gene flow or greater philopatry of females was observed; there was little difference between markers with different modes of inheritance (pairwise nuclear DNA F ST = 0.004–0.325; mtDNA F ST = 0.009–0.544), and males were no more likely than females to be recent immigrants. Historical patterns based on mtDNA indicate separate northern and southern lineages and a pattern of expansion following regional glacial retreat. Boundaries of genetic clusters aligned geographically with prominent mountain ranges, icefields, and major river valleys based on Bayesian and hierarchical modeling of microsatellite and mtDNA data. Our results suggest that fine-scale genetic structure in Dall’s sheep is influenced by limited dispersal, and structure may be weaker in populations occurring near ancestral levels of density and distribution in continuous habitats compared to other alpine ungulates that have experienced declines and marked habitat fragmentation.

Genome-Wide Estimates of Transposable Element Insertion and Deletion Rates in Drosophila Melanogaster

Science.gov (United States)

Adrion, Jeffrey R.; Song, Michael J.; Schrider, Daniel R.; Hahn, Matthew W.

2017-01-01

Abstract Knowing the rate at which transposable elements (TEs) insert and delete is critical for understanding their role in genome evolution. We estimated spontaneous rates of insertion and deletion for all known, active TE superfamilies present in a set of Drosophila melanogaster mutation-accumulation (MA) lines using whole genome sequence data. Our results demonstrate that TE insertions far outpace TE deletions in D. melanogaster. We found a significant effect of background genotype on TE activity, with higher rates of insertions in one MA line. We also found significant rate heterogeneity between the chromosomes, with both insertion and deletion rates elevated on the X relative to the autosomes. Further, we identified significant associations between TE activity and chromatin state, and tested for associations between TE activity and other features of the local genomic environment such as TE content, exon content, GC content, and recombination rate. Our results provide the most detailed assessment of TE mobility in any organism to date, and provide a useful benchmark for both addressing theoretical predictions of TE dynamics and for exploring large-scale patterns of TE movement in D. melanogaster and other species. PMID:28338986

Dissecting the large-scale galactic conformity

Science.gov (United States)

Seo, Seongu

2018-01-01

Galactic conformity is an observed phenomenon that galaxies located in the same region have similar properties such as star formation rate, color, gas fraction, and so on. The conformity was first observed among galaxies within in the same halos (“one-halo conformity”). The one-halo conformity can be readily explained by mutual interactions among galaxies within a halo. Recent observations however further witnessed a puzzling connection among galaxies with no direct interaction. In particular, galaxies located within a sphere of ~5 Mpc radius tend to show similarities, even though the galaxies do not share common halos with each other ("two-halo conformity" or “large-scale conformity”). Using a cosmological hydrodynamic simulation, Illustris, we investigate the physical origin of the two-halo conformity and put forward two scenarios. First, back-splash galaxies are likely responsible for the large-scale conformity. They have evolved into red galaxies due to ram-pressure stripping in a given galaxy cluster and happen to reside now within a ~5 Mpc sphere. Second, galaxies in strong tidal field induced by large-scale structure also seem to give rise to the large-scale conformity. The strong tides suppress star formation in the galaxies. We discuss the importance of the large-scale conformity in the context of galaxy evolution.

Canis mtDNA HV1 database: a web-based tool for collecting and surveying Canis mtDNA HV1 haplotype in public database.

Science.gov (United States)

Thai, Quan Ke; Chung, Dung Anh; Tran, Hoang-Dung

2017-06-26

Canine and wolf mitochondrial DNA haplotypes, which can be used for forensic or phylogenetic analyses, have been defined in various schemes depending on the region analyzed. In recent studies, the 582 bp fragment of the HV1 region is most commonly used. 317 different canine HV1 haplotypes have been reported in the rapidly growing public database GenBank. These reported haplotypes contain several inconsistencies in their haplotype information. To overcome this issue, we have developed a Canis mtDNA HV1 database. This database collects data on the HV1 582 bp region in dog mitochondrial DNA from the GenBank to screen and correct the inconsistencies. It also supports users in detection of new novel mutation profiles and assignment of new haplotypes. The Canis mtDNA HV1 database (CHD) contains 5567 nucleotide entries originating from 15 subspecies in the species Canis lupus. Of these entries, 3646 were haplotypes and grouped into 804 distinct sequences. 319 sequences were recognized as previously assigned haplotypes, while the remaining 485 sequences had new mutation profiles and were marked as new haplotype candidates awaiting further analysis for haplotype assignment. Of the 3646 nucleotide entries, only 414 were annotated with correct haplotype information, while 3232 had insufficient or lacked haplotype information and were corrected or modified before storing in the CHD. The CHD can be accessed at http://chd.vnbiology.com . It provides sequences, haplotype information, and a web-based tool for mtDNA HV1 haplotyping. The CHD is updated monthly and supplies all data for download. The Canis mtDNA HV1 database contains information about canine mitochondrial DNA HV1 sequences with reconciled annotation. It serves as a tool for detection of inconsistencies in GenBank and helps identifying new HV1 haplotypes. Thus, it supports the scientific community in naming new HV1 haplotypes and to reconcile existing annotation of HV1 582 bp sequences.

PCR detection of retinoblastoma gene deletions in radiation-induced mouse lung adenocarcinomas

International Nuclear Information System (INIS)

Churchill, M.E.; Gemmell, M.A.; Woloschak, G.E.

1993-01-01

From 1971 to 1986, Argonne National Laboratory conducted a series of large-scale studies of tumor incidence in 40,000 BCF 1 mice irradiated with 60 Co γ rays or JANUS fission-spectrum neutrons; normal and tumor tissues from mice in these studies were preserved in paraffin blocks. A polymerase chain reaction (PCR) technique has been developed to detect deletions in the mouse retinoblastoma (mRb) gene in the paraffin-embedded tissues. Microtomed sections were used as the DNA source in PCR reaction mixtures. Six mRb gene exon fragments were amplified in a 40-cycle, 3-temperature PCR protocol. The absence of any of these fragments (relative to control PCR products) on a Southern blot indicated a deletion of that portion of the mRb gene. The tumors chosen for analysis were lung adenocarcinomas that were judged to be the cause of death in post-mortem analyses. Spontaneous tumors as well as those from irradiated mice (569 cGy of 60 Co γ rays or 60 cGy of JANUS neutrons, doses that have been found to have approximately equal biological effectiveness in the BCF, mouse) were analyzed for mRb deletions. In all normal mouse tissues studies, all six mRb exon fragments were present on Southem blots. Tumors in six neutron-irradiated mice also had no mRb deletions. However, I of 6 tumors from γ-irradiated mice and 6 of 18 spontaneous tumors from unirradiated mice had a deletion in one or both mRb alleles. All deletions detected were in the 5' region of the mRb gene

Large-scale perspective as a challenge

NARCIS (Netherlands)

Plomp, M.G.A.

2012-01-01

1. Scale forms a challenge for chain researchers: when exactly is something ‘large-scale’? What are the underlying factors (e.g. number of parties, data, objects in the chain, complexity) that determine this? It appears to be a continuum between small- and large-scale, where positioning on that

Algorithm 896: LSA: Algorithms for Large-Scale Optimization

Czech Academy of Sciences Publication Activity Database

Lukšan, Ladislav; Matonoha, Ctirad; Vlček, Jan

2009-01-01

Roč. 36, č. 3 (2009), 16-1-16-29 ISSN 0098-3500 R&D Pro jects: GA AV ČR IAA1030405; GA ČR GP201/06/P397 Institutional research plan: CEZ:AV0Z10300504 Keywords : algorithms * design * large-scale optimization * large-scale nonsmooth optimization * large-scale nonlinear least squares * large-scale nonlinear minimax * large-scale systems of nonlinear equations * sparse pro blems * partially separable pro blems * limited-memory methods * discrete Newton methods * quasi-Newton methods * primal interior-point methods Subject RIV: BB - Applied Statistics, Operational Research Impact factor: 1.904, year: 2009

Scale interactions in a mixing layer – the role of the large-scale gradients

KAUST Repository

Fiscaletti, D.

2016-02-15

© 2016 Cambridge University Press. The interaction between the large and the small scales of turbulence is investigated in a mixing layer, at a Reynolds number based on the Taylor microscale of , via direct numerical simulations. The analysis is performed in physical space, and the local vorticity root-mean-square (r.m.s.) is taken as a measure of the small-scale activity. It is found that positive large-scale velocity fluctuations correspond to large vorticity r.m.s. on the low-speed side of the mixing layer, whereas, they correspond to low vorticity r.m.s. on the high-speed side. The relationship between large and small scales thus depends on position if the vorticity r.m.s. is correlated with the large-scale velocity fluctuations. On the contrary, the correlation coefficient is nearly constant throughout the mixing layer and close to unity if the vorticity r.m.s. is correlated with the large-scale velocity gradients. Therefore, the small-scale activity appears closely related to large-scale gradients, while the correlation between the small-scale activity and the large-scale velocity fluctuations is shown to reflect a property of the large scales. Furthermore, the vorticity from unfiltered (small scales) and from low pass filtered (large scales) velocity fields tend to be aligned when examined within vortical tubes. These results provide evidence for the so-called \\'scale invariance\\' (Meneveau & Katz, Annu. Rev. Fluid Mech., vol. 32, 2000, pp. 1-32), and suggest that some of the large-scale characteristics are not lost at the small scales, at least at the Reynolds number achieved in the present simulation.

Deletion 22q13.3 syndrome

Directory of Open Access Journals (Sweden)

Phelan Mary C

2008-05-01

Full Text Available Abstract The deletion 22q13.3 syndrome (deletion 22q13 syndrome or Phelan-McDermid syndrome is a chromosome microdeletion syndrome characterized by neonatal hypotonia, global developmental delay, normal to accelerated growth, absent to severely delayed speech, and minor dysmorphic features. The deletion occurs with equal frequency in males and females and has been reported in mosaic and non-mosaic forms. Due to lack of clinical recognition and often insufficient laboratory testing, the syndrome is under-diagnosed and its true incidence remains unknown. Common physical traits include long eye lashes, large or unusual ears, relatively large hands, dysplastic toenails, full brow, dolicocephaly, full cheeks, bulbous nose, and pointed chin. Behavior is autistic-like with decreased perception of pain and habitual chewing or mouthing. The loss of 22q13.3 can result from simple deletion, translocation, ring chromosome formation and less common structural changes affecting the long arm of chromosome 22, specifically the region containing the SHANK3 gene. The diagnosis of deletion 22q13 syndrome should be considered in all cases of hypotonia of unknown etiology and in individuals with absent speech. Although the deletion can sometimes be detected by high resolution chromosome analysis, fluorescence in situ hybridization (FISH or array comparative genomic hybridization (CGH is recommended for confirmation. Differential diagnosis includes syndromes associated with hypotonia, developmental delay, speech delay and/or autistic-like affect (Prader-Willi, Angelman, Williams, Smith-Magenis, Fragile X, Sotos, FG, trichorhinophalangeal and velocardiofacial syndromes, autism spectrum disorders, cerebral palsy. Genetic counseling is recommended and parental laboratory studies should be considered to identify cryptic rearrangements and detect parental mosaicism. Prenatal diagnosis should be offered for future pregnancies in those families with inherited rearrangements

Clinical and genetic characterization of chanarin-dorfman syndrome patients: first report of large deletions in the ABHD5 gene

Directory of Open Access Journals (Sweden)

Prati Daniele

2010-12-01

Full Text Available Abstract Background Chanarin-Dorfman syndrome (CDS is a rare autosomal recessive disorder characterized by nonbullous congenital ichthyosiform erythroderma (NCIE and an intracellular accumulation of triacylglycerol (TG droplets in most tissues. The clinical phenotype involves multiple organs and systems, including liver, eyes, ears, skeletal muscle and central nervous system (CNS. Mutations in ABHD5/CGI58 gene are associated with CDS. Methods Eight CDS patients belonging to six different families from Mediterranean countries were enrolled for genetic study. Molecular analysis of the ABHD5 gene included the sequencing of the 7 coding exons and of the putative 5' regulatory regions, as well as reverse transcript-polymerase chain reaction analysis and sequencing of normal and aberrant ABHD5 cDNAs. Results Five different mutations were identified, four of which were novel, including two splice-site mutations (c.47+1G>A and c.960+5G>A and two large deletions (c.898_*320del and c.662-1330_773+46del. All the reported mutations are predicted to be pathogenic because they lead to an early stop codon or a frameshift producing a premature termination of translation. While nonsense, missense, frameshift and splice-site mutations have been identified in CDS patients, large genomic deletions have not previously been described. Conclusions These results emphasize the need for an efficient approach for genomic deletion screening to ensure an accurate molecular diagnosis of CDS. Moreover, in spite of intensive molecular screening, no mutations were identified in one patient with a confirmed clinical diagnosis of CDS, appointing to genetic heterogeneity of the syndrome.

Large-scale matrix-handling subroutines 'ATLAS'

International Nuclear Information System (INIS)

Tsunematsu, Toshihide; Takeda, Tatsuoki; Fujita, Keiichi; Matsuura, Toshihiko; Tahara, Nobuo

1978-03-01

Subroutine package ''ATLAS'' has been developed for handling large-scale matrices. The package is composed of four kinds of subroutines, i.e., basic arithmetic routines, routines for solving linear simultaneous equations and for solving general eigenvalue problems and utility routines. The subroutines are useful in large scale plasma-fluid simulations. (auth.)

Identification of West Eurasian mitochondrial haplogroups by mtDNA SNP screening: results of the 2006-2007 EDNAP collaborative exercise

DEFF Research Database (Denmark)

Parson, Walther; Fendt, Liane; Ballard, David

2008-01-01

no previous experience with the technology and/or mtDNA analysis. The results of this collaborative exercise stimulate the expansion of screening methods in forensic laboratories to increase efficiency and performance of mtDNA typing, and thus demonstrates that mtDNA SNP typing is a powerful tool for forensic......The European DNA Profiling (EDNAP) Group performed a collaborative exercise on a mitochondrial (mt) DNA screening assay that targeted 16 nucleotide positions in the coding region and allowed for the discrimination of major west Eurasian mtDNA haplogroups. The purpose of the exercise was to evaluate...

Large-scale solar heat

Energy Technology Data Exchange (ETDEWEB)

Tolonen, J.; Konttinen, P.; Lund, P. [Helsinki Univ. of Technology, Otaniemi (Finland). Dept. of Engineering Physics and Mathematics

1998-12-31

In this project a large domestic solar heating system was built and a solar district heating system was modelled and simulated. Objectives were to improve the performance and reduce costs of a large-scale solar heating system. As a result of the project the benefit/cost ratio can be increased by 40 % through dimensioning and optimising the system at the designing stage. (orig.)

Demography or selection on linked cultural traits or genes? Investigating the driver of low mtDNA diversity in the sperm whale using complementary mitochondrial and nuclear genome analyses.

Science.gov (United States)

Morin, Phillip A; Foote, Andrew D; Baker, C Scott; Hancock-Hanser, Brittany L; Kaschner, Kristin; Mate, Bruce R; Mesnick, Sarah L; Pease, Victoria L; Rosel, Patricia E; Alexander, Alana

2018-04-19

Mitochondrial DNA has been heavily utilized in phylogeography studies for several decades. However, underlying patterns of demography and phylogeography may be misrepresented due to coalescence stochasticity, selection, variation in mutation rates, and cultural hitchhiking (linkage of genetic variation to culturally transmitted traits affecting fitness). Cultural hitchhiking has been suggested as an explanation for low genetic diversity in species with strong social structures, counteracting even high mobility, abundance and limited barriers to dispersal. One such species is the sperm whale, which shows very limited phylogeographic structure and low mtDNA diversity despite a worldwide distribution and large population. Here, we use analyses of 175 globally distributed mitogenomes and three nuclear genomes to evaluate hypotheses of a population bottleneck/expansion versus a selective sweep due to cultural-hitchhiking or selection on mtDNA as the mechanism contributing to low worldwide mitochondrial diversity in sperm whales. In contrast to mtDNA control region (CR) data, mitogenome haplotypes are largely ocean-specific, with only one of 80 shared between the Atlantic and Pacific. Demographic analyses of nuclear genomes suggest low mtDNA diversity is consistent with a global reduction in population size that ended approximately 125,000 years ago, correlated with the Eemian interglacial. Phylogeographic analysis suggests that extant sperm whales descend from maternal lineages endemic to the Pacific during the period of reduced abundance, and have subsequently colonized the Atlantic several times. Results highlight the apparent impact of past climate change, and suggest selection and hitchhiking are not the sole processes responsible for low mtDNA diversity in this highly social species. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Construction of a psb C deletion strain in Synechocystis 6803.

Science.gov (United States)

Goldfarb, N; Knoepfle, N; Putnam-Evans, C

1997-01-01

Synechocystis 6803 is a cyanobacterium that carries out-oxygenic photosynthesis. We are interested in the introduction of mutations in the large extrinsic loop region of the CP43 protein of Photosystem II (PSII). CP43 appears to be required for the stable assembly of the PSII complex and also appears to play a role in photosynthetic oxygen evolution. Deletion of short segments of the large extrinsic loop results in mutants incapable of evolving oxygen. Alterations in psbC, the gene encoding CP43, are introduced into Synechocystis 6803 by transformation and homologous recombination. Specifically, plasmid constructs bearing the site-directed mutations are introduced into a deletion strain where the portion of the gene encoding the area of mutation has been deleted and replaced by a gene conferring antibiotic resistance. We have constructed a deletion strain of Synechocystis appropriate for the introduction of mutations in the large extrinsic loop of CP43 and have used it successfully to produce site-directed mutants.

Probes of large-scale structure in the Universe

International Nuclear Information System (INIS)

Suto, Yasushi; Gorski, K.; Juszkiewicz, R.; Silk, J.

1988-01-01

Recent progress in observational techniques has made it possible to confront quantitatively various models for the large-scale structure of the Universe with detailed observational data. We develop a general formalism to show that the gravitational instability theory for the origin of large-scale structure is now capable of critically confronting observational results on cosmic microwave background radiation angular anisotropies, large-scale bulk motions and large-scale clumpiness in the galaxy counts. (author)

Large-scale grid management; Storskala Nettforvaltning

Energy Technology Data Exchange (ETDEWEB)

Langdal, Bjoern Inge; Eggen, Arnt Ove

2003-07-01

The network companies in the Norwegian electricity industry now have to establish a large-scale network management, a concept essentially characterized by (1) broader focus (Broad Band, Multi Utility,...) and (2) bigger units with large networks and more customers. Research done by SINTEF Energy Research shows so far that the approaches within large-scale network management may be structured according to three main challenges: centralization, decentralization and out sourcing. The article is part of a planned series.

The effect of chronic alcohol consumption on mitochondrial DNA mutagenesis in human blood

Energy Technology Data Exchange (ETDEWEB)

Wurmb-Schwark, N. von [Institute of Legal Medicine, Christian Albrecht University of Kiel, Arnold-Heller-Str. 12, 24105 Kiel (Germany)], E-mail: nvonwurmb@rechtsmedizin.uni-kiel.de; Ringleb, A.; Schwark, T. [Institute of Legal Medicine, Christian Albrecht University of Kiel, Arnold-Heller-Str. 12, 24105 Kiel (Germany); Broese, T.; Weirich, S.; Schlaefke, D. [Clinic of Psychiatry and Psychotherapy, University of Rostock, Gehlsheimer Str. 20, Rostock (Germany); Wegener, R. [Institute of Legal Medicine, St-Georg-Str. 108, University of Rostock, 18055 Rostock (Germany); Oehmichen, M. [Institute of Legal Medicine, Christian Albrecht University of Kiel, Arnold-Heller-Str. 12, 24105 Kiel (Germany)

2008-01-01

The 4977 bp deletion of mitochondrial DNA (mtDNA) is known to accumulate with increasing age in post mitotic tissues. Recently, studies came out detecting this specific alteration also in fast replicating cells, e.g. in blood or skin tissue, often in correlation to specific diseases or - specifically in skin - external stressors such as UV radiation. In this study, we investigated mitochondrial mutagenesis in 69 patients with a chronic alcoholic disease and 46 age matched controls with a moderate drinking behavior. Two different fragments, specific for total and for deleted mtDNA (dmtDNA) were amplified in a duplex-PCR. A subsequent fragment analysis was performed and for relative quantification, the quotient of the peak areas of amplification products specific for deleted and total mtDNA was determined. Additionally, a real time PCR was performed to quantify mtDNA copy number. The relative amount of 4977 bp deleted mtDNA in alcoholics was significantly increased compared to controls. On the other hand, no difference regarding the mtDNA/nuclear DNA ratio in both investigated groups was detected. Additionally, no age dependence could be found nor in alcoholics, neither in the control group. These findings indicate that mtDNA mutagenesis in blood can be influenced by stressors such as alcohol. Ethanol seems to be a significant factor to alter mitochondrial DNA in blood and might be an additional contributor for the cellular aging process.

The effect of chronic alcohol consumption on mitochondrial DNA mutagenesis in human blood

International Nuclear Information System (INIS)

Wurmb-Schwark, N. von; Ringleb, A.; Schwark, T.; Broese, T.; Weirich, S.; Schlaefke, D.; Wegener, R.; Oehmichen, M.

2008-01-01

The 4977 bp deletion of mitochondrial DNA (mtDNA) is known to accumulate with increasing age in post mitotic tissues. Recently, studies came out detecting this specific alteration also in fast replicating cells, e.g. in blood or skin tissue, often in correlation to specific diseases or - specifically in skin - external stressors such as UV radiation. In this study, we investigated mitochondrial mutagenesis in 69 patients with a chronic alcoholic disease and 46 age matched controls with a moderate drinking behavior. Two different fragments, specific for total and for deleted mtDNA (dmtDNA) were amplified in a duplex-PCR. A subsequent fragment analysis was performed and for relative quantification, the quotient of the peak areas of amplification products specific for deleted and total mtDNA was determined. Additionally, a real time PCR was performed to quantify mtDNA copy number. The relative amount of 4977 bp deleted mtDNA in alcoholics was significantly increased compared to controls. On the other hand, no difference regarding the mtDNA/nuclear DNA ratio in both investigated groups was detected. Additionally, no age dependence could be found nor in alcoholics, neither in the control group. These findings indicate that mtDNA mutagenesis in blood can be influenced by stressors such as alcohol. Ethanol seems to be a significant factor to alter mitochondrial DNA in blood and might be an additional contributor for the cellular aging process

Markerless deletion of putative alanine dehydrogenase genes in Bacillus licheniformis using a codBA-based counterselection technique.

Science.gov (United States)

Kostner, David; Rachinger, Michael; Liebl, Wolfgang; Ehrenreich, Armin

2017-11-01

Bacillus licheniformis strains are used for the large-scale production of industrial exoenzymes from proteinaceous substrates, but details of the amino acid metabolism involved are largely unknown. In this study, two chromosomal genes putatively involved in amino acid metabolism of B. licheniformis were deleted to clarify their role. For this, a convenient counterselection system for markerless in-frame deletions was developed for B. licheniformis. A deletion plasmid containing up- and downstream DNA segments of the chromosomal deletion target was conjugated to B. licheniformis and integrated into the genome by homologous recombination. Thereafter, the counterselection was done by using a codBA cassette. The presence of cytosine deaminase and cytosine permease exerted a conditionally lethal phenotype on B. licheniformis cells in the presence of the cytosine analogue 5-fluorocytosine. Thereby clones were selected that lost the integrated vector sequence and the anticipated deletion target after a second recombination step. This method allows the construction of markerless mutants in Bacillus strains in iterative cycles. B. licheniformis MW3 derivatives lacking either one of the ORFs BL03009 or BL00190, encoding a putative alanine dehydrogenase and a similar putative enzyme, respectively, retained the ability to grow in minimal medium supplemented with alanine as the carbon source. In the double deletion mutant MW3 ΔBL03009 ΔBL00190, however, growth on alanine was completely abolished. These data indicate that the two encoded enzymes are paralogues fulfilling mutually replaceable functions in alanine utilization, and suggest that in B. licheniformis MW3 alanine utilization is initiated by direct oxidative transamination to pyruvate and ammonium.

Japanese large-scale interferometers

CERN Document Server

Kuroda, K; Miyoki, S; Ishizuka, H; Taylor, C T; Yamamoto, K; Miyakawa, O; Fujimoto, M K; Kawamura, S; Takahashi, R; Yamazaki, T; Arai, K; Tatsumi, D; Ueda, A; Fukushima, M; Sato, S; Shintomi, T; Yamamoto, A; Suzuki, T; Saitô, Y; Haruyama, T; Sato, N; Higashi, Y; Uchiyama, T; Tomaru, T; Tsubono, K; Ando, M; Takamori, A; Numata, K; Ueda, K I; Yoneda, H; Nakagawa, K; Musha, M; Mio, N; Moriwaki, S; Somiya, K; Araya, A; Kanda, N; Telada, S; Sasaki, M; Tagoshi, H; Nakamura, T; Tanaka, T; Ohara, K

2002-01-01

The objective of the TAMA 300 interferometer was to develop advanced technologies for kilometre scale interferometers and to observe gravitational wave events in nearby galaxies. It was designed as a power-recycled Fabry-Perot-Michelson interferometer and was intended as a step towards a final interferometer in Japan. The present successful status of TAMA is presented. TAMA forms a basis for LCGT (large-scale cryogenic gravitational wave telescope), a 3 km scale cryogenic interferometer to be built in the Kamioka mine in Japan, implementing cryogenic mirror techniques. The plan of LCGT is schematically described along with its associated R and D.

Therapeutic Targeting of the Mitochondria Initiates Excessive Superoxide Production and Mitochondrial Depolarization Causing Decreased mtDNA Integrity.

Science.gov (United States)

Pokrzywinski, Kaytee L; Biel, Thomas G; Kryndushkin, Dmitry; Rao, V Ashutosh

2016-01-01

Mitochondrial dysregulation is closely associated with excessive reactive oxygen species (ROS) production. Altered redox homeostasis has been implicated in the onset of several diseases including cancer. Mitochondrial DNA (mtDNA) and proteins are particularly sensitive to ROS as they are in close proximity to the respiratory chain (RC). Mitoquinone (MitoQ), a mitochondria-targeted redox agent, selectively damages breast cancer cells possibly through damage induced via enhanced ROS production. However, the effects of MitoQ and other triphenylphosphonium (TPP+) conjugated agents on cancer mitochondrial homeostasis remain unknown. The primary objective of this study was to determine the impact of mitochondria-targeted agent [(MTAs) conjugated to TPP+: mitoTEMPOL, mitoquinone and mitochromanol-acetate] on mitochondrial physiology and mtDNA integrity in breast (MDA-MB-231) and lung (H23) cancer cells. The integrity of the mtDNA was assessed by quantifying the degree of mtDNA fragmentation and copy number, as well as by measuring mitochondrial proteins essential to mtDNA stability and maintenance (TFAM, SSBP1, TWINKLE, POLG and POLRMT). Mitochondrial status was evaluated by measuring superoxide production, mitochondrial membrane depolarization, oxygen consumption, extracellular acidification and mRNA or protein levels of the RC complexes along with TCA cycle activity. In this study, we demonstrated that all investigated MTAs impair mitochondrial health and decrease mtDNA integrity in MDA-MB-231 and H23 cells. However, differences in the degree of mitochondrial damage and mtDNA degradation suggest unique properties among each MTA that may be cell line, dose and time dependent. Collectively, our study indicates the potential for TPP+ conjugated molecules to impair breast and lung cancer cells by targeting mitochondrial homeostasis.

Large scale model testing

International Nuclear Information System (INIS)

Brumovsky, M.; Filip, R.; Polachova, H.; Stepanek, S.

1989-01-01

Fracture mechanics and fatigue calculations for WWER reactor pressure vessels were checked by large scale model testing performed using large testing machine ZZ 8000 (with a maximum load of 80 MN) at the SKODA WORKS. The results are described from testing the material resistance to fracture (non-ductile). The testing included the base materials and welded joints. The rated specimen thickness was 150 mm with defects of a depth between 15 and 100 mm. The results are also presented of nozzles of 850 mm inner diameter in a scale of 1:3; static, cyclic, and dynamic tests were performed without and with surface defects (15, 30 and 45 mm deep). During cyclic tests the crack growth rate in the elastic-plastic region was also determined. (author). 6 figs., 2 tabs., 5 refs

Endurance exercise rescues progeroid aging and induces systemic mitochondrial rejuvenation in mtDNA mutator mice

Science.gov (United States)

Safdar, Adeel; Bourgeois, Jacqueline M.; Ogborn, Daniel I.; Little, Jonathan P.; Hettinga, Bart P.; Akhtar, Mahmood; Thompson, James E.; Melov, Simon; Mocellin, Nicholas J.; Kujoth, Gregory C.; Prolla, Tomas A.; Tarnopolsky, Mark A.

2011-01-01

A causal role for mitochondrial DNA (mtDNA) mutagenesis in mammalian aging is supported by recent studies demonstrating that the mtDNA mutator mouse, harboring a defect in the proofreading-exonuclease activity of mitochondrial polymerase gamma, exhibits accelerated aging phenotypes characteristic of human aging, systemic mitochondrial dysfunction, multisystem pathology, and reduced lifespan. Epidemiologic studies in humans have demonstrated that endurance training reduces the risk of chronic diseases and extends life expectancy. Whether endurance exercise can attenuate the cumulative systemic decline observed in aging remains elusive. Here we show that 5 mo of endurance exercise induced systemic mitochondrial biogenesis, prevented mtDNA depletion and mutations, increased mitochondrial oxidative capacity and respiratory chain assembly, restored mitochondrial morphology, and blunted pathological levels of apoptosis in multiple tissues of mtDNA mutator mice. These adaptations conferred complete phenotypic protection, reduced multisystem pathology, and prevented premature mortality in these mice. The systemic mitochondrial rejuvenation through endurance exercise promises to be an effective therapeutic approach to mitigating mitochondrial dysfunction in aging and related comorbidities. PMID:21368114

Why small-scale cannabis growers stay small: five mechanisms that prevent small-scale growers from going large scale.

Science.gov (United States)

Hammersvik, Eirik; Sandberg, Sveinung; Pedersen, Willy

2012-11-01

Over the past 15-20 years, domestic cultivation of cannabis has been established in a number of European countries. New techniques have made such cultivation easier; however, the bulk of growers remain small-scale. In this study, we explore the factors that prevent small-scale growers from increasing their production. The study is based on 1 year of ethnographic fieldwork and qualitative interviews conducted with 45 Norwegian cannabis growers, 10 of whom were growing on a large-scale and 35 on a small-scale. The study identifies five mechanisms that prevent small-scale indoor growers from going large-scale. First, large-scale operations involve a number of people, large sums of money, a high work-load and a high risk of detection, and thus demand a higher level of organizational skills than for small growing operations. Second, financial assets are needed to start a large 'grow-site'. Housing rent, electricity, equipment and nutrients are expensive. Third, to be able to sell large quantities of cannabis, growers need access to an illegal distribution network and knowledge of how to act according to black market norms and structures. Fourth, large-scale operations require advanced horticultural skills to maximize yield and quality, which demands greater skills and knowledge than does small-scale cultivation. Fifth, small-scale growers are often embedded in the 'cannabis culture', which emphasizes anti-commercialism, anti-violence and ecological and community values. Hence, starting up large-scale production will imply having to renegotiate or abandon these values. Going from small- to large-scale cannabis production is a demanding task-ideologically, technically, economically and personally. The many obstacles that small-scale growers face and the lack of interest and motivation for going large-scale suggest that the risk of a 'slippery slope' from small-scale to large-scale growing is limited. Possible political implications of the findings are discussed. Copyright

Atherosclerotic lesions and mitochondria DNA deletions in brain microvessels: implication in the pathogenesis of Alzheimer's disease.

Science.gov (United States)

Aliev, Gjumrakch; Gasimov, Eldar; Obrenovich, Mark E; Fischbach, Kathryn; Shenk, Justin C; Smith, Mark A; Perry, George

2008-01-01

The pathogenesis that is primarily responsible for Alzheimer's disease (AD) and cerebrovascular accidents (CVA) appears to involve chronic hypoperfusion. We studied the ultrastructural features of vascular lesions and mitochondria in brain vascular wall cells from human AD biopsy samples and two transgenic mouse models of AD, yeast artificial chromosome (YAC) and C57B6/SJL Tg (+), which overexpress human amyloid beta precursor protein (AbetaPP). In situ hybridization using probes for normal and 5 kb deleted human and mouse mitochondrial DNA (mtDNA) was performed along with immunocytochemistry using antibodies against the Abeta peptide processed from AbetaPP, 8-hydroxy-2'-guanosine (8OHG), and cytochrome c oxidase (COX). More amyloid deposition, oxidative stress markers as well as mitochondrial DNA deletions and structural abnormalities were present in the vascular walls of the human AD samples and the AbetaPP-YAC and C57B6/SJL Tg (+) transgenic mice compared to age-matched controls. Ultrastructural damage in perivascular cells highly correlated with endothelial lesions in all samples. Therefore, pharmacological interventions, directed at correcting the chronic hypoperfusion state, may change the natural course of the development of dementing neurodegeneration.

Distributed large-scale dimensional metrology new insights

CERN Document Server

Franceschini, Fiorenzo; Maisano, Domenico

2011-01-01

Focuses on the latest insights into and challenges of distributed large scale dimensional metrology Enables practitioners to study distributed large scale dimensional metrology independently Includes specific examples of the development of new system prototypes

MtDNA and Y-chromosomal diversity in the Chachapoya, a population from the northeast Peruvian Andes-Amazon divide.

Science.gov (United States)

Guevara, Evelyn K; Palo, Jukka U; Guillén, Sonia; Sajantila, Antti

2016-11-01

The ancient Chachapoya were an aggregate of several ethnic groups that shared a common language, religion, and material culture. They inhabited a territory at the juncture of the Andes and the Amazon basin. Their position between those ecozones most likely influenced their genetic composition. We attempted to better understand their population history by assessing the contemporary genetic diversity in the Chachapoya and three of their immediate neighbors (Huancas, Jivaro, and Cajamarca). We inferred signatures of demographic history and genetic affinities, and contrasted the findings with data from other populations on local and continental scales. We studied mitochondrial DNA (mtDNA; hypervariable segment [HVSI and HVSII]) and Y chromosome (23 short tandem repeats (STRs)) marker data in 382 modern individuals. We used Sanger sequencing for mtDNA and a commercially available kit for Y-chromosomal STR typing. The Chachapoya had affinities with various populations of Andean and Amazonian origin. When examining the Native American component, the Chachapoya displayed high levels of genetic diversity. Together with other parameters, for example, large Tajima's D and Fu's Fs, the data indicated no drastic reduction of the population size in the past. The high level of diversity in the Chachapoya, the lack of evidence of drift in the past, and genetic affinities with a broad range of populations in the Americas reflects an intricate population history in the region. The new genetic data from the Chachapoya indeed seems to point to a genetic complexity that is not yet resolved but beginning to be elucidated. Am. J. Hum. Biol. 28:857-867, 2016. © 2016Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

SCALE INTERACTION IN A MIXING LAYER. THE ROLE OF THE LARGE-SCALE GRADIENTS

KAUST Repository

Fiscaletti, Daniele; Attili, Antonio; Bisetti, Fabrizio; Elsinga, Gerrit E.

2015-01-01

from physical considerations we would expect the scales to interact in a qualitatively similar way within the flow and across different turbulent flows. Therefore, instead of the large-scale fluctuations, the large-scale gradients modulation of the small scales has been additionally investigated.

Genomic Variability of Mycobacterium tuberculosis Strains of the Euro-American Lineage Based on Large Sequence Deletions and 15-Locus MIRU-VNTR Polymorphism

Science.gov (United States)

Rindi, Laura; Medici, Chiara; Bimbi, Nicola; Buzzigoli, Andrea; Lari, Nicoletta; Garzelli, Carlo

2014-01-01

A sample of 260 Mycobacterium tuberculosis strains assigned to the Euro-American family was studied to identify phylogenetically informative genomic regions of difference (RD). Mutually exclusive deletions of regions RD115, RD122, RD174, RD182, RD183, RD193, RD219, RD726 and RD761 were found in 202 strains; the RDRio deletion was detected exclusively among the RD174-deleted strains. Although certain deletions were found more frequently in certain spoligotype families (i.e., deletion RD115 in T and LAM, RD174 in LAM, RD182 in Haarlem, RD219 in T and RD726 in the “Cameroon” family), the RD-defined sublineages did not specifically match with spoligotype-defined families, thus arguing against the use of spoligotyping for establishing exact phylogenetic relationships between strains. Notably, when tested for katG463/gyrA95 polymorphism, all the RD-defined sublineages belonged to Principal Genotypic Group (PGG) 2, except sublineage RD219 exclusively belonging to PGG3; the 58 Euro-American strains with no deletion were of either PGG2 or 3. A representative sample of 197 isolates was then analyzed by standard 15-locus MIRU-VNTR typing, a suitable approach to independently assess genetic relationships among the strains. Analysis of the MIRU-VNTR typing results by using a minimum spanning tree (MST) and a classical dendrogram showed groupings that were largely concordant with those obtained by RD-based analysis. Isolates of a given RD profile show, in addition to closely related MIRU-VNTR profiles, related spoligotype profiles that can serve as a basis for better spoligotype-based classification. PMID:25197794

Effects of a sex-ratio distorting endosymbiont on mtDNA variation in a global insect pest

Directory of Open Access Journals (Sweden)

Cook James M

2009-03-01

Full Text Available Abstract Background Patterns of mtDNA variation within a species reflect long-term population structure, but may also be influenced by maternally inherited endosymbionts, such as Wolbachia. These bacteria often alter host reproductive biology and can drive particular mtDNA haplotypes through populations. We investigated the impacts of Wolbachia infection and geography on mtDNA variation in the diamondback moth, a major global pest whose geographic distribution reflects both natural processes and transport via human agricultural activities. Results The mtDNA phylogeny of 95 individuals sampled from 10 countries on four continents revealed two major clades. One contained only Wolbachia-infected individuals from Malaysia and Kenya, while the other contained only uninfected individuals, from all countries including Malaysia and Kenya. Within the uninfected group was a further clade containing all individuals from Australasia and displaying very limited sequence variation. In contrast, a biparental nuclear gene phylogeny did not have infected and uninfected clades, supporting the notion that maternally-inherited Wolbachia are responsible for the mtDNA pattern. Only about 5% (15/306 of our global sample of individuals was infected with the plutWB1 isolate and even within infected local populations, many insects were uninfected. Comparisons of infected and uninfected isofemale lines revealed that plutWB1 is associated with sex ratio distortion. Uninfected lines have a 1:1 sex ratio, while infected ones show a 2:1 female bias. Conclusion The main correlate of mtDNA variation in P. xylostella is presence or absence of the plutWB1 infection. This is associated with substantial sex ratio distortion and the underlying mechanisms deserve further study. In contrast, geographic origin is a poor predictor of moth mtDNA sequences, reflecting human activity in moving the insects around the globe. The exception is a clade of Australasian individuals, which may

The phylogeny of the four pan-American MtDNA haplogroups: implications for evolutionary and disease studies.

Directory of Open Access Journals (Sweden)

Alessandro Achilli

Full Text Available Only a limited number of complete mitochondrial genome sequences belonging to Native American haplogroups were available until recently, which left America as the continent with the least amount of information about sequence variation of entire mitochondrial DNAs. In this study, a comprehensive overview of all available complete mitochondrial DNA (mtDNA genomes of the four pan-American haplogroups A2, B2, C1, and D1 is provided by revising the information scattered throughout GenBank and the literature, and adding 14 novel mtDNA sequences. The phylogenies of haplogroups A2, B2, C1, and D1 reveal a large number of sub-haplogroups but suggest that the ancestral Beringian population(s contributed only six (successful founder haplotypes to these haplogroups. The derived clades are overall starlike with coalescence times ranging from 18,000 to 21,000 years (with one exception using the conventional calibration. The average of about 19,000 years somewhat contrasts with the corresponding lower age of about 13,500 years that was recently proposed by employing a different calibration and estimation approach. Our estimate indicates a human entry and spread of the pan-American haplogroups into the Americas right after the peak of the Last Glacial Maximum and comfortably agrees with the undisputed ages of the earliest Paleoindians in South America. In addition, the phylogenetic approach also indicates that the pathogenic status proposed for various mtDNA mutations, which actually define branches of Native American haplogroups, was based on insufficient grounds.

MtDNA T4216C variation in multiple sclerosis

DEFF Research Database (Denmark)

Andalib, Sasan; Emamhadi, Mohammadreza; Yousefzadeh-Chabok, Shahrokh

2016-01-01

MtDNA T4216C variation has frequently been investigated in Multiple Sclerosis (MS) patients; nonetheless, controversy has existed about the evidence of association of this variation with susceptibility to MS. The present systematic review and meta-analysis converge the results of the preceding pu...

Understanding influences of culture and history on mtDNA variation and population structure in three populations from Assam, Northeast India.

Science.gov (United States)

Rej, Peter H; Deka, Ranjan; Norton, Heather L

2017-05-06

Positioned at the nexus of India, China, and Southeast Asia, Northeast India is presumed to have served as a channel for land-based human migration since the Upper Pleistocene. Assam is the largest state in the Northeast. We characterized the genetic background of three populations and examined the ways in which their population histories and cultural practices have influenced levels of intrasample and intersample variation. We examined sequence data from the mtDNA hypervariable control region and selected diagnostic mutations from the coding region in 128 individuals from three ethnic groups currently living in Assam: two Scheduled tribes (Sonowal Kachari and Rabha), and the non-Scheduled Tai Ahom. The populations of Assam sampled here express mtDNA lineages indicative of South Asian, Southeast Asian, and East Asian ancestry. We discovered two completely novel haplogroups in Assam that accounted for 6.2% of the lineages in our sample. We also identified a new subhaplogroup of M9a that is prevalent in the Sonowal Kachari of Assam (19.1%), but not present in neighboring Arunachal Pradesh, indicating substantial regional population structuring. Employing a large comparative dataset into a series of multidimensional scaling (MDS) analyses, we saw the Rabha cluster with populations sampled from Yunnan Province, indicating that the historical matrilineality of the Rabha has maintained lineages from Southern China. Assam has undergone multiple colonization events in the time since the initial peopling event, with populations from Southern China and Southeast Asia having the greatest influence on maternal lineages in the region. © 2017 Wiley Periodicals, Inc.

Trends in large-scale testing of reactor structures

International Nuclear Information System (INIS)

Blejwas, T.E.

2003-01-01

Large-scale tests of reactor structures have been conducted at Sandia National Laboratories since the late 1970s. This paper describes a number of different large-scale impact tests, pressurization tests of models of containment structures, and thermal-pressure tests of models of reactor pressure vessels. The advantages of large-scale testing are evident, but cost, in particular limits its use. As computer models have grown in size, such as number of degrees of freedom, the advent of computer graphics has made possible very realistic representation of results - results that may not accurately represent reality. A necessary condition to avoiding this pitfall is the validation of the analytical methods and underlying physical representations. Ironically, the immensely larger computer models sometimes increase the need for large-scale testing, because the modeling is applied to increasing more complex structural systems and/or more complex physical phenomena. Unfortunately, the cost of large-scale tests is a disadvantage that will likely severely limit similar testing in the future. International collaborations may provide the best mechanism for funding future programs with large-scale tests. (author)

Evolutionary analyses of entire genomes do not support the association of mtDNA mutations with Ras/MAPK pathway syndromes.

Directory of Open Access Journals (Sweden)

Alberto Gómez-Carballa

Full Text Available BACKGROUND: There are several known autosomal genes responsible for Ras/MAPK pathway syndromes, including Noonan syndrome (NS and related disorders (such as LEOPARD, neurofibromatosis type 1, although mutations of these genes do not explain all cases. Due to the important role played by the mitochondrion in the energetic metabolism of cardiac muscle, it was recently proposed that variation in the mitochondrial DNA (mtDNA genome could be a risk factor in the Noonan phenotype and in hypertrophic cardiomyopathy (HCM, which is a common clinical feature in Ras/MAPK pathway syndromes. In order to test these hypotheses, we sequenced entire mtDNA genomes in the largest series of patients suffering from Ras/MAPK pathway syndromes analyzed to date (n = 45, most of them classified as NS patients (n = 42. METHODS/PRINCIPAL FINDINGS: The results indicate that the observed mtDNA lineages were mostly of European ancestry, reproducing in a nutshell the expected haplogroup (hg patterns of a typical Iberian dataset (including hgs H, T, J, and U. Three new branches of the mtDNA phylogeny (H1j1, U5b1e, and L2a5 are described for the first time, but none of these are likely to be related to NS or Ras/MAPK pathway syndromes when observed under an evolutionary perspective. Patterns of variation in tRNA and protein genes, as well as redundant, private and heteroplasmic variants, in the mtDNA genomes of patients were as expected when compared with the patterns inferred from a worldwide mtDNA phylogeny based on more than 8700 entire genomes. Moreover, most of the mtDNA variants found in patients had already been reported in healthy individuals and constitute common polymorphisms in human population groups. CONCLUSIONS/SIGNIFICANCE: As a whole, the observed mtDNA genome variation in the NS patients was difficult to reconcile with previous findings that indicated a pathogenic role of mtDNA variants in NS.

Evolutionary Analyses of Entire Genomes Do Not Support the Association of mtDNA Mutations with Ras/MAPK Pathway Syndromes

Science.gov (United States)

Cerezo, María; Balboa, Emilia; Heredia, Claudia; Castro-Feijóo, Lidia; Rica, Itxaso; Barreiro, Jesús; Eirís, Jesús; Cabanas, Paloma; Martínez-Soto, Isabel; Fernández-Toral, Joaquín; Castro-Gago, Manuel; Pombo, Manuel; Carracedo, Ángel; Barros, Francisco

2011-01-01

Background There are several known autosomal genes responsible for Ras/MAPK pathway syndromes, including Noonan syndrome (NS) and related disorders (such as LEOPARD, neurofibromatosis type 1), although mutations of these genes do not explain all cases. Due to the important role played by the mitochondrion in the energetic metabolism of cardiac muscle, it was recently proposed that variation in the mitochondrial DNA (mtDNA) genome could be a risk factor in the Noonan phenotype and in hypertrophic cardiomyopathy (HCM), which is a common clinical feature in Ras/MAPK pathway syndromes. In order to test these hypotheses, we sequenced entire mtDNA genomes in the largest series of patients suffering from Ras/MAPK pathway syndromes analyzed to date (n = 45), most of them classified as NS patients (n = 42). Methods/Principal Findings The results indicate that the observed mtDNA lineages were mostly of European ancestry, reproducing in a nutshell the expected haplogroup (hg) patterns of a typical Iberian dataset (including hgs H, T, J, and U). Three new branches of the mtDNA phylogeny (H1j1, U5b1e, and L2a5) are described for the first time, but none of these are likely to be related to NS or Ras/MAPK pathway syndromes when observed under an evolutionary perspective. Patterns of variation in tRNA and protein genes, as well as redundant, private and heteroplasmic variants, in the mtDNA genomes of patients were as expected when compared with the patterns inferred from a worldwide mtDNA phylogeny based on more than 8700 entire genomes. Moreover, most of the mtDNA variants found in patients had already been reported in healthy individuals and constitute common polymorphisms in human population groups. Conclusions/Significance As a whole, the observed mtDNA genome variation in the NS patients was difficult to reconcile with previous findings that indicated a pathogenic role of mtDNA variants in NS. PMID:21526175

mtDNA copy number in oocytes of different sizes from individual pre- and post-pubertal pigs

DEFF Research Database (Denmark)

Pedersen, Hanne Skovsgaard; Løvendahl, Peter; Larsen, Knud Erik

2014-01-01

from ovaries of 10 pre- and 10 post-pubertal pigs. Cumulus cells were removed and the oocytes were measured (inside-ZP-diameter). Oocytes were transferred to DNAase-free tubes, snap-frozen, and stored at –80°C. The genes ND1 and COX1 were used to determine the mtDNA copy number. Plasmid preparations...... Reproduction 131, 233–245). However, the correlation between size and mtDNA copy number in single oocytes has not been determined. This study describes the relation between oocytes of defined diameters from individual pre- and postpubertal pigs and mtDNA copy number. Cumulus-oocyte complexes were aspirated...

Altered ultrasonic vocalization and impaired learning and memory in Angelman syndrome mouse model with a large maternal deletion from Ube3a to Gabrb3.

Directory of Open Access Journals (Sweden)

Yong-Hui Jiang

2010-08-01

Full Text Available Angelman syndrome (AS is a neurobehavioral disorder associated with mental retardation, absence of language development, characteristic electroencephalography (EEG abnormalities and epilepsy, happy disposition, movement or balance disorders, and autistic behaviors. The molecular defects underlying AS are heterogeneous, including large maternal deletions of chromosome 15q11-q13 (70%, paternal uniparental disomy (UPD of chromosome 15 (5%, imprinting mutations (rare, and mutations in the E6-AP ubiquitin ligase gene UBE3A (15%. Although patients with UBE3A mutations have a wide spectrum of neurological phenotypes, their features are usually milder than AS patients with deletions of 15q11-q13. Using a chromosomal engineering strategy, we generated mutant mice with a 1.6-Mb chromosomal deletion from Ube3a to Gabrb3, which inactivated the Ube3a and Gabrb3 genes and deleted the Atp10a gene. Homozygous deletion mutant mice died in the perinatal period due to a cleft palate resulting from the null mutation in Gabrb3 gene. Mice with a maternal deletion (m-/p+ were viable and did not have any obvious developmental defects. Expression analysis of the maternal and paternal deletion mice confirmed that the Ube3a gene is maternally expressed in brain, and showed that the Atp10a and Gabrb3 genes are biallelically expressed in all brain sub-regions studied. Maternal (m-/p+, but not paternal (m+/p-, deletion mice had increased spontaneous seizure activity and abnormal EEG. Extensive behavioral analyses revealed significant impairment in motor function, learning and memory tasks, and anxiety-related measures assayed in the light-dark box in maternal deletion but not paternal deletion mice. Ultrasonic vocalization (USV recording in newborns revealed that maternal deletion pups emitted significantly more USVs than wild-type littermates. The increased USV in maternal deletion mice suggests abnormal signaling behavior between mothers and pups that may reflect abnormal

Large Scale Computations in Air Pollution Modelling

DEFF Research Database (Denmark)

Zlatev, Z.; Brandt, J.; Builtjes, P. J. H.

Proceedings of the NATO Advanced Research Workshop on Large Scale Computations in Air Pollution Modelling, Sofia, Bulgaria, 6-10 July 1998......Proceedings of the NATO Advanced Research Workshop on Large Scale Computations in Air Pollution Modelling, Sofia, Bulgaria, 6-10 July 1998...

Effect of modified wuzi yanzong granule on patients with mild cognitive impairment from oxidative damage aspect.

Science.gov (United States)

Wang, Xue-mei; Fu, Hong; Liu, Geng-xin; Zhu, Wei; Li, Li; Yang, Jin-xia

2007-12-01

To observe the effects of modified Wuzi Yanzong Granule (WYG) on memory function and the activity of serum superoxide dismutase (SOD), malondialdehyde (MDA) levels, leukocyte mitochondrial DNA (mtDNA) deletion rate and beta-amyloid protein(1-28) (A beta(1-28)) in patients with mild cognitive impairment (MCI). Thirty-six patients with MCI were selected based on the internationally recognized Petersen's criteria, and equally and randomly assigned to two groups. The treated group was treated with WYG and the control group was treated with placebo for 3 months. In addition, 20 healthy subjects were included in the study as the normal control group. Changes of memory function, SOD activity, MDA content, leukocyte mtDNA deletion rate and A beta(1-28) content were observed before and after treatment. Compared with the normal control group, the memory quotient and SOD activity in patients with MCI decreased significantly (P < 0.01), while MDA, A beta(1-28) levels and the leukocyte mtDNA deletion rate increased significantly (P < 0.01). After treatment, levels of memory quotient and serum SOD activity increased while the serum MDA level, leukocyte mtDNA deletion rate and A beta(1-28) level decreased in the treated group compared with those before treatment (P<0.01, P<0.05). Meanwhile, leukocyte mtDNA deletion rate and A beta(1-28) content in the treated group were all lower than those in the control group (P<0.05). WYG could improve memory function in patients with MCI and the therapeutic mechanism is possibly related to the increased activity of anti-oxidase, the improved free radical metabolism and the alleviation of leukocyte mtDNA oxidation damage. WYG shows clinical significance in delaying the progression of MCI.

Prevalence and spectrum of large deletions or duplications in the major long QT syndrome-susceptibility genes and implications for long QT syndrome genetic testing.

Science.gov (United States)

Tester, David J; Benton, Amber J; Train, Laura; Deal, Barbara; Baudhuin, Linnea M; Ackerman, Michael J

2010-10-15

Long QT syndrome (LQTS) is a cardiac channelopathy associated with syncope, seizures, and sudden death. Approximately 75% of LQTS is due to mutations in genes encoding for 3 cardiac ion channel α-subunits (LQT1 to LQT3). However, traditional mutational analyses have limited detection capabilities for atypical mutations such as large gene rearrangements. We set out to determine the prevalence and spectrum of large deletions/duplications in the major LQTS-susceptibility genes in unrelated patients who were mutation negative after point mutation analysis of LQT1- to LQT12-susceptibility genes. Forty-two unrelated, clinically strong LQTS patients were analyzed using multiplex ligation-dependent probe amplification, a quantitative fluorescent technique for detecting multiple exon deletions and duplications. The SALSA multiplex ligation-dependent probe amplification LQTS kit from MRC-Holland was used to analyze the 3 major LQTS-associated genes, KCNQ1, KCNH2, and SCN5A, and the 2 minor genes, KCNE1 and KCNE2. Overall, 2 gene rearrangements were found in 2 of 42 unrelated patients (4.8%, confidence interval 1.7 to 11). A deletion of KCNQ1 exon 3 was identified in a 10-year-old Caucasian boy with a corrected QT duration of 660 ms, a personal history of exercise-induced syncope, and a family history of syncope. A deletion of KCNQ1 exon 7 was identified in a 17-year-old Caucasian girl with a corrected QT duration of 480 ms, a personal history of exercise-induced syncope, and a family history of sudden cardiac death. In conclusion, because nearly 5% of patients with genetically elusive LQTS had large genomic rearrangements involving the canonical LQTS-susceptibility genes, reflex genetic testing to investigate genomic rearrangements may be of clinical value. Copyright © 2010 Elsevier Inc. All rights reserved.

Large-Scale 3D Printing: The Way Forward

Science.gov (United States)

Jassmi, Hamad Al; Najjar, Fady Al; Ismail Mourad, Abdel-Hamid

2018-03-01

Research on small-scale 3D printing has rapidly evolved, where numerous industrial products have been tested and successfully applied. Nonetheless, research on large-scale 3D printing, directed to large-scale applications such as construction and automotive manufacturing, yet demands a great a great deal of efforts. Large-scale 3D printing is considered an interdisciplinary topic and requires establishing a blended knowledge base from numerous research fields including structural engineering, materials science, mechatronics, software engineering, artificial intelligence and architectural engineering. This review article summarizes key topics of relevance to new research trends on large-scale 3D printing, particularly pertaining (1) technological solutions of additive construction (i.e. the 3D printers themselves), (2) materials science challenges, and (3) new design opportunities.

Growth Limits in Large Scale Networks

DEFF Research Database (Denmark)

Knudsen, Thomas Phillip

limitations. The rising complexity of network management with the convergence of communications platforms is shown as problematic for both automatic management feasibility and for manpower resource management. In the fourth step the scope is extended to include the present society with the DDN project as its......The Subject of large scale networks is approached from the perspective of the network planner. An analysis of the long term planning problems is presented with the main focus on the changing requirements for large scale networks and the potential problems in meeting these requirements. The problems...... the fundamental technological resources in network technologies are analysed for scalability. Here several technological limits to continued growth are presented. The third step involves a survey of major problems in managing large scale networks given the growth of user requirements and the technological...

Accelerating sustainability in large-scale facilities

CERN Multimedia

Marina Giampietro

2011-01-01

Scientific research centres and large-scale facilities are intrinsically energy intensive, but how can big science improve its energy management and eventually contribute to the environmental cause with new cleantech? CERN’s commitment to providing tangible answers to these questions was sealed in the first workshop on energy management for large scale scientific infrastructures held in Lund, Sweden, on the 13-14 October.   Participants at the energy management for large scale scientific infrastructures workshop. The workshop, co-organised with the European Spallation Source (ESS) and  the European Association of National Research Facilities (ERF), tackled a recognised need for addressing energy issues in relation with science and technology policies. It brought together more than 150 representatives of Research Infrastrutures (RIs) and energy experts from Europe and North America. “Without compromising our scientific projects, we can ...

Replication stalling by catalytically impaired Twinkle induces mitochondrial DNA rearrangements in cultured cells

NARCIS (Netherlands)

Pohjoismaki, J.L.; Goffart, S.; Spelbrink, J.N.

2011-01-01

Pathological mitochondrial DNA (mtDNA) rearrangements have been proposed to result from repair of double-strand breaks caused by blockage of mitochondrial DNA (mtDNA) replication. As mtDNA deletions are seen only in post-mitotic tissues, it has been suggested that they are selected out in actively

Large scale reflood test

International Nuclear Information System (INIS)

Hirano, Kemmei; Murao, Yoshio

1980-01-01

The large-scale reflood test with a view to ensuring the safety of light water reactors was started in fiscal 1976 based on the special account act for power source development promotion measures by the entrustment from the Science and Technology Agency. Thereafter, to establish the safety of PWRs in loss-of-coolant accidents by joint international efforts, the Japan-West Germany-U.S. research cooperation program was started in April, 1980. Thereupon, the large-scale reflood test is now included in this program. It consists of two tests using a cylindrical core testing apparatus for examining the overall system effect and a plate core testing apparatus for testing individual effects. Each apparatus is composed of the mock-ups of pressure vessel, primary loop, containment vessel and ECCS. The testing method, the test results and the research cooperation program are described. (J.P.N.)

Rare deletions at 16p13.11 predispose to a diverse spectrum of sporadic epilepsy syndromes.

Science.gov (United States)

Heinzen, Erin L; Radtke, Rodney A; Urban, Thomas J; Cavalleri, Gianpiero L; Depondt, Chantal; Need, Anna C; Walley, Nicole M; Nicoletti, Paola; Ge, Dongliang; Catarino, Claudia B; Duncan, John S; Kasperaviciūte, Dalia; Tate, Sarah K; Caboclo, Luis O; Sander, Josemir W; Clayton, Lisa; Linney, Kristen N; Shianna, Kevin V; Gumbs, Curtis E; Smith, Jason; Cronin, Kenneth D; Maia, Jessica M; Doherty, Colin P; Pandolfo, Massimo; Leppert, David; Middleton, Lefkos T; Gibson, Rachel A; Johnson, Michael R; Matthews, Paul M; Hosford, David; Kälviäinen, Reetta; Eriksson, Kai; Kantanen, Anne-Mari; Dorn, Thomas; Hansen, Jörg; Krämer, Günter; Steinhoff, Bernhard J; Wieser, Heinz-Gregor; Zumsteg, Dominik; Ortega, Marcos; Wood, Nicholas W; Huxley-Jones, Julie; Mikati, Mohamad; Gallentine, William B; Husain, Aatif M; Buckley, Patrick G; Stallings, Ray L; Podgoreanu, Mihai V; Delanty, Norman; Sisodiya, Sanjay M; Goldstein, David B

2010-05-14

Deletions at 16p13.11 are associated with schizophrenia, mental retardation, and most recently idiopathic generalized epilepsy. To evaluate the role of 16p13.11 deletions, as well as other structural variation, in epilepsy disorders, we used genome-wide screens to identify copy number variation in 3812 patients with a diverse spectrum of epilepsy syndromes and in 1299 neurologically-normal controls. Large deletions (> 100 kb) at 16p13.11 were observed in 23 patients, whereas no control had a deletion greater than 16 kb. Patients, even those with identically sized 16p13.11 deletions, presented with highly variable epilepsy phenotypes. For a subset of patients with a 16p13.11 deletion, we show a consistent reduction of expression for included genes, suggesting that haploinsufficiency might contribute to pathogenicity. We also investigated another possible mechanism of pathogenicity by using hybridization-based capture and next-generation sequencing of the homologous chromosome for ten 16p13.11-deletion patients to look for unmasked recessive mutations. Follow-up genotyping of suggestive polymorphisms failed to identify any convincing recessive-acting mutations in the homologous interval corresponding to the deletion. The observation that two of the 16p13.11 deletions were larger than 2 Mb in size led us to screen for other large deletions. We found 12 additional genomic regions harboring deletions > 2 Mb in epilepsy patients, and none in controls. Additional evaluation is needed to characterize the role of these exceedingly large, non-locus-specific deletions in epilepsy. Collectively, these data implicate 16p13.11 and possibly other large deletions as risk factors for a wide range of epilepsy disorders, and they appear to point toward haploinsufficiency as a contributor to the pathogenicity of deletions. Copyright (c) 2010 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Large Scale Cosmological Anomalies and Inhomogeneous Dark Energy

Directory of Open Access Journals (Sweden)

Leandros Perivolaropoulos

2014-01-01

Full Text Available A wide range of large scale observations hint towards possible modifications on the standard cosmological model which is based on a homogeneous and isotropic universe with a small cosmological constant and matter. These observations, also known as “cosmic anomalies” include unexpected Cosmic Microwave Background perturbations on large angular scales, large dipolar peculiar velocity flows of galaxies (“bulk flows”, the measurement of inhomogenous values of the fine structure constant on cosmological scales (“alpha dipole” and other effects. The presence of the observational anomalies could either be a large statistical fluctuation in the context of ΛCDM or it could indicate a non-trivial departure from the cosmological principle on Hubble scales. Such a departure is very much constrained by cosmological observations for matter. For dark energy however there are no significant observational constraints for Hubble scale inhomogeneities. In this brief review I discuss some of the theoretical models that can naturally lead to inhomogeneous dark energy, their observational constraints and their potential to explain the large scale cosmic anomalies.

Large-scale patterns in Rayleigh-Benard convection

International Nuclear Information System (INIS)

Hardenberg, J. von; Parodi, A.; Passoni, G.; Provenzale, A.; Spiegel, E.A.

2008-01-01

Rayleigh-Benard convection at large Rayleigh number is characterized by the presence of intense, vertically moving plumes. Both laboratory and numerical experiments reveal that the rising and descending plumes aggregate into separate clusters so as to produce large-scale updrafts and downdrafts. The horizontal scales of the aggregates reported so far have been comparable to the horizontal extent of the containers, but it has not been clear whether that represents a limitation imposed by domain size. In this work, we present numerical simulations of convection at sufficiently large aspect ratio to ascertain whether there is an intrinsic saturation scale for the clustering process when that ratio is large enough. From a series of simulations of Rayleigh-Benard convection with Rayleigh numbers between 10 5 and 10 8 and with aspect ratios up to 12π, we conclude that the clustering process has a finite horizontal saturation scale with at most a weak dependence on Rayleigh number in the range studied

The significance of chromosome deletions in atomic-bomb survivors

International Nuclear Information System (INIS)

Tanaka, Kimio; Shigeta, Chiharu; Oguma, Nobuo; Kamada, Nanao; Deng, Z.; Niimi, Masanobu; Aisaka, Tadaichi.

1986-01-01

In 39 A-bomb survivors 40 years after exposure at ≤ 1,000 m from ground zero, the frequency and features of chromosome deletions in peripheral lymphocytes were examined using a differential staining technique. Simultaneously, in vitro irradiation experiment with Cf-252 was made to infer chromosome aberrations occuring immediately after exposure. Californium-252 with 100 rad induced dicentric and ring chromosomes in 40 % of the cells and acentric fragments in 44 %. Among the A-bomb survivors, chromosome aberrations were observed in 651 (21 %) of the total 3,136 cells. There were 146 cells with deletions (22 % of abnormal cells; 5 % of the total cells), and 10 cells with acentric fragment (0.3 % of the total cells). The figure for deletions was far higher than that reported in the literature. A large number of deletions were seen in chromosomes no.4, no.21, and no.22, and a few deletions in chromosomes no.7 and no.20. Significance of chromosome deletions is discussed. (Namekawa, K.)

SG-ADVISER mtDNA: a web server for mitochondrial DNA annotation with data from 200 samples of a healthy aging cohort.

Science.gov (United States)

Rueda, Manuel; Torkamani, Ali

2017-08-18

Whole genome and exome sequencing usually include reads containing mitochondrial DNA (mtDNA). Yet, state-of-the-art pipelines and services for human nuclear genome variant calling and annotation do not handle mitochondrial genome data appropriately. As a consequence, any researcher desiring to add mtDNA variant analysis to their investigations is forced to explore the literature for mtDNA pipelines, evaluate them, and implement their own instance of the desired tool. This task is far from trivial, and can be prohibitive for non-bioinformaticians. We have developed SG-ADVISER mtDNA, a web server to facilitate the analysis and interpretation of mtDNA genomic data coming from next generation sequencing (NGS) experiments. The server was built in the context of our SG-ADVISER framework and on top of the MtoolBox platform (Calabrese et al., Bioinformatics 30(21):3115-3117, 2014), and includes most of its functionalities (i.e., assembly of mitochondrial genomes, heteroplasmic fractions, haplogroup assignment, functional and prioritization analysis of mitochondrial variants) as well as a back-end and a front-end interface. The server has been tested with unpublished data from 200 individuals of a healthy aging cohort (Erikson et al., Cell 165(4):1002-1011, 2016) and their data is made publicly available here along with a preliminary analysis of the variants. We observed that individuals over ~90 years old carried low levels of heteroplasmic variants in their genomes. SG-ADVISER mtDNA is a fast and functional tool that allows for variant calling and annotation of human mtDNA data coming from NGS experiments. The server was built with simplicity in mind, and builds on our own experience in interpreting mtDNA variants in the context of sudden death and rare diseases. Our objective is to provide an interface for non-bioinformaticians aiming to acquire (or contrast) mtDNA annotations via MToolBox. SG-ADVISER web server is freely available to all users at https://genomics.scripps.edu/mtdna .

Quantitative Genome-Wide Analysis of Yeast Deletion Strain Sensitivities to Oxidative and Chemical Stress

Directory of Open Access Journals (Sweden)

Stanley Fields

2006-03-01

Full Text Available Understanding the actions of drugs and toxins in a cell is of critical importance to medicine, yet many of the molecular events involved in chemical resistance are relatively uncharacterized. In order to identify the cellular processes and pathways targeted by chemicals, we took advantage of the haploid Saccharomyces cerevisiae deletion strains (Winzeler et al., 1999. Although ~4800 of the strains are viable, the loss of a gene in a pathway affected by a drug can lead to a synthetic lethal effect in which the combination of a deletion and a normally sublethal dose of a chemical results in loss of viability. WE carried out genome-wide screens to determine quantitative sensitivities of the deletion set to four chemicals: hydrogen peroxide, menadione, ibuprofen and mefloquine. Hydrogen peroxide and menadione induce oxidative stress in the cell, whereas ibuprofen and mefloquine are toxic to yeast by unknown mechanisms. Here we report the sensitivities of 659 deletion strains that are sensitive to one or more of these four compounds, including 163 multichemicalsensitive strains, 394 strains specific to hydrogen peroxide and/or menadione, 47 specific to ibuprofen and 55 specific to mefloquine.We correlate these results with data from other large-scale studies to yield novel insights into cellular function.

ABCA7 frameshift deletion associated with Alzheimer disease in African Americans

Science.gov (United States)

Cukier, Holly N.; Kunkle, Brian W.; Vardarajan, Badri N.; Rolati, Sophie; Hamilton-Nelson, Kara L.; Kohli, Martin A.; Whitehead, Patrice L.; Dombroski, Beth A.; Van Booven, Derek; Lang, Rosalyn; Dykxhoorn, Derek M.; Farrer, Lindsay A.; Cuccaro, Michael L.; Vance, Jeffery M.; Gilbert, John R.; Beecham, Gary W.; Martin, Eden R.; Carney, Regina M.; Mayeux, Richard; Schellenberg, Gerard D.; Byrd, Goldie S.; Haines, Jonathan L.

2016-01-01

Objective: To identify a causative variant(s) that may contribute to Alzheimer disease (AD) in African Americans (AA) in the ATP-binding cassette, subfamily A (ABC1), member 7 (ABCA7) gene, a known risk factor for late-onset AD. Methods: Custom capture sequencing was performed on ∼150 kb encompassing ABCA7 in 40 AA cases and 37 AA controls carrying the AA risk allele (rs115550680). Association testing was performed for an ABCA7 deletion identified in large AA data sets (discovery n = 1,068; replication n = 1,749) and whole exome sequencing of Caribbean Hispanic (CH) AD families. Results: A 44-base pair deletion (rs142076058) was identified in all 77 risk genotype carriers, which shows that the deletion is in high linkage disequilibrium with the risk allele. The deletion was assessed in a large data set (531 cases and 527 controls) and, after adjustments for age, sex, and APOE status, was significantly associated with disease (p = 0.0002, odds ratio [OR] = 2.13 [95% confidence interval (CI): 1.42–3.20]). An independent data set replicated the association (447 cases and 880 controls, p = 0.0117, OR = 1.65 [95% CI: 1.12–2.44]), and joint analysis increased the significance (p = 1.414 × 10−5, OR = 1.81 [95% CI: 1.38–2.37]). The deletion is common in AA cases (15.2%) and AA controls (9.74%), but in only 0.12% of our non-Hispanic white cohort. Whole exome sequencing of multiplex, CH families identified the deletion cosegregating with disease in a large sibship. The deleted allele produces a stable, detectable RNA strand and is predicted to result in a frameshift mutation (p.Arg578Alafs) that could interfere with protein function. Conclusions: This common ABCA7 deletion could represent an ethnic-specific pathogenic alteration in AD. PMID:27231719

Human iPSC-Derived Neural Progenitors Are an Effective Drug Discovery Model for Neurological mtDNA Disorders.

Science.gov (United States)

Lorenz, Carmen; Lesimple, Pierre; Bukowiecki, Raul; Zink, Annika; Inak, Gizem; Mlody, Barbara; Singh, Manvendra; Semtner, Marcus; Mah, Nancy; Auré, Karine; Leong, Megan; Zabiegalov, Oleksandr; Lyras, Ekaterini-Maria; Pfiffer, Vanessa; Fauler, Beatrix; Eichhorst, Jenny; Wiesner, Burkhard; Huebner, Norbert; Priller, Josef; Mielke, Thorsten; Meierhofer, David; Izsvák, Zsuzsanna; Meier, Jochen C; Bouillaud, Frédéric; Adjaye, James; Schuelke, Markus; Wanker, Erich E; Lombès, Anne; Prigione, Alessandro

2017-05-04

Mitochondrial DNA (mtDNA) mutations frequently cause neurological diseases. Modeling of these defects has been difficult because of the challenges associated with engineering mtDNA. We show here that neural progenitor cells (NPCs) derived from human induced pluripotent stem cells (iPSCs) retain the parental mtDNA profile and exhibit a metabolic switch toward oxidative phosphorylation. NPCs derived in this way from patients carrying a deleterious homoplasmic mutation in the mitochondrial gene MT-ATP6 (m.9185T>C) showed defective ATP production and abnormally high mitochondrial membrane potential (MMP), plus altered calcium homeostasis, which represents a potential cause of neural impairment. High-content screening of FDA-approved drugs using the MMP phenotype highlighted avanafil, which we found was able to partially rescue the calcium defect in patient NPCs and differentiated neurons. Overall, our results show that iPSC-derived NPCs provide an effective model for drug screening to target mtDNA disorders that affect the nervous system. Copyright © 2016 Elsevier Inc. All rights reserved.

Regional Variation in mtDNA of the Lesser Prairie-Chicken

Science.gov (United States)

Hagen, Christian A.; Pitman, James C.; Sandercock, Brett K.; Wolfe, Don H.; Robel, Robel J.; Applegate, Roger D.; Oyler-McCance, Sara J.

2010-01-01

Cumulative loss of habitat and long-term decline in the populations of the Lesser Prairie-Chicken (Tympanuchus pallidicinctus) have led to concerns for the species' viability throughout its range in the southern Great Plains. For more efficient conservation past and present distributions of genetic variation need to be understood. We examined the distribution of mitochondrial DNA (mtDNA) variation in the Lesser Prairie-Chicken across Kansas, Colorado, Oklahoma, and New Mexico. Throughout the range we found little genetic differentiation except for the population in New Mexico, which was significantly different from most other publications. We did, however, find significant isolation by distance at the rangewide scale (r=0.698). We found no relationship between haplotype phylogeny and geography, and our analyses provide evidence for a post-glacial population expansion within the species that is consistent with the idea that speciation within Tympanuchus is recent. Conservation actions that increase the likelihood of genetically viable populations in the future should be evaluated for implementation.

Manufacturing test of large scale hollow capsule and long length cladding in the large scale oxide dispersion strengthened (ODS) martensitic steel

International Nuclear Information System (INIS)

Narita, Takeshi; Ukai, Shigeharu; Kaito, Takeji; Ohtsuka, Satoshi; Fujiwara, Masayuki

2004-04-01

Mass production capability of oxide dispersion strengthened (ODS) martensitic steel cladding (9Cr) has being evaluated in the Phase II of the Feasibility Studies on Commercialized Fast Reactor Cycle System. The cost for manufacturing mother tube (raw materials powder production, mechanical alloying (MA) by ball mill, canning, hot extrusion, and machining) is a dominant factor in the total cost for manufacturing ODS ferritic steel cladding. In this study, the large-sale 9Cr-ODS martensitic steel mother tube which is made with a large-scale hollow capsule, and long length claddings were manufactured, and the applicability of these processes was evaluated. Following results were obtained in this study. (1) Manufacturing the large scale mother tube in the dimension of 32 mm OD, 21 mm ID, and 2 m length has been successfully carried out using large scale hollow capsule. This mother tube has a high degree of accuracy in size. (2) The chemical composition and the micro structure of the manufactured mother tube are similar to the existing mother tube manufactured by a small scale can. And the remarkable difference between the bottom and top sides in the manufactured mother tube has not been observed. (3) The long length cladding has been successfully manufactured from the large scale mother tube which was made using a large scale hollow capsule. (4) For reducing the manufacturing cost of the ODS steel claddings, manufacturing process of the mother tubes using a large scale hollow capsules is promising. (author)

Amplification of large-scale magnetic field in nonhelical magnetohydrodynamics

KAUST Repository

Kumar, Rohit

2017-08-11

It is typically assumed that the kinetic and magnetic helicities play a crucial role in the growth of large-scale dynamo. In this paper, we demonstrate that helicity is not essential for the amplification of large-scale magnetic field. For this purpose, we perform nonhelical magnetohydrodynamic (MHD) simulation, and show that the large-scale magnetic field can grow in nonhelical MHD when random external forcing is employed at scale 1/10 the box size. The energy fluxes and shell-to-shell transfer rates computed using the numerical data show that the large-scale magnetic energy grows due to the energy transfers from the velocity field at the forcing scales.

Hydrometeorological variability on a large french catchment and its relation to large-scale circulation across temporal scales

Science.gov (United States)

Massei, Nicolas; Dieppois, Bastien; Fritier, Nicolas; Laignel, Benoit; Debret, Maxime; Lavers, David; Hannah, David

2015-04-01

In the present context of global changes, considerable efforts have been deployed by the hydrological scientific community to improve our understanding of the impacts of climate fluctuations on water resources. Both observational and modeling studies have been extensively employed to characterize hydrological changes and trends, assess the impact of climate variability or provide future scenarios of water resources. In the aim of a better understanding of hydrological changes, it is of crucial importance to determine how and to what extent trends and long-term oscillations detectable in hydrological variables are linked to global climate oscillations. In this work, we develop an approach associating large-scale/local-scale correlation, enmpirical statistical downscaling and wavelet multiresolution decomposition of monthly precipitation and streamflow over the Seine river watershed, and the North Atlantic sea level pressure (SLP) in order to gain additional insights on the atmospheric patterns associated with the regional hydrology. We hypothesized that: i) atmospheric patterns may change according to the different temporal wavelengths defining the variability of the signals; and ii) definition of those hydrological/circulation relationships for each temporal wavelength may improve the determination of large-scale predictors of local variations. The results showed that the large-scale/local-scale links were not necessarily constant according to time-scale (i.e. for the different frequencies characterizing the signals), resulting in changing spatial patterns across scales. This was then taken into account by developing an empirical statistical downscaling (ESD) modeling approach which integrated discrete wavelet multiresolution analysis for reconstructing local hydrometeorological processes (predictand : precipitation and streamflow on the Seine river catchment) based on a large-scale predictor (SLP over the Euro-Atlantic sector) on a monthly time-step. This approach

Superconducting materials for large scale applications

International Nuclear Information System (INIS)

Dew-Hughes, D.

1975-01-01

Applications of superconductors capable of carrying large current densities in large-scale electrical devices are examined. Discussions are included on critical current density, superconducting materials available, and future prospects for improved superconducting materials. (JRD)

Large-scale influences in near-wall turbulence.

Science.gov (United States)

Hutchins, Nicholas; Marusic, Ivan

2007-03-15

Hot-wire data acquired in a high Reynolds number facility are used to illustrate the need for adequate scale separation when considering the coherent structure in wall-bounded turbulence. It is found that a large-scale motion in the log region becomes increasingly comparable in energy to the near-wall cycle as the Reynolds number increases. Through decomposition of fluctuating velocity signals, it is shown that this large-scale motion has a distinct modulating influence on the small-scale energy (akin to amplitude modulation). Reassessment of DNS data, in light of these results, shows similar trends, with the rate and intensity of production due to the near-wall cycle subject to a modulating influence from the largest-scale motions.

Comparative genome analysis identifies two large deletions in the genome of highly-passaged attenuated Streptococcus agalactiae strain YM001 compared to the parental pathogenic strain HN016.

Science.gov (United States)

Wang, Rui; Li, Liping; Huang, Yan; Luo, Fuguang; Liang, Wanwen; Gan, Xi; Huang, Ting; Lei, Aiying; Chen, Ming; Chen, Lianfu

2015-11-04

Streptococcus agalactiae (S. agalactiae), also known as group B Streptococcus (GBS), is an important pathogen for neonatal pneumonia, meningitis, bovine mastitis, and fish meningoencephalitis. The global outbreaks of Streptococcus disease in tilapia cause huge economic losses and threaten human food hygiene safety as well. To investigate the mechanism of S. agalactiae pathogenesis in tilapia and develop attenuated S. agalactiae vaccine, this study sequenced and comparatively analyzed the whole genomes of virulent wild-type S. agalactiae strain HN016 and its highly-passaged attenuated strain YM001 derived from tilapia. We performed Illumina sequencing of DNA prepared from strain HN016 and YM001. Sequencedreads were assembled and nucleotide comparisons, single nucleotide polymorphism (SNP) , indels were analyzed between the draft genomes of HN016 and YM001. Clustered regularly interspaced short palindromic repeats (CRISPRs) and prophage were detected and analyzed in different S. agalactiae strains. The genome of S. agalactiae YM001 was 2,047,957 bp with a GC content of 35.61 %; it contained 2044 genes and 88 RNAs. Meanwhile, the genome of S. agalactiae HN016 was 2,064,722 bp with a GC content of 35.66 %; it had 2063 genes and 101 RNAs. Comparative genome analysis indicated that compared with HN016, YM001 genome had two significant large deletions, at the sizes of 5832 and 11,116 bp respectively, resulting in the deletion of three rRNA and ten tRNA genes, as well as the deletion and functional damage of ten genes related to metabolism, transport, growth, anti-stress, etc. Besides these two large deletions, other ten deletions and 28 single nucleotide variations (SNVs) were also identified, mainly affecting the metabolism- and growth-related genes. The genome of attenuated S. agalactiae YM001 showed significant variations, resulting in the deletion of 10 functional genes, compared to the parental pathogenic strain HN016. The deleted and mutated functional genes all

Internucleotide correlations and nucleotide periodicity in Drosophila mtDNA: New evidence for panselective evolution

Directory of Open Access Journals (Sweden)

Carlos Y Valenzuela

2010-01-01

Full Text Available Analysis for the homogeneity of the distribution of the second base of dinucleotides in relation to the first, whose bases are separated by 0, 1, 2,... 21 nucleotide sites, was performed with the VIH-1 genome (cDNA, the Drosophila mtDNA, the Drosophila Torso gene and the human p-globin gene. These four DNA segments showed highly significant heterogeneities of base distributions that cannot be accounted for by neutral or nearly neutral evolution or by the "neighbor influence" of nucleotides on mutation rates. High correlations are found in the bases of dinucleotides separated by 0, 1 and more number of sites. A periodicity of three consecutive significance values (measured by the x²9 was found only in Drosophila mtDNA. This periodicity may be due to an unknown structure or organization of mtDNA. This non-random distribution of the two bases of dinucleotides widespread throughout these DNA segments is rather compatible with panselective evolution and generalized internucleotide co-adaptation.

PKI security in large-scale healthcare networks.

Science.gov (United States)

Mantas, Georgios; Lymberopoulos, Dimitrios; Komninos, Nikos

2012-06-01

During the past few years a lot of PKI (Public Key Infrastructures) infrastructures have been proposed for healthcare networks in order to ensure secure communication services and exchange of data among healthcare professionals. However, there is a plethora of challenges in these healthcare PKI infrastructures. Especially, there are a lot of challenges for PKI infrastructures deployed over large-scale healthcare networks. In this paper, we propose a PKI infrastructure to ensure security in a large-scale Internet-based healthcare network connecting a wide spectrum of healthcare units geographically distributed within a wide region. Furthermore, the proposed PKI infrastructure facilitates the trust issues that arise in a large-scale healthcare network including multi-domain PKI infrastructures.

Deletion of Indian hedgehog gene causes dominant semi-lethal Creeper trait in chicken

Science.gov (United States)

Jin, Sihua; Zhu, Feng; Wang, Yanyun; Yi, Guoqiang; Li, Junying; Lian, Ling; Zheng, Jiangxia; Xu, Guiyun; Jiao, Rengang; Gong, Yu; Hou, Zhuocheng; Yang, Ning

2016-01-01

The Creeper trait, a classical monogenic phenotype of chicken, is controlled by a dominant semi-lethal gene. This trait has been widely cited in the genetics and molecular biology textbooks for illustrating autosomal dominant semi-lethal inheritance over decades. However, the genetic basis of the Creeper trait remains unknown. Here we have utilized ultra-deep sequencing and extensive analysis for targeting causative mutation controlling the Creeper trait. Our results indicated that the deletion of Indian hedgehog (IHH) gene was only found in the whole-genome sequencing data of lethal embryos and Creeper chickens. Large scale segregation analysis demonstrated that the deletion of IHH was fully linked with early embryonic death and the Creeper trait. Expression analysis showed a much lower expression of IHH in Creeper than wild-type chickens. We therefore suggest the deletion of IHH to be the causative mutation for the Creeper trait in chicken. Our findings unravel the genetic basis of the longstanding Creeper phenotype mystery in chicken as the same gene also underlies bone dysplasia in human and mouse, and thus highlight the significance of IHH in animal development and human haploinsufficiency disorders. PMID:27439785

Emerging large-scale solar heating applications

International Nuclear Information System (INIS)

Wong, W.P.; McClung, J.L.

2009-01-01

Currently the market for solar heating applications in Canada is dominated by outdoor swimming pool heating, make-up air pre-heating and domestic water heating in homes, commercial and institutional buildings. All of these involve relatively small systems, except for a few air pre-heating systems on very large buildings. Together these applications make up well over 90% of the solar thermal collectors installed in Canada during 2007. These three applications, along with the recent re-emergence of large-scale concentrated solar thermal for generating electricity, also dominate the world markets. This paper examines some emerging markets for large scale solar heating applications, with a focus on the Canadian climate and market. (author)

Emerging large-scale solar heating applications

Energy Technology Data Exchange (ETDEWEB)

Wong, W.P.; McClung, J.L. [Science Applications International Corporation (SAIC Canada), Ottawa, Ontario (Canada)

2009-07-01

Currently the market for solar heating applications in Canada is dominated by outdoor swimming pool heating, make-up air pre-heating and domestic water heating in homes, commercial and institutional buildings. All of these involve relatively small systems, except for a few air pre-heating systems on very large buildings. Together these applications make up well over 90% of the solar thermal collectors installed in Canada during 2007. These three applications, along with the recent re-emergence of large-scale concentrated solar thermal for generating electricity, also dominate the world markets. This paper examines some emerging markets for large scale solar heating applications, with a focus on the Canadian climate and market. (author)

Mechanisms of mtDNA segregation and mitochondrial signalling in cells with the pathogenic A3243G mutation

NARCIS (Netherlands)

Jahangir Tafrechi, Roshan Sakineh

2008-01-01

Using newly developed single cell A3243G mutation load assays a novel mechanism of mtDNA segregation was identified in which the multi-copy mtDNA nucleoid takes a central position. Furthermore, likely due to low level changes in gene expression, no genes or gene sets could be identified with gene

The rates and patterns of deletions in the human factor IX gene

Energy Technology Data Exchange (ETDEWEB)

Ketterling, R.P.; Vielhaber, E.L.; Lind, T.J.; Thorland, E.C.; Sommer S.S. (Mayo Clinic/Foundation, Rochester, MN (United States))

1994-02-01

Deletions are commonly observed in genes with either segments of highly homologous sequences or excessive gene length. However, in the factor IX gene and in most genes, deletions (of [ge]21 bp) are uncommon. The authors have analyzed DNA from 290 families with hemophilia B (203 independent mutations) and have found 12 deletions >20 bp. Eleven of these are >2 kb (range >3-163 kb), and one is 1.1 kb. The junctions of the four deletions that are completely contained within the factor IX gene have been determined. A novel mutation occurred in patient HB128: the data suggest that a 26.8-kb deletion occurred between two segments of alternating purines and pyrimidines and that a 2.3-kb sense strand segment derived from the deleted region was inserted. For a sample of 203 independent mutations, the authors estimate the [open quotes]baseline[close quotes] rates of deletional mutation per base pair per generation as a function of size. The rate for large (>2 kb)I deletions is exceedingly low. For every mutational event in which a given base is at the junction of a large deletion, there are an estimated 58 microdeletions (<20 bp) and 985 single-base substitutions at that base. Analysis of the nine reported deletion junctions in the factor IX gene literature reveals that (i) five are associated with inversion, orphan sequences, or sense strand insertions; (ii) four are simple deletions that display an excess of short direct repeats at their junctions; (iii) there is no dramatic clustering of junctions within the gene; and (iv) with the exception of alternating purines and pyrimidines, deletion junctions are not preferentially associated with repetitive DNA. 58 refs., 5 figs., 5 tabs.

SOX2 anophthalmia syndrome: 12 new cases demonstrating broader phenotype and high frequency of large gene deletions.

Science.gov (United States)

Bakrania, P; Robinson, D O; Bunyan, D J; Salt, A; Martin, A; Crolla, J A; Wyatt, A; Fielder, A; Ainsworth, J; Moore, A; Read, S; Uddin, J; Laws, D; Pascuel-Salcedo, D; Ayuso, C; Allen, L; Collin, J R O; Ragge, N K

2007-11-01

Developmental eye anomalies, which include anophthalmia (absent eye) or microphthalmia (small eye) are an important cause of severe visual impairment in infants and young children. Heterozygous mutations in SOX2, a SOX1B-HMG box transcription factor, have been found in up to 10% of individuals with severe microphthalmia or anophthalmia and such mutations could also be associated with a range of non-ocular abnormalities. We performed mutation analysis on a new cohort of 120 patients with congenital eye abnormalities, mainly anophthalmia, microphthalmia and coloboma. Multiplex ligation-dependent probe amplification (MLPA) and fluorescence in situ hybridisation (FISH) were used to detect whole gene deletion. We identified four novel intragenic SOX2 mutations (one single base deletion, one single base duplication and two point mutations generating premature translational termination codons) and two further cases with the previously reported c.70del20 mutation. Of 52 patients with severe microphthalmia or anophthalmia analysed by MLPA, 5 were found to be deleted for the whole SOX2 gene and 1 had a partial deletion. In two of these, FISH studies identified sub-microscopic deletions involving a minimum of 328 Kb and 550 Kb. The SOX2 phenotypes include a patient with anophthalmia, oesophageal abnormalities and horseshoe kidney, and a patient with a retinal dystrophy implicating SOX2 in retinal development. Our results provide further evidence that SOX2 haploinsufficiency is a common cause of severe developmental ocular malformations and that background genetic variation determines the varying phenotypes. Given the high incidence of whole gene deletion we recommend that all patients with severe microphthalmia or anophthalmia, including unilateral cases be screened by MLPA and FISH for SOX2 deletions.

A trans-Amazonian screening of mtDNA reveals deep intraspecific divergence in forest birds and suggests a vast underestimation of species diversity.

Directory of Open Access Journals (Sweden)

Borja Milá

Full Text Available The Amazonian avifauna remains severely understudied relative to that of the temperate zone, and its species richness is thought to be underestimated by current taxonomy. Recent molecular systematic studies using mtDNA sequence reveal that traditionally accepted species-level taxa often conceal genetically divergent subspecific lineages found to represent new species upon close taxonomic scrutiny, suggesting that intraspecific mtDNA variation could be useful in species discovery. Surveys of mtDNA variation in Holarctic species have revealed patterns of variation that are largely congruent with species boundaries. However, little information exists on intraspecific divergence in most Amazonian species. Here we screen intraspecific mtDNA genetic variation in 41 Amazonian forest understory species belonging to 36 genera and 17 families in 6 orders, using 758 individual samples from Ecuador and French Guiana. For 13 of these species, we also analyzed trans-Andean populations from the Ecuadorian Chocó. A consistent pattern of deep intraspecific divergence among trans-Amazonian haplogroups was found for 33 of the 41 taxa, and genetic differentiation and genetic diversity among them was highly variable, suggesting a complex range of evolutionary histories. Mean sequence divergence within families was the same as that found in North American birds (13%, yet mean intraspecific divergence in Neotropical species was an order of magnitude larger (2.13% vs. 0.23%, with mean distance between intraspecific lineages reaching 3.56%. We found no clear relationship between genetic distances and differentiation in plumage color. Our results identify numerous genetically and phenotypically divergent lineages which may result in new species-level designations upon closer taxonomic scrutiny and thorough sampling, although lineages in the tropical region could be older than those in the temperate zone without necessarily representing separate species. In

Large-scale regions of antimatter

International Nuclear Information System (INIS)

Grobov, A. V.; Rubin, S. G.

2015-01-01

Amodified mechanism of the formation of large-scale antimatter regions is proposed. Antimatter appears owing to fluctuations of a complex scalar field that carries a baryon charge in the inflation era

Large-scale regions of antimatter

Energy Technology Data Exchange (ETDEWEB)

Grobov, A. V., E-mail: alexey.grobov@gmail.com; Rubin, S. G., E-mail: sgrubin@mephi.ru [National Research Nuclear University MEPhI (Russian Federation)

2015-07-15

Amodified mechanism of the formation of large-scale antimatter regions is proposed. Antimatter appears owing to fluctuations of a complex scalar field that carries a baryon charge in the inflation era.

A local-world node deleting evolving network model

International Nuclear Information System (INIS)

Gu Yuying; Sun Jitao

2008-01-01

A new type network growth rule which comprises node addition with the concept of local-world connectivity and node deleting is studied. A series of theoretical analysis and numerical simulation to the LWD network are conducted in this Letter. Firstly, the degree distribution p(k) of this network changes no longer pure scale free but truncates by an exponential tail and the truncation in p(k) increases as p a decreases. Secondly, the connectivity is tighter, as the local-world size M increases. Thirdly, the average path length L increases and the clustering coefficient decreases as generally node deleting increases. Finally, trends up when the local-world size M increases, so as to k max . Hence, the expanding local-world can compensate the infection of the node deleting

A local-world node deleting evolving network model

Energy Technology Data Exchange (ETDEWEB)

Gu Yuying [Department of Mathematics, Tongji University, Shanghai 200092 (China); Sun Jitao [Department of Mathematics, Tongji University, Shanghai 200092 (China)], E-mail: sunjt@sh163.net

2008-06-16

A new type network growth rule which comprises node addition with the concept of local-world connectivity and node deleting is studied. A series of theoretical analysis and numerical simulation to the LWD network are conducted in this Letter. Firstly, the degree distribution p(k) of this network changes no longer pure scale free but truncates by an exponential tail and the truncation in p(k) increases as p{sub a} decreases. Secondly, the connectivity is tighter, as the local-world size M increases. Thirdly, the average path length L increases and the clustering coefficient decreases as generally node deleting increases. Finally, trends up when the local-world size M increases, so as to k{sub max}. Hence, the expanding local-world can compensate the infection of the node deleting.

Files synchronization from a large number of insertions and deletions

Science.gov (United States)

Ellappan, Vijayan; Kumari, Savera

2017-11-01

Synchronization between different versions of files is becoming a major issue that most of the applications are facing. To make the applications more efficient a economical algorithm is developed from the previously used algorithm of “File Loading Algorithm”. I am extending this algorithm in three ways: First, dealing with non-binary files, Second backup is generated for uploaded files and lastly each files are synchronized with insertions and deletions. User can reconstruct file from the former file with minimizing the error and also provides interactive communication by eliminating the frequency without any disturbance. The drawback of previous system is overcome by using synchronization, in which multiple copies of each file/record is created and stored in backup database and is efficiently restored in case of any unwanted deletion or loss of data. That is, to introduce a protocol that user B may use to reconstruct file X from file Y with suitably low probability of error. Synchronization algorithms find numerous areas of use, including data storage, file sharing, source code control systems, and cloud applications. For example, cloud storage services such as Drop box synchronize between local copies and cloud backups each time users make changes to local versions. Similarly, synchronization tools are necessary in mobile devices. Specialized synchronization algorithms are used for video and sound editing. Synchronization tools are also capable of performing data duplication.

Large-Scale Analysis of Art Proportions

DEFF Research Database (Denmark)

Jensen, Karl Kristoffer

2014-01-01

While literature often tries to impute mathematical constants into art, this large-scale study (11 databases of paintings and photos, around 200.000 items) shows a different truth. The analysis, consisting of the width/height proportions, shows a value of rarely if ever one (square) and with majo......While literature often tries to impute mathematical constants into art, this large-scale study (11 databases of paintings and photos, around 200.000 items) shows a different truth. The analysis, consisting of the width/height proportions, shows a value of rarely if ever one (square...

The Expanded Large Scale Gap Test

Science.gov (United States)

1987-03-01

NSWC TR 86-32 DTIC THE EXPANDED LARGE SCALE GAP TEST BY T. P. LIDDIARD D. PRICE RESEARCH AND TECHNOLOGY DEPARTMENT ’ ~MARCH 1987 Ap~proved for public...arises, to reduce the spread in the LSGT 50% gap value.) The worst charges, such as those with the highest or lowest densities, the largest re-pressed...Arlington, VA 22217 PE 62314N INS3A 1 RJ14E31 7R4TBK 11 TITLE (Include Security CIlmsilficatiorn The Expanded Large Scale Gap Test . 12. PEIRSONAL AUTHOR() T

The first case report of a large deletion of the BRCA1 gene in Croatia: A case report.

Science.gov (United States)

Musani, Vesna; Sušac, Ilona; Ozretić, Petar; Eljuga, Domagoj; Levanat, Sonja

2017-12-01

Breast cancer is one of the most common cancers in women, and it is the leading cause of cancer related deaths in Croatia. BRCA1 and BRCA2 gene mutations are the most common cause of hereditary breast cancer. In this report we describe a Croatian patient with no apparent family history of cancer, who developed breast cancer first at 29, and again at 33. Due to the early development of first breast cancer and triple negative status of the second, the attending physician suspected a hereditary aspect. Patient was sent to BRCA1 genetic testing. Subsequently, her mother and sister were sent to check for the mutation found in the patient. BRCA1 exons 4-6 deletion was determined and sequencing confirmed the deletion as NG_005905.2:g.107648_117905del10257. Mother and sister were not affected, but since there were no available family members on the fathers' side, it was not possible to determine if this was a case of de novo mutation. Until now, only in three reports with the similar mutation the exact mutation borders were determined. The mutation in this case was not the same as previously reported and was more than twice in size. All large deletions should be described at the nucleotide level, so that in cases with missing family data it would be possible to deduce if the mutation is already known. If the mutation is already known, it is probably not a de novo event, since it is unlikely that the breakpoints would be exactly the same more than once.

The mitochondrial DNA makeup of Romanians: A forensic mtDNA control region database and phylogenetic characterization.

Science.gov (United States)

Turchi, Chiara; Stanciu, Florin; Paselli, Giorgia; Buscemi, Loredana; Parson, Walther; Tagliabracci, Adriano

2016-09-01

To evaluate the pattern of Romanian population from a mitochondrial perspective and to establish an appropriate mtDNA forensic database, we generated a high-quality mtDNA control region dataset from 407 Romanian subjects belonging to four major historical regions: Moldavia, Transylvania, Wallachia and Dobruja. The entire control region (CR) was analyzed by Sanger-type sequencing assays and the resulting 306 different haplotypes were classified into haplogroups according to the most updated mtDNA phylogeny. The Romanian gene pool is mainly composed of West Eurasian lineages H (31.7%), U (12.8%), J (10.8%), R (10.1%), T (9.1%), N (8.1%), HV (5.4%),K (3.7%), HV0 (4.2%), with exceptions of East Asian haplogroup M (3.4%) and African haplogroup L (0.7%). The pattern of mtDNA variation observed in this study indicates that the mitochondrial DNA pool is geographically homogeneous across Romania and that the haplogroup composition reveals signals of admixture of populations of different origin. The PCA scatterplot supported this scenario, with Romania located in southeastern Europe area, close to Bulgaria and Hungary, and as a borderland with respect to east Mediterranean and other eastern European countries. High haplotype diversity (0.993) and nucleotide diversity indices (0.00838±0.00426), together with low random match probability (0.0087) suggest the usefulness of this control region dataset as a forensic database in routine forensic mtDNA analysis and in the investigation of maternal genetic lineages in the Romanian population. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Li-Fraumeni-like syndrome associated with a large BRCA1 intragenic deletion

International Nuclear Information System (INIS)

Silva, Amanda Gonçalves; Achatz, Maria Isabel W; Rosenberg, Carla; Krepischi, Ana C V; Ewald, Ingrid Petroni; Sapienza, Marina; Pinheiro, Manuela; Peixoto, Ana; Nóbrega, Amanda França de; Carraro, Dirce M; Teixeira, Manuel R; Ashton-Prolla, Patricia

2012-01-01

Li-Fraumeni (LFS) and Li-Fraumeni-like (LFL) syndromes are associated to germline TP53 mutations, and are characterized by the development of central nervous system tumors, sarcomas, adrenocortical carcinomas, and other early-onset tumors. Due to the high frequency of breast cancer in LFS/LFL families, these syndromes clinically overlap with hereditary breast cancer (HBC). Germline point mutations in BRCA1, BRCA2, and TP53 genes are associated with high risk of breast cancer. Large rearrangements involving these genes are also implicated in the HBC phenotype. We have screened DNA copy number changes by MLPA on BRCA1, BRCA2, and TP53 genes in 23 breast cancer patients with a clinical diagnosis consistent with LFS/LFL; most of these families also met the clinical criteria for other HBC syndromes. We found no DNA copy number alterations in the BRCA2 and TP53 genes, but we detected in one patient a 36.4 Kb BRCA1 microdeletion, confirmed and further mapped by array-CGH, encompassing exons 9–19. Breakpoints sequencing analysis suggests that this rearrangement was mediated by flanking Alu sequences. This is the first description of a germline intragenic BRCA1 deletion in a breast cancer patient with a family history consistent with both LFL and HBC syndromes. Our results show that large rearrangements in these known cancer predisposition genes occur, but are not a frequent cause of cancer susceptibility

Effects of tectonics and large scale climatic changes on the evolutionary history of Hyalomma ticks.

Science.gov (United States)

Sands, Arthur F; Apanaskevich, Dmitry A; Matthee, Sonja; Horak, Ivan G; Harrison, Alan; Karim, Shahid; Mohammad, Mohammad K; Mumcuoglu, Kosta Y; Rajakaruna, Rupika S; Santos-Silva, Maria M; Matthee, Conrad A

2017-09-01

Hyalomma Koch, 1844 are ixodid ticks that infest mammals, birds and reptiles, to which 27 recognized species occur across the Afrotropical, Palearctic and Oriental regions. Despite their medical and veterinary importance, the evolutionary history of the group is enigmatic. To investigate various taxonomic hypotheses based on morphology, and also some of the mechanisms involved in the diversification of the genus, we sequenced and analysed data derived from two mtDNA fragments, three nuclear DNA genes and 47 morphological characters. Bayesian and Parsimony analyses based on the combined data (2242 characters for 84 taxa) provided maximum resolution and strongly supported the monophyly of Hyalomma and the subgenus Euhyalomma Filippova, 1984 (including H. punt Hoogstraal, Kaiser and Pedersen, 1969). A predicted close evolutionary association was found between morphologically similar H. dromedarii Koch, 1844, H. somalicum Tonelli Rondelli, 1935, H. impeltatum Schulze and Schlottke, 1929 and H. punt, and together they form a sister lineage to H. asiaticum Schulze and Schlottke, 1929, H. schulzei Olenev, 1931 and H. scupense Schulze, 1919. Congruent with morphological suggestions, H. anatolicum Koch, 1844, H. excavatum Koch, 1844 and H. lusitanicum Koch, 1844 form a clade and so also H. glabrum Delpy, 1949, H. marginatum Koch, 1844, H. turanicum Pomerantzev, 1946 and H. rufipes Koch, 1844. Wide scale continental sampling revealed cryptic divergences within African H. truncatum Koch, 1844 and H. rufipes and suggested that the taxonomy of these lineages is in need of a revision. The most basal lineages in Hyalomma represent taxa currently confined to Eurasia and molecular clock estimates suggest that members of the genus started to diverge approximately 36.25 million years ago (Mya). The early diversification event coincides well with the collision of the Indian and Eurasian Plates, an event that was also characterized by large scale faunal turnover in the region. Using S

Large scale and big data processing and management

CERN Document Server

Sakr, Sherif

2014-01-01

Large Scale and Big Data: Processing and Management provides readers with a central source of reference on the data management techniques currently available for large-scale data processing. Presenting chapters written by leading researchers, academics, and practitioners, it addresses the fundamental challenges associated with Big Data processing tools and techniques across a range of computing environments.The book begins by discussing the basic concepts and tools of large-scale Big Data processing and cloud computing. It also provides an overview of different programming models and cloud-bas

Clustering of Caucasian Leber hereditary optic neuropathy patients containing the 11778 or 14484 mutations on an mtDNA lineage

Energy Technology Data Exchange (ETDEWEB)

Brown, M.D.; Sun, F.; Wallace, D.C. [Emory Univ. School of Medicine, Atlanta, GA (United States)

1997-02-01

Leber hereditary optic neuropathy (LHON) is a type of blindness caused by mtDNA mutations. Three LHON mtDNA mutations at nucleotide positions 3460, 11778, and 14484 are specific for LHON and account for 90% of worldwide cases and are thus designated as {open_quotes}primary{close_quotes} LHON mutations. Fifteen other {open_quotes}secondary{close_quotes} LHON mtDNA mutations have been identified, but their pathogenicity is unclear. mtDNA haplotype and phylogenetic analysis of the primary LHON mutations in North American Caucasian patients and controls has shown that, unlike the 3460 and 11778 mutations, which are distributed throughout the European-derived (Caucasian) mtDNA phylogeny, patients containing the 14484 mutation tended to be associated with European mtDNA haplotype J. To investigate this apparent clustering, we performed {chi}{sup 2}-based statistical analyses to compare the distribution of LHON patients on the Caucasian phylogenetic tree. Our results indicate that, unlike the 3460 and 11778 mutations, the 14484 mutation was not distributed on the phylogeny in proportion to the frequencies of the major Caucasian mtDNA haplogroups found in North America. The 14484 mutation was next shown to occur on the haplogroup J background more frequently that expected, consistent with the observation that {approximately}75% of worldwide 14484-positive LHON patients occur in association with haplogroup J. The 11778 mutation also exhibited a moderate clustering on haplogroup J. These observations were supported by statistical analysis using all available mutation frequencies reported in the literature. This paper thus illustrates the potential importance of genetic background in certain mtDNA-based diseases, speculates on a pathogenic role for a subset of LHON secondary mutations and their interaction with primary mutations, and provides support for a polygenic model for LHON expression in some cases. 18 refs., 3 tabs.

Large scale cluster computing workshop

International Nuclear Information System (INIS)

Dane Skow; Alan Silverman

2002-01-01

Recent revolutions in computer hardware and software technologies have paved the way for the large-scale deployment of clusters of commodity computers to address problems heretofore the domain of tightly coupled SMP processors. Near term projects within High Energy Physics and other computing communities will deploy clusters of scale 1000s of processors and be used by 100s to 1000s of independent users. This will expand the reach in both dimensions by an order of magnitude from the current successful production facilities. The goals of this workshop were: (1) to determine what tools exist which can scale up to the cluster sizes foreseen for the next generation of HENP experiments (several thousand nodes) and by implication to identify areas where some investment of money or effort is likely to be needed. (2) To compare and record experimences gained with such tools. (3) To produce a practical guide to all stages of planning, installing, building and operating a large computing cluster in HENP. (4) To identify and connect groups with similar interest within HENP and the larger clustering community

Allozyme and mtDNA variation of white seabream Diplodus sargus ...

African Journals Online (AJOL)

These results can be explained by the chaotic genetic patchiness hypothesis. In contrast, the mtDNA data indicated genetic homogeneity among localities showing the absence of structure in white seabream populations across the Siculo-Tunisian Strait. Historical demography of this species suggests that it has undergone ...

Large-Scale Agriculture and Outgrower Schemes in Ethiopia

DEFF Research Database (Denmark)

Wendimu, Mengistu Assefa

, the impact of large-scale agriculture and outgrower schemes on productivity, household welfare and wages in developing countries is highly contentious. Chapter 1 of this thesis provides an introduction to the study, while also reviewing the key debate in the contemporary land ‘grabbing’ and historical large...... sugarcane outgrower scheme on household income and asset stocks. Chapter 5 examines the wages and working conditions in ‘formal’ large-scale and ‘informal’ small-scale irrigated agriculture. The results in Chapter 2 show that moisture stress, the use of untested planting materials, and conflict over land...... commands a higher wage than ‘formal’ large-scale agriculture, while rather different wage determination mechanisms exist in the two sectors. Human capital characteristics (education and experience) partly explain the differences in wages within the formal sector, but play no significant role...

Molecular Characterization of Sudanese and Southern Sudanese Chicken Breeds Using mtDNA D-Loop

Directory of Open Access Journals (Sweden)

Charles E. Wani

2014-01-01

Full Text Available The objective of this study was to assess the genetic relationships and diversity and to estimate the amount of gene flow among the five chicken populations from Sudan and South Sudan and commercial strain of egg line White Leghorn chickens. The chicken populations were genotyped using mtDNA D-loop as a molecular marker. PCR product of the mtDNA D-loop segment was 600 bp and 14 haplotypes were identified. The neighbor-joining phylogenetic tree indicated that the indigenous Sudanese chickens can be grouped into two clades, IV and IIIa only. Median joining networks analysis showed that haplotype LBB49 has the highest frequency. The hierarchal analysis of molecular variance (AMOVA showed that genetic variation within the population was 88.6% and the differentiation among the population was 11.4%. When the populations was redefined into two geographical zones, rich and poor Savanna, the results were fractioned into three genetic variations: between individuals within population 95.5%, between populations within the group 0.75%, and genetic variation between groups 3.75%. The pair wise Fst showed high genetic difference between Betwil populations and the rest with Fst ranging from 0.1492 to 0.2447. We found that there is large number of gene exchanges within the Sudanese indigenous chicken (Nm=4.622.

Economically viable large-scale hydrogen liquefaction

Science.gov (United States)

Cardella, U.; Decker, L.; Klein, H.

2017-02-01

The liquid hydrogen demand, particularly driven by clean energy applications, will rise in the near future. As industrial large scale liquefiers will play a major role within the hydrogen supply chain, production capacity will have to increase by a multiple of today’s typical sizes. The main goal is to reduce the total cost of ownership for these plants by increasing energy efficiency with innovative and simple process designs, optimized in capital expenditure. New concepts must ensure a manageable plant complexity and flexible operability. In the phase of process development and selection, a dimensioning of key equipment for large scale liquefiers, such as turbines and compressors as well as heat exchangers, must be performed iteratively to ensure technological feasibility and maturity. Further critical aspects related to hydrogen liquefaction, e.g. fluid properties, ortho-para hydrogen conversion, and coldbox configuration, must be analysed in detail. This paper provides an overview on the approach, challenges and preliminary results in the development of efficient as well as economically viable concepts for large-scale hydrogen liquefaction.

Large scale chromatographic separations using continuous displacement chromatography (CDC)

International Nuclear Information System (INIS)

Taniguchi, V.T.; Doty, A.W.; Byers, C.H.

1988-01-01

A process for large scale chromatographic separations using a continuous chromatography technique is described. The process combines the advantages of large scale batch fixed column displacement chromatography with conventional analytical or elution continuous annular chromatography (CAC) to enable large scale displacement chromatography to be performed on a continuous basis (CDC). Such large scale, continuous displacement chromatography separations have not been reported in the literature. The process is demonstrated with the ion exchange separation of a binary lanthanide (Nd/Pr) mixture. The process is, however, applicable to any displacement chromatography separation that can be performed using conventional batch, fixed column chromatography

Novel 12S mtDNA findings in sloths (Pilosa, Folivora and anteaters (Pilosa, Vermilingua suggest a true case of long branch attraction

Directory of Open Access Journals (Sweden)

Maria Claudene Barros

2008-01-01

Full Text Available We sequenced 12S RNA mtDNA for the majority of the extant species of sloths and anteaters and compared our results with previous data obtained by our group using 16S RNA mtDNA in the same specimens and to GenBank sequences of the extinct giant sloth Mylodon. Our results suggest that pigmy-anteaters may be a case of the long-branch attraction phenomenon and also show the large genetic difference between the Amazonian and Atlantic forest three-toed sloths, contrasting with the small differences observed between the two non-Atlantic forest forms of sloths. These results have important implications for the taxonomy of sloths and anteaters and strongly suggest the placement of pigmy anteaters in their own family (Cyclopidae and raising the taxonomic status of Bradypus torquatus to a genus.

Large Scale Processes and Extreme Floods in Brazil

Science.gov (United States)

Ribeiro Lima, C. H.; AghaKouchak, A.; Lall, U.

2016-12-01

Persistent large scale anomalies in the atmospheric circulation and ocean state have been associated with heavy rainfall and extreme floods in water basins of different sizes across the world. Such studies have emerged in the last years as a new tool to improve the traditional, stationary based approach in flood frequency analysis and flood prediction. Here we seek to advance previous studies by evaluating the dominance of large scale processes (e.g. atmospheric rivers/moisture transport) over local processes (e.g. local convection) in producing floods. We consider flood-prone regions in Brazil as case studies and the role of large scale climate processes in generating extreme floods in such regions is explored by means of observed streamflow, reanalysis data and machine learning methods. The dynamics of the large scale atmospheric circulation in the days prior to the flood events are evaluated based on the vertically integrated moisture flux and its divergence field, which are interpreted in a low-dimensional space as obtained by machine learning techniques, particularly supervised kernel principal component analysis. In such reduced dimensional space, clusters are obtained in order to better understand the role of regional moisture recycling or teleconnected moisture in producing floods of a given magnitude. The convective available potential energy (CAPE) is also used as a measure of local convection activities. We investigate for individual sites the exceedance probability in which large scale atmospheric fluxes dominate the flood process. Finally, we analyze regional patterns of floods and how the scaling law of floods with drainage area responds to changes in the climate forcing mechanisms (e.g. local vs large scale).

Deep sequencing shows that oocytes are not prone to accumulate mtDNA heteroplasmic mutations during ovarian ageing.

Science.gov (United States)

Boucret, L; Bris, C; Seegers, V; Goudenège, D; Desquiret-Dumas, V; Domin-Bernhard, M; Ferré-L'Hotellier, V; Bouet, P E; Descamps, P; Reynier, P; Procaccio, V; May-Panloup, P

2017-10-01

Does ovarian ageing increase the number of heteroplasmic mitochondrial DNA (mtDNA) point mutations in oocytes? Our results suggest that oocytes are not subject to the accumulation of mtDNA point mutations during ovarian ageing. Ageing is associated with the alteration of mtDNA integrity in various tissues. Primary oocytes, present in the ovary since embryonic life, may accumulate mtDNA mutations during the process of ovarian ageing. This was an observational study of 53 immature oocyte-cumulus complexes retrieved from 35 women undergoing IVF at the University Hospital of Angers, France, from March 2013 to March 2014. The women were classified in two groups, one including 19 women showing signs of ovarian ageing objectified by a diminished ovarian reserve (DOR), and the other, including 16 women with a normal ovarian reserve (NOR), which served as a control group. mtDNA was extracted from isolated oocytes, and from their corresponding cumulus cells (CCs) considered as a somatic cell compartment. The average mtDNA content of each sample was assessed by using a quantitative real-time PCR technique. Deep sequencing was performed using the Ion Torrent Proton for Next-Generation Sequencing. Signal processing and base calling were done by the embedded pre-processing pipeline and the variants were analyzed using an in-house workflow. The distribution of the different variants between DOR and NOR patients, on one hand, and oocyte and CCs, on the other, was analyzed with the generalized mixed linear model to take into account the cluster of cells belonging to a given mother. There were no significant differences between the numbers of mtDNA variants between the DOR and the NOR patients, either in the oocytes (P = 0.867) or in the surrounding CCs (P = 0.154). There were also no differences in terms of variants with potential functional consequences. De-novo mtDNA variants were found in 28% of the oocytes and in 66% of the CCs with the mean number of variants being

Computing in Large-Scale Dynamic Systems

NARCIS (Netherlands)

Pruteanu, A.S.

2013-01-01

Software applications developed for large-scale systems have always been difficult to de- velop due to problems caused by the large number of computing devices involved. Above a certain network size (roughly one hundred), necessary services such as code updating, topol- ogy discovery and data

Fires in large scale ventilation systems

International Nuclear Information System (INIS)

Gregory, W.S.; Martin, R.A.; White, B.W.; Nichols, B.D.; Smith, P.R.; Leslie, I.H.; Fenton, D.L.; Gunaji, M.V.; Blythe, J.P.

1991-01-01

This paper summarizes the experience gained simulating fires in large scale ventilation systems patterned after ventilation systems found in nuclear fuel cycle facilities. The series of experiments discussed included: (1) combustion aerosol loading of 0.61x0.61 m HEPA filters with the combustion products of two organic fuels, polystyrene and polymethylemethacrylate; (2) gas dynamic and heat transport through a large scale ventilation system consisting of a 0.61x0.61 m duct 90 m in length, with dampers, HEPA filters, blowers, etc.; (3) gas dynamic and simultaneous transport of heat and solid particulate (consisting of glass beads with a mean aerodynamic diameter of 10μ) through the large scale ventilation system; and (4) the transport of heat and soot, generated by kerosene pool fires, through the large scale ventilation system. The FIRAC computer code, designed to predict fire-induced transients in nuclear fuel cycle facility ventilation systems, was used to predict the results of experiments (2) through (4). In general, the results of the predictions were satisfactory. The code predictions for the gas dynamics, heat transport, and particulate transport and deposition were within 10% of the experimentally measured values. However, the code was less successful in predicting the amount of soot generation from kerosene pool fires, probably due to the fire module of the code being a one-dimensional zone model. The experiments revealed a complicated three-dimensional combustion pattern within the fire room of the ventilation system. Further refinement of the fire module within FIRAC is needed. (orig.)

BFAST: an alignment tool for large scale genome resequencing.

Directory of Open Access Journals (Sweden)

Nils Homer

2009-11-01

Full Text Available The new generation of massively parallel DNA sequencers, combined with the challenge of whole human genome resequencing, result in the need for rapid and accurate alignment of billions of short DNA sequence reads to a large reference genome. Speed is obviously of great importance, but equally important is maintaining alignment accuracy of short reads, in the 25-100 base range, in the presence of errors and true biological variation.We introduce a new algorithm specifically optimized for this task, as well as a freely available implementation, BFAST, which can align data produced by any of current sequencing platforms, allows for user-customizable levels of speed and accuracy, supports paired end data, and provides for efficient parallel and multi-threaded computation on a computer cluster. The new method is based on creating flexible, efficient whole genome indexes to rapidly map reads to candidate alignment locations, with arbitrary multiple independent indexes allowed to achieve robustness against read errors and sequence variants. The final local alignment uses a Smith-Waterman method, with gaps to support the detection of small indels.We compare BFAST to a selection of large-scale alignment tools -- BLAT, MAQ, SHRiMP, and SOAP -- in terms of both speed and accuracy, using simulated and real-world datasets. We show BFAST can achieve substantially greater sensitivity of alignment in the context of errors and true variants, especially insertions and deletions, and minimize false mappings, while maintaining adequate speed compared to other current methods. We show BFAST can align the amount of data needed to fully resequence a human genome, one billion reads, with high sensitivity and accuracy, on a modest computer cluster in less than 24 hours. BFAST is available at (http://bfast.sourceforge.net.

Large-scale Complex IT Systems

OpenAIRE

Sommerville, Ian; Cliff, Dave; Calinescu, Radu; Keen, Justin; Kelly, Tim; Kwiatkowska, Marta; McDermid, John; Paige, Richard

2011-01-01

This paper explores the issues around the construction of large-scale complex systems which are built as 'systems of systems' and suggests that there are fundamental reasons, derived from the inherent complexity in these systems, why our current software engineering methods and techniques cannot be scaled up to cope with the engineering challenges of constructing such systems. It then goes on to propose a research and education agenda for software engineering that identifies the major challen...

Large-scale complex IT systems

OpenAIRE

Sommerville, Ian; Cliff, Dave; Calinescu, Radu; Keen, Justin; Kelly, Tim; Kwiatkowska, Marta; McDermid, John; Paige, Richard

2012-01-01

12 pages, 2 figures This paper explores the issues around the construction of large-scale complex systems which are built as 'systems of systems' and suggests that there are fundamental reasons, derived from the inherent complexity in these systems, why our current software engineering methods and techniques cannot be scaled up to cope with the engineering challenges of constructing such systems. It then goes on to propose a research and education agenda for software engineering that ident...

First Mile Challenges for Large-Scale IoT

KAUST Repository

Bader, Ahmed; Elsawy, Hesham; Gharbieh, Mohammad; Alouini, Mohamed-Slim; Adinoyi, Abdulkareem; Alshaalan, Furaih

2017-01-01

The Internet of Things is large-scale by nature. This is not only manifested by the large number of connected devices, but also by the sheer scale of spatial traffic intensity that must be accommodated, primarily in the uplink direction. To that end

Mutations of mtDNA polymerase-γ and hyperlactataemia in the HIV ...

African Journals Online (AJOL)

Mutations of mtDNA polymerase-γ and hyperlactataemia in the HIV-infected Zulu population of South Africa. ... D B A Ojwach, C Aldous, P Kocheleff, B Sartorius ... of their capacity to impede human mitochondrial DNA polymerase-γ (POLG), ...

mtDNA variation in caste populations of Andhra Pradesh, India.

Science.gov (United States)

Bamshad, M; Fraley, A E; Crawford, M H; Cann, R L; Busi, B R; Naidu, J M; Jorde, L B

1996-02-01

Various anthropological analyses have documented extensive regional variation among populations on the subcontinent of India using morphological, protein, blood group, and nuclear DNA polymorphisms. These patterns are the product of complex population structure (genetic drift, gene flow) and a population history noted for numerous branching events. As a result, the interpretation of relationships among caste populations of South India and between Indians and continental populations remains controversial. The Hindu caste system is a general model of genetic differentiation among endogamous populations stratified by social forces (e.g., religion and occupation). The mitochondrial DNA (mtDNA) molecule has unique properties that facilitate the exploration of population structure. We analyzed 36 Hindu men born in Andhra Pradesh who were unrelated matrilineally through at least 3 generations and who represent 4 caste populations: Brahmin (9), Yadava (10), Kapu (7), and Relli (10). Individuals from Africa (36), Asia (36), and Europe (36) were sampled for comparison. A 200-base-pair segment of hypervariable segment 2 (HVS2) of the mtDNA control region was sequenced in all individuals. In the Indian castes 25 distinct haplotypes are identified. Aside from the Cambridge reference sequence, only two haplotypes are shared between caste populations. Middle castes form a highly supported cluster in a neighbor-joining network. Mean nucleotide diversity within each caste is 0.015, 0.012, 0.011, and 0.012 for the Brahmin, Yadava, Kapu, and Relli, respectively. mtDNA variation is highly structured between castes (GST = 0.17; p caste populations of Andhra Pradesh cluster more often with Africans than with Asians or Europeans. This is suggestive of admixture with African populations.

A novel common large genomic deletion and two new missense mutations identified in the Romanian phenylketonuria population.

Science.gov (United States)

Gemperle-Britschgi, Corinne; Iorgulescu, Daniela; Mager, Monica Alina; Anton-Paduraru, Dana; Vulturar, Romana; Thöny, Beat

2016-01-15

The mutation spectrum for the phenylalanine hydroxylase (PAH) gene was investigated in a cohort of 84 hyperphenylalaninemia (HPA) patients from Romania identified through newborn screening or neurometabolic investigations. Differential diagnosis identified 81 patients with classic PAH deficiency while 3 had tetrahydropterin-cofactor deficiency and/or remained uncertain due to insufficient specimen. PAH-genetic analysis included a combination of Sanger sequencing of exons and exon–intron boundaries, MLPA and NGS with genomic DNA, and cDNA analysis from immortalized lymphoblasts. A diagnostic efficiency of 99.4% was achieved, as for one allele (out of a total of 162 alleles) no mutation could be identified. The most prevalent mutation was p.Arg408Trp which was found in ~ 38% of all PKU alleles. Three novel mutations were identified, including the two missense mutations p.Gln226Lys and p.Tyr268Cys that were both disease causing by prediction algorithms, and the large genomic deletion EX6del7831 (c.509 + 4140_706 + 510del7831) that resulted in skipping of exon 6 based on PAH-cDNA analysis in immortalized lymphocytes. The genomic deletion was present in a heterozygous state in 12 patients, i.e. in ~ 8% of all the analyzed PKU alleles, and might have originated from a Romanian founder.

Prospects for large scale electricity storage in Denmark

DEFF Research Database (Denmark)

Krog Ekman, Claus; Jensen, Søren Højgaard

2010-01-01

In a future power systems with additional wind power capacity there will be an increased need for large scale power management as well as reliable balancing and reserve capabilities. Different technologies for large scale electricity storage provide solutions to the different challenges arising w...

Species phylogeny and diversification process of Northeast Asian Pungitius revealed by AFLP and mtDNA markers

DEFF Research Database (Denmark)

Takahashi, Hiroshi; Møller, Peter Rask; Shedko, Sergei V.

2016-01-01

Pungitius is a highly diversified genus of sticklebacks (Gasterosteidae) occurring widely in northern parts of the Northern Hemisphere. Several ecologically and genetically divergent types that are largely isolated reproductively but occasionally hybridize in sympatry have been discovered...... of hybridization and mtDNA introgression among distinct species. Our results highlight that the marginal seas of Northeast Asia played a key role as barriers to or facilitators of gene flow in the evolution of species diversity of Pungitius concentrated in this region...

Evolution of scaling emergence in large-scale spatial epidemic spreading.

Science.gov (United States)

Wang, Lin; Li, Xiang; Zhang, Yi-Qing; Zhang, Yan; Zhang, Kan

2011-01-01

Zipf's law and Heaps' law are two representatives of the scaling concepts, which play a significant role in the study of complexity science. The coexistence of the Zipf's law and the Heaps' law motivates different understandings on the dependence between these two scalings, which has still hardly been clarified. In this article, we observe an evolution process of the scalings: the Zipf's law and the Heaps' law are naturally shaped to coexist at the initial time, while the crossover comes with the emergence of their inconsistency at the larger time before reaching a stable state, where the Heaps' law still exists with the disappearance of strict Zipf's law. Such findings are illustrated with a scenario of large-scale spatial epidemic spreading, and the empirical results of pandemic disease support a universal analysis of the relation between the two laws regardless of the biological details of disease. Employing the United States domestic air transportation and demographic data to construct a metapopulation model for simulating the pandemic spread at the U.S. country level, we uncover that the broad heterogeneity of the infrastructure plays a key role in the evolution of scaling emergence. The analyses of large-scale spatial epidemic spreading help understand the temporal evolution of scalings, indicating the coexistence of the Zipf's law and the Heaps' law depends on the collective dynamics of epidemic processes, and the heterogeneity of epidemic spread indicates the significance of performing targeted containment strategies at the early time of a pandemic disease.

[Asymmetric effects of addition versus deletion on change detection task: the role of feeling of something strange].

Science.gov (United States)

Uchino, Yashio; Hakoda, Yuji; Shibata, Mariko

2005-06-01

Two experiments were conducted to examine the asymmetric effect of alterations (i.e., addition versus deletion) on recognition memory. In Experiment 1, a scale for measuring the FSS (Feeling of Something Strange) was developed (n=50) using added or deleted pictures from previous research (e.g., Uchino, Hakoda, & Yamada, 2000). Result showed that altered pictures were evaluated by "pleasant" and "odd" factors. In Experiment 2, 80 participants observed 20 pictures, and then they answered whether each test picture was altered or not. Test pictures varied in significance of the objects added or deleted on a scene. Additions were detected more easily than deletions only when added object was unexpected or unusual, while deleted object was essential to a scene (TD: typicality-disrupted condition). Then, 60 participants rated the FSS scale for test pictures. Ratings of odd factor for added pictures were higher than deleted pictures presented in the TD condition. These results suggest that superiority of addition over deletion might be due to their different effect on FSS.

Large-Scale Structure and Hyperuniformity of Amorphous Ices

Science.gov (United States)

Martelli, Fausto; Torquato, Salvatore; Giovambattista, Nicolas; Car, Roberto

2017-09-01

We investigate the large-scale structure of amorphous ices and transitions between their different forms by quantifying their large-scale density fluctuations. Specifically, we simulate the isothermal compression of low-density amorphous ice (LDA) and hexagonal ice to produce high-density amorphous ice (HDA). Both HDA and LDA are nearly hyperuniform; i.e., they are characterized by an anomalous suppression of large-scale density fluctuations. By contrast, in correspondence with the nonequilibrium phase transitions to HDA, the presence of structural heterogeneities strongly suppresses the hyperuniformity and the system becomes hyposurficial (devoid of "surface-area fluctuations"). Our investigation challenges the largely accepted "frozen-liquid" picture, which views glasses as structurally arrested liquids. Beyond implications for water, our findings enrich our understanding of pressure-induced structural transformations in glasses.

mtDNA variation predicts population size in humans and reveals a major Southern Asian chapter in human prehistory.

Science.gov (United States)

Atkinson, Quentin D; Gray, Russell D; Drummond, Alexei J

2008-02-01

The relative timing and size of regional human population growth following our expansion from Africa remain unknown. Human mitochondrial DNA (mtDNA) diversity carries a legacy of our population history. Given a set of sequences, we can use coalescent theory to estimate past population size through time and draw inferences about human population history. However, recent work has challenged the validity of using mtDNA diversity to infer species population sizes. Here we use Bayesian coalescent inference methods, together with a global data set of 357 human mtDNA coding-region sequences, to infer human population sizes through time across 8 major geographic regions. Our estimates of relative population sizes show remarkable concordance with the contemporary regional distribution of humans across Africa, Eurasia, and the Americas, indicating that mtDNA diversity is a good predictor of population size in humans. Plots of population size through time show slow growth in sub-Saharan Africa beginning 143-193 kya, followed by a rapid expansion into Eurasia after the emergence of the first non-African mtDNA lineages 50-70 kya. Outside Africa, the earliest and fastest growth is inferred in Southern Asia approximately 52 kya, followed by a succession of growth phases in Northern and Central Asia (approximately 49 kya), Australia (approximately 48 kya), Europe (approximately 42 kya), the Middle East and North Africa (approximately 40 kya), New Guinea (approximately 39 kya), the Americas (approximately 18 kya), and a second expansion in Europe (approximately 10-15 kya). Comparisons of relative regional population sizes through time suggest that between approximately 45 and 20 kya most of humanity lived in Southern Asia. These findings not only support the use of mtDNA data for estimating human population size but also provide a unique picture of human prehistory and demonstrate the importance of Southern Asia to our recent evolutionary past.

Genomic rearrangements by LINE-1 insertion-mediated deletion in the human and chimpanzee lineages.

Science.gov (United States)

Han, Kyudong; Sen, Shurjo K; Wang, Jianxin; Callinan, Pauline A; Lee, Jungnam; Cordaux, Richard; Liang, Ping; Batzer, Mark A

2005-01-01

Long INterspersed Elements (LINE-1s or L1s) are abundant non-LTR retrotransposons in mammalian genomes that are capable of insertional mutagenesis. They have been associated with target site deletions upon insertion in cell culture studies of retrotransposition. Here, we report 50 deletion events in the human and chimpanzee genomes directly linked to the insertion of L1 elements, resulting in the loss of approximately 18 kb of sequence from the human genome and approximately 15 kb from the chimpanzee genome. Our data suggest that during the primate radiation, L1 insertions may have deleted up to 7.5 Mb of target genomic sequences. While the results of our in vivo analysis differ from those of previous cell culture assays of L1 insertion-mediated deletions in terms of the size and rate of sequence deletion, evolutionary factors can reconcile the differences. We report a pattern of genomic deletion sizes similar to those created during the retrotransposition of Alu elements. Our study provides support for the existence of different mechanisms for small and large L1-mediated deletions, and we present a model for the correlation of L1 element size and the corresponding deletion size. In addition, we show that internal rearrangements can modify L1 structure during retrotransposition events associated with large deletions.

Double inflation: A possible resolution of the large-scale structure problem

International Nuclear Information System (INIS)

Turner, M.S.; Villumsen, J.V.; Vittorio, N.; Silk, J.; Juszkiewicz, R.

1986-11-01

A model is presented for the large-scale structure of the universe in which two successive inflationary phases resulted in large small-scale and small large-scale density fluctuations. This bimodal density fluctuation spectrum in an Ω = 1 universe dominated by hot dark matter leads to large-scale structure of the galaxy distribution that is consistent with recent observational results. In particular, large, nearly empty voids and significant large-scale peculiar velocity fields are produced over scales of ∼100 Mpc, while the small-scale structure over ≤ 10 Mpc resembles that in a low density universe, as observed. Detailed analytical calculations and numerical simulations are given of the spatial and velocity correlations. 38 refs., 6 figs

Large-scale fracture mechancis testing -- requirements and possibilities

International Nuclear Information System (INIS)

Brumovsky, M.

1993-01-01

Application of fracture mechanics to very important and/or complicated structures, like reactor pressure vessels, brings also some questions about the reliability and precision of such calculations. These problems become more pronounced in cases of elastic-plastic conditions of loading and/or in parts with non-homogeneous materials (base metal and austenitic cladding, property gradient changes through material thickness) or with non-homogeneous stress fields (nozzles, bolt threads, residual stresses etc.). For such special cases some verification by large-scale testing is necessary and valuable. This paper discusses problems connected with planning of such experiments with respect to their limitations, requirements to a good transfer of received results to an actual vessel. At the same time, an analysis of possibilities of small-scale model experiments is also shown, mostly in connection with application of results between standard, small-scale and large-scale experiments. Experience from 30 years of large-scale testing in SKODA is used as an example to support this analysis. 1 fig

Ethics of large-scale change

DEFF Research Database (Denmark)

Arler, Finn

2006-01-01

, which kind of attitude is appropriate when dealing with large-scale changes like these from an ethical point of view. Three kinds of approaches are discussed: Aldo Leopold's mountain thinking, the neoclassical economists' approach, and finally the so-called Concentric Circle Theories approach...

Thymidine Kinase 2 Deficiency-Induced mtDNA Depletion in Mouse Liver Leads to Defect beta-Oxidation

OpenAIRE

Zhou, Xiaoshan; Kannisto, Kristina; Curbo, Sophie; von Dobeln, Ulrika; Hultenby, Kjell; Isetun, Sindra; Gåfvels, Mats; Karlsson, Anna

2013-01-01

Thymidine kinase 2 (TK2) deficiency in humans causes mitochondrial DNA (mtDNA) depletion syndrome. To study the molecular mechanisms underlying the disease and search for treatment options, we previously generated and described a TK2 deficient mouse strain (TK2(-/-)) that progressively loses its mtDNA. The TK2(-/-) mouse model displays symptoms similar to humans harboring TK2 deficient infantile fatal encephalomyopathy. Here, we have studied the TK2(-/-) mouse model to clarify the pathologica...

Comparison Between Overtopping Discharge in Small and Large Scale Models

DEFF Research Database (Denmark)

Helgason, Einar; Burcharth, Hans F.

2006-01-01

The present paper presents overtopping measurements from small scale model test performed at the Haudraulic & Coastal Engineering Laboratory, Aalborg University, Denmark and large scale model tests performed at the Largde Wave Channel,Hannover, Germany. Comparison between results obtained from...... small and large scale model tests show no clear evidence of scale effects for overtopping above a threshold value. In the large scale model no overtopping was measured for waveheights below Hs = 0.5m as the water sunk into the voids between the stones on the crest. For low overtopping scale effects...

A large deletion in GPR98 causes type IIC Usher syndrome in male and female members of an Iranian family.

Science.gov (United States)

Hilgert, N; Kahrizi, K; Dieltjens, N; Bazazzadegan, N; Najmabadi, H; Smith, R J H; Van Camp, G

2009-04-01

Usher syndrome (USH) is a clinically and genetically heterogeneous disease. The three recognised clinical phenotypes (types I, II and III; USH1, USH2 and USH3) are caused by mutations in nine different genes. USH2C is characterised by moderate to severe hearing loss, retinitis pigmentosa and normal vestibular function. One earlier report describes mutations in GPR98 (VLGR1) in four families segregating this phenotype. To detect the disease-causing mutation in an Iranian family segregating USH2C. In this family, five members had a phenotype compatible with Usher syndrome, and two others had nonsyndromic hearing loss. Mutation analysis of all 90 coding exons of GPR98. Consistent with these clinical findings, the five subjects with USH carried a haplotype linked to the USH2C locus, whereas the two subjects with nonsyndromic hearing loss did not. We identified a new mutation in GPR98 segregating with USH2C in this family. The mutation is a large deletion g.371657_507673del of exons 84 and 85, presumably leading to a frameshift. A large GPR98 deletion of 136 017 bp segregates with USH2C in an Iranian family. To our knowledge, this is only the second report of a GPR98 mutation, and the first report on male subjects with USH2C and a GPR98 mutation.

Feline infectious peritonitis virus with a large deletion in the 5'-terminal region of the spike gene retains its virulence for cats.

Science.gov (United States)

Terada, Yutaka; Shiozaki, Yuto; Shimoda, Hiroshi; Mahmoud, Hassan Youssef Abdel Hamid; Noguchi, Keita; Nagao, Yumiko; Shimojima, Masayuki; Iwata, Hiroyuki; Mizuno, Takuya; Okuda, Masaru; Morimoto, Masahiro; Hayashi, Toshiharu; Tanaka, Yoshikazu; Mochizuki, Masami; Maeda, Ken

2012-09-01

In this study, the Japanese strain of type I feline infectious peritonitis virus (FIPV), C3663, was found to have a large deletion of 735 bp within the gene encoding the spike (S) protein, with a deduced loss of 245 aa of the N-terminal region of the S protein. This deletion is similar to that observed in porcine respiratory coronavirus (PRCoV) when compared to transmissible gastroenteritis virus, which correlates with reduced virulence. By analogy to PRCoV, we expected that the pathogenicity of C3663 may be attenuated in cats. However, two of four cats inoculated with C3663 died of FIP, and a third C3663-inoculated cat showed FIP lesions at 91 days after challenge. These results indicate that the 5'-terminal region of the S gene is not essential for the development of FIP.

Needs, opportunities, and options for large scale systems research

Energy Technology Data Exchange (ETDEWEB)

Thompson, G.L.

1984-10-01

The Office of Energy Research was recently asked to perform a study of Large Scale Systems in order to facilitate the development of a true large systems theory. It was decided to ask experts in the fields of electrical engineering, chemical engineering and manufacturing/operations research for their ideas concerning large scale systems research. The author was asked to distribute a questionnaire among these experts to find out their opinions concerning recent accomplishments and future research directions in large scale systems research. He was also requested to convene a conference which included three experts in each area as panel members to discuss the general area of large scale systems research. The conference was held on March 26--27, 1984 in Pittsburgh with nine panel members, and 15 other attendees. The present report is a summary of the ideas presented and the recommendations proposed by the attendees.

Molecular studies of deletions at the human steroid sulfatase locus

International Nuclear Information System (INIS)

Shapiro, L.J.; Yen, P.; Pomerantz, D.; Martin, E.; Rolewic, L.; Mohandas, T.

1989-01-01

The human steroid sulfatase gene (STS) is located on the distal X chromosome short arm close to the pseudoautosomal region but in a segment of DNA that is unique to the X chromosome. In contrast to most X chromosome-encoded genes, STS expression is not extinguished during the process of X chromosome inactivation. Deficiency of STS activity produced the syndrome of X chromosome-linked ichthyosis, which is one of the most common inborn errors of metabolism in man. Approximately 90% of STS - individuals have large deletions at the STS locus. The authors and others have found that the end points of such deletions are heterogeneous in their location. One recently ascertained subject was observed to have a 40-kilobase deletion that is entirely intragenic, permitting the cloning and sequencing of the deletion junction. Studies of this patient and of other X chromosome sequences in other subjects permit some insight into the mechanism(s) responsible for generating frequent deletions on the short arm of the X chromosome

Large-scale structure of the Universe

International Nuclear Information System (INIS)

Doroshkevich, A.G.

1978-01-01

The problems, discussed at the ''Large-scale Structure of the Universe'' symposium are considered on a popular level. Described are the cell structure of galaxy distribution in the Universe, principles of mathematical galaxy distribution modelling. The images of cell structures, obtained after reprocessing with the computer are given. Discussed are three hypothesis - vortical, entropic, adiabatic, suggesting various processes of galaxy and galaxy clusters origin. A considerable advantage of the adiabatic hypothesis is recognized. The relict radiation, as a method of direct studying the processes taking place in the Universe is considered. The large-scale peculiarities and small-scale fluctuations of the relict radiation temperature enable one to estimate the turbance properties at the pre-galaxy stage. The discussion of problems, pertaining to studying the hot gas, contained in galaxy clusters, the interactions within galaxy clusters and with the inter-galaxy medium, is recognized to be a notable contribution into the development of theoretical and observational cosmology

Improving Genetic Algorithm with Fine-Tuned Crossover and Scaled Architecture

Directory of Open Access Journals (Sweden)

Ajay Shrestha

2016-01-01

Full Text Available Genetic Algorithm (GA is a metaheuristic used in solving combinatorial optimization problems. Inspired by evolutionary biology, GA uses selection, crossover, and mutation operators to efficiently traverse the solution search space. This paper proposes nature inspired fine-tuning to the crossover operator using the untapped idea of Mitochondrial DNA (mtDNA. mtDNA is a small subset of the overall DNA. It differentiates itself by inheriting entirely from the female, while the rest of the DNA is inherited equally from both parents. This unique characteristic of mtDNA can be an effective mechanism to identify members with similar genes and restrict crossover between them. It can reduce the rate of dilution of diversity and result in delayed convergence. In addition, we scale the well-known Island Model, where instances of GA are run independently and population members exchanged periodically, to a Continental Model. In this model, multiple web services are executed with each web service running an island model. We applied the concept of mtDNA in solving Traveling Salesman Problem and to train Neural Network for function approximation. Our implementation tests show that leveraging these new concepts of mtDNA and Continental Model results in relative improvement of the optimization quality of GA.

Seismic safety in conducting large-scale blasts

Science.gov (United States)

Mashukov, I. V.; Chaplygin, V. V.; Domanov, V. P.; Semin, A. A.; Klimkin, M. A.

2017-09-01

In mining enterprises to prepare hard rocks for excavation a drilling and blasting method is used. With the approach of mining operations to settlements the negative effect of large-scale blasts increases. To assess the level of seismic impact of large-scale blasts the scientific staff of Siberian State Industrial University carried out expertise for coal mines and iron ore enterprises. Determination of the magnitude of surface seismic vibrations caused by mass explosions was performed using seismic receivers, an analog-digital converter with recording on a laptop. The registration results of surface seismic vibrations during production of more than 280 large-scale blasts at 17 mining enterprises in 22 settlements are presented. The maximum velocity values of the Earth’s surface vibrations are determined. The safety evaluation of seismic effect was carried out according to the permissible value of vibration velocity. For cases with exceedance of permissible values recommendations were developed to reduce the level of seismic impact.

The mitochondrial ND1 m.3337G>A mutation associated to multiple mitochondrial DNA deletions in a patient with Wolfram syndrome and cardiomyopathy

Energy Technology Data Exchange (ETDEWEB)

Mezghani, Najla [Laboratoire de Genetique Moleculaire Humaine, Faculte de Medecine de Sfax, Universite de Sfax (Tunisia); Mnif, Mouna [Service d' endocrinologie, C.H.U. Habib Bourguiba de Sfax (Tunisia); Mkaouar-Rebai, Emna, E-mail: emna_mkaouar@mail2world.com [Laboratoire de Genetique Moleculaire Humaine, Faculte de Medecine de Sfax, Universite de Sfax (Tunisia); Kallel, Nozha [Service d' endocrinologie, C.H.U. Habib Bourguiba de Sfax (Tunisia); Salem, Ikhlass Haj [Laboratoire de Genetique Moleculaire Humaine, Faculte de Medecine de Sfax, Universite de Sfax (Tunisia); Charfi, Nadia; Abid, Mohamed [Service d' endocrinologie, C.H.U. Habib Bourguiba de Sfax (Tunisia); Fakhfakh, Faiza [Laboratoire de Genetique Moleculaire Humaine, Faculte de Medecine de Sfax, Universite de Sfax (Tunisia)

2011-07-29

Highlights: {yields} We reported a patient with Wolfram syndrome and dilated cardiomyopathy. {yields} We detected the ND1 mitochondrial m.3337G>A mutation in 3 tested tissues (blood leukocytes, buccal mucosa and skeletal muscle). {yields} Long-range PCR amplification revealed the presence of multiple mitochondrial deletions in the skeletal muscle. {yields} The deletions remove several tRNA and protein-coding genes. -- Abstract: Wolfram syndrome (WFS) is a rare hereditary disorder also known as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). It is a heterogeneous disease and full characterization of all clinical and biological features of this disorder is difficult. The wide spectrum of clinical expression, affecting several organs and tissues, and the similarity in phenotype between patients with Wolfram syndrome and those with certain types of respiratory chain diseases suggests mitochondrial DNA (mtDNA) involvement in Wolfram syndrome patients. We report a Tunisian patient with clinical features of moderate Wolfram syndrome including diabetes, dilated cardiomyopathy and neurological complications. The results showed the presence of the mitochondrial ND1 m.3337G>A mutation in almost homoplasmic form in 3 tested tissues of the proband (blood leukocytes, buccal mucosa and skeletal muscle). In addition, the long-range PCR amplifications revealed the presence of multiple deletions of the mitochondrial DNA extracted from the patient's skeletal muscle removing several tRNA and protein-coding genes. Our study reported a Tunisian patient with clinical features of moderate Wolfram syndrome associated with cardiomyopathy, in whom we detected the ND1 m.3337G>A mutation with mitochondrial multiple deletions.

The mitochondrial ND1 m.3337G>A mutation associated to multiple mitochondrial DNA deletions in a patient with Wolfram syndrome and cardiomyopathy

International Nuclear Information System (INIS)

Mezghani, Najla; Mnif, Mouna; Mkaouar-Rebai, Emna; Kallel, Nozha; Salem, Ikhlass Haj; Charfi, Nadia; Abid, Mohamed; Fakhfakh, Faiza

2011-01-01

Highlights: → We reported a patient with Wolfram syndrome and dilated cardiomyopathy. → We detected the ND1 mitochondrial m.3337G>A mutation in 3 tested tissues (blood leukocytes, buccal mucosa and skeletal muscle). → Long-range PCR amplification revealed the presence of multiple mitochondrial deletions in the skeletal muscle. → The deletions remove several tRNA and protein-coding genes. -- Abstract: Wolfram syndrome (WFS) is a rare hereditary disorder also known as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). It is a heterogeneous disease and full characterization of all clinical and biological features of this disorder is difficult. The wide spectrum of clinical expression, affecting several organs and tissues, and the similarity in phenotype between patients with Wolfram syndrome and those with certain types of respiratory chain diseases suggests mitochondrial DNA (mtDNA) involvement in Wolfram syndrome patients. We report a Tunisian patient with clinical features of moderate Wolfram syndrome including diabetes, dilated cardiomyopathy and neurological complications. The results showed the presence of the mitochondrial ND1 m.3337G>A mutation in almost homoplasmic form in 3 tested tissues of the proband (blood leukocytes, buccal mucosa and skeletal muscle). In addition, the long-range PCR amplifications revealed the presence of multiple deletions of the mitochondrial DNA extracted from the patient's skeletal muscle removing several tRNA and protein-coding genes. Our study reported a Tunisian patient with clinical features of moderate Wolfram syndrome associated with cardiomyopathy, in whom we detected the ND1 m.3337G>A mutation with mitochondrial multiple deletions.

Image-based Exploration of Large-Scale Pathline Fields

KAUST Repository

Nagoor, Omniah H.

2014-05-27

While real-time applications are nowadays routinely used in visualizing large nu- merical simulations and volumes, handling these large-scale datasets requires high-end graphics clusters or supercomputers to process and visualize them. However, not all users have access to powerful clusters. Therefore, it is challenging to come up with a visualization approach that provides insight to large-scale datasets on a single com- puter. Explorable images (EI) is one of the methods that allows users to handle large data on a single workstation. Although it is a view-dependent method, it combines both exploration and modification of visual aspects without re-accessing the original huge data. In this thesis, we propose a novel image-based method that applies the concept of EI in visualizing large flow-field pathlines data. The goal of our work is to provide an optimized image-based method, which scales well with the dataset size. Our approach is based on constructing a per-pixel linked list data structure in which each pixel contains a list of pathlines segments. With this view-dependent method it is possible to filter, color-code and explore large-scale flow data in real-time. In addition, optimization techniques such as early-ray termination and deferred shading are applied, which further improves the performance and scalability of our approach.

Homogenization of Large-Scale Movement Models in Ecology

Science.gov (United States)

Garlick, M.J.; Powell, J.A.; Hooten, M.B.; McFarlane, L.R.

2011-01-01

A difficulty in using diffusion models to predict large scale animal population dispersal is that individuals move differently based on local information (as opposed to gradients) in differing habitat types. This can be accommodated by using ecological diffusion. However, real environments are often spatially complex, limiting application of a direct approach. Homogenization for partial differential equations has long been applied to Fickian diffusion (in which average individual movement is organized along gradients of habitat and population density). We derive a homogenization procedure for ecological diffusion and apply it to a simple model for chronic wasting disease in mule deer. Homogenization allows us to determine the impact of small scale (10-100 m) habitat variability on large scale (10-100 km) movement. The procedure generates asymptotic equations for solutions on the large scale with parameters defined by small-scale variation. The simplicity of this homogenization procedure is striking when compared to the multi-dimensional homogenization procedure for Fickian diffusion,and the method will be equally straightforward for more complex models. ?? 2010 Society for Mathematical Biology.

The role of large-scale, extratropical dynamics in climate change

Energy Technology Data Exchange (ETDEWEB)

Shepherd, T.G. [ed.

1994-02-01

The climate modeling community has focused recently on improving our understanding of certain processes, such as cloud feedbacks and ocean circulation, that are deemed critical to climate-change prediction. Although attention to such processes is warranted, emphasis on these areas has diminished a general appreciation of the role played by the large-scale dynamics of the extratropical atmosphere. Lack of interest in extratropical dynamics may reflect the assumption that these dynamical processes are a non-problem as far as climate modeling is concerned, since general circulation models (GCMs) calculate motions on this scale from first principles. Nevertheless, serious shortcomings in our ability to understand and simulate large-scale dynamics exist. Partly due to a paucity of standard GCM diagnostic calculations of large-scale motions and their transports of heat, momentum, potential vorticity, and moisture, a comprehensive understanding of the role of large-scale dynamics in GCM climate simulations has not been developed. Uncertainties remain in our understanding and simulation of large-scale extratropical dynamics and their interaction with other climatic processes, such as cloud feedbacks, large-scale ocean circulation, moist convection, air-sea interaction and land-surface processes. To address some of these issues, the 17th Stanstead Seminar was convened at Bishop`s University in Lennoxville, Quebec. The purpose of the Seminar was to promote discussion of the role of large-scale extratropical dynamics in global climate change. Abstracts of the talks are included in this volume. On the basis of these talks, several key issues emerged concerning large-scale extratropical dynamics and their climatic role. Individual records are indexed separately for the database.

The role of large-scale, extratropical dynamics in climate change

International Nuclear Information System (INIS)

Shepherd, T.G.

1994-02-01

The climate modeling community has focused recently on improving our understanding of certain processes, such as cloud feedbacks and ocean circulation, that are deemed critical to climate-change prediction. Although attention to such processes is warranted, emphasis on these areas has diminished a general appreciation of the role played by the large-scale dynamics of the extratropical atmosphere. Lack of interest in extratropical dynamics may reflect the assumption that these dynamical processes are a non-problem as far as climate modeling is concerned, since general circulation models (GCMs) calculate motions on this scale from first principles. Nevertheless, serious shortcomings in our ability to understand and simulate large-scale dynamics exist. Partly due to a paucity of standard GCM diagnostic calculations of large-scale motions and their transports of heat, momentum, potential vorticity, and moisture, a comprehensive understanding of the role of large-scale dynamics in GCM climate simulations has not been developed. Uncertainties remain in our understanding and simulation of large-scale extratropical dynamics and their interaction with other climatic processes, such as cloud feedbacks, large-scale ocean circulation, moist convection, air-sea interaction and land-surface processes. To address some of these issues, the 17th Stanstead Seminar was convened at Bishop's University in Lennoxville, Quebec. The purpose of the Seminar was to promote discussion of the role of large-scale extratropical dynamics in global climate change. Abstracts of the talks are included in this volume. On the basis of these talks, several key issues emerged concerning large-scale extratropical dynamics and their climatic role. Individual records are indexed separately for the database

Detection of genomic deletions in rice using oligonucleotide microarrays

Directory of Open Access Journals (Sweden)

Bordeos Alicia

2009-03-01

Full Text Available Abstract Background The induction of genomic deletions by physical- or chemical- agents is an easy and inexpensive means to generate a genome-saturating collection of mutations. Different mutagens can be selected to ensure a mutant collection with a range of deletion sizes. This would allow identification of mutations in single genes or, alternatively, a deleted group of genes that might collectively govern a trait (e.g., quantitative trait loci, QTL. However, deletion mutants have not been widely used in functional genomics, because the mutated genes are not tagged and therefore, difficult to identify. Here, we present a microarray-based approach to identify deleted genomic regions in rice mutants selected from a large collection generated by gamma ray or fast neutron treatment. Our study focuses not only on the utility of this method for forward genetics, but also its potential as a reverse genetics tool through accumulation of hybridization data for a collection of deletion mutants harboring multiple genetic lesions. Results We demonstrate that hybridization of labeled genomic DNA directly onto the Affymetrix Rice GeneChip® allows rapid localization of deleted regions in rice mutants. Deletions ranged in size from one gene model to ~500 kb and were predicted on all 12 rice chromosomes. The utility of the technique as a tool in forward genetics was demonstrated in combination with an allelic series of mutants to rapidly narrow the genomic region, and eventually identify a candidate gene responsible for a lesion mimic phenotype. Finally, the positions of mutations in 14 mutants were aligned onto the rice pseudomolecules in a user-friendly genome browser to allow for rapid identification of untagged mutations http://irfgc.irri.org/cgi-bin/gbrowse/IR64_deletion_mutants/. Conclusion We demonstrate the utility of oligonucleotide arrays to discover deleted genes in rice. The density and distribution of deletions suggests the feasibility of a

Y-chromosome and mtDNA genetics reveal significant contrasts in affinities of modern Middle Eastern populations with European and African populations.

Science.gov (United States)

Badro, Danielle A; Douaihy, Bouchra; Haber, Marc; Youhanna, Sonia C; Salloum, Angélique; Ghassibe-Sabbagh, Michella; Johnsrud, Brian; Khazen, Georges; Matisoo-Smith, Elizabeth; Soria-Hernanz, David F; Wells, R Spencer; Tyler-Smith, Chris; Platt, Daniel E; Zalloua, Pierre A

2013-01-01

The Middle East was a funnel of human expansion out of Africa, a staging area for the Neolithic Agricultural Revolution, and the home to some of the earliest world empires. Post LGM expansions into the region and subsequent population movements created a striking genetic mosaic with distinct sex-based genetic differentiation. While prior studies have examined the mtDNA and Y-chromosome contrast in focal populations in the Middle East, none have undertaken a broad-spectrum survey including North and sub-Saharan Africa, Europe, and Middle Eastern populations. In this study 5,174 mtDNA and 4,658 Y-chromosome samples were investigated using PCA, MDS, mean-linkage clustering, AMOVA, and Fisher exact tests of F(ST)'s, R(ST)'s, and haplogroup frequencies. Geographic differentiation in affinities of Middle Eastern populations with Africa and Europe showed distinct contrasts between mtDNA and Y-chromosome data. Specifically, Lebanon's mtDNA shows a very strong association to Europe, while Yemen shows very strong affinity with Egypt and North and East Africa. Previous Y-chromosome results showed a Levantine coastal-inland contrast marked by J1 and J2, and a very strong North African component was evident throughout the Middle East. Neither of these patterns were observed in the mtDNA. While J2 has penetrated into Europe, the pattern of Y-chromosome diversity in Lebanon does not show the widespread affinities with Europe indicated by the mtDNA data. Lastly, while each population shows evidence of connections with expansions that now define the Middle East, Africa, and Europe, many of the populations in the Middle East show distinctive mtDNA and Y-haplogroup characteristics that indicate long standing settlement with relatively little impact from and movement into other populations.

Status: Large-scale subatmospheric cryogenic systems

International Nuclear Information System (INIS)

Peterson, T.

1989-01-01

In the late 1960's and early 1970's an interest in testing and operating RF cavities at 1.8K motivated the development and construction of four large (300 Watt) 1.8K refrigeration systems. in the past decade, development of successful superconducting RF cavities and interest in obtaining higher magnetic fields with the improved Niobium-Titanium superconductors has once again created interest in large-scale 1.8K refrigeration systems. The L'Air Liquide plant for Tore Supra is a recently commissioned 300 Watt 1.8K system which incorporates new technology, cold compressors, to obtain the low vapor pressure for low temperature cooling. CEBAF proposes to use cold compressors to obtain 5KW at 2.0K. Magnetic refrigerators of 10 Watt capacity or higher at 1.8K are now being developed. The state of the art of large-scale refrigeration in the range under 4K will be reviewed. 28 refs., 4 figs., 7 tabs

An economical mtDNA SNP assay detecting different mitochondrial haplogroups in identical HVR 1 samples of Caucasian ancestry.

Science.gov (United States)

Köhnemann, Stephan; Hohoff, Carsten; Pfeiffer, Heidi

2009-09-01

We had sequenced 329 Caucasian samples in Hypervariable Region 1 (HVR 1) and found that they belong to eleven different mitochondrial DNA (mtDNA) haplotypes. The sample set was further analysed by an mtDNA assay examining 32 single nucleotide polymorphisms (SNPs) for haplogroup discrimination. In a validation study on 160 samples of different origin it was shown that these SNPs were able to discriminate between the evolved superhaplogroups worldwide (L, M and N) and between the nine most common Caucasian haplogroups (H, I, J, K, T, U, V, W and X). The 32 mtDNA SNPs comprised 42 different SNP haplotypes instead of only eleven haplotypes after HVR 1 sequencing. The assay provided stable results in a range of 5ng genomic DNA down to virtually no genomic DNA per reaction. It was possible to detect samples of African, Asian and Eurasian ancestry, respectively. The 32 mtDNA SNP assay is a helpful adjunct to further distinguish between identical HVR 1 sequences of Caucasian origin. Our results suggest that haplogroup prediction using HVR 1 sequencing provides instable results. The use of coding region SNPs for haplogroup assignment is more suited than using HVR 1 haplotypes.

Large-scale weakly supervised object localization via latent category learning.

Science.gov (United States)

Chong Wang; Kaiqi Huang; Weiqiang Ren; Junge Zhang; Maybank, Steve

2015-04-01

Localizing objects in cluttered backgrounds is challenging under large-scale weakly supervised conditions. Due to the cluttered image condition, objects usually have large ambiguity with backgrounds. Besides, there is also a lack of effective algorithm for large-scale weakly supervised localization in cluttered backgrounds. However, backgrounds contain useful latent information, e.g., the sky in the aeroplane class. If this latent information can be learned, object-background ambiguity can be largely reduced and background can be suppressed effectively. In this paper, we propose the latent category learning (LCL) in large-scale cluttered conditions. LCL is an unsupervised learning method which requires only image-level class labels. First, we use the latent semantic analysis with semantic object representation to learn the latent categories, which represent objects, object parts or backgrounds. Second, to determine which category contains the target object, we propose a category selection strategy by evaluating each category's discrimination. Finally, we propose the online LCL for use in large-scale conditions. Evaluation on the challenging PASCAL Visual Object Class (VOC) 2007 and the large-scale imagenet large-scale visual recognition challenge 2013 detection data sets shows that the method can improve the annotation precision by 10% over previous methods. More importantly, we achieve the detection precision which outperforms previous results by a large margin and can be competitive to the supervised deformable part model 5.0 baseline on both data sets.

Large-scale networks in engineering and life sciences

CERN Document Server

Findeisen, Rolf; Flockerzi, Dietrich; Reichl, Udo; Sundmacher, Kai

2014-01-01

This edited volume provides insights into and tools for the modeling, analysis, optimization, and control of large-scale networks in the life sciences and in engineering. Large-scale systems are often the result of networked interactions between a large number of subsystems, and their analysis and control are becoming increasingly important. The chapters of this book present the basic concepts and theoretical foundations of network theory and discuss its applications in different scientific areas such as biochemical reactions, chemical production processes, systems biology, electrical circuits, and mobile agents. The aim is to identify common concepts, to understand the underlying mathematical ideas, and to inspire discussions across the borders of the various disciplines.  The book originates from the interdisciplinary summer school “Large Scale Networks in Engineering and Life Sciences” hosted by the International Max Planck Research School Magdeburg, September 26-30, 2011, and will therefore be of int...

A recombinant E1-deleted porcine adenovirus-3 as an expression vector

International Nuclear Information System (INIS)

Zakhartchouk, Alexander; Zhou Yan; Tikoo, Suresh Kumar

2003-01-01

Replication-defective E1-deleted porcine adenoviruses (PAVs) are attractive vectors for vaccination. As a prerequisite for generating PAV-3 vectors containing complete deletion of E1, we transfected VIDO R1 cells (fetal porcine retina cells transformed with E1 region of human adenovirus 5) with a construct containing PAV-3 E1B large coding sequences under the control of HCMV promoter. A cell line named VR1BL could be isolated that expressed E1B large of PAV-3 and also complemented PAV214 (E1A+E1B small deleted). The VR1BL cells could be efficiently transfected with DNA and allowed the rescue and propagation of recombinant PAV507 containing a triple stop codon inserted in the E1B large coding sequence. In addition, recombinant PAV227 containing complete deletion of E1 (E1A+E1B small + E1B large ) could be successfully rescued using VR1BL cell line. Recombinant PAV227 replicated as efficiently as wild-type in VR1BL cells but not in VIDO R1 cells, suggesting that E1B large was essential for replication of PAV-3. Next, we constructed recombinant PAV219 by inserting green fluorescent (GFP) protein gene flanked by a promoter and a poly(A) in the E1 region of the PAV227 genome. We demonstrated that PAV219 was able to transduce and direct expression of GFP in some human cell lines

Genotype call for chromosomal deletions using read-depth from whole genome sequence variants in cattle

DEFF Research Database (Denmark)

Mesbah-Uddin, Md; Guldbrandtsen, Bernt; Lund, Mogens Sandø

2018-01-01

We presented a deletion genotyping (copy-number estimation) method that leverages population-scale whole genome sequence variants data from 1K bull genomes project (1KBGP) to build reference panel for imputation. To estimate deletion-genotype likelihood, we extracted read-depth (RD) data of all...

An Novel Architecture of Large-scale Communication in IOT

Science.gov (United States)

Ma, Wubin; Deng, Su; Huang, Hongbin

2018-03-01

In recent years, many scholars have done a great deal of research on the development of Internet of Things and networked physical systems. However, few people have made the detailed visualization of the large-scale communications architecture in the IOT. In fact, the non-uniform technology between IPv6 and access points has led to a lack of broad principles of large-scale communications architectures. Therefore, this paper presents the Uni-IPv6 Access and Information Exchange Method (UAIEM), a new architecture and algorithm that addresses large-scale communications in the IOT.

Benefits of transactive memory systems in large-scale development

OpenAIRE

Aivars, Sablis

2016-01-01

Context. Large-scale software development projects are those consisting of a large number of teams, maybe even spread across multiple locations, and working on large and complex software tasks. That means that neither a team member individually nor an entire team holds all the knowledge about the software being developed and teams have to communicate and coordinate their knowledge. Therefore, teams and team members in large-scale software development projects must acquire and manage expertise...

Study of a large scale neutron measurement channel

International Nuclear Information System (INIS)

Amarouayache, Anissa; Ben Hadid, Hayet.

1982-12-01

A large scale measurement channel allows the processing of the signal coming from an unique neutronic sensor, during three different running modes: impulses, fluctuations and current. The study described in this note includes three parts: - A theoretical study of the large scale channel and its brief description are given. The results obtained till now in that domain are presented. - The fluctuation mode is thoroughly studied and the improvements to be done are defined. The study of a fluctuation linear channel with an automatic commutation of scales is described and the results of the tests are given. In this large scale channel, the method of data processing is analogical. - To become independent of the problems generated by the use of a an analogical processing of the fluctuation signal, a digital method of data processing is tested. The validity of that method is improved. The results obtained on a test system realized according to this method are given and a preliminary plan for further research is defined [fr

Capabilities of the Large-Scale Sediment Transport Facility

Science.gov (United States)

2016-04-01

pump flow meters, sediment trap weigh tanks , and beach profiling lidar. A detailed discussion of the original LSTF features and capabilities can be...ERDC/CHL CHETN-I-88 April 2016 Approved for public release; distribution is unlimited. Capabilities of the Large-Scale Sediment Transport...describes the Large-Scale Sediment Transport Facility (LSTF) and recent upgrades to the measurement systems. The purpose of these upgrades was to increase

Spatiotemporal property and predictability of large-scale human mobility

Science.gov (United States)

Zhang, Hai-Tao; Zhu, Tao; Fu, Dongfei; Xu, Bowen; Han, Xiao-Pu; Chen, Duxin

2018-04-01

Spatiotemporal characteristics of human mobility emerging from complexity on individual scale have been extensively studied due to the application potential on human behavior prediction and recommendation, and control of epidemic spreading. We collect and investigate a comprehensive data set of human activities on large geographical scales, including both websites browse and mobile towers visit. Numerical results show that the degree of activity decays as a power law, indicating that human behaviors are reminiscent of scale-free random walks known as Lévy flight. More significantly, this study suggests that human activities on large geographical scales have specific non-Markovian characteristics, such as a two-segment power-law distribution of dwelling time and a high possibility for prediction. Furthermore, a scale-free featured mobility model with two essential ingredients, i.e., preferential return and exploration, and a Gaussian distribution assumption on the exploration tendency parameter is proposed, which outperforms existing human mobility models under scenarios of large geographical scales.

Problems of large-scale vertically-integrated aquaculture

Energy Technology Data Exchange (ETDEWEB)

Webber, H H; Riordan, P F

1976-01-01

The problems of vertically-integrated aquaculture are outlined; they are concerned with: species limitations (in the market, biological and technological); site selection, feed, manpower needs, and legal, institutional and financial requirements. The gaps in understanding of, and the constraints limiting, large-scale aquaculture are listed. Future action is recommended with respect to: types and diversity of species to be cultivated, marketing, biotechnology (seed supply, disease control, water quality and concerted effort), siting, feed, manpower, legal and institutional aids (granting of water rights, grants, tax breaks, duty-free imports, etc.), and adequate financing. The last of hard data based on experience suggests that large-scale vertically-integrated aquaculture is a high risk enterprise, and with the high capital investment required, banks and funding institutions are wary of supporting it. Investment in pilot projects is suggested to demonstrate that large-scale aquaculture can be a fully functional and successful business. Construction and operation of such pilot farms is judged to be in the interests of both the public and private sector.

eCOMPAGT integrates mtDNA: import, validation and export of mitochondrial DNA profiles for population genetics, tumour dynamics and genotype-phenotype association studies

Directory of Open Access Journals (Sweden)

Specht Günther

2010-03-01

Full Text Available Abstract Background Mitochondrial DNA (mtDNA is widely being used for population genetics, forensic DNA fingerprinting and clinical disease association studies. The recent past has uncovered severe problems with mtDNA genotyping, not only due to the genotyping method itself, but mainly to the post-lab transcription, storage and report of mtDNA genotypes. Description eCOMPAGT, a system to store, administer and connect phenotype data to all kinds of genotype data is now enhanced by the possibility of storing mtDNA profiles and allowing their validation, linking to phenotypes and export as numerous formats. mtDNA profiles can be imported from different sequence evaluation programs, compared between evaluations and their haplogroup affiliations stored. Furthermore, eCOMPAGT has been improved in its sophisticated transparency (support of MySQL and Oracle, security aspects (by using database technology and the option to import, manage and store genotypes derived from various genotyping methods (SNPlex, TaqMan, and STRs. It is a software solution designed for project management, laboratory work and the evaluation process all-in-one. Conclusions The extended mtDNA version of eCOMPAGT was designed to enable error-free post-laboratory data handling of human mtDNA profiles. This software is suited for small to medium-sized human genetic, forensic and clinical genetic laboratories. The direct support of MySQL and the improved database security options render eCOMPAGT a powerful tool to build an automated workflow architecture for several genotyping methods. eCOMPAGT is freely available at http://dbis-informatik.uibk.ac.at/ecompagt.

eCOMPAGT integrates mtDNA: import, validation and export of mitochondrial DNA profiles for population genetics, tumour dynamics and genotype-phenotype association studies.

Science.gov (United States)

Weissensteiner, Hansi; Schönherr, Sebastian; Specht, Günther; Kronenberg, Florian; Brandstätter, Anita

2010-03-09

Mitochondrial DNA (mtDNA) is widely being used for population genetics, forensic DNA fingerprinting and clinical disease association studies. The recent past has uncovered severe problems with mtDNA genotyping, not only due to the genotyping method itself, but mainly to the post-lab transcription, storage and report of mtDNA genotypes. eCOMPAGT, a system to store, administer and connect phenotype data to all kinds of genotype data is now enhanced by the possibility of storing mtDNA profiles and allowing their validation, linking to phenotypes and export as numerous formats. mtDNA profiles can be imported from different sequence evaluation programs, compared between evaluations and their haplogroup affiliations stored. Furthermore, eCOMPAGT has been improved in its sophisticated transparency (support of MySQL and Oracle), security aspects (by using database technology) and the option to import, manage and store genotypes derived from various genotyping methods (SNPlex, TaqMan, and STRs). It is a software solution designed for project management, laboratory work and the evaluation process all-in-one. The extended mtDNA version of eCOMPAGT was designed to enable error-free post-laboratory data handling of human mtDNA profiles. This software is suited for small to medium-sized human genetic, forensic and clinical genetic laboratories. The direct support of MySQL and the improved database security options render eCOMPAGT a powerful tool to build an automated workflow architecture for several genotyping methods. eCOMPAGT is freely available at http://dbis-informatik.uibk.ac.at/ecompagt.

Large-scale computing with Quantum Espresso

International Nuclear Information System (INIS)

Giannozzi, P.; Cavazzoni, C.

2009-01-01

This paper gives a short introduction to Quantum Espresso: a distribution of software for atomistic simulations in condensed-matter physics, chemical physics, materials science, and to its usage in large-scale parallel computing.

Cytoplasmic transfer of heritable elements other than mtDNA from SAMP1 mice into mouse tumor cells suppresses their ability to form tumors in C57BL6 mice.

Science.gov (United States)

Shimizu, Akinori; Tani, Haruna; Takibuchi, Gaku; Ishikawa, Kaori; Sakurazawa, Ryota; Inoue, Takafumi; Hashimoto, Tetsuo; Nakada, Kazuto; Takenaga, Keizo; Hayashi, Jun-Ichi

2017-11-04

In a previous study, we generated transmitochondrial P29mtSAMP1 cybrids, which had nuclear DNA from the C57BL6 (referred to as B6) mouse strain-derived P29 tumor cells and mitochondrial DNA (mtDNA) exogenously-transferred from the allogeneic strain SAMP1. Because P29mtSAMP1 cybrids did not form tumors in syngeneic B6 mice, we proposed that allogeneic SAMP1 mtDNA suppressed tumor formation of P29mtSAMP1 cybrids. To test this hypothesis, current study generated P29mt(sp)B6 cybrids carrying all genomes (nuclear DNA and mtDNA) from syngeneic B6 mice by eliminating SAMP1 mtDNA from P29mtSAMP1 cybrids and reintroducing B6 mtDNA. However, the P29mt(sp)B6 cybrids did not form tumors in B6 mice, even though they had no SAMP1 mtDNA, suggesting that SAMP1 mtDNA is not involved in tumor suppression. Then, we examined another possibility of whether SAMP1 mtDNA fragments potentially integrated into the nuclear DNA of P29mtSAMP1 cybrids are responsible for tumor suppression. We generated P29 H (sp)B6 cybrids by eliminating nuclear DNA from P29mt(sp)B6 cybrids and reintroducing nuclear DNA with no integrated SAMP1 mtDNA fragment from mtDNA-less P29 cells resistant to hygromycin in selection medium containing hygromycin. However, the P29 H (sp)B6 cybrids did not form tumors in B6 mice, even though they carried neither SAMP1 mtDNA nor nuclear DNA with integrated SAMP1 mtDNA fragments. Moreover, overproduction of reactive oxygen species (ROS) and bacterial infection were not involved in tumor suppression. These observations suggest that tumor suppression was caused not by mtDNA with polymorphic mutations or infection of cytozoic bacteria but by hypothetical heritable cytoplasmic elements other than mtDNA from SAMP1 mice. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Updating the profile of C-terminal MECP2 deletions in Rett syndrome

Science.gov (United States)

Bebbington, A; Percy, A; Christodoulou, J; Ravine, D; Ho, G; Jacoby, P; Anderson, A; Pineda, M; Ben Zeev, B; Bahi-Buisson, N; Smeets, E; Leonard, H

2014-01-01

Objectives This study aimed to compare the phenotype of Rett syndrome cases with C-terminal deletions to that of cases with different MECP2 mutations and to examine the phenotypic variation within C-terminal deletions. Methods Cases were selected from InterRett, an international database and from the population-based Australian Rett Syndrome Database. Cases (n=832) were included if they had a pathogenic MECP2 mutation in which the nature of the amino acid change was known. Three severity scale systems were used, and individual aspects of the phenotype were also compared. Results Lower severity was associated with C-terminal deletions (n=79) compared to all other MECP2 mutations (e.g. Pineda scale C-terminals mean 15.0 (95% CI 14.0–16.0) vs 16.2 (15.9–16.5). Cases with C-terminal deletions were more likely to have a normal head circumference (odds ratio 3.22, 95% CI 1.53 – 6.79) and weight (odds ratio 2.97, 95% CI 1.25–5.76). Onset of stereotypies tended to be later (median age 2.5 years vs 2 years, pmiddle of the range. In terms of individual aspects of phenotype growth and ability to ambulate appear to be particular strengths. By pooling data internationally this study has achieved the case numbers to provide a phenotypic profile of C-terminal deletions in Rett syndrome. PMID:19914908

The current status of studies on mitochondrial DNA with tumor, radiation biological effects and aging

International Nuclear Information System (INIS)

Liu Qingjie; Sang Lu

2004-01-01

The mitochondrial plays a very important role in sustaining the normal physiological function, because it is the center of energy making and mitochondrial DNA (mtDNA) is the only genetic material outside the nuclear. The result of studies showed that many diseases have a close relationship with mtDNA mutation and deletion. This article reviewed the current status of research on mtDNA with tumor, radiation biological effects and aging, in order to initiate the application study of mtDNA in the circle of radiation medicine

VESPA: Very large-scale Evolutionary and Selective Pressure Analyses

Directory of Open Access Journals (Sweden)

Andrew E. Webb

2017-06-01

Full Text Available Background Large-scale molecular evolutionary analyses of protein coding sequences requires a number of preparatory inter-related steps from finding gene families, to generating alignments and phylogenetic trees and assessing selective pressure variation. Each phase of these analyses can represent significant challenges, particularly when working with entire proteomes (all protein coding sequences in a genome from a large number of species. Methods We present VESPA, software capable of automating a selective pressure analysis using codeML in addition to the preparatory analyses and summary statistics. VESPA is written in python and Perl and is designed to run within a UNIX environment. Results We have benchmarked VESPA and our results show that the method is consistent, performs well on both large scale and smaller scale datasets, and produces results in line with previously published datasets. Discussion Large-scale gene family identification, sequence alignment, and phylogeny reconstruction are all important aspects of large-scale molecular evolutionary analyses. VESPA provides flexible software for simplifying these processes along with downstream selective pressure variation analyses. The software automatically interprets results from codeML and produces simplified summary files to assist the user in better understanding the results. VESPA may be found at the following website: http://www.mol-evol.org/VESPA.

RESTRUCTURING OF THE LARGE-SCALE SPRINKLERS

Directory of Open Access Journals (Sweden)

Paweł Kozaczyk

2016-09-01

Full Text Available One of the best ways for agriculture to become independent from shortages of precipitation is irrigation. In the seventies and eighties of the last century a number of large-scale sprinklers in Wielkopolska was built. At the end of 1970’s in the Poznan province 67 sprinklers with a total area of 6400 ha were installed. The average size of the sprinkler reached 95 ha. In 1989 there were 98 sprinklers, and the area which was armed with them was more than 10 130 ha. The study was conducted on 7 large sprinklers with the area ranging from 230 to 520 hectares in 1986÷1998. After the introduction of the market economy in the early 90’s and ownership changes in agriculture, large-scale sprinklers have gone under a significant or total devastation. Land on the State Farms of the State Agricultural Property Agency has leased or sold and the new owners used the existing sprinklers to a very small extent. This involved a change in crop structure, demand structure and an increase in operating costs. There has also been a threefold increase in electricity prices. Operation of large-scale irrigation encountered all kinds of barriers in practice and limitations of system solutions, supply difficulties, high levels of equipment failure which is not inclined to rational use of available sprinklers. An effect of a vision of the local area was to show the current status of the remaining irrigation infrastructure. The adopted scheme for the restructuring of Polish agriculture was not the best solution, causing massive destruction of assets previously invested in the sprinkler system.

Large-scale synthesis of YSZ nanopowder by Pechini method

Indian Academy of Sciences (India)

Administrator

structure and chemical purity of 99⋅1% by inductively coupled plasma optical emission spectroscopy on a large scale. Keywords. Sol–gel; yttria-stabilized zirconia; large scale; nanopowder; Pechini method. 1. Introduction. Zirconia has attracted the attention of many scientists because of its tremendous thermal, mechanical ...

The Phoenix series large scale LNG pool fire experiments.

Energy Technology Data Exchange (ETDEWEB)

Simpson, Richard B.; Jensen, Richard Pearson; Demosthenous, Byron; Luketa, Anay Josephine; Ricks, Allen Joseph; Hightower, Marion Michael; Blanchat, Thomas K.; Helmick, Paul H.; Tieszen, Sheldon Robert; Deola, Regina Anne; Mercier, Jeffrey Alan; Suo-Anttila, Jill Marie; Miller, Timothy J.

2010-12-01

The increasing demand for natural gas could increase the number and frequency of Liquefied Natural Gas (LNG) tanker deliveries to ports across the United States. Because of the increasing number of shipments and the number of possible new facilities, concerns about the potential safety of the public and property from an accidental, and even more importantly intentional spills, have increased. While improvements have been made over the past decade in assessing hazards from LNG spills, the existing experimental data is much smaller in size and scale than many postulated large accidental and intentional spills. Since the physics and hazards from a fire change with fire size, there are concerns about the adequacy of current hazard prediction techniques for large LNG spills and fires. To address these concerns, Congress funded the Department of Energy (DOE) in 2008 to conduct a series of laboratory and large-scale LNG pool fire experiments at Sandia National Laboratories (Sandia) in Albuquerque, New Mexico. This report presents the test data and results of both sets of fire experiments. A series of five reduced-scale (gas burner) tests (yielding 27 sets of data) were conducted in 2007 and 2008 at Sandia's Thermal Test Complex (TTC) to assess flame height to fire diameter ratios as a function of nondimensional heat release rates for extrapolation to large-scale LNG fires. The large-scale LNG pool fire experiments were conducted in a 120 m diameter pond specially designed and constructed in Sandia's Area III large-scale test complex. Two fire tests of LNG spills of 21 and 81 m in diameter were conducted in 2009 to improve the understanding of flame height, smoke production, and burn rate and therefore the physics and hazards of large LNG spills and fires.

Diagnostic dilemma: a young woman with Fabry disease symptoms, no family history, and a "sequencing cryptic" α-galactosidase a large deletion

DEFF Research Database (Denmark)

Feldt-Rasmussen, Ulla; Dobrovolny, Robert; Nazarenko, Irina

2011-01-01

Fabry disease, an X-linked lysosomal storage disorder, results from the deficient activity of a-galactosidase A (a-Gal A). In affected males, the clinical diagnosis is confirmed by the markedly decreased a-Gal A activity. However, in female heterozygotes, the a-Gal A activity can range from low t...... on enzyme replacement therapy. Thus, gene dosage analyses can detect large deletions (>50bp) in suspect heterozygotes for X-linked and autosomal dominant diseases that are "sequencing cryptic," resolving molecular diagnostic dilemmas....

Geospatial Optimization of Siting Large-Scale Solar Projects

Energy Technology Data Exchange (ETDEWEB)

Macknick, Jordan [National Renewable Energy Lab. (NREL), Golden, CO (United States); Quinby, Ted [National Renewable Energy Lab. (NREL), Golden, CO (United States); Caulfield, Emmet [Stanford Univ., CA (United States); Gerritsen, Margot [Stanford Univ., CA (United States); Diffendorfer, Jay [U.S. Geological Survey, Boulder, CO (United States); Haines, Seth [U.S. Geological Survey, Boulder, CO (United States)

2014-03-01

Recent policy and economic conditions have encouraged a renewed interest in developing large-scale solar projects in the U.S. Southwest. However, siting large-scale solar projects is complex. In addition to the quality of the solar resource, solar developers must take into consideration many environmental, social, and economic factors when evaluating a potential site. This report describes a proof-of-concept, Web-based Geographical Information Systems (GIS) tool that evaluates multiple user-defined criteria in an optimization algorithm to inform discussions and decisions regarding the locations of utility-scale solar projects. Existing siting recommendations for large-scale solar projects from governmental and non-governmental organizations are not consistent with each other, are often not transparent in methods, and do not take into consideration the differing priorities of stakeholders. The siting assistance GIS tool we have developed improves upon the existing siting guidelines by being user-driven, transparent, interactive, capable of incorporating multiple criteria, and flexible. This work provides the foundation for a dynamic siting assistance tool that can greatly facilitate siting decisions among multiple stakeholders.

Does aerobic exercises induce mtDNA mutation in human blood ...

African Journals Online (AJOL)

The aim of this study was to determine the effect of eight weeks aerobic training on mitochondrial DNA (mtDNA) mutation in human blood leucocytes. Twenty untrained healthy students (training group: n =10, age = 20.7±1.5 yrs, weight = 67.7±10 kg, BF% = 17.5±7.35 & control group: n =10, age = 21±1.3 yrs, weight ...

Large-scale Agricultural Land Acquisitions in West Africa | IDRC ...

International Development Research Centre (IDRC) Digital Library (Canada)

This project will examine large-scale agricultural land acquisitions in nine West African countries -Burkina Faso, Guinea-Bissau, Guinea, Benin, Mali, Togo, Senegal, Niger, and Côte d'Ivoire. ... They will use the results to increase public awareness and knowledge about the consequences of large-scale land acquisitions.

The Mitochondrial DNA (mtDNA)-Associated Protein SWIB5 Influences mtDNA Architecture and Homologous Recombination

KAUST Repository

Blomme, Jonas

2017-04-19

In addition to the nucleus, mitochondria and chloroplasts in plant cells also contain genomes. Efficient DNA repair pathways are crucial in these organelles to fix damage resulting from endogenous and exogenous factors. Plant organellar genomes are complex compared with their animal counterparts, and although several plant-specific mediators of organelle DNA repair have been reported, many regulators remain to be identified. Here, we show that a mitochondrial SWI/SNF (nucleosome remodeling) complex B protein, SWIB5, is capable of associating with mitochondrial DNA (mtDNA) in Arabidopsis thaliana. Gainand loss-of-function mutants provided evidence for a role of SWIB5 in influencing mtDNA architecture and homologous recombination at specific intermediate-sized repeats both under normal and genotoxic conditions. SWIB5 interacts with other mitochondrial SWIB proteins. Gene expression and mutant phenotypic analysis of SWIB5 and SWIB family members suggests a link between organellar genome maintenance and cell proliferation. Taken together, our work presents a protein family that influences mtDNA architecture and homologous recombination in plants and suggests a link between organelle functioning and plant development.

Large-scale motions in the universe: a review

International Nuclear Information System (INIS)

Burstein, D.

1990-01-01

The expansion of the universe can be retarded in localised regions within the universe both by the presence of gravity and by non-gravitational motions generated in the post-recombination universe. The motions of galaxies thus generated are called 'peculiar motions', and the amplitudes, size scales and coherence of these peculiar motions are among the most direct records of the structure of the universe. As such, measurements of these properties of the present-day universe provide some of the severest tests of cosmological theories. This is a review of the current evidence for large-scale motions of galaxies out to a distance of ∼5000 km s -1 (in an expanding universe, distance is proportional to radial velocity). 'Large-scale' in this context refers to motions that are correlated over size scales larger than the typical sizes of groups of galaxies, up to and including the size of the volume surveyed. To orient the reader into this relatively new field of study, a short modern history is given together with an explanation of the terminology. Careful consideration is given to the data used to measure the distances, and hence the peculiar motions, of galaxies. The evidence for large-scale motions is presented in a graphical fashion, using only the most reliable data for galaxies spanning a wide range in optical properties and over the complete range of galactic environments. The kinds of systematic errors that can affect this analysis are discussed, and the reliability of these motions is assessed. The predictions of two models of large-scale motion are compared to the observations, and special emphasis is placed on those motions in which our own Galaxy directly partakes. (author)

State of the Art in Large-Scale Soil Moisture Monitoring

Science.gov (United States)

Ochsner, Tyson E.; Cosh, Michael Harold; Cuenca, Richard H.; Dorigo, Wouter; Draper, Clara S.; Hagimoto, Yutaka; Kerr, Yan H.; Larson, Kristine M.; Njoku, Eni Gerald; Small, Eric E.;

A route to explosive large-scale magnetic reconnection in a super-ion-scale current sheet

Directory of Open Access Journals (Sweden)

K. G. Tanaka

2009-01-01

Full Text Available How to trigger magnetic reconnection is one of the most interesting and important problems in space plasma physics. Recently, electron temperature anisotropy (αeo=Te⊥/Te|| at the center of a current sheet and non-local effect of the lower-hybrid drift instability (LHDI that develops at the current sheet edges have attracted attention in this context. In addition to these effects, here we also study the effects of ion temperature anisotropy (αio=Ti⊥/Ti||. Electron anisotropy effects are known to be helpless in a current sheet whose thickness is of ion-scale. In this range of current sheet thickness, the LHDI effects are shown to weaken substantially with a small increase in thickness and the obtained saturation level is too low for a large-scale reconnection to be achieved. Then we investigate whether introduction of electron and ion temperature anisotropies in the initial stage would couple with the LHDI effects to revive quick triggering of large-scale reconnection in a super-ion-scale current sheet. The results are as follows. (1 The initial electron temperature anisotropy is consumed very quickly when a number of minuscule magnetic islands (each lateral length is 1.5~3 times the ion inertial length form. These minuscule islands do not coalesce into a large-scale island to enable large-scale reconnection. (2 The subsequent LHDI effects disturb the current sheet filled with the small islands. This makes the triggering time scale to be accelerated substantially but does not enhance the saturation level of reconnected flux. (3 When the ion temperature anisotropy is added, it survives through the small island formation stage and makes even quicker triggering to happen when the LHDI effects set-in. Furthermore the saturation level is seen to be elevated by a factor of ~2 and large-scale reconnection is achieved only in this case. Comparison with two-dimensional simulations that exclude the LHDI effects confirms that the saturation level

Large-scale Labeled Datasets to Fuel Earth Science Deep Learning Applications

Science.gov (United States)

Maskey, M.; Ramachandran, R.; Miller, J.

2017-12-01

Deep learning has revolutionized computer vision and natural language processing with various algorithms scaled using high-performance computing. However, generic large-scale labeled datasets such as the ImageNet are the fuel that drives the impressive accuracy of deep learning results. Large-scale labeled datasets already exist in domains such as medical science, but creating them in the Earth science domain is a challenge. While there are ways to apply deep learning using limited labeled datasets, there is a need in the Earth sciences for creating large-scale labeled datasets for benchmarking and scaling deep learning applications. At the NASA Marshall Space Flight Center, we are using deep learning for a variety of Earth science applications where we have encountered the need for large-scale labeled datasets. We will discuss our approaches for creating such datasets and why these datasets are just as valuable as deep learning algorithms. We will also describe successful usage of these large-scale labeled datasets with our deep learning based applications.

Mitochondrial DNA (mtDNA) variants in the European haplogroups HV, JT, and U do not have a major role in schizophrenia.

Science.gov (United States)

Torrell, Helena; Salas, Antonio; Abasolo, Nerea; Morén, Constanza; Garrabou, Glòria; Valero, Joaquín; Alonso, Yolanda; Vilella, Elisabet; Costas, Javier; Martorell, Lourdes

2014-10-01

It has been reported that certain genetic factors involved in schizophrenia could be located in the mitochondrial DNA (mtDNA). Therefore, we hypothesized that mtDNA mutations and/or variants would be present in schizophrenia patients and may be related to schizophrenia characteristics and mitochondrial function. This study was performed in three steps: (1) identification of pathogenic mutations and variants in 14 schizophrenia patients with an apparent maternal inheritance of the disease by sequencing the entire mtDNA; (2) case-control association study of 23 variants identified in step 1 (16 missense, 3 rRNA, and 4 tRNA variants) in 495 patients and 615 controls, and (3) analyses of the associated variants according to the clinical, psychopathological, and neuropsychological characteristics and according to the oxidative and enzymatic activities of the mitochondrial respiratory chain. We did not identify pathogenic mtDNA mutations in the 14 sequenced patients. Two known variants were nominally associated with schizophrenia and were further studied. The MT-RNR2 1811A > G variant likely does not play a major role in schizophrenia, as it was not associated with clinical, psychopathological, or neuropsychological variables, and the MT-ATP6 9110T > C p.Ile195Thr variant did not result in differences in the oxidative and enzymatic functions of the mitochondrial respiratory chain. The patients with apparent maternal inheritance of schizophrenia did not exhibit any mutations in their mtDNA. The variants nominally associated with schizophrenia in the present study were not related either to phenotypic characteristics or to mitochondrial function. We did not find evidence pointing to a role for mtDNA sequence variation in schizophrenia. © 2014 Wiley Periodicals, Inc.

Large-scale structure observables in general relativity

International Nuclear Information System (INIS)

Jeong, Donghui; Schmidt, Fabian

2015-01-01

We review recent studies that rigorously define several key observables of the large-scale structure of the Universe in a general relativistic context. Specifically, we consider (i) redshift perturbation of cosmic clock events; (ii) distortion of cosmic rulers, including weak lensing shear and magnification; and (iii) observed number density of tracers of the large-scale structure. We provide covariant and gauge-invariant expressions of these observables. Our expressions are given for a linearly perturbed flat Friedmann–Robertson–Walker metric including scalar, vector, and tensor metric perturbations. While we restrict ourselves to linear order in perturbation theory, the approach can be straightforwardly generalized to higher order. (paper)

Fatigue Analysis of Large-scale Wind turbine

Directory of Open Access Journals (Sweden)

Zhu Yongli

2017-01-01

Full Text Available The paper does research on top flange fatigue damage of large-scale wind turbine generator. It establishes finite element model of top flange connection system with finite element analysis software MSC. Marc/Mentat, analyzes its fatigue strain, implements load simulation of flange fatigue working condition with Bladed software, acquires flange fatigue load spectrum with rain-flow counting method, finally, it realizes fatigue analysis of top flange with fatigue analysis software MSC. Fatigue and Palmgren-Miner linear cumulative damage theory. The analysis result indicates that its result provides new thinking for flange fatigue analysis of large-scale wind turbine generator, and possesses some practical engineering value.

Real-time simulation of large-scale floods

Science.gov (United States)

Liu, Q.; Qin, Y.; Li, G. D.; Liu, Z.; Cheng, D. J.; Zhao, Y. H.

2016-08-01

According to the complex real-time water situation, the real-time simulation of large-scale floods is very important for flood prevention practice. Model robustness and running efficiency are two critical factors in successful real-time flood simulation. This paper proposed a robust, two-dimensional, shallow water model based on the unstructured Godunov- type finite volume method. A robust wet/dry front method is used to enhance the numerical stability. An adaptive method is proposed to improve the running efficiency. The proposed model is used for large-scale flood simulation on real topography. Results compared to those of MIKE21 show the strong performance of the proposed model.

Tracing the phylogeography of human populations in Britain based on 4th-11th century mtDNA genotypes.

Science.gov (United States)

Töpf, A L; Gilbert, M T P; Dumbacher, J P; Hoelzel, A R

2006-01-01

Some of the transitional periods of Britain during the first millennium A.D. are traditionally associated with the movement of people from continental Europe, composed largely of invading armies (e.g., the Roman, Saxon, and Viking invasions). However, the extent to which these were migrations (as opposed to cultural exchange) remains controversial. We investigated the history of migration by women by amplifying mitochondrial DNA (mtDNA) from ancient Britons who lived between approximately A.D. 300-1,000 and compared these with 3,549 modern mtDNA database genotypes from England, Europe, and the Middle East. The objective was to assess the dynamics of the historical population composition by comparing genotypes in a temporal context. Towards this objective we test and calibrate the use of rho statistics to identify relationships between founder and source populations. We find evidence for shared ancestry between the earliest sites (predating Viking invasions) with modern populations across the north of Europe from Norway to Estonia, possibly reflecting common ancestors dating back to the last glacial epoch. This is in contrast with a late Saxon site in Norwich, where the genetic signature is consistent with more recent immigrations from the south, possibly as part of the Saxon invasions.

ErasuCrypto: A Light-weight Secure Data Deletion Scheme for Solid State Drives

Directory of Open Access Journals (Sweden)

Liu Chen

2017-01-01

Full Text Available Securely deleting invalid data from secondary storage is critical to protect users’ data privacy against unauthorized accesses. However, secure deletion is very costly for solid state drives (SSDs, which unlike hard disks do not support in-place update. When applied to SSDs, both erasure-based and cryptography-based secure deletion methods inevitably incur large amount of valid data migrations and/or block erasures, which not only introduce extra latency and energy consumption, but also harm SSD lifetime.

Large-scale numerical simulations of plasmas

International Nuclear Information System (INIS)

Hamaguchi, Satoshi

2004-01-01

The recent trend of large scales simulations of fusion plasma and processing plasmas is briefly summarized. Many advanced simulation techniques have been developed for fusion plasmas and some of these techniques are now applied to analyses of processing plasmas. (author)

Nearly incompressible fluids: Hydrodynamics and large scale inhomogeneity

International Nuclear Information System (INIS)

Hunana, P.; Zank, G. P.; Shaikh, D.

2006-01-01

A system of hydrodynamic equations in the presence of large-scale inhomogeneities for a high plasma beta solar wind is derived. The theory is derived under the assumption of low turbulent Mach number and is developed for the flows where the usual incompressible description is not satisfactory and a full compressible treatment is too complex for any analytical studies. When the effects of compressibility are incorporated only weakly, a new description, referred to as 'nearly incompressible hydrodynamics', is obtained. The nearly incompressible theory, was originally applied to homogeneous flows. However, large-scale gradients in density, pressure, temperature, etc., are typical in the solar wind and it was unclear how inhomogeneities would affect the usual incompressible and nearly incompressible descriptions. In the homogeneous case, the lowest order expansion of the fully compressible equations leads to the usual incompressible equations, followed at higher orders by the nearly incompressible equations, as introduced by Zank and Matthaeus. With this work we show that the inclusion of large-scale inhomogeneities (in this case time-independent and radially symmetric background solar wind) modifies the leading-order incompressible description of solar wind flow. We find, for example, that the divergence of velocity fluctuations is nonsolenoidal and that density fluctuations can be described to leading order as a passive scalar. Locally (for small lengthscales), this system of equations converges to the usual incompressible equations and we therefore use the term 'locally incompressible' to describe the equations. This term should be distinguished from the term 'nearly incompressible', which is reserved for higher-order corrections. Furthermore, we find that density fluctuations scale with Mach number linearly, in contrast to the original homogeneous nearly incompressible theory, in which density fluctuations scale with the square of Mach number. Inhomogeneous nearly

Performance Health Monitoring of Large-Scale Systems

Energy Technology Data Exchange (ETDEWEB)

Rajamony, Ram [IBM Research, Austin, TX (United States)

2014-11-20

This report details the progress made on the ASCR funded project Performance Health Monitoring for Large Scale Systems. A large-­scale application may not achieve its full performance potential due to degraded performance of even a single subsystem. Detecting performance faults, isolating them, and taking remedial action is critical for the scale of systems on the horizon. PHM aims to develop techniques and tools that can be used to identify and mitigate such performance problems. We accomplish this through two main aspects. The PHM framework encompasses diagnostics, system monitoring, fault isolation, and performance evaluation capabilities that indicates when a performance fault has been detected, either due to an anomaly present in the system itself or due to contention for shared resources between concurrently executing jobs. Software components called the PHM Control system then build upon the capabilities provided by the PHM framework to mitigate degradation caused by performance problems.

Somatic point mutations in mtDNA control region are influenced by genetic background and associated with healthy aging: a GEHA study

DEFF Research Database (Denmark)

Rose, Giuseppina; Romeo, Giuseppe; Dato, Serena

2010-01-01

and of mortality risk in the elderly. Our study provides new evidence on the relevance of mtDNA somatic mutations in aging and longevity and confirms that the occurrence of specific point mutations in the mtDNA control region may represent a strategy for the age-related remodelling of organismal functions....

The fate of deleted DNA produced during programmed genomic deletion events in Tetrahymena thermophila.

Science.gov (United States)

Saveliev, S V; Cox, M M

1994-01-01

Thousands of DNA deletion events occur during macronuclear development in the ciliate Tetrahymena thermophila. In two deleted genomic regions, designated M and R, the eliminated sequences form circles that can be detected by PCR. However, the circles are not normal products of the reaction pathway. The circular forms occur at very low levels in conjugating cells, but are stable. Sequencing analysis showed that many of the circles (as many as 50% of those examined) reflected a precise deletion in the M and R regions. The remaining circles were either smaller or larger and contained varying lengths of sequences derived from the chromosomal DNA surrounding the eliminated region. The chromosomal junctions left behind after deletion were more precise, although deletions in either the M or R regions can generate any of several alternative junctions (1). Some new chromosomal junctions were detected in the present study. The results suggest that the deleted segment is released as a linear DNA species that is degraded rapidly. The species is only rarely converted to the stable circles we detect. The deletion mechanism is different from those proposed for deletion events in hypotrichous ciliates (2-4), and does not reflect a conservative site-specific recombination process such as that promoted by the bacteriophage lambda integrase (5). Images PMID:7838724

Whole genome HBV deletion profiles and the accumulation of preS deletion mutant during antiviral treatment

Science.gov (United States)

2012-01-01

Background Hepatitis B virus (HBV), because of its error-prone viral polymerase, has a high mutation rate leading to widespread substitutions, deletions, and insertions in the HBV genome. Deletions may significantly change viral biological features complicating the progression of liver diseases. However, the clinical conditions correlating to the accumulation of deleted mutants remain unclear. In this study, we explored HBV deletion patterns and their association with disease status and antiviral treatment by performing whole genome sequencing on samples from 51 hepatitis B patients and by monitoring changes in deletion variants during treatment. Clone sequencing was used to analyze preS regions in another cohort of 52 patients. Results Among the core, preS, and basic core promoter (BCP) deletion hotspots, we identified preS to have the highest frequency and the most complex deletion pattern using whole genome sequencing. Further clone sequencing analysis on preS identified 70 deletions which were classified into 4 types, the most common being preS2. Also, in contrast to the core and BCP regions, most preS deletions were in-frame. Most deletions interrupted viral surface epitopes, and are possibly involved in evading immuno-surveillance. Among various clinical factors examined, logistic regression showed that antiviral medication affected the accumulation of deletion mutants (OR = 6.81, 95% CI = 1.296 ~ 35.817, P = 0.023). In chronic carriers of the virus, and individuals with chronic hepatitis, the deletion rate was significantly higher in the antiviral treatment group (Fisher exact test, P = 0.007). Particularly, preS2 deletions were associated with the usage of nucleos(t)ide analog therapy (Fisher exact test, P = 0.023). Dynamic increases in preS1 or preS2 deletions were also observed in quasispecies from samples taken from patients before and after three months of ADV therapy. In vitro experiments demonstrated that preS2 deletions alone

Migration and interaction in a contact zone: mtDNA variation among Bantu-speakers in Southern Africa.

Directory of Open Access Journals (Sweden)

Chiara Barbieri

Full Text Available Bantu speech communities expanded over large parts of sub-Saharan Africa within the last 4000-5000 years, reaching different parts of southern Africa 1200-2000 years ago. The Bantu languages subdivide in several major branches, with languages belonging to the Eastern and Western Bantu branches spreading over large parts of Central, Eastern, and Southern Africa. There is still debate whether this linguistic divide is correlated with a genetic distinction between Eastern and Western Bantu speakers. During their expansion, Bantu speakers would have come into contact with diverse local populations, such as the Khoisan hunter-gatherers and pastoralists of southern Africa, with whom they may have intermarried. In this study, we analyze complete mtDNA genome sequences from over 900 Bantu-speaking individuals from Angola, Zambia, Namibia, and Botswana to investigate the demographic processes at play during the last stages of the Bantu expansion. Our results show that most of these Bantu-speaking populations are genetically very homogenous, with no genetic division between speakers of Eastern and Western Bantu languages. Most of the mtDNA diversity in our dataset is due to different degrees of admixture with autochthonous populations. Only the pastoralist Himba and Herero stand out due to high frequencies of particular L3f and L3d lineages; the latter are also found in the neighboring Damara, who speak a Khoisan language and were foragers and small-stock herders. In contrast, the close cultural and linguistic relatives of the Herero and Himba, the Kuvale, are genetically similar to other Bantu-speakers. Nevertheless, as demonstrated by resampling tests, the genetic divergence of Herero, Himba, and Kuvale is compatible with a common shared ancestry with high levels of drift, while the similarity of the Herero, Himba, and Damara probably reflects admixture, as also suggested by linguistic analyses.

Learning from large scale neural simulations

DEFF Research Database (Denmark)

Serban, Maria

2017-01-01

Large-scale neural simulations have the marks of a distinct methodology which can be fruitfully deployed to advance scientific understanding of the human brain. Computer simulation studies can be used to produce surrogate observational data for better conceptual models and new how...

Phenomenology of two-dimensional stably stratified turbulence under large-scale forcing

KAUST Repository

Kumar, Abhishek; Verma, Mahendra K.; Sukhatme, Jai

2017-01-01

In this paper, we characterise the scaling of energy spectra, and the interscale transfer of energy and enstrophy, for strongly, moderately and weakly stably stratified two-dimensional (2D) turbulence, restricted in a vertical plane, under large-scale random forcing. In the strongly stratified case, a large-scale vertically sheared horizontal flow (VSHF) coexists with small scale turbulence. The VSHF consists of internal gravity waves and the turbulent flow has a kinetic energy (KE) spectrum that follows an approximate k−3 scaling with zero KE flux and a robust positive enstrophy flux. The spectrum of the turbulent potential energy (PE) also approximately follows a k−3 power-law and its flux is directed to small scales. For moderate stratification, there is no VSHF and the KE of the turbulent flow exhibits Bolgiano–Obukhov scaling that transitions from a shallow k−11/5 form at large scales, to a steeper approximate k−3 scaling at small scales. The entire range of scales shows a strong forward enstrophy flux, and interestingly, large (small) scales show an inverse (forward) KE flux. The PE flux in this regime is directed to small scales, and the PE spectrum is characterised by an approximate k−1.64 scaling. Finally, for weak stratification, KE is transferred upscale and its spectrum closely follows a k−2.5 scaling, while PE exhibits a forward transfer and its spectrum shows an approximate k−1.6 power-law. For all stratification strengths, the total energy always flows from large to small scales and almost all the spectral indicies are well explained by accounting for the scale-dependent nature of the corresponding flux.

Phenomenology of two-dimensional stably stratified turbulence under large-scale forcing

KAUST Repository

Kumar, Abhishek

2017-01-11

In this paper, we characterise the scaling of energy spectra, and the interscale transfer of energy and enstrophy, for strongly, moderately and weakly stably stratified two-dimensional (2D) turbulence, restricted in a vertical plane, under large-scale random forcing. In the strongly stratified case, a large-scale vertically sheared horizontal flow (VSHF) coexists with small scale turbulence. The VSHF consists of internal gravity waves and the turbulent flow has a kinetic energy (KE) spectrum that follows an approximate k−3 scaling with zero KE flux and a robust positive enstrophy flux. The spectrum of the turbulent potential energy (PE) also approximately follows a k−3 power-law and its flux is directed to small scales. For moderate stratification, there is no VSHF and the KE of the turbulent flow exhibits Bolgiano–Obukhov scaling that transitions from a shallow k−11/5 form at large scales, to a steeper approximate k−3 scaling at small scales. The entire range of scales shows a strong forward enstrophy flux, and interestingly, large (small) scales show an inverse (forward) KE flux. The PE flux in this regime is directed to small scales, and the PE spectrum is characterised by an approximate k−1.64 scaling. Finally, for weak stratification, KE is transferred upscale and its spectrum closely follows a k−2.5 scaling, while PE exhibits a forward transfer and its spectrum shows an approximate k−1.6 power-law. For all stratification strengths, the total energy always flows from large to small scales and almost all the spectral indicies are well explained by accounting for the scale-dependent nature of the corresponding flux.

Genetic diversity of mtDNA D-loop sequences in four native Chinese chicken breeds.

Science.gov (United States)

Guo, H W; Li, C; Wang, X N; Li, Z J; Sun, G R; Li, G X; Liu, X J; Kang, X T; Han, R L

2017-10-01

1. To explore the genetic diversity of Chinese indigenous chicken breeds, a 585 bp fragment of the mitochondrial DNA (mtDNA) region was sequenced in 102 birds from the Xichuan black-bone chicken, Yunyang black-bone chicken and Lushi chicken. In addition, 30 mtDNA D-loop sequences of Silkie fowls were downloaded from NCBI. The mtDNA D-loop sequence polymorphism and maternal origin of 4 chicken breeds were analysed in this study. 2. The results showed that a total of 33 mutation sites and 28 haplotypes were detected in the 4 chicken breeds. The haplotype diversity and nucleotide diversity of these 4 native breeds were 0.916 ± 0.014 and 0.012 ± 0.002, respectively. Three clusters were formed in 4 Chinese native chickens and 12 reference breeds. Both the Xichuan black-bone chicken and Yunyang black-bone chicken were grouped into one cluster. Four haplogroups (A, B, C and E) emerged in the median-joining network in these breeds. 3. It was concluded that these 4 Chinese chicken breeds had high genetic diversity. The phylogenetic tree and median network profiles showed that Chinese native chickens and its neighbouring countries had at least two maternal origins, one from Yunnan, China and another from Southeast Asia or its surrounding area.

Exploring the large-scale structure of Taylor–Couette turbulence through Large-Eddy Simulations

Science.gov (United States)

Ostilla-Mónico, Rodolfo; Zhu, Xiaojue; Verzicco, Roberto

2018-04-01

Large eddy simulations (LES) of Taylor-Couette (TC) flow, the flow between two co-axial and independently rotating cylinders are performed in an attempt to explore the large-scale axially-pinned structures seen in experiments and simulations. Both static and dynamic LES models are used. The Reynolds number is kept fixed at Re = 3.4 · 104, and the radius ratio η = ri /ro is set to η = 0.909, limiting the effects of curvature and resulting in frictional Reynolds numbers of around Re τ ≈ 500. Four rotation ratios from Rot = ‑0.0909 to Rot = 0.3 are simulated. First, the LES of TC is benchmarked for different rotation ratios. Both the Smagorinsky model with a constant of cs = 0.1 and the dynamic model are found to produce reasonable results for no mean rotation and cyclonic rotation, but deviations increase for increasing rotation. This is attributed to the increasing anisotropic character of the fluctuations. Second, “over-damped” LES, i.e. LES with a large Smagorinsky constant is performed and is shown to reproduce some features of the large-scale structures, even when the near-wall region is not adequately modeled. This shows the potential for using over-damped LES for fast explorations of the parameter space where large-scale structures are found.

Large-scale preparation of hollow graphitic carbon nanospheres

International Nuclear Information System (INIS)

Feng, Jun; Li, Fu; Bai, Yu-Jun; Han, Fu-Dong; Qi, Yong-Xin; Lun, Ning; Lu, Xi-Feng

2013-01-01

Hollow graphitic carbon nanospheres (HGCNSs) were synthesized on large scale by a simple reaction between glucose and Mg at 550 °C in an autoclave. Characterization by X-ray diffraction, Raman spectroscopy and transmission electron microscopy demonstrates the formation of HGCNSs with an average diameter of 10 nm or so and a wall thickness of a few graphenes. The HGCNSs exhibit a reversible capacity of 391 mAh g −1 after 60 cycles when used as anode materials for Li-ion batteries. -- Graphical abstract: Hollow graphitic carbon nanospheres could be prepared on large scale by the simple reaction between glucose and Mg at 550 °C, which exhibit superior electrochemical performance to graphite. Highlights: ► Hollow graphitic carbon nanospheres (HGCNSs) were prepared on large scale at 550 °C ► The preparation is simple, effective and eco-friendly. ► The in situ yielded MgO nanocrystals promote the graphitization. ► The HGCNSs exhibit superior electrochemical performance to graphite.

Accelerating large-scale phase-field simulations with GPU

Directory of Open Access Journals (Sweden)

Xiaoming Shi

2017-10-01

Full Text Available A new package for accelerating large-scale phase-field simulations was developed by using GPU based on the semi-implicit Fourier method. The package can solve a variety of equilibrium equations with different inhomogeneity including long-range elastic, magnetostatic, and electrostatic interactions. Through using specific algorithm in Compute Unified Device Architecture (CUDA, Fourier spectral iterative perturbation method was integrated in GPU package. The Allen-Cahn equation, Cahn-Hilliard equation, and phase-field model with long-range interaction were solved based on the algorithm running on GPU respectively to test the performance of the package. From the comparison of the calculation results between the solver executed in single CPU and the one on GPU, it was found that the speed on GPU is enormously elevated to 50 times faster. The present study therefore contributes to the acceleration of large-scale phase-field simulations and provides guidance for experiments to design large-scale functional devices.

First Mile Challenges for Large-Scale IoT

KAUST Repository

Bader, Ahmed

2017-03-16

The Internet of Things is large-scale by nature. This is not only manifested by the large number of connected devices, but also by the sheer scale of spatial traffic intensity that must be accommodated, primarily in the uplink direction. To that end, cellular networks are indeed a strong first mile candidate to accommodate the data tsunami to be generated by the IoT. However, IoT devices are required in the cellular paradigm to undergo random access procedures as a precursor to resource allocation. Such procedures impose a major bottleneck that hinders cellular networks\\' ability to support large-scale IoT. In this article, we shed light on the random access dilemma and present a case study based on experimental data as well as system-level simulations. Accordingly, a case is built for the latent need to revisit random access procedures. A call for action is motivated by listing a few potential remedies and recommendations.

Human aging and somatic point mutations in mtDNA: a comparative study of generational differences (grandparents and grandchildren

Directory of Open Access Journals (Sweden)

Anderson Nonato do Rosário Marinho

2011-01-01

Full Text Available The accumulation of somatic mutations in mtDNA is correlated with aging. In this work, we sought to identify somatic mutations in the HVS-1 region (D-loop of mtDNA that might be associated with aging. For this, we compared 31 grandmothers (mean age: 63 ± 2.3 years and their 62 grandchildren (mean age: 15 ± 4.1 years, the offspring of their daughters. Direct DNA sequencing showed that mutations absent in the grandchildren were detected in a presumably homoplasmic state in three grandmothers and in a heteroplasmic state in an additional 13 grandmothers; no mutations were detected in the remaining 15 grandmothers. However, cloning followed by DNA sequencing in 12 grandmothers confirmed homoplasia in only one of the three mutations previously considered to be homoplasmic and did not confirm heteroplasmy in three out of nine grandmothers found to be heteroplasmic by direct sequencing. Thus, of 12 grandmothers in whom mtDNA was analyzed by cloning, eight were heteroplasmic for mutations not detected in their grandchildren. In this study, the use of genetically related subjects allowed us to demonstrate the occurrence of age-related (> 60 years old mutations (homoplasia and heteroplasmy. It is possible that both of these situations (homoplasia and heteroplasmy were a long-term consequence of mitochondrial oxidative phosphorylation that can lead to the accumulation of mtDNA mutations throughout life.

Thermal power generation projects ``Large Scale Solar Heating``; EU-Thermie-Projekte ``Large Scale Solar Heating``

Energy Technology Data Exchange (ETDEWEB)

Kuebler, R.; Fisch, M.N. [Steinbeis-Transferzentrum Energie-, Gebaeude- und Solartechnik, Stuttgart (Germany)

1998-12-31

The aim of this project is the preparation of the ``Large-Scale Solar Heating`` programme for an Europe-wide development of subject technology. The following demonstration programme was judged well by the experts but was not immediately (1996) accepted for financial subsidies. In November 1997 the EU-commission provided 1,5 million ECU which allowed the realisation of an updated project proposal. By mid 1997 a small project was approved, that had been requested under the lead of Chalmes Industriteteknik (CIT) in Sweden and is mainly carried out for the transfer of technology. (orig.) [Deutsch] Ziel dieses Vorhabens ist die Vorbereitung eines Schwerpunktprogramms `Large Scale Solar Heating`, mit dem die Technologie europaweit weiterentwickelt werden sollte. Das daraus entwickelte Demonstrationsprogramm wurde von den Gutachtern positiv bewertet, konnte jedoch nicht auf Anhieb (1996) in die Foerderung aufgenommen werden. Im November 1997 wurden von der EU-Kommission dann kurzfristig noch 1,5 Mio ECU an Foerderung bewilligt, mit denen ein aktualisierter Projektvorschlag realisiert werden kann. Bereits Mitte 1997 wurde ein kleineres Vorhaben bewilligt, das unter Federfuehrung von Chalmers Industriteknik (CIT) in Schweden beantragt worden war und das vor allem dem Technologietransfer dient. (orig.)

Large-scale retrieval for medical image analytics: A comprehensive review.

Science.gov (United States)

Li, Zhongyu; Zhang, Xiaofan; Müller, Henning; Zhang, Shaoting

2018-01-01

Over the past decades, medical image analytics was greatly facilitated by the explosion of digital imaging techniques, where huge amounts of medical images were produced with ever-increasing quality and diversity. However, conventional methods for analyzing medical images have achieved limited success, as they are not capable to tackle the huge amount of image data. In this paper, we review state-of-the-art approaches for large-scale medical image analysis, which are mainly based on recent advances in computer vision, machine learning and information retrieval. Specifically, we first present the general pipeline of large-scale retrieval, summarize the challenges/opportunities of medical image analytics on a large-scale. Then, we provide a comprehensive review of algorithms and techniques relevant to major processes in the pipeline, including feature representation, feature indexing, searching, etc. On the basis of existing work, we introduce the evaluation protocols and multiple applications of large-scale medical image retrieval, with a variety of exploratory and diagnostic scenarios. Finally, we discuss future directions of large-scale retrieval, which can further improve the performance of medical image analysis. Copyright © 2017 Elsevier B.V. All rights reserved.

Schizophrenia and chromosomal deletions

Energy Technology Data Exchange (ETDEWEB)

Lindsay, E.A.; Baldini, A. [Baylor College of Medicine, Houston, TX (United States); Morris, M. A. [Univ. of Geneva School of Medicine, NY (United States)] [and others

1995-06-01

Recent genetic linkage analysis studies have suggested the presence of a schizophrenia locus on the chromosomal region 22q11-q13. Schizophrenia has also been frequently observed in patients affected with velo-cardio-facial syndrome (VCFS), a disorder frequently associated with deletions within 22q11.1. It has been hypothesized that psychosis in VCFS may be due to deletion of the catechol-o-methyl transferase gene. Prompted by these observations, we screened for 22q11 deletions in a population of 100 schizophrenics selected from the Maryland Epidemiological Sample. Our results show that there are schizophrenic patients carrying a deletion of 22q11.1 and a mild VCFS phenotype that might remain unrecognized. These findings should encourage a search for a schizophrenia-susceptibility gene within the deleted region and alert those in clinical practice to the possible presence of a mild VCFS phenotype associated with schizophrenia. 9 refs.

Photorealistic large-scale urban city model reconstruction.

Science.gov (United States)

Poullis, Charalambos; You, Suya

2009-01-01

The rapid and efficient creation of virtual environments has become a crucial part of virtual reality applications. In particular, civil and defense applications often require and employ detailed models of operations areas for training, simulations of different scenarios, planning for natural or man-made events, monitoring, surveillance, games, and films. A realistic representation of the large-scale environments is therefore imperative for the success of such applications since it increases the immersive experience of its users and helps reduce the difference between physical and virtual reality. However, the task of creating such large-scale virtual environments still remains a time-consuming and manual work. In this work, we propose a novel method for the rapid reconstruction of photorealistic large-scale virtual environments. First, a novel, extendible, parameterized geometric primitive is presented for the automatic building identification and reconstruction of building structures. In addition, buildings with complex roofs containing complex linear and nonlinear surfaces are reconstructed interactively using a linear polygonal and a nonlinear primitive, respectively. Second, we present a rendering pipeline for the composition of photorealistic textures, which unlike existing techniques, can recover missing or occluded texture information by integrating multiple information captured from different optical sensors (ground, aerial, and satellite).

Prototype Vector Machine for Large Scale Semi-Supervised Learning

Energy Technology Data Exchange (ETDEWEB)

Zhang, Kai; Kwok, James T.; Parvin, Bahram

2009-04-29

Practicaldataminingrarelyfalls exactlyinto the supervisedlearning scenario. Rather, the growing amount of unlabeled data poses a big challenge to large-scale semi-supervised learning (SSL). We note that the computationalintensivenessofgraph-based SSLarises largely from the manifold or graph regularization, which in turn lead to large models that are dificult to handle. To alleviate this, we proposed the prototype vector machine (PVM), a highlyscalable,graph-based algorithm for large-scale SSL. Our key innovation is the use of"prototypes vectors" for effcient approximation on both the graph-based regularizer and model representation. The choice of prototypes are grounded upon two important criteria: they not only perform effective low-rank approximation of the kernel matrix, but also span a model suffering the minimum information loss compared with the complete model. We demonstrate encouraging performance and appealing scaling properties of the PVM on a number of machine learning benchmark data sets.

Deletions induced by gamma rays in the genome of Escherichia coli

International Nuclear Information System (INIS)

Raha, Manidipa; Hutchinson, Franklin

1991-01-01

An Escherichia coli lysogen was constructed with a lambda phage bearing a lacZ gene surrounded by about 100 x 10 3 base-pairs of dispensable DNA. The lacZ mutants induced by gamma rays in this lysogen were more than 10% large deletions, ranging in size from 0.6 x 10 -3 to 70 x 10 3 base-pairs. These deletions were centered, not on lacZ, but on a ColE1 origin of DNA replication located 1.2 x 10 3 bases downstream from lacZ, suggesting that this origin of replication was involved in the process by which deletions were formed. In agreement with this hypothesis, a lysogen of the same phage without the ColE1 origin showed a very much lower percentage of radiation-induced deletions, as did a second lysogen of a lambda phage without any known plasmid origin of replication. Indirect evidence is presented for radiation-induced deletions centered on the lambda origin of DNA replication in a lysogen. (author)

A Tool for Multiple Targeted Genome Deletions that Is Precise, Scar-Free, and Suitable for Automation.

Directory of Open Access Journals (Sweden)

Wayne Aubrey

Full Text Available Many advances in synthetic biology require the removal of a large number of genomic elements from a genome. Most existing deletion methods leave behind markers, and as there are a limited number of markers, such methods can only be applied a fixed number of times. Deletion methods that recycle markers generally are either imprecise (remove untargeted sequences, or leave scar sequences which can cause genome instability and rearrangements. No existing marker recycling method is automation-friendly. We have developed a novel openly available deletion tool that consists of: 1 a method for deleting genomic elements that can be repeatedly used without limit, is precise, scar-free, and suitable for automation; and 2 software to design the method's primers. Our tool is sequence agnostic and could be used to delete large numbers of coding sequences, promoter regions, transcription factor binding sites, terminators, etc in a single genome. We have validated our tool on the deletion of non-essential open reading frames (ORFs from S. cerevisiae. The tool is applicable to arbitrary genomes, and we provide primer sequences for the deletion of: 90% of the ORFs from the S. cerevisiae genome, 88% of the ORFs from S. pombe genome, and 85% of the ORFs from the L. lactis genome.

Retrospective assessment of the most common mitochondrial DNA mutations in a large Hungarian cohort of suspect mitochondrial cases.

Science.gov (United States)

Remenyi, Viktoria; Inczedy-Farkas, Gabriella; Komlosi, Katalin; Horvath, Rita; Maasz, Anita; Janicsek, Ingrid; Pentelenyi, Klara; Gal, Aniko; Karcagi, Veronika; Melegh, Bela; Molnar, Maria Judit

2015-08-01

Prevalence estimations for mitochondrial disorders still vary widely and only few epidemiologic studies have been carried out so far. With the present work we aim to give a comprehensive overview about frequencies of the most common mitochondrial mutations in Hungarian patients. A total of 1328 patients were tested between 1999 and 2012. Among them, 882 were screened for the m.3243A > G, m.8344A > G, m.8993T > C/G mutations and deletions, 446 for LHON primary mutations. The mutation frequency in our cohort was 2.61% for the m.3243A > G, 1.47% for the m.8344A > G, 17.94% for Leber's Hereditary Optic Neuropathy (m.3460G > A, m.11778G > A, m.14484T > C) and 0.45% for the m.8993T > C/G substitutions. Single mtDNA deletions were detected in 14.97%, while multiple deletions in 6.01% of the cases. The mutation frequency in Hungarian patients suggestive of mitochondrial disease was similar to other Caucasian populations. Further retrospective studies of different populations are needed in order to accurately assess the importance of mitochondrial diseases and manage these patients.

Quantitation of heteroplasmy of mtDNA sequence variants identified in a population of AD patients and controls by array-based resequencing.

Science.gov (United States)

Coon, Keith D; Valla, Jon; Szelinger, Szabolics; Schneider, Lonnie E; Niedzielko, Tracy L; Brown, Kevin M; Pearson, John V; Halperin, Rebecca; Dunckley, Travis; Papassotiropoulos, Andreas; Caselli, Richard J; Reiman, Eric M; Stephan, Dietrich A

2006-08-01

The role of mitochondrial dysfunction in the pathogenesis of Alzheimer's disease (AD) has been well documented. Though evidence for the role of mitochondria in AD seems incontrovertible, the impact of mitochondrial DNA (mtDNA) mutations in AD etiology remains controversial. Though mutations in mitochondrially encoded genes have repeatedly been implicated in the pathogenesis of AD, many of these studies have been plagued by lack of replication as well as potential contamination of nuclear-encoded mitochondrial pseudogenes. To assess the role of mtDNA mutations in the pathogenesis of AD, while avoiding the pitfalls of nuclear-encoded mitochondrial pseudogenes encountered in previous investigations and showcasing the benefits of a novel resequencing technology, we sequenced the entire coding region (15,452 bp) of mtDNA from 19 extremely well-characterized AD patients and 18 age-matched, unaffected controls utilizing a new, reliable, high-throughput array-based resequencing technique, the Human MitoChip. High-throughput, array-based DNA resequencing of the entire mtDNA coding region from platelets of 37 subjects revealed the presence of 208 loci displaying a total of 917 sequence variants. There were no statistically significant differences in overall mutational burden between cases and controls, however, 265 independent sites of statistically significant change between cases and controls were identified. Changed sites were found in genes associated with complexes I (30.2%), III (3.0%), IV (33.2%), and V (9.1%) as well as tRNA (10.6%) and rRNA (14.0%). Despite their statistical significance, the subtle nature of the observed changes makes it difficult to determine whether they represent true functional variants involved in AD etiology or merely naturally occurring dissimilarity. Regardless, this study demonstrates the tremendous value of this novel mtDNA resequencing platform, which avoids the pitfalls of erroneously amplifying nuclear-encoded mtDNA pseudogenes, and

Deletion mutations of bacteriophage

International Nuclear Information System (INIS)

Ryo, Yeikou

1975-01-01

Resolution of mutation mechanism with structural changes of DNA was discussed through the studies using bacteriophage lambda. One of deletion mutations inductions of phage lambda is the irradiation of ultraviolet ray. It is not clear if the inductions are caused by errors in reparation of ultraviolet-induced damage or by the activation of int gene. Because the effective site of int gene lies within the regions unnecessary for existing, it is considered that int gene is connected to deletion mutations induction. A certain system using prophage complementarity enables to detect deletion mutations at essential hereditary sites and to solve the relations of deletion mutations with other recombination system, DNA reproduction and repairment system. Duplication and multiplication of hereditary elements were discussed. If lambda deletion mutations of the system, which can control recombination, reproduction and repairment of added DNA, are constructed, mutations mechanism with great changes of DNA structure can be solved by phage lambda. (Ichikawa, K.)

Accelerating Relevance Vector Machine for Large-Scale Data on Spark

Directory of Open Access Journals (Sweden)

Liu Fang

2017-01-01

Full Text Available Relevance vector machine (RVM is a machine learning algorithm based on a sparse Bayesian framework, which performs well when running classification and regression tasks on small-scale datasets. However, RVM also has certain drawbacks which restricts its practical applications such as (1 slow training process, (2 poor performance on training large-scale datasets. In order to solve these problem, we propose Discrete AdaBoost RVM (DAB-RVM which incorporate ensemble learning in RVM at first. This method performs well with large-scale low-dimensional datasets. However, as the number of features increases, the training time of DAB-RVM increases as well. To avoid this phenomenon, we utilize the sufficient training samples of large-scale datasets and propose all features boosting RVM (AFB-RVM, which modifies the way of obtaining weak classifiers. In our experiments we study the differences between various boosting techniques with RVM, demonstrating the performance of the proposed approaches on Spark. As a result of this paper, two proposed approaches on Spark for different types of large-scale datasets are available.

Exercise intervention in a family with exercise intolerance and a novel mutation in the mitochondrial POLG gene

OpenAIRE

Morán, María; Blázquez, A.; Fiuza Luces, María del Carmen; Díez Bermejo, Jorge; Delmiro, Aitor; Docampo, J.; Serrano Lorenzo, Pablo; González Quintana, Adrián; Arenas, Joaquín; Laín Hernández, A.; Lucía Mulas, Alejandro; Domínguez González, C.; Martín, M.

2016-01-01

Mutations in the POLG gene, encoding the mitochondrial DNA (mtDNA) polymerase subunit gamma-1, have been identified in severe mtDNA depletion syndromes and mtDNA deletion disorders which include ataxia neuropathy spectrum disorders and AR and AD forms of progressive external ophthalmoplegia (PEO) and PEO-plus disorders. We report on a family with exercise intolerance. The proband was a 50-year-old man with severe muscle pain and premature fatigue after exercise of mild to moderate intensity. ...

Bayesian hierarchical model for large-scale covariance matrix estimation.

Science.gov (United States)

Zhu, Dongxiao; Hero, Alfred O

2007-12-01

Many bioinformatics problems implicitly depend on estimating large-scale covariance matrix. The traditional approaches tend to give rise to high variance and low accuracy due to "overfitting." We cast the large-scale covariance matrix estimation problem into the Bayesian hierarchical model framework, and introduce dependency between covariance parameters. We demonstrate the advantages of our approaches over the traditional approaches using simulations and OMICS data analysis.

Analysis of spontaneous deletions and gene amplification in the lac region of Escherichia coli

International Nuclear Information System (INIS)

Albertini, A.M.; Hofer, M.; Calos, M.P.; Tlsty, T.D.; Miller, J.H.

1983-01-01

Spontaneous rearrangements, such as large deletions and duplications, have important implications for the structure of the genome. It is therefore of great interest to analyze these events at the molecular level. We have constructed derivatives of a lacI-Z fusion strain, which allow us to study deletions in a more systematic manner than was previously possible. These derivatives have been used to investigate how frequently larger deletions (> 700 bp) occur between short homologies on both recA and recA - strains and to determine the effect of the lengths of the short homologies and of the distance between homologies on the frequency of deletion formation. 38 references, 11 figures

Creating Large Scale Database Servers

International Nuclear Information System (INIS)

Becla, Jacek

2001-01-01

The BaBar experiment at the Stanford Linear Accelerator Center (SLAC) is designed to perform a high precision investigation of the decays of the B-meson produced from electron-positron interactions. The experiment, started in May 1999, will generate approximately 300TB/year of data for 10 years. All of the data will reside in Objectivity databases accessible via the Advanced Multi-threaded Server (AMS). To date, over 70TB of data have been placed in Objectivity/DB, making it one of the largest databases in the world. Providing access to such a large quantity of data through a database server is a daunting task. A full-scale testbed environment had to be developed to tune various software parameters and a fundamental change had to occur in the AMS architecture to allow it to scale past several hundred terabytes of data. Additionally, several protocol extensions had to be implemented to provide practical access to large quantities of data. This paper will describe the design of the database and the changes that we needed to make in the AMS for scalability reasons and how the lessons we learned would be applicable to virtually any kind of database server seeking to operate in the Petabyte region

Creating Large Scale Database Servers

Energy Technology Data Exchange (ETDEWEB)

Becla, Jacek

2001-12-14

The BaBar experiment at the Stanford Linear Accelerator Center (SLAC) is designed to perform a high precision investigation of the decays of the B-meson produced from electron-positron interactions. The experiment, started in May 1999, will generate approximately 300TB/year of data for 10 years. All of the data will reside in Objectivity databases accessible via the Advanced Multi-threaded Server (AMS). To date, over 70TB of data have been placed in Objectivity/DB, making it one of the largest databases in the world. Providing access to such a large quantity of data through a database server is a daunting task. A full-scale testbed environment had to be developed to tune various software parameters and a fundamental change had to occur in the AMS architecture to allow it to scale past several hundred terabytes of data. Additionally, several protocol extensions had to be implemented to provide practical access to large quantities of data. This paper will describe the design of the database and the changes that we needed to make in the AMS for scalability reasons and how the lessons we learned would be applicable to virtually any kind of database server seeking to operate in the Petabyte region.

Large-scale pool fires

Directory of Open Access Journals (Sweden)

Steinhaus Thomas

2007-01-01

Full Text Available A review of research into the burning behavior of large pool fires and fuel spill fires is presented. The features which distinguish such fires from smaller pool fires are mainly associated with the fire dynamics at low source Froude numbers and the radiative interaction with the fire source. In hydrocarbon fires, higher soot levels at increased diameters result in radiation blockage effects around the perimeter of large fire plumes; this yields lower emissive powers and a drastic reduction in the radiative loss fraction; whilst there are simplifying factors with these phenomena, arising from the fact that soot yield can saturate, there are other complications deriving from the intermittency of the behavior, with luminous regions of efficient combustion appearing randomly in the outer surface of the fire according the turbulent fluctuations in the fire plume. Knowledge of the fluid flow instabilities, which lead to the formation of large eddies, is also key to understanding the behavior of large-scale fires. Here modeling tools can be effectively exploited in order to investigate the fluid flow phenomena, including RANS- and LES-based computational fluid dynamics codes. The latter are well-suited to representation of the turbulent motions, but a number of challenges remain with their practical application. Massively-parallel computational resources are likely to be necessary in order to be able to adequately address the complex coupled phenomena to the level of detail that is necessary.

Detailed mtDNA genotypes permit a reassessment of the settlement and population structure of the Andaman Islands.

Science.gov (United States)

Barik, S S; Sahani, R; Prasad, B V R; Endicott, P; Metspalu, M; Sarkar, B N; Bhattacharya, S; Annapoorna, P C H; Sreenath, J; Sun, D; Sanchez, J J; Ho, S Y W; Chandrasekar, A; Rao, V R

2008-05-01

The population genetics of the Indian subcontinent is central to understanding early human prehistory due to its strategic location on the proposed corridor of human movement from Africa to Australia during the late Pleistocene. Previous genetic research using mtDNA has emphasized the relative isolation of the late Pleistocene colonizers, and the physically isolated Andaman Island populations of Island South-East Asia remain the source of claims supporting an early split between the populations that formed the patchy settlement pattern along the coast of the Indian Ocean. Using whole-genome sequencing, combined with multiplexed SNP typing, this study investigates the deep structure of mtDNA haplogroups M31 and M32 in India and the Andaman Islands. The identification of a so far unnoticed rare polymorphism shared between these two lineages suggests that they are actually sister groups within a single haplogroup, M31'32. The enhanced resolution of M31 allows for the inference of a more recent colonization of the Andaman Islands than previously suggested, but cannot reject the very early peopling scenario. We further demonstrate a widespread overlap of mtDNA and cultural markers between the two major language groups of the Andaman archipelago. Given the "completeness" of the genealogy based on whole genome sequences, and the multiple scenarios for the peopling of the Andaman Islands sustained by this inferred genealogy, our study hints that further mtDNA based phylogeographic studies are unlikely to unequivocally support any one of these possibilities. (c) 2008 Wiley-Liss, Inc.

Phylogeographical analysis of mtDNA data indicates postglacial expansion from multiple glacial refugia in woodland caribou (Rangifer tarandus caribou.

Directory of Open Access Journals (Sweden)

Cornelya F C Klütsch

Full Text Available Glacial refugia considerably shaped the phylogeographical structure of species and may influence intra-specific morphological, genetic, and adaptive differentiation. However, the impact of the Quaternary ice ages on the phylogeographical structure of North American temperate mammalian species is not well-studied. Here, we surveyed ~1600 individuals of the widely distributed woodland caribou (Rangifer tarandus caribou using mtDNA control region sequences to investigate if glacial refugia contributed to the phylogeographical structure in this subspecies. Phylogenetic tree reconstruction, a median-joining network, and mismatch distributions supported postglacial expansions of woodland caribou from three glacial refugia dating back to 13544-22005 years. These three lineages consisted almost exclusively of woodland caribou mtDNA haplotypes, indicating that phylogeographical structure was mainly shaped by postglacial expansions. The putative centres of these lineages are geographically separated; indicating disconnected glacial refugia in the Rocky Mountains, east of the Mississippi, and the Appalachian Mountains. This is in congruence with the fossil record that caribou were distributed in these areas during the Pleistocene. Our results suggest that the last glacial maximum substantially shaped the phylogeographical structure of this large mammalian North American species that will be affected by climatic change. Therefore, the presented results will be essential for future conservation planning in woodland caribou.

Decentralised stabilising controllers for a class of large-scale linear ...

Indian Academy of Sciences (India)

subsystems resulting from a new aggregation-decomposition technique. The method has been illustrated through a numerical example of a large-scale linear system consisting of three subsystems each of the fourth order. Keywords. Decentralised stabilisation; large-scale linear systems; optimal feedback control; algebraic ...

Large Scale Survey Data in Career Development Research

Science.gov (United States)

Diemer, Matthew A.

2008-01-01

Large scale survey datasets have been underutilized but offer numerous advantages for career development scholars, as they contain numerous career development constructs with large and diverse samples that are followed longitudinally. Constructs such as work salience, vocational expectations, educational expectations, work satisfaction, and…

An efficient system for deletion of large DNA fragments in Escherichia coli via introduction of both Cas9 and the non-homologous end joining system from Mycobacterium smegmatis.

Science.gov (United States)

Zheng, Xuan; Li, Shi-Yuan; Zhao, Guo-Ping; Wang, Jin

2017-04-15

Accompanied with the internal non-homologous end joining (NHEJ) system, Cas9 can be used to easily inactivate a gene or delete a fragment through introduction of DNA double-stranded breaks (DSBs) in eukaryotic cells. While in most prokaryotes (e.g. Escherichia coli), due to the lack of NHEJ, homologous recombination (HR) is required for repair of DSBs, which is less convenient. Here, a markerless system was developed for rapid gene inactivation or fragment deletion in E. coli via introduction of both Cas9 and a bacterial NHEJ system. Three bacterial NHEJ systems, i.e. Mycobacterium smegmatis (Msm), Mycobacterium tuberculosis (Mtb) and Bacillus subtilis (Bs), were tested in E. coli, and the MsmNHEJ system showed the best efficiency. With the employment of Cas9 and MsmNHEJ, we efficiently mutated lacZ gene, deleted glnALG operon and two large DNA fragments (67 kb and 123 kb) in E. coli, respectively. Moreover, the system was further designed to allow for continuous inactivation of genes or deletion of DNA fragments in E. coli. We envision this system can be extended to other bacteria, especially those with low HR efficiency. Copyright © 2017 Elsevier Inc. All rights reserved.

Forensic and phylogeographic characterisation of mtDNA lineages from Somalia.

Science.gov (United States)

Mikkelsen, Martin; Fendt, Liane; Röck, Alexander W; Zimmermann, Bettina; Rockenbauer, Eszter; Hansen, Anders J; Parson, Walther; Morling, Niels

2012-07-01

The African mitochondrial (mt) phylogeny is coarsely resolved but the majority of population data generated so far is limited to the analysis of the first hypervariable segment (HVS-1) of the control region (CR). Therefore, this study aimed on the investigation of the entire CR of 190 unrelated Somali individuals to enrich the severely underrepresented African mtDNA pool. The majority (60.5 %) of the haplotypes were of sub-Saharan origin with L0a1d, L2a1h and L3f being the most frequently observed haplogroups. This is in sharp contrast to previous data reported from the Y-chromosome, where only about 5 % of the observed haplogroups were of sub-Saharan provenance. We compared the genetic distances based on population pairwise F (st) values between 11 published East, Central and North African as well as western Asian populations and the Somali sequences and displayed them in a multi-dimensional scaling plot. Genetic proximity evidenced by clustering roughly reflected the relative geographic location of the populations. The sequences will be included in the EMPOP database ( www.empop.org ) under accession number EMP00397 upon publication (Parson and Dür Forensic Sci Int Genet 1:88-92, 2007).

Similitude and scaling of large structural elements: Case study

Directory of Open Access Journals (Sweden)

M. Shehadeh

2015-06-01

Full Text Available Scaled down models are widely used for experimental investigations of large structures due to the limitation in the capacities of testing facilities along with the expenses of the experimentation. The modeling accuracy depends upon the model material properties, fabrication accuracy and loading techniques. In the present work the Buckingham π theorem is used to develop the relations (i.e. geometry, loading and properties between the model and a large structural element as that is present in the huge existing petroleum oil drilling rigs. The model is to be designed, loaded and treated according to a set of similitude requirements that relate the model to the large structural element. Three independent scale factors which represent three fundamental dimensions, namely mass, length and time need to be selected for designing the scaled down model. Numerical prediction of the stress distribution within the model and its elastic deformation under steady loading is to be made. The results are compared with those obtained from the full scale structure numerical computations. The effect of scaled down model size and material on the accuracy of the modeling technique is thoroughly examined.

A role for recombination junctions in the segregation of mitochondrial DNA in yeast.

Science.gov (United States)

Lockshon, D; Zweifel, S G; Freeman-Cook, L L; Lorimer, H E; Brewer, B J; Fangman, W L

1995-06-16

In S. cerevisiae, mitochondrial DNA (mtDNA) molecules, in spite of their high copy number, segregate as if there were a small number of heritable units. The rapid segregation of mitochondrial genomes can be analyzed using mtDNA deletion variants. These small, amplified genomes segregate preferentially from mixed zygotes relative to wild-type mtDNA. This segregation advantage is abolished by mutations in a gene, MGT1, that encodes a recombination junction-resolving enzyme. We show here that resolvase deficiency causes a larger proportion of molecules to be linked together by recombination junctions, resulting in the aggregation of mtDNA into a small number of cytological structures. This change in mtDNA structure can account for the increased mitotic loss of mtDNA and the altered pattern of mtDNA segregation from zygotes. We propose that the level of unresolved recombination junctions influences the number of heritable units of mtDNA.

Large-scale preparation of hollow graphitic carbon nanospheres

Energy Technology Data Exchange (ETDEWEB)

Feng, Jun; Li, Fu [Key Laboratory for Liquid-Solid Structural Evolution and Processing of Materials, Ministry of Education, Shandong University, Jinan 250061 (China); Bai, Yu-Jun, E-mail: byj97@126.com [Key Laboratory for Liquid-Solid Structural Evolution and Processing of Materials, Ministry of Education, Shandong University, Jinan 250061 (China); State Key laboratory of Crystal Materials, Shandong University, Jinan 250100 (China); Han, Fu-Dong; Qi, Yong-Xin; Lun, Ning [Key Laboratory for Liquid-Solid Structural Evolution and Processing of Materials, Ministry of Education, Shandong University, Jinan 250061 (China); Lu, Xi-Feng [Lunan Institute of Coal Chemical Engineering, Jining 272000 (China)

2013-01-15

Hollow graphitic carbon nanospheres (HGCNSs) were synthesized on large scale by a simple reaction between glucose and Mg at 550 Degree-Sign C in an autoclave. Characterization by X-ray diffraction, Raman spectroscopy and transmission electron microscopy demonstrates the formation of HGCNSs with an average diameter of 10 nm or so and a wall thickness of a few graphenes. The HGCNSs exhibit a reversible capacity of 391 mAh g{sup -1} after 60 cycles when used as anode materials for Li-ion batteries. -- Graphical abstract: Hollow graphitic carbon nanospheres could be prepared on large scale by the simple reaction between glucose and Mg at 550 Degree-Sign C, which exhibit superior electrochemical performance to graphite. Highlights: Black-Right-Pointing-Pointer Hollow graphitic carbon nanospheres (HGCNSs) were prepared on large scale at 550 Degree-Sign C Black-Right-Pointing-Pointer The preparation is simple, effective and eco-friendly. Black-Right-Pointing-Pointer The in situ yielded MgO nanocrystals promote the graphitization. Black-Right-Pointing-Pointer The HGCNSs exhibit superior electrochemical performance to graphite.

Large-scale impact cratering on the terrestrial planets

International Nuclear Information System (INIS)

Grieve, R.A.F.

1982-01-01

The crater densities on the earth and moon form the basis for a standard flux-time curve that can be used in dating unsampled planetary surfaces and constraining the temporal history of endogenic geologic processes. Abundant evidence is seen not only that impact cratering was an important surface process in planetary history but also that large imapact events produced effects that were crucial in scale. By way of example, it is noted that the formation of multiring basins on the early moon was as important in defining the planetary tectonic framework as plate tectonics is on the earth. Evidence from several planets suggests that the effects of very-large-scale impacts go beyond the simple formation of an impact structure and serve to localize increased endogenic activity over an extended period of geologic time. Even though no longer occurring with the frequency and magnitude of early solar system history, it is noted that large scale impact events continue to affect the local geology of the planets. 92 references

Strikingly different penetrance of LHON in two Chinese families with primary mutation G11778A is independent of mtDNA haplogroup background and secondary mutation G13708A

International Nuclear Information System (INIS)

Wang Huawei; Jia Xiaoyun; Ji Yanli; Kong Qingpeng; Zhang Qingjiong; Yao Yonggang; Zhang Yaping

2008-01-01

The penetrance of Leber's hereditary optic neuropathy (LHON) in families with primary mitochondrial DNA (mtDNA) mutations is very complex. Matrilineal and nuclear genetic background, as well as environmental factors, have been reported to be involved in different affected pedigrees. Here we describe two large Chinese families that show a striking difference in the penetrance of LHON, in which 53.3% and 15.0% of members were affected (P < 0.02), respectively. Analysis of the complete mtDNA genome of the two families revealed the presence of the primary mutation G11778A and several other variants suggesting the same haplogroup status G2a. The family with higher penetrance contained a previously described secondary mutation G13708A, which presents a polymorphism in normal Chinese samples and does not affect in vivo mitochondrial oxidative metabolism as described in a previous study. Evolutionary analysis failed to indicate any putatively pathogenic mutation that cosegregated with G11778A in these two pedigrees. Our results suggest that the variable penetrance of LHON in the two Chinese families is independent of both their mtDNA haplotype background and a secondary mutation G13708A. As a result, it is likely that unknown nuclear gene involvement and/or other factors contribute to the strikingly different penetrance of LHON

Optical interconnect for large-scale systems

Science.gov (United States)

Dress, William

2013-02-01

This paper presents a switchless, optical interconnect module that serves as a node in a network of identical distribution modules for large-scale systems. Thousands to millions of hosts or endpoints may be interconnected by a network of such modules, avoiding the need for multi-level switches. Several common network topologies are reviewed and their scaling properties assessed. The concept of message-flow routing is discussed in conjunction with the unique properties enabled by the optical distribution module where it is shown how top-down software control (global routing tables, spanning-tree algorithms) may be avoided.

Strategies for state-dependent quantum deleting

International Nuclear Information System (INIS)

Song Wei; Yang Ming; Cao Zhuoliang

2004-01-01

A quantum state-dependent quantum deleting machine is constructed. We obtain a upper bound of the global fidelity on N-to-M quantum deleting from a set of K non-orthogonal states. Quantum networks are constructed for the above state-dependent quantum deleting machine when K=2. Our deleting protocol only involves a unitary interaction among the initial copies, with no ancilla. We also present some analogies between quantum cloning and deleting

Circumpolar diversity and geographic differentiation of mtDNA in the critically endangered Antarctic blue whale (Balaenoptera musculus intermedia.

Directory of Open Access Journals (Sweden)

Angela L Sremba

Full Text Available The Antarctic blue whale (Balaenoptera musculus intermedia was hunted to near extinction between 1904 and 1972, declining from an estimated initial abundance of more than 250,000 to fewer than 400. Here, we describe mtDNA control region diversity and geographic differentiation in the surviving population of the Antarctic blue whale, using 218 biopsy samples collected under the auspices of the International Whaling Commission (IWC during research cruises from 1990-2009. Microsatellite genotypes and mtDNA sequences identified 166 individuals among the 218 samples and documented movement of a small number of individuals, including a female that traveled at least 6,650 km or 131° longitude over four years. mtDNA sequences from the 166 individuals were aligned with published sequences from 17 additional individuals, resolving 52 unique haplotypes from a consensus length of 410 bp. From this minimum census, a rarefaction analysis predicted that only 72 haplotypes (95% CL, 64, 86 have survived in the contemporary population of Antarctic blue whales. However, haplotype diversity was relatively high (0.968±0.004, perhaps as a result of the longevity of blue whales and the relatively recent timing of the bottleneck. Despite the potential for circumpolar dispersal, we found significant differentiation in mtDNA diversity (F(ST = 0.032, p<0.005 and microsatellite alleles (F(ST = 0.005, p<0.05 among the six Antarctic Areas historically used by the IWC for management of blue whales.

[A large-scale accident in Alpine terrain].

Science.gov (United States)

Wildner, M; Paal, P

2015-02-01

Due to the geographical conditions, large-scale accidents amounting to mass casualty incidents (MCI) in Alpine terrain regularly present rescue teams with huge challenges. Using an example incident, specific conditions and typical problems associated with such a situation are presented. The first rescue team members to arrive have the elementary tasks of qualified triage and communication to the control room, which is required to dispatch the necessary additional support. Only with a clear "concept", to which all have to adhere, can the subsequent chaos phase be limited. In this respect, a time factor confounded by adverse weather conditions or darkness represents enormous pressure. Additional hazards are frostbite and hypothermia. If priorities can be established in terms of urgency, then treatment and procedure algorithms have proven successful. For evacuation of causalities, a helicopter should be strived for. Due to the low density of hospitals in Alpine regions, it is often necessary to distribute the patients over a wide area. Rescue operations in Alpine terrain have to be performed according to the particular conditions and require rescue teams to have specific knowledge and expertise. The possibility of a large-scale accident should be considered when planning events. With respect to optimization of rescue measures, regular training and exercises are rational, as is the analysis of previous large-scale Alpine accidents.

Hierarchical Cantor set in the large scale structure with torus geometry

Energy Technology Data Exchange (ETDEWEB)

Murdzek, R. [Physics Department, ' Al. I. Cuza' University, Blvd. Carol I, Nr. 11, Iassy 700506 (Romania)], E-mail: rmurdzek@yahoo.com

2008-12-15

The formation of large scale structures is considered within a model with string on toroidal space-time. Firstly, the space-time geometry is presented. In this geometry, the Universe is represented by a string describing a torus surface. Thereafter, the large scale structure of the Universe is derived from the string oscillations. The results are in agreement with the cellular structure of the large scale distribution and with the theory of a Cantorian space-time.

Large-scale Reconstructions and Independent, Unbiased Clustering Based on Morphological Metrics to Classify Neurons in Selective Populations.

Science.gov (United States)

Bragg, Elise M; Briggs, Farran

2017-02-15

This protocol outlines large-scale reconstructions of neurons combined with the use of independent and unbiased clustering analyses to create a comprehensive survey of the morphological characteristics observed among a selective neuronal population. Combination of these techniques constitutes a novel approach for the collection and analysis of neuroanatomical data. Together, these techniques enable large-scale, and therefore more comprehensive, sampling of selective neuronal populations and establish unbiased quantitative methods for describing morphologically unique neuronal classes within a population. The protocol outlines the use of modified rabies virus to selectively label neurons. G-deleted rabies virus acts like a retrograde tracer following stereotaxic injection into a target brain structure of interest and serves as a vehicle for the delivery and expression of EGFP in neurons. Large numbers of neurons are infected using this technique and express GFP throughout their dendrites, producing "Golgi-like" complete fills of individual neurons. Accordingly, the virus-mediated retrograde tracing method improves upon traditional dye-based retrograde tracing techniques by producing complete intracellular fills. Individual well-isolated neurons spanning all regions of the brain area under study are selected for reconstruction in order to obtain a representative sample of neurons. The protocol outlines procedures to reconstruct cell bodies and complete dendritic arborization patterns of labeled neurons spanning multiple tissue sections. Morphological data, including positions of each neuron within the brain structure, are extracted for further analysis. Standard programming functions were utilized to perform independent cluster analyses and cluster evaluations based on morphological metrics. To verify the utility of these analyses, statistical evaluation of a cluster analysis performed on 160 neurons reconstructed in the thalamic reticular nucleus of the thalamus

Large-scale Motion of Solar Filaments

Indian Academy of Sciences (India)

tribpo

Large-scale Motion of Solar Filaments. Pavel Ambrož, Astronomical Institute of the Acad. Sci. of the Czech Republic, CZ-25165. Ondrejov, The Czech Republic. e-mail: pambroz@asu.cas.cz. Alfred Schroll, Kanzelhöehe Solar Observatory of the University of Graz, A-9521 Treffen,. Austria. e-mail: schroll@solobskh.ac.at.

Sensitivity analysis for large-scale problems

Science.gov (United States)

Noor, Ahmed K.; Whitworth, Sandra L.

1987-01-01

The development of efficient techniques for calculating sensitivity derivatives is studied. The objective is to present a computational procedure for calculating sensitivity derivatives as part of performing structural reanalysis for large-scale problems. The scope is limited to framed type structures. Both linear static analysis and free-vibration eigenvalue problems are considered.

Topology Optimization of Large Scale Stokes Flow Problems

DEFF Research Database (Denmark)

Aage, Niels; Poulsen, Thomas Harpsøe; Gersborg-Hansen, Allan

2008-01-01

This note considers topology optimization of large scale 2D and 3D Stokes flow problems using parallel computations. We solve problems with up to 1.125.000 elements in 2D and 128.000 elements in 3D on a shared memory computer consisting of Sun UltraSparc IV CPUs.......This note considers topology optimization of large scale 2D and 3D Stokes flow problems using parallel computations. We solve problems with up to 1.125.000 elements in 2D and 128.000 elements in 3D on a shared memory computer consisting of Sun UltraSparc IV CPUs....

The Cosmology Large Angular Scale Surveyor

Science.gov (United States)

Harrington, Kathleen; Marriage, Tobias; Ali, Aamir; Appel, John; Bennett, Charles; Boone, Fletcher; Brewer, Michael; Chan, Manwei; Chuss, David T.; Colazo, Felipe;

Non-virulence of a recombinant shrimp nidovirus is associated with its non structural gene sequence and not a large structural gene deletion

International Nuclear Information System (INIS)

Gangnonngiw, Warachin; Anantasomboon, Gun; Sang-oum, Wiwat; Sriurairatana, Siriporn; Sritunyalucksana, Kallaya; Flegel, Timothy W.

2009-01-01

RT-PCR using a commercial kit for yellow head virus (YHV) detection in growth-retarded shrimp yielded an unusual 777 bp amplicon instead of expected amplicons of 277 bp for YHV type-1 (YHV-1) or 406 bp for YHV type-2 (YHV-2). Cloning and sequencing (GenBank (EU170438)) revealed approximately 80% identity to non-structural (NS) ORF1b sequences of both YHV-1 (GenBank (AA083987)) and YHV-2 (GenBank (AF227196)), indicating an atypical YHV type (A-YHV) phylogenetically equidistant from both types. An RT-PCR test specifically designed for A-YHV revealed that it was uncommon and that its occurrence in shrimp culture ponds did not correlate with growth retardation or mortality. By immunohistochemistry with YHV-specific monoclonal antibodies, the A-YHV gave positive reactions for envelope protein gp64 and capsid protein p20, but not for envelope protein gp116, even though gp116 and gp64 originate from a polyprotein of ORF3. Lack of gp116 immunoreactivity correlated with a large ORF3 deletion (GenBank (EU123854)) in the region of the protein targeted by an MAb against gp116. Transmission electron microscopy of A-YHV-infected shrimp revealed only unenveloped pre-virions. During manuscript revision, information received revealed that typing of YHV isolates based on sequences of ORF1b and ORF3 had yielded several geographical types, including one virulent type (YHV-1b) with an ORF3 deletion sequence that matched the sequence of A-YHV. Using these sequences and an additional A-YHV sequence ( (EU853170)) from the ORF1b typing region, A-YHV potentially represents a recombinant between type 1b and type 5. SDS-PAGE and Western blot analysis revealed that type 1b produced a gp116 deletion protein that did not bind with the MAb or polyclonal Ab to normal gp116. Overall, the information suggested that lack of A-YHV virulence was associated with the NS gene sequence linked to ORF1b rather than the deletion in ORF3

Prehospital Acute Stroke Severity Scale to Predict Large Artery Occlusion: Design and Comparison With Other Scales.

Science.gov (United States)

Hastrup, Sidsel; Damgaard, Dorte; Johnsen, Søren Paaske; Andersen, Grethe

2016-07-01

We designed and validated a simple prehospital stroke scale to identify emergent large vessel occlusion (ELVO) in patients with acute ischemic stroke and compared the scale to other published scales for prediction of ELVO. A national historical test cohort of 3127 patients with information on intracranial vessel status (angiography) before reperfusion therapy was identified. National Institutes of Health Stroke Scale (NIHSS) items with the highest predictive value of occlusion of a large intracranial artery were identified, and the most optimal combination meeting predefined criteria to ensure usefulness in the prehospital phase was determined. The predictive performance of Prehospital Acute Stroke Severity (PASS) scale was compared with other published scales for ELVO. The PASS scale was composed of 3 NIHSS scores: level of consciousness (month/age), gaze palsy/deviation, and arm weakness. In derivation of PASS 2/3 of the test cohort was used and showed accuracy (area under the curve) of 0.76 for detecting large arterial occlusion. Optimal cut point ≥2 abnormal scores showed: sensitivity=0.66 (95% CI, 0.62-0.69), specificity=0.83 (0.81-0.85), and area under the curve=0.74 (0.72-0.76). Validation on 1/3 of the test cohort showed similar performance. Patients with a large artery occlusion on angiography with PASS ≥2 had a median NIHSS score of 17 (interquartile range=6) as opposed to PASS <2 with a median NIHSS score of 6 (interquartile range=5). The PASS scale showed equal performance although more simple when compared with other scales predicting ELVO. The PASS scale is simple and has promising accuracy for prediction of ELVO in the field. © 2016 American Heart Association, Inc.

Use of a wine yeast deletion collection reveals genes that influence fermentation performance under low-nitrogen conditions.

Science.gov (United States)

Peter, Josephine J; Watson, Tommaso L; Walker, Michelle E; Gardner, Jennifer M; Lang, Tom A; Borneman, Anthony; Forgan, Angus; Tran, Tina; Jiranek, Vladimir

2018-05-01

A deficiency of nitrogenous nutrients in grape juice can cause stuck and sluggish alcoholic fermentation, which has long been a problem in winemaking. Nitrogen requirements vary between wine yeast strains, and the ability of yeast to assimilate nitrogen depends on the nature and concentration of nitrogen present in the medium. In this study, a wine yeast gene deletion collection (1844 deletants in the haploid AWRI1631 background) was screened to identify genes whose deletion resulted in a reduction in the time taken to utilise all sugars when grown in a chemically defined grape juice medium supplemented with limited nitrogen (75 mg L-1 as a free amino acid mixture). Through micro-scale and laboratory-scale fermentations, 15 deletants were identified that completed fermentation in a shorter time than the wildtype (c.a. 15%-59% time reduction). This group of genes was annotated to biological processes including protein modification, transport, metabolism and ubiquitination (UBC13, MMS2, UBP7, UBI4, BRO1, TPK2, EAR1, MRP17, MFA2 and MVB12), signalling (MFA2) and amino acid metabolism (AAT2). Deletion of MFA2, encoding mating factor-a, resulted in a 55% decrease in fermentation duration. Mfa2Δ was chosen for further investigation to understand how this gene deletion conferred fermentation efficiency in limited nitrogen conditions.

Analysis using large-scale ringing data

Directory of Open Access Journals (Sweden)

Baillie, S. R.

2004-06-01

Full Text Available Birds are highly mobile organisms and there is increasing evidence that studies at large spatial scales are needed if we are to properly understand their population dynamics. While classical metapopulation models have rarely proved useful for birds, more general metapopulation ideas involving collections of populations interacting within spatially structured landscapes are highly relevant (Harrison, 1994. There is increasing interest in understanding patterns of synchrony, or lack of synchrony, between populations and the environmental and dispersal mechanisms that bring about these patterns (Paradis et al., 2000. To investigate these processes we need to measure abundance, demographic rates and dispersal at large spatial scales, in addition to gathering data on relevant environmental variables. There is an increasing realisation that conservation needs to address rapid declines of common and widespread species (they will not remain so if such trends continue as well as the management of small populations that are at risk of extinction. While the knowledge needed to support the management of small populations can often be obtained from intensive studies in a few restricted areas, conservation of widespread species often requires information on population trends and processes measured at regional, national and continental scales (Baillie, 2001. While management prescriptions for widespread populations may initially be developed from a small number of local studies or experiments, there is an increasing need to understand how such results will scale up when applied across wider areas. There is also a vital role for monitoring at large spatial scales both in identifying such population declines and in assessing population recovery. Gathering data on avian abundance and demography at large spatial scales usually relies on the efforts of large numbers of skilled volunteers. Volunteer studies based on ringing (for example Constant Effort Sites [CES

Fast Simulation of Large-Scale Floods Based on GPU Parallel Computing

OpenAIRE

Qiang Liu; Yi Qin; Guodong Li

2018-01-01

Computing speed is a significant issue of large-scale flood simulations for real-time response to disaster prevention and mitigation. Even today, most of the large-scale flood simulations are generally run on supercomputers due to the massive amounts of data and computations necessary. In this work, a two-dimensional shallow water model based on an unstructured Godunov-type finite volume scheme was proposed for flood simulation. To realize a fast simulation of large-scale floods on a personal...

Managing Risk and Uncertainty in Large-Scale University Research Projects

Science.gov (United States)

Moore, Sharlissa; Shangraw, R. F., Jr.

2011-01-01

Both publicly and privately funded research projects managed by universities are growing in size and scope. Complex, large-scale projects (over $50 million) pose new management challenges and risks for universities. This paper explores the relationship between project success and a variety of factors in large-scale university projects. First, we…

Parallel clustering algorithm for large-scale biological data sets.

Science.gov (United States)

Wang, Minchao; Zhang, Wu; Ding, Wang; Dai, Dongbo; Zhang, Huiran; Xie, Hao; Chen, Luonan; Guo, Yike; Xie, Jiang

2014-01-01

Recent explosion of biological data brings a great challenge for the traditional clustering algorithms. With increasing scale of data sets, much larger memory and longer runtime are required for the cluster identification problems. The affinity propagation algorithm outperforms many other classical clustering algorithms and is widely applied into the biological researches. However, the time and space complexity become a great bottleneck when handling the large-scale data sets. Moreover, the similarity matrix, whose constructing procedure takes long runtime, is required before running the affinity propagation algorithm, since the algorithm clusters data sets based on the similarities between data pairs. Two types of parallel architectures are proposed in this paper to accelerate the similarity matrix constructing procedure and the affinity propagation algorithm. The memory-shared architecture is used to construct the similarity matrix, and the distributed system is taken for the affinity propagation algorithm, because of its large memory size and great computing capacity. An appropriate way of data partition and reduction is designed in our method, in order to minimize the global communication cost among processes. A speedup of 100 is gained with 128 cores. The runtime is reduced from serval hours to a few seconds, which indicates that parallel algorithm is capable of handling large-scale data sets effectively. The parallel affinity propagation also achieves a good performance when clustering large-scale gene data (microarray) and detecting families in large protein superfamilies.

Klf5 deletion promotes Pten deletion-initiated luminal-type mouse prostate tumors through multiple oncogenic signaling pathways.

Science.gov (United States)

Xing, Changsheng; Ci, Xinpei; Sun, Xiaodong; Fu, Xiaoying; Zhang, Zhiqian; Dong, Eric N; Hao, Zhao-Zhe; Dong, Jin-Tang

2014-11-01

Krüppel-like factor 5 (KLF5) regulates multiple biologic processes. Its function in tumorigenesis appears contradictory though, showing both tumor suppressor and tumor promoting activities. In this study, we examined whether and how Klf5 functions in prostatic tumorigenesis using mice with prostate-specific deletion of Klf5 and phosphatase and tensin homolog (Pten), both of which are frequently inactivated in human prostate cancer. Histologic analysis demonstrated that when one Pten allele was deleted, which causes mouse prostatic intraepithelial neoplasia (mPIN), Klf5 deletion accelerated the emergence and progression of mPIN. When both Pten alleles were deleted, which causes prostate cancer, Klf5 deletion promoted tumor growth, increased cell proliferation, and caused more severe morphologic and molecular alterations. Homozygous deletion of Klf5 was more effective than hemizygous deletion. Unexpectedly, while Pten deletion alone expanded basal cell population in a tumor as reported, Klf5 deletion in the Pten-null background clearly reduced basal cell population while expanding luminal cell population. Global gene expression profiling, pathway analysis, and experimental validation indicate that multiple mechanisms could mediate the tumor-promoting effect of Klf5 deletion, including the up-regulation of epidermal growth factor and its downstream signaling molecules AKT and ERK and the inactivation of the p15 cell cycle inhibitor. KLF5 also appears to cooperate with several transcription factors, including CREB1, Sp1, Myc, ER and AR, to regulate gene expression. These findings validate the tumor suppressor function of KLF5. They also yield a mouse model that shares two common genetic alterations with human prostate cancer-mutation/deletion of Pten and deletion of Klf5.

Evolutionary history of the European whitefish Coregonus lavaretus (L.) species complex as inferred from mtDNA phylogeography and gill-raker numbers.

Science.gov (United States)

Østbye, K; Bernatchez, L; Naesje, T F; Himberg, K-J M; Hindar, K

2005-12-01

We compared mitochondrial DNA and gill-raker number variation in populations of the European whitefish Coregonus lavaretus (L.) species complex to illuminate their evolutionary history, and discuss mechanisms behind diversification. Using single-strand conformation polymorphism (SSCP) and sequencing 528 bp of combined parts of the cytochrome oxidase b (cyt b) and NADH dehydrogenase subunit 3 (ND3) mithochondrial DNA (mtDNA) regions, we documented phylogeographic relationships among populations and phylogeny of mtDNA haplotypes. Demographic events behind geographical distribution of haplotypes were inferred using nested clade analysis (NCA) and mismatch distribution. Concordance between operational taxonomical groups, based on gill-raker numbers, and mtDNA patterns was tested. Three major mtDNA clades were resolved in Europe: a North European clade from northwest Russia to Denmark, a Siberian clade from the Arctic Sea to southwest Norway, and a South European clade from Denmark to the European Alps, reflecting occupation in different glacial refugia. Demographic events inferred from NCA were isolation by distance, range expansion, and fragmentation. Mismatch analysis suggested that clades which colonized Fennoscandia and the Alps expanded in population size 24 500-5800 years before present, with minute female effective population sizes, implying small founder populations during colonization. Gill-raker counts did not commensurate with hierarchical mtDNA clades, and poorly with haplotypes, suggesting recent origin of gill-raker variation. Whitefish designations based on gill-raker numbers were not associated with ancient clades. Lack of congruence in morphology and evolutionary lineages implies that the taxonomy of this species complex should be reconsidered.

Defects of mtDNA Replication Impaired Mitochondrial Biogenesis During Trypanosoma cruzi Infection in Human Cardiomyocytes and Chagasic Patients: The Role of Nrf1/2 and Antioxidant Response

Science.gov (United States)

Wan, Xianxiu; Gupta, Shivali; Zago, Maria P.; Davidson, Mercy M.; Dousset, Pierre; Amoroso, Alejandro; Garg, Nisha Jain

2012-01-01

Background Mitochondrial dysfunction is a key determinant in chagasic cardiomyopathy development in mice; however, its relevance in human Chagas disease is not known. We determined if defects in mitochondrial biogenesis and dysregulation of peroxisome proliferator-activated receptor gamma (PPARγ) coactivator-1 (PGC-1)–regulated transcriptional pathways constitute a mechanism or mechanisms underlying mitochondrial oxidative-phosphorylation (OXPHOS) deficiency in human Chagas disease. Methods and Results We utilized human cardiomyocytes and left-ventricular tissue from chagasic and other cardiomyopathy patients and healthy donors (n>6/group). We noted no change in citrate synthase activity, yet mRNA and/or protein levels of subunits of the respiratory complexes were significantly decreased in Trypanosoma cruzi–infected cardiomyocytes (0 to 24 hours) and chagasic hearts. We observed increased mRNA and decreased nuclear localization of PGC-1-coactivated transcription factors, yet the expression of genes for PPARγ-regulated fatty acid oxidation and nuclear respiratory factor (NRF1/2)–regulated mtDNA replication and transcription machinery was enhanced in infected cardiomyocytes and chagasic hearts. The D-loop formation was normal or higher, but mtDNA replication and mtDNA content were decreased by 83% and 40% to 65%, respectively. Subsequently, we noted that reactive oxygen species (ROS), oxidative stress, and mtDNA oxidation were significantly increased, yet NRF1/2-regulated antioxidant gene expression remained compromised in infected cardiomyocytes and chagasic hearts. Conclusions The replication of mtDNA was severely compromised, resulting in a significant loss of mtDNA and expression of OXPHOS genes in T cruzi–infected cardiomyocytes and chagasic hearts. Our data suggest increased ROS generation and selective functional incapacity of NRF2-mediated antioxidant gene expression played a role in the defects in mtDNA replication and unfitness of mtDNA for

[Sequence polymorphism of mtDNA HVR Iand HVR II of Oroqen ethnic group in Inner Mongolia].

Science.gov (United States)

Yan, Chun-Xia; Chen, Feng; Dang, Yong-Hui; Li, Tao; Zheng, Hai-Bo; Chen, Teng; Li, Sheng-Bin

2008-04-01

Venous blood samples from 50 unrelated Oroqen individuals living in Inner Mongolia were collected and their mtDNA HVR I and HVR II sequences were detected by using ABI PRISM377 sequencers. The number of polymorphic loci, haplotype, haplotype frequence, average nucleotide variability and other polymorphic parameters were calculated. Based on Oroqen mtDNA sequence data obtained in our experiments and published data, genetic distance between Oroqen ethnic group and other populations were computered by Nei's measure. Phylogenetic tree was constructed by Neighbor Joining method. Comparing with Anderson sequence, 52 polymorphic loci in HVR I and 24 loci in HVR II were found in Oroqen mtDNA sequence, 38 and 27 haplotypes were defined herewith. Haplotype diversity and average nucleotide variability were 0.964+/-0.018 and 7.379 in HVR I, 0.929+/-0.019 and 2.408 in HVR II respectively. Fst and dA genetic distance between 12 populations were calculated based on HVR I sequence, and their relative coefficients were 0.993(P HVR I and HVR II in Oroqen ethnic group has some specificities compared with that of other populations. These data provide a useful tool in forensic identification, population genetic study and other research fields.

Comparative mtDNA analyses of three sympatric macropodids from a conservation area on the Huon Peninsula, Papua New Guinea.

Science.gov (United States)

McGreevy, Thomas J; Dabek, Lisa; Husband, Thomas P

2016-07-01

Matschie's tree kangaroo (Dendrolagus matschiei), New Guinea pademelon (Thylogale browni), and small dorcopsis (Dorcopsulus vanheurni) are sympatric macropodid taxa, of conservation concern, that inhabit the Yopno-Urawa-Som (YUS) Conservation Area on the Huon Peninsula, Papua New Guinea. We sequenced three partial mitochondrial DNA (mtDNA) genes from the three taxa to (i) investigate network structure; and (ii) identify conservation units within the YUS Conservation Area. All three taxa displayed a similar pattern in the spatial distribution of their mtDNA haplotypes and the Urawa and Som rivers on the Huon may have acted as a barrier to maternal gene flow. Matschie's tree kangaroo and New Guinea pademelon within the YUS Conservation Area should be managed as single conservation units because mtDNA nucleotides were not fixed for a given geographic area. However, two distinct conservation units were identified for small dorcopsis from the two different mountain ranges within the YUS Conservation Area.

Adaptive visualization for large-scale graph

International Nuclear Information System (INIS)

Nakamura, Hiroko; Shinano, Yuji; Ohzahata, Satoshi

2010-01-01

We propose an adoptive visualization technique for representing a large-scale hierarchical dataset within limited display space. A hierarchical dataset has nodes and links showing the parent-child relationship between the nodes. These nodes and links are described using graphics primitives. When the number of these primitives is large, it is difficult to recognize the structure of the hierarchical data because many primitives are overlapped within a limited region. To overcome this difficulty, we propose an adaptive visualization technique for hierarchical datasets. The proposed technique selects an appropriate graph style according to the nodal density in each area. (author)

Stabilization Algorithms for Large-Scale Problems

DEFF Research Database (Denmark)

Jensen, Toke Koldborg

2006-01-01

The focus of the project is on stabilization of large-scale inverse problems where structured models and iterative algorithms are necessary for computing approximate solutions. For this purpose, we study various iterative Krylov methods and their abilities to produce regularized solutions. Some......-curve. This heuristic is implemented as a part of a larger algorithm which is developed in collaboration with G. Rodriguez and P. C. Hansen. Last, but not least, a large part of the project has, in different ways, revolved around the object-oriented Matlab toolbox MOORe Tools developed by PhD Michael Jacobsen. New...

The mitochondrial ND1 m.3337G>A mutation associated to multiple mitochondrial DNA deletions in a patient with Wolfram syndrome and cardiomyopathy.

Science.gov (United States)

Mezghani, Najla; Mnif, Mouna; Mkaouar-Rebai, Emna; Kallel, Nozha; Salem, Ikhlass Haj; Charfi, Nadia; Abid, Mohamed; Fakhfakh, Faiza

2011-07-29

Wolfram syndrome (WFS) is a rare hereditary disorder also known as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). It is a heterogeneous disease and full characterization of all clinical and biological features of this disorder is difficult. The wide spectrum of clinical expression, affecting several organs and tissues, and the similarity in phenotype between patients with Wolfram syndrome and those with certain types of respiratory chain diseases suggests mitochondrial DNA (mtDNA) involvement in Wolfram syndrome patients. We report a Tunisian patient with clinical features of moderate Wolfram syndrome including diabetes, dilated cardiomyopathy and neurological complications. The results showed the presence of the mitochondrial ND1 m.3337G>A mutation in almost homoplasmic form in 3 tested tissues of the proband (blood leukocytes, buccal mucosa and skeletal muscle). In addition, the long-range PCR amplifications revealed the presence of multiple deletions of the mitochondrial DNA extracted from the patient's skeletal muscle removing several tRNA and protein-coding genes. Our study reported a Tunisian patient with clinical features of moderate Wolfram syndrome associated with cardiomyopathy, in whom we detected the ND1 m.3337G>A mutation with mitochondrial multiple deletions. Copyright © 2011 Elsevier Inc. All rights reserved.

Exploration of methods to localize DNA sequences missing from c-locus deletions

International Nuclear Information System (INIS)

Albritton, L.M.; Russell, L.B.; Montgomery, C.S.

1987-01-01

The authors have earlier characterized a large number of radiation-induced mutations at the c locus (on Chromosome 7) through genetic analysis, including extensive complementation tests. Based on this work, they have postulated that many of these mutations are deletions of various lengths, overlapping at c (the marker used in the mutation-rate experiments that generated the mutants). It was possible to apportion these deletions among 13 complementation groups and to fit them to a linear map of 8 functional units. Collectively, the deletions extend from a point between tp and c to one between sh-1 and Hbb, i.e., a genetic distance of from 6 to 10 cM, corresponding to at least 10 4 Kb of DNA. This year, the authors completed a pilot study designed to explore methods for finding DNA sequences that map to the region covered by the various c-deletions. The general plan was to probe DNA with clones derived from Chromosome-7-enriched libraries or with sequences known (or suspected) to reside in Chromosome 7. Three methods were explored for deriving the c-region-deficient DNA: (a) from mouse-hamster somatic-cell hydrids retaining a deleted mouse Chromosome 7, but no homologue; (b) from F 1 hybrids of M. musculus domesticus (carrying a c-locus deletion) by M. spretus; and (c) from F 1 hybrids of M. domesticus stocks carrying complementing deletions

PGen: large-scale genomic variations analysis workflow and browser in SoyKB.

Science.gov (United States)

Liu, Yang; Khan, Saad M; Wang, Juexin; Rynge, Mats; Zhang, Yuanxun; Zeng, Shuai; Chen, Shiyuan; Maldonado Dos Santos, Joao V; Valliyodan, Babu; Calyam, Prasad P; Merchant, Nirav; Nguyen, Henry T; Xu, Dong; Joshi, Trupti

2016-10-06

With the advances in next-generation sequencing (NGS) technology and significant reductions in sequencing costs, it is now possible to sequence large collections of germplasm in crops for detecting genome-scale genetic variations and to apply the knowledge towards improvements in traits. To efficiently facilitate large-scale NGS resequencing data analysis of genomic variations, we have developed "PGen", an integrated and optimized workflow using the Extreme Science and Engineering Discovery Environment (XSEDE) high-performance computing (HPC) virtual system, iPlant cloud data storage resources and Pegasus workflow management system (Pegasus-WMS). The workflow allows users to identify single nucleotide polymorphisms (SNPs) and insertion-deletions (indels), perform SNP annotations and conduct copy number variation analyses on multiple resequencing datasets in a user-friendly and seamless way. We have developed both a Linux version in GitHub ( https://github.com/pegasus-isi/PGen-GenomicVariations-Workflow ) and a web-based implementation of the PGen workflow integrated within the Soybean Knowledge Base (SoyKB), ( http://soykb.org/Pegasus/index.php ). Using PGen, we identified 10,218,140 single-nucleotide polymorphisms (SNPs) and 1,398,982 indels from analysis of 106 soybean lines sequenced at 15X coverage. 297,245 non-synonymous SNPs and 3330 copy number variation (CNV) regions were identified from this analysis. SNPs identified using PGen from additional soybean resequencing projects adding to 500+ soybean germplasm lines in total have been integrated. These SNPs are being utilized for trait improvement using genotype to phenotype prediction approaches developed in-house. In order to browse and access NGS data easily, we have also developed an NGS resequencing data browser ( http://soykb.org/NGS_Resequence/NGS_index.php ) within SoyKB to provide easy access to SNP and downstream analysis results for soybean researchers. PGen workflow has been optimized for the most

Targeted transgenic overexpression of mitochondrial thymidine kinase (TK2) alters mitochondrial DNA (mtDNA) and mitochondrial polypeptide abundance: transgenic TK2, mtDNA, and antiretrovirals.

Science.gov (United States)

Hosseini, Seyed H; Kohler, James J; Haase, Chad P; Tioleco, Nina; Stuart, Tami; Keebaugh, Erin; Ludaway, Tomika; Russ, Rodney; Green, Elgin; Long, Robert; Wang, Liya; Eriksson, Staffan; Lewis, William

2007-03-01

Mitochondrial toxicity limits nucleoside reverse transcriptase inhibitors (NRTIs) for acquired immune deficiency syndrome. NRTI triphosphates, the active moieties, inhibit human immunodeficiency virus reverse transcriptase and eukaryotic mitochondrial DNA polymerase pol-gamma. NRTI phosphorylation seems to correlate with mitochondrial toxicity, but experimental evidence is lacking. Transgenic mice (TGs) with cardiac overexpression of thymidine kinase isoforms (mitochondrial TK2 and cytoplasmic TK1) were used to study NRTI mitochondrial toxicity. Echocardiography and nuclear magnetic resonance imaging defined cardiac performance and structure. TK gene copy and enzyme activity, mitochondrial (mt) DNA and polypeptide abundance, succinate dehydrogenase and cytochrome oxidase histochemistry, and electron microscopy correlated with transgenesis, mitochondrial structure, and biogenesis. Antiretroviral combinations simulated therapy. Untreated hTK1 or TK2 TGs exhibited normal left ventricle mass. In TK2 TGs, cardiac TK2 gene copy doubled, activity increased 300-fold, and mtDNA abundance doubled. Abundance of the 17-kd subunit of complex I, succinate dehydrogenase histochemical activity, and cristae density increased. NRTIs increased left ventricle mass 20% in TK2 TGs. TK activity increased 3 logs in hTK1 TGs, but no cardiac phenotype resulted. NRTIs abrogated functional effects of transgenically increased TK2 activity but had no effect on TK2 mtDNA abundance. Thus, NRTI mitochondrial phosphorylation by TK2 is integral to clinical NRTI mitochondrial toxicity.

Design study on sodium cooled large-scale reactor

International Nuclear Information System (INIS)

Murakami, Tsutomu; Hishida, Masahiko; Kisohara, Naoyuki

2004-07-01

In Phase 1 of the 'Feasibility Studies on Commercialized Fast Reactor Cycle Systems (F/S)', an advanced loop type reactor has been selected as a promising concept of sodium-cooled large-scale reactor, which has a possibility to fulfill the design requirements of the F/S. In Phase 2, design improvement for further cost reduction of establishment of the plant concept has been performed. This report summarizes the results of the design study on the sodium-cooled large-scale reactor performed in JFY2003, which is the third year of Phase 2. In the JFY2003 design study, critical subjects related to safety, structural integrity and thermal hydraulics which found in the last fiscal year has been examined and the plant concept has been modified. Furthermore, fundamental specifications of main systems and components have been set and economy has been evaluated. In addition, as the interim evaluation of the candidate concept of the FBR fuel cycle is to be conducted, cost effectiveness and achievability for the development goal were evaluated and the data of the three large-scale reactor candidate concepts were prepared. As a results of this study, the plant concept of the sodium-cooled large-scale reactor has been constructed, which has a prospect to satisfy the economic goal (construction cost: less than 200,000 yens/kWe, etc.) and has a prospect to solve the critical subjects. From now on, reflecting the results of elemental experiments, the preliminary conceptual design of this plant will be preceded toward the selection for narrowing down candidate concepts at the end of Phase 2. (author)

Design study on sodium-cooled large-scale reactor

International Nuclear Information System (INIS)

Shimakawa, Yoshio; Nibe, Nobuaki; Hori, Toru

2002-05-01

In Phase 1 of the 'Feasibility Study on Commercialized Fast Reactor Cycle Systems (F/S)', an advanced loop type reactor has been selected as a promising concept of sodium-cooled large-scale reactor, which has a possibility to fulfill the design requirements of the F/S. In Phase 2 of the F/S, it is planed to precede a preliminary conceptual design of a sodium-cooled large-scale reactor based on the design of the advanced loop type reactor. Through the design study, it is intended to construct such a plant concept that can show its attraction and competitiveness as a commercialized reactor. This report summarizes the results of the design study on the sodium-cooled large-scale reactor performed in JFY2001, which is the first year of Phase 2. In the JFY2001 design study, a plant concept has been constructed based on the design of the advanced loop type reactor, and fundamental specifications of main systems and components have been set. Furthermore, critical subjects related to safety, structural integrity, thermal hydraulics, operability, maintainability and economy have been examined and evaluated. As a result of this study, the plant concept of the sodium-cooled large-scale reactor has been constructed, which has a prospect to satisfy the economic goal (construction cost: less than 200,000yens/kWe, etc.) and has a prospect to solve the critical subjects. From now on, reflecting the results of elemental experiments, the preliminary conceptual design of this plant will be preceded toward the selection for narrowing down candidate concepts at the end of Phase 2. (author)

The extremely divergent maternally- and paternally-transmitted mitochondrial genomes are co-expressed in somatic tissues of two freshwater mussel species with doubly uniparental inheritance of mtDNA

Science.gov (United States)

Breton, Sophie; Bouvet, Karim; Auclair, Gabrielle; Ghazal, Stephanie; Sietman, Bernard E.; Johnson, Nathan A.; Bettinazzi, Stefano; Dtewart, Donald T.; Guerra, Davide

2017-01-01

Freshwater mussel species with doubly uniparental inheritance (DUI) of mtDNA are unique because they are naturally heteroplasmic for two extremely divergent mtDNAs with ~50% amino acid differences for protein-coding genes. The paternally-transmitted mtDNA (or M mtDNA) clearly functions in sperm in these species, but it is still unknown whether it is transcribed when present in male or female soma. In the present study, we used PCR and RT-PCR to detect the presence and expression of the M mtDNA in male and female somatic and gonadal tissues of the freshwater mussel species Venustaconcha ellipsiformis and Utterbackia peninsularis (Unionidae). This is the first study demonstrating that the M mtDNA is transcribed not only in male gonads, but also in male and female soma in freshwater mussels with DUI. Because of the potentially deleterious nature of heteroplasmy, we suggest the existence of different mechanisms in DUI species to deal with this possibly harmful situation, such as silencing mechanisms for the M mtDNA at the transcriptional, post-transcriptional and/or post-translational levels. These hypotheses will necessitate additional studies in distantly-related DUI species that could possess different mechanisms of action to deal with heteroplasmy.

Large scale CMB anomalies from thawing cosmic strings

Energy Technology Data Exchange (ETDEWEB)

Ringeval, Christophe [Centre for Cosmology, Particle Physics and Phenomenology, Institute of Mathematics and Physics, Louvain University, 2 Chemin du Cyclotron, 1348 Louvain-la-Neuve (Belgium); Yamauchi, Daisuke; Yokoyama, Jun' ichi [Research Center for the Early Universe (RESCEU), Graduate School of Science, The University of Tokyo, Tokyo 113-0033 (Japan); Bouchet, François R., E-mail: christophe.ringeval@uclouvain.be, E-mail: yamauchi@resceu.s.u-tokyo.ac.jp, E-mail: yokoyama@resceu.s.u-tokyo.ac.jp, E-mail: bouchet@iap.fr [Institut d' Astrophysique de Paris, UMR 7095-CNRS, Université Pierre et Marie Curie, 98bis boulevard Arago, 75014 Paris (France)

2016-02-01

Cosmic strings formed during inflation are expected to be either diluted over super-Hubble distances, i.e., invisible today, or to have crossed our past light cone very recently. We discuss the latter situation in which a few strings imprint their signature in the Cosmic Microwave Background (CMB) Anisotropies after recombination. Being almost frozen in the Hubble flow, these strings are quasi static and evade almost all of the previously derived constraints on their tension while being able to source large scale anisotropies in the CMB sky. Using a local variance estimator on thousand of numerically simulated Nambu-Goto all sky maps, we compute the expected signal and show that it can mimic a dipole modulation at large angular scales while being negligible at small angles. Interestingly, such a scenario generically produces one cold spot from the thawing of a cosmic string loop. Mixed with anisotropies of inflationary origin, we find that a few strings of tension GU = O(1) × 10{sup −6} match the amplitude of the dipole modulation reported in the Planck satellite measurements and could be at the origin of other large scale anomalies.

mtDNA depletion myopathy: elucidation of the tissue specificity in the mitochondrial thymidine kinase (TK2) deficiency.

Science.gov (United States)

Saada, Ann; Shaag, Avraham; Elpeleg, Orly

2003-05-01

Decreased mitochondrial thymidine kinase (TK2) activity is associated with mitochondrial DNA (mtDNA) depletion and respiratory chain dysfunction and is manifested by isolated, fatal skeletal myopathy. Other tissues such as liver, brain, heart, and skin remain unaffected throughout the patients' life. In order to elucidate the mechanism of tissue specificity in the disease we have investigated the expression of the mitochondrial deoxynucleotide carrier, the mtDNA content and the activity of TK2 in mitochondria of various tissues. Our results suggest that low basal TK2 activity combined with a high requirement for mitochondrial encoded proteins in muscle predispose this tissue to the devastating effect of TK2 deficiency.

Effect of gamma rays at the dihydrofolate reductase locus: deletions and inversions

International Nuclear Information System (INIS)

Urlaub, G.; Mitchell, P.J.; Kas, E.; Chasin, L.A.; Funanage, V.L.; Myoda, T.T.; Hamlin, J.

1986-01-01

A series 11 gamma-ray-induced mutants at the dihydrofolate reductase (dhfr) locus in Chinese hamster ovary cells has been examined for the types of DNA sequence change brought about by this form of ionizing radiation. All 11 mutants were found to have suffered major structural changes affecting the dhfr gene. In eight of the mutants, all or part of the dhfr gene has been deleted. The extent of these deletions was examined in seven of these mutants and, for comparison, in two deletion mutants that were induced by UV irradiation. For this purpose, probes from an overlapping set of cosmids that span 210 kb of DNA in this region were used. Three of seven gamma-ray-induced mutants and one UV-induced mutant were shown to have deleted the entire 210-kb region. In the remaining mutants, endpoints ranging from within the dhfr gene to 100 kb downstream were observed. No upstream endpoints were detected, so that an upper limit on the size of these large deletions could not be assigned. Three of the 11 gamma-ray-induced mutants contained an interruption in the dhfr gene without any detectable loss of sequence. Restriction analysis of these interrupted mutants showed that at least 8-14 kb of foreign DNA sequence became joined to the gene at the point of disruption. Cytogenetic analysis of these mutants showed that in two cases an inversion of the banding pattern on chromosome Z-2 had taken place. The inverted dhfr mutants contain very low amounts of dhfr RNA sequences, and the 5' end of an inversion mutant gene exhibits the same pattern of DNA methylation and DNase I-hypersensitivity as the wild-type gene. Our results suggest that ionizing radiation causes primarily, if not exclusively, large deletions and inversions in mammalian cells

Exploiting multi-scale parallelism for large scale numerical modelling of laser wakefield accelerators

International Nuclear Information System (INIS)

Fonseca, R A; Vieira, J; Silva, L O; Fiuza, F; Davidson, A; Tsung, F S; Mori, W B

2013-01-01

A new generation of laser wakefield accelerators (LWFA), supported by the extreme accelerating fields generated in the interaction of PW-Class lasers and underdense targets, promises the production of high quality electron beams in short distances for multiple applications. Achieving this goal will rely heavily on numerical modelling to further understand the underlying physics and identify optimal regimes, but large scale modelling of these scenarios is computationally heavy and requires the efficient use of state-of-the-art petascale supercomputing systems. We discuss the main difficulties involved in running these simulations and the new developments implemented in the OSIRIS framework to address these issues, ranging from multi-dimensional dynamic load balancing and hybrid distributed/shared memory parallelism to the vectorization of the PIC algorithm. We present the results of the OASCR Joule Metric program on the issue of large scale modelling of LWFA, demonstrating speedups of over 1 order of magnitude on the same hardware. Finally, scalability to over ∼10 6 cores and sustained performance over ∼2 P Flops is demonstrated, opening the way for large scale modelling of LWFA scenarios. (paper)

Balancing modern Power System with large scale of wind power

DEFF Research Database (Denmark)

Basit, Abdul; Altin, Müfit; Hansen, Anca Daniela

2014-01-01

Power system operators must ensure robust, secure and reliable power system operation even with a large scale integration of wind power. Electricity generated from the intermittent wind in large propor-tion may impact on the control of power system balance and thus deviations in the power system...... frequency in small or islanded power systems or tie line power flows in interconnected power systems. Therefore, the large scale integration of wind power into the power system strongly concerns the secure and stable grid operation. To ensure the stable power system operation, the evolving power system has...... to be analysed with improved analytical tools and techniques. This paper proposes techniques for the active power balance control in future power systems with the large scale wind power integration, where power balancing model provides the hour-ahead dispatch plan with reduced planning horizon and the real time...

Large-Scale Graph Processing Using Apache Giraph

KAUST Repository

Sakr, Sherif

2017-01-07

This book takes its reader on a journey through Apache Giraph, a popular distributed graph processing platform designed to bring the power of big data processing to graph data. Designed as a step-by-step self-study guide for everyone interested in large-scale graph processing, it describes the fundamental abstractions of the system, its programming models and various techniques for using the system to process graph data at scale, including the implementation of several popular and advanced graph analytics algorithms.

Large-Scale Graph Processing Using Apache Giraph

KAUST Repository

Sakr, Sherif; Orakzai, Faisal Moeen; Abdelaziz, Ibrahim; Khayyat, Zuhair

2017-01-01

This book takes its reader on a journey through Apache Giraph, a popular distributed graph processing platform designed to bring the power of big data processing to graph data. Designed as a step-by-step self-study guide for everyone interested in large-scale graph processing, it describes the fundamental abstractions of the system, its programming models and various techniques for using the system to process graph data at scale, including the implementation of several popular and advanced graph analytics algorithms.

An interactive display system for large-scale 3D models

Science.gov (United States)

Liu, Zijian; Sun, Kun; Tao, Wenbing; Liu, Liman

2018-04-01

With the improvement of 3D reconstruction theory and the rapid development of computer hardware technology, the reconstructed 3D models are enlarging in scale and increasing in complexity. Models with tens of thousands of 3D points or triangular meshes are common in practical applications. Due to storage and computing power limitation, it is difficult to achieve real-time display and interaction with large scale 3D models for some common 3D display software, such as MeshLab. In this paper, we propose a display system for large-scale 3D scene models. We construct the LOD (Levels of Detail) model of the reconstructed 3D scene in advance, and then use an out-of-core view-dependent multi-resolution rendering scheme to realize the real-time display of the large-scale 3D model. With the proposed method, our display system is able to render in real time while roaming in the reconstructed scene and 3D camera poses can also be displayed. Furthermore, the memory consumption can be significantly decreased via internal and external memory exchange mechanism, so that it is possible to display a large scale reconstructed scene with over millions of 3D points or triangular meshes in a regular PC with only 4GB RAM.

Large-scale hydrology in Europe : observed patterns and model performance

Energy Technology Data Exchange (ETDEWEB)

Gudmundsson, Lukas

2011-06-15

In a changing climate, terrestrial water storages are of great interest as water availability impacts key aspects of ecosystem functioning. Thus, a better understanding of the variations of wet and dry periods will contribute to fully grasp processes of the earth system such as nutrient cycling and vegetation dynamics. Currently, river runoff from small, nearly natural, catchments is one of the few variables of the terrestrial water balance that is regularly monitored with detailed spatial and temporal coverage on large scales. River runoff, therefore, provides a foundation to approach European hydrology with respect to observed patterns on large scales, with regard to the ability of models to capture these.The analysis of observed river flow from small catchments, focused on the identification and description of spatial patterns of simultaneous temporal variations of runoff. These are dominated by large-scale variations of climatic variables but also altered by catchment processes. It was shown that time series of annual low, mean and high flows follow the same atmospheric drivers. The observation that high flows are more closely coupled to large scale atmospheric drivers than low flows, indicates the increasing influence of catchment properties on runoff under dry conditions. Further, it was shown that the low-frequency variability of European runoff is dominated by two opposing centres of simultaneous variations, such that dry years in the north are accompanied by wet years in the south.Large-scale hydrological models are simplified representations of our current perception of the terrestrial water balance on large scales. Quantification of the models strengths and weaknesses is the prerequisite for a reliable interpretation of simulation results. Model evaluations may also enable to detect shortcomings with model assumptions and thus enable a refinement of the current perception of hydrological systems. The ability of a multi model ensemble of nine large-scale