Experimental study of single event burnout and single event gate rupture in power MOSFETs and IGBT

International Nuclear Information System (INIS)

Tang Benqi; Wang Yanping; Geng Bin

2001-01-01

An experimental study was carried out to determine the single event burnout and single event gate rupture sensitivities in power MOSFETs and IGBT which were exposed to heavy ions from 252 Cf source. The test method, test results, a description of observed burnout current waveforms and a discussion of a possible failure mechanism were presented. Current measurements have been performed with a specially designed circuit. The test results include the observed dependence upon applied drain or gate to source bias and versus with external capacitors and limited resistors

Equivalent properties of single event burnout induced by different sources

International Nuclear Information System (INIS)

Yang Shiyu; Cao Zhou; Da Daoan; Xue Yuxiong

2009-01-01

The experimental results of single event burnout induced by heavy ions and 252 Cf fission fragments in power MOSFET devices have been investigated. It is concluded that the characteristics of single event burnout induced by 252 Cf fission fragments is consistent to that in heavy ions. The power MOSFET in the 'turn-off' state is more susceptible to single event burnout than it is in the 'turn-on' state. The thresholds of the drain-source voltage for single event burnout induced by 173 MeV bromine ions and 252 Cf fission fragments are close to each other, and the burnout cross section is sensitive to variation of the drain-source voltage above the threshold of single event burnout. In addition, the current waveforms of single event burnouts induced by different sources are similar. Different power MOSFET devices may have different probabilities for the occurrence of single event burnout. (authors)

Mild and severe muscular dystrophy caused by a single {gamma}-sarcoglycan mutation

Energy Technology Data Exchange (ETDEWEB)

McNally, E.M.; Boennemann, C.G.; Lidov, H.G.W. [Brigham and Women`s Hospital, Boston, MA (United States)] [and others

1996-11-01

Autosomal recessive muscular dystrophy is genetically heterogeneous. One form of this disorder, limb-girdle muscular dystrophy type 2C (LGMD 2C), is prevalent in northern Africa and has been shown to be associated with a single mutation in the gene encoding the dystrophin-associated protein {gamma}-sarcoglycan. The previous mutation analysis of {gamma}-sarcoglycan required the availability of muscle biopsies. To establish a mutation assay for genomic DNA, the intron-exon structure of the {gamma}-sarcoglycan gene was determined, and primers were designed to amplify each of the exons encoding {gamma}-sarcoglycan. We studied a group of Brazilian muscular dystrophy patients for mutations in the {gamma}-sarcoglycan gene. These patients were selected on the basis of autosomal inheritance and/or the presence of normal dystrophin and/or deficiency of {alpha}-sarcoglycan immunostaining. Four of 19 patients surveyed had a single, homozygous mutation in the {gamma}-sarcoglycan gene. The mutation identified in these patients, all of African-Brazilian descent, is identical to that seen in the North African population, suggesting that even patients of remote African descent may carry this mutation. The phenotype in these patients varied considerably. Of four families with an identical mutation, three have a severe Duchenne-like muscular dystrophy. However, one family has much milder symptoms, suggesting that other loci may be present that modify the severity of the clinical course resulting from {gamma}-sarcoglycan gene mutations. 19 refs., 5 figs., 3 tabs.

Identifying EGFR-Expressed Cells and Detecting EGFR Multi-Mutations at Single-Cell Level by Microfluidic Chip

Science.gov (United States)

Li, Ren; Zhou, Mingxing; Li, Jine; Wang, Zihua; Zhang, Weikai; Yue, Chunyan; Ma, Yan; Peng, Hailin; Wei, Zewen; Hu, Zhiyuan

2018-03-01

EGFR mutations companion diagnostics have been proved to be crucial for the efficacy of tyrosine kinase inhibitor targeted cancer therapies. To uncover multiple mutations occurred in minority of EGFR-mutated cells, which may be covered by the noises from majority of un-mutated cells, is currently becoming an urgent clinical requirement. Here we present the validation of a microfluidic-chip-based method for detecting EGFR multi-mutations at single-cell level. By trapping and immunofluorescently imaging single cells in specifically designed silicon microwells, the EGFR-expressed cells were easily identified. By in situ lysing single cells, the cell lysates of EGFR-expressed cells were retrieved without cross-contamination. Benefited from excluding the noise from cells without EGFR expression, the simple and cost-effective Sanger's sequencing, but not the expensive deep sequencing of the whole cell population, was used to discover multi-mutations. We verified the new method with precisely discovering three most important EGFR drug-related mutations from a sample in which EGFR-mutated cells only account for a small percentage of whole cell population. The microfluidic chip is capable of discovering not only the existence of specific EGFR multi-mutations, but also other valuable single-cell-level information: on which specific cells the mutations occurred, or whether different mutations coexist on the same cells. This microfluidic chip constitutes a promising method to promote simple and cost-effective Sanger's sequencing to be a routine test before performing targeted cancer therapy.[Figure not available: see fulltext.

Mutational jackpot events generate effective frequency-dependent selection in adapting populations

Science.gov (United States)

Hallatschek, Oskar

The site-frequency spectrum is one the most easily measurable quantities that characterize the genetic diversity of a population. While most neutral models predict that site frequency spectra should decay with increasing frequency, a high-frequency uptick has been reported in many populations. Anomalies in the high-frequency tail are particularly unsettling because the highest frequencies can be measured with greatest accuracy. Here, we show that an uptick in the spectrum of neutral mutations generally arises when mutant frequencies are dominated by rare jackpot events, mutational events with large descendant numbers. This leads to an effective pattern of frequency-dependent selection (or unstable internal equilibrium at one half frequency) that causes an accumulation of high-frequency polymorphic sites. We reproduce the known uptick occurring for recurrent hitchhiking (genetic draft) as well as rapid adaptation, and (in the future) generalize the shape of the high-frequency tail to other scenarios that are dominated by jackpot events, such as frequent range expansions. We also tackle (in the future) the inverse approach to use the high-frequency uptick for learning about the tail of the offspring number distribution. Positively selected alleles need to surpass, typically, an u NSF Career Award (PoLS), NIH NIGMS R01, Simons Foundation.

Heavy ion and proton-induced single event multiple upset

International Nuclear Information System (INIS)

Reed, R.A.; Carts, M.A.; Marshall, P.W.

1997-01-01

Individual ionizing heavy ion events are shown to cause two or more adjacent memory cells to change logic states in a high density CMOS SRAM. A majority of the upsets produced by normally incident heavy ions are due to single-particle events that causes a single cell to upset. However, for grazing angles a majority of the upsets produced by heavy-ion irradiation are due to single-particle events that cause two or more cells to change logic states. Experimental evidence of a single proton-induced spallation reaction that causes two adjacent memory cells to change logic states is presented. Results from a dual volume Monte-Carlo simulation code for proton-induced single-event multiple upsets are within a factor of three of experimental data for protons at normal incidence and 70 degrees

Precise estimates of mutation rate and spectrum in yeast

Science.gov (United States)

Zhu, Yuan O.; Siegal, Mark L.; Hall, David W.; Petrov, Dmitri A.

2014-01-01

Mutation is the ultimate source of genetic variation. The most direct and unbiased method of studying spontaneous mutations is via mutation accumulation (MA) lines. Until recently, MA experiments were limited by the cost of sequencing and thus provided us with small numbers of mutational events and therefore imprecise estimates of rates and patterns of mutation. We used whole-genome sequencing to identify nearly 1,000 spontaneous mutation events accumulated over ∼311,000 generations in 145 diploid MA lines of the budding yeast Saccharomyces cerevisiae. MA experiments are usually assumed to have negligible levels of selection, but even mild selection will remove strongly deleterious events. We take advantage of such patterns of selection and show that mutation classes such as indels and aneuploidies (especially monosomies) are proportionately much more likely to contribute mutations of large effect. We also provide conservative estimates of indel, aneuploidy, environment-dependent dominant lethal, and recessive lethal mutation rates. To our knowledge, for the first time in yeast MA data, we identified a sufficiently large number of single-nucleotide mutations to measure context-dependent mutation rates and were able to (i) confirm strong AT bias of mutation in yeast driven by high rate of mutations from C/G to T/A and (ii) detect a higher rate of mutation at C/G nucleotides in two specific contexts consistent with cytosine methylation in S. cerevisiae. PMID:24847077

Multi-Unit Initiating Event Analysis for a Single-Unit Internal Events Level 1 PSA

Energy Technology Data Exchange (ETDEWEB)

Kim, Dong San; Park, Jin Hee; Lim, Ho Gon [KAERI, Daejeon (Korea, Republic of)

2016-05-15

The Fukushima nuclear accident in 2011 highlighted the importance of considering the risks from multi-unit accidents at a site. The ASME/ANS probabilistic risk assessment (PRA) standard also includes some requirements related to multi-unit aspects, one of which (IE-B5) is as follows: 'For multi-unit sites with shared systems, DO NOT SUBSUME multi-unit initiating events if they impact mitigation capability [1].' However, the existing single-unit PSA models do not explicitly consider multi-unit initiating events and hence systems shared by multiple units (e.g., alternate AC diesel generator) are fully credited for the single unit and ignores the need for the shared systems by other units at the same site [2]. This paper describes the results of the multi-unit initiating event (IE) analysis performed as a part of the at-power internal events Level 1 probabilistic safety assessment (PSA) for an OPR1000 single unit ('reference unit'). In this study, a multi-unit initiating event analysis for a single-unit PSA was performed, and using the results, dual-unit LOOP initiating event was added to the existing PSA model for the reference unit (OPR1000 type). Event trees were developed for dual-unit LOOP and dual-unit SBO which can be transferred from dual- unit LOOP. Moreover, CCF basic events for 5 diesel generators were modelled. In case of simultaneous SBO occurrences in both units, this study compared two different assumptions on the availability of the AAC D/G. As a result, when dual-unit LOOP initiating event was added to the existing single-unit PSA model, the total CDF increased by 1∼ 2% depending on the probability that the AAC D/G is available to a specific unit in case of simultaneous SBO in both units.

Detecting β-thalassaemia mutations from a single cell by PEP and RDB

Institute of Scientific and Technical Information of China (English)

YI Ping; LI Li; YAO Hong; ZHOU Yuan-guo; DENG Bing; CHEN Zhu-qin

2006-01-01

Objective:To evaluate the possibility of the technology involving PEP and RDB for detecting β-thalassaemia multipoint mutations from a single cell simultaneously. Methods: A set of allele specific oligonucleotide (ASO) probes used for detecting 8 familiar β-thalassaemia mutations (CD41-42, IVS- Ⅱ -654, CD17, TATA box nt-28, CD71-72, TATA box nt-29, CD26, IVS- Ⅰ -5) were immobilized on a strip of nylon membrane. The genome of a individual cell was amplified by primer extension preamplification (PEP) with the mixture of15-base random oligonucleotides. The aliquots from PEP were used to amplify the objective gene fractions of β-thalassaemia gene by nested or semi-nested PCR. The membrane was hybridized with the final amplified products and then treated with Streptavidin-HRP and color development.Results :Totally 30 lymphocytes were picked up from blood samples of 1 healthy female and 4 patients with known β-thalassaemia mutations respectively. Each single lymphocyte was lysed in the proteinase K buffer. The amplification efficacy was 94.0% and alle drop-out(ADO) rate was 8.0%. Revert dot blot (RDB) was applied to the final amplified products from the 5 participants. The results of diagnosis were the same to the expected, and their genotypes were N/N, CD17 (A→T)/N, IVS- Ⅱ -654(C→T)/CD17(A → T), CD41-42 (-CTTT)/N and TATA box nt-28 (A→G)/N, respectively. Conclusion: The technology involving PEP and RDB could detectmultiple β-thalassaemia mutations from a single cell simultaneously,and the research provides experimental evidences for the feasibility of applying PEP and DNA array technology to screening multiple genetic mutations from a single cell, and will be applied to preimplantation genetic diagnosis and non-invasive prenatal diagnosis for β-thalassaemia.

European accelerator facilities for single event effects testing

Energy Technology Data Exchange (ETDEWEB)

Adams, L; Nickson, R; Harboe-Sorensen, R [ESA-ESTEC, Noordwijk (Netherlands); Hajdas, W; Berger, G

1997-03-01

Single event effects are an important hazard to spacecraft and payloads. The advances in component technology, with shrinking dimensions and increasing complexity will give even more importance to single event effects in the future. The ground test facilities are complex and expensive and the complexities of installing a facility are compounded by the requirement that maximum control is to be exercised by users largely unfamiliar with accelerator technology. The PIF and the HIF are the result of experience gained in the field of single event effects testing and represent a unique collaboration between space technology and accelerator experts. Both facilities form an essential part of the European infrastructure supporting space projects. (J.P.N.)

Single event phenomena in atmospheric neutron environments

International Nuclear Information System (INIS)

Gossett, C.A.; Hughlock, B.W.; Katoozi, M.; LaRue, G.S.; Wender, S.A.

1993-01-01

As integrated circuit technology achieves higher density through smaller feature sizes and as the airplane manufacturing industry integrates more sophisticated electronic components into the design of new aircraft, it has become increasingly important to evaluate the contribution of single event effects, primarily Single Event Upset (SEU), to the safety and reliability of commercial aircraft. In contrast to the effects of radiation on electronic systems in space applications for which protons and heavy ions are of major concern, in commercial aircraft applications the interactions of high energy neutrons are the dominant cause of single event effects. These high energy neutrons are produced by the interaction of solar and galactic cosmic rays, principally protons and heavy ions, in the upper atmosphere. This paper will describe direct experimental measurements of neutron-induced Single Event Effect (SEE) rates in commercial high density static random access memories in a neutron environment characteristic of that at commercial airplane altitudes. The first experimental measurements testing current models for neutron-silicon burst generation rates will be presented, as well as measurements of charge collection in silicon test structures as a function of neutron energy. These are the first laboratory SEE and charge collection measurements using a particle beam having a continuum energy spectrum and with a shape nearly identical to that observed during flight

The single-event effect evaluation technology for nano integrated circuits

International Nuclear Information System (INIS)

Zheng Hongchao; Zhao Yuanfu; Yue Suge; Fan Long; Du Shougang; Chen Maoxin; Yu Chunqing

2015-01-01

Single-event effects of nano scale integrated circuits are investigated. Evaluation methods for single-event transients, single-event upsets, and single-event functional interrupts in nano circuits are summarized and classified in detail. The difficulties in SEE testing are discussed as well as the development direction of test technology, with emphasis placed on the experimental evaluation of a nano circuit under heavy ion, proton, and laser irradiation. The conclusions in this paper are based on many years of testing at accelerator facilities and our present understanding of the mechanisms for SEEs, which have been well verified experimentally. (paper)

Analysis of early initiating event(s) in radiation-induced thymic lymphomagenesis

International Nuclear Information System (INIS)

Muto, Masahiro; Ying Chen; Kubo, Eiko; Mita, Kazuei

1996-01-01

Since the T cell receptor rearrangement is a sequential process and unique to the progeny of each clone, we investigated the early initiating events in radiation-induced thymic lymphomagenesis by comparing the oncogenic alterations with the pattern of γ T cell receptor (TCR) rearrangements. We reported previously that after leukemogenic irradiation, preneoplastic cells developed, albeit infrequently, from thymic leukemia antigen-2 + (TL-2 + ) thymocytes. Limited numbers of TL-2 + cells from individual irradiated B10.Thy-1.1 mice were injected into B10.Thy-1.2 mice intrathymically, and the common genetic changes among the donor-type T cell lymphomas were investigated with regard to p53 gene and chromosome aberrations. The results indicated that some mutations in the p53 gene had taken place in these lymphomas, but there was no common mutation among the donor-type lymphomas from individual irradiated mice, suggesting that these mutations were late-occurring events in the process of oncogenesis. On the other hand, there were common chromosome aberrations or translocations such as trisomy 15, t(7F; 10C), t(1A; 13D) or t(6A; XB) among the donor-type lymphomas derived from half of the individual irradiated mice. This indicated that the aberrations/translocations, which occurred in single progenitor cells at the early T cell differentiation either just before or after γ T cell receptor rearrangements, might be important candidates for initiating events. In the donor-type lymphomas from the other half of the individual irradiated mice, microgenetic changes were suggested to be initial events and also might take place in single progenitor cells just before or right after γ TCR rearrangements. (author)

Future challenges in single event effects for advanced CMOS technologies

International Nuclear Information System (INIS)

Guo Hongxia; Wang Wei; Luo Yinhong; Zhao Wen; Guo Xiaoqiang; Zhang Keying

2010-01-01

SEE have became a substantial Achilles heel for the reliability of space-based advanced CMOS technologies with features size downscaling. Future space and defense systems require identification and understanding of single event effects to develop hardening approaches for advanced technologies, including changes in device geometry and materials affect energy deposition, charge collection,circuit upset, parametric degradation devices. Topics covered include the impact of technology scaling on radiation response, including single event transients in high speed digital circuits, evidence for single event effects caused by proton direct ionization, and the impact for SEU induced by particle energy effects and indirect ionization. The single event effects in CMOS replacement technologies are introduced briefly. (authors)

Preleukemic and second-hit mutational events in an acute myeloid leukemia patient with a novel germline RUNX1 mutation.

Science.gov (United States)

Ng, Isaac Ks; Lee, Joanne; Ng, Christopher; Kosmo, Bustamin; Chiu, Lily; Seah, Elaine; Mok, Michelle Meng Huang; Tan, Karen; Osato, Motomi; Chng, Wee-Joo; Yan, Benedict; Tan, Lip Kun

2018-01-01

Germline mutations in the RUNX1 transcription factor give rise to a rare autosomal dominant genetic condition classified under the entity: Familial Platelet Disorders with predisposition to Acute Myeloid Leukaemia (FPD/AML). While several studies have identified a myriad of germline RUNX1 mutations implicated in this disorder, second-hit mutational events are necessary for patients with hereditary thrombocytopenia to develop full-blown AML. The molecular picture behind this process remains unclear. We describe a patient of Malay descent with an unreported 7-bp germline RUNX1 frameshift deletion, who developed second-hit mutations that could have brought about the leukaemic transformation from a pre-leukaemic state. These mutations were charted through the course of the treatment and stem cell transplant, showing a clear correlation between her clinical presentation and the mutations present. The patient was a 27-year-old Malay woman who presented with AML on the background of hereditary thrombocytopenia affecting her father and 3 brothers. Initial molecular testing revealed the same novel RUNX1 mutation in all 5 individuals. The patient received standard induction, consolidation chemotherapy, and a haploidentical stem cell transplant from her mother with normal RUNX1 profile. Comprehensive genomic analyses were performed at diagnosis, post-chemotherapy and post-transplant. A total of 8 mutations ( RUNX1 , GATA2 , DNMT3A , BCORL1 , BCOR , 2 PHF6 and CDKN2A ) were identified in the pre-induction sample, of which 5 remained ( RUNX1 , DNMT3A , BCORL1 , BCOR and 1 out of 2 PHF6 ) in the post-treatment sample and none were present post-transplant. In brief, the 3 mutations which were lost along with the leukemic cells at complete morphological remission were most likely acquired leukemic driver mutations that were responsible for the AML transformation from a pre-leukemic germline RUNX1 -mutated state. On the contrary, the 5 mutations that persisted post

The effect of a single recombination event

DEFF Research Database (Denmark)

Schierup, Mikkel Heide; Jensen, Thomas Mailund; Wiuf, Carsten

We investigate the variance in how visible a single recombination event is in a SNP data set as a function of the type of recombination event and its age. Data is simulated under the coalescent with recombination and inference is by the popular composite likelihood methods. The major determinant...

Discrimination of three mutational events that result in a disruption of the R122 primary autolysis site of the human cationic trypsinogen (PRSS1 by denaturing high performance liquid chromatography

Directory of Open Access Journals (Sweden)

Férec Claude

2001-11-01

Full Text Available Abstract Background R122, the primary autolysis site of the human cationic trypsinogen (PRSS1, constitutes an important "self-destruct" or "fail-safe" defensive mechanism against premature trypsin activation within the pancreas. Disruption of this site by a missense mutation, R122H, was found to cause hereditary pancreatitis. In addition to a c.365G>A (CGC>CAC single nucleotide substitution, a c.365~366GC>AT (CGC>CAT gene conversion event in exon 3 of PRSS1 was also found to result in a R122H mutation. This imposes a serious concern on the genotyping of pancreatitis by a widely used polymerase chain reaction-restriction fragment length polymorphism assay, which could only detect the commonest c.365G>A variant. Materials and methods DNA samples containing either the known c.365G>A or c.365~366GC>AT variant in exon 3 of PRSS1 were used as positive controls to establish a denaturing high performance liquid chromatography (DHPLC assay. Results DHPLC could readily discriminate the two known different mutational events resulting in the R122H mutation. More importantly, under the same experimental conditions, it identified a further mutational event that also occurs in the R122 primary autolysis site but results in a different amino acid substitution: c.364C>T (CGC>TGC; R122C. Conclusions A rapid, simple, and low-cost assay for detecting both the known and new mutations occuring in the R122 primary autolysis site of PRSS1 was established. In addition, the newly found R122C variant represents a likely pancreatitis-predisposing mutation.

Measuring Single Event Upsets in the ATLAS Inner Tracker

CERN Multimedia

CERN. Geneva

2015-01-01

When the HL-LHC starts collecting data, the electronics inside will be subject to massive amounts of radiation. As a result, single event upsets could pose a threat to the ATLAS readout chain. The ABC130, a prototype front-end ASIC for the ATLAS inner tracker, must be tested for its susceptibility to single event upsets.

Single event burnout sensitivity of embedded field effect transistors

International Nuclear Information System (INIS)

Koga, R.; Crain, S.H.; Crawford, K.B.; Yu, P.; Gordon, M.J.

1999-01-01

Observations of single event burnout (SEB) in embedded field effect transistors are reported. Both SEB and other single event effects are presented for several pulse width modulation and high frequency devices. The microscope has been employed to locate and to investigate the damaged areas. A model of the damage mechanism based on the results so obtained is described

Single event burnout sensitivity of embedded field effect transistors

Energy Technology Data Exchange (ETDEWEB)

Koga, R.; Crain, S.H.; Crawford, K.B.; Yu, P.; Gordon, M.J.

1999-12-01

Observations of single event burnout (SEB) in embedded field effect transistors are reported. Both SEB and other single event effects are presented for several pulse width modulation and high frequency devices. The microscope has been employed to locate and to investigate the damaged areas. A model of the damage mechanism based on the results so obtained is described.

Crystal ball single event display

International Nuclear Information System (INIS)

Grosnick, D.; Gibson, A.; Allgower, C.; Alyea, J.; Argonne National Lab., IL

1997-01-01

The Single Event Display (SED) is a routine that is designed to provide information graphically about a triggered event within the Crystal Ball. The SED is written entirely in FORTRAN and uses the CERN-based HICZ graphing package. The primary display shows the amount of energy deposited in each of the NaI crystals on a Mercator-like projection of the crystals. Ten different shades and colors correspond to varying amounts of energy deposited within a crystal. Information about energy clusters is displayed on the crystal map by outlining in red the thirteen (or twelve) crystals contained within a cluster and assigning each cluster a number. Additional information about energy clusters is provided in a series of boxes containing useful data about the energy distribution among the crystals within the cluster. Other information shown on the event display include the event trigger type and data about π o 's and η's formed from pairs of clusters as found by the analyzer. A description of the major features is given, along with some information on how to install the SED into the analyzer

Fast recognition of single molecules based on single-event photon statistics

International Nuclear Information System (INIS)

Dong Shuangli; Huang Tao; Liu Yuan; Wang Jun; Zhang Guofeng; Xiao Liantuan; Jia Suotang

2007-01-01

Mandel's Q parameter, which is determined from single-event photon statistics, provides an alternative way to recognize single molecules with fluorescence detection, other than the second-order correlation function. It is shown that the Q parameter of an assumed ideal double-molecule fluorescence with the same average photon number as that of the sample fluorescence can act as the criterion for single-molecule recognition. The influence of signal-to-background ratio and the error estimates for photon statistics are also presented. We have applied this method to ascertain single Cy5 dye molecules within hundreds of milliseconds

Mature Microsatellites: Mechanisms Underlying Dinucleotide Microsatellite Mutational Biases in Human Cells

OpenAIRE

Baptiste, Beverly A.; Ananda, Guruprasad; Strubczewski, Noelle; Lutzkanin, Andrew; Khoo, Su Jen; Srikanth, Abhinaya; Kim, Nari; Makova, Kateryna D.; Krasilnikova, Maria M.; Eckert, Kristin A.

2013-01-01

Dinucleotide microsatellites are dynamic DNA sequences that affect genome stability. Here, we focused on mature microsatellites, defined as pure repeats of lengths above the threshold and unlikely to mutate below it in a single mutational event. We investigated the prevalence and mutational behavior of these sequences by using human genome sequence data, human cells in culture, and purified DNA polymerases. Mature dinucleotides (?10 units) are present within exonic sequences of >350 genes, re...

Conditions and consequences of a BRCA mutation in young, single women of childbearing age.

Science.gov (United States)

Hamilton, Rebekah; Hurley, Karen E

2010-09-01

To explore the experiences of young, single women who are at increased risk for hereditary breast and ovarian cancer (HBOC) because of a BRCA mutation. Qualitative. Seven states and Canada. 11 single women aged 18-35 years who tested positive for a BRCA mutation. Grounded theory with in-depth individual interviews conducted via e-mail or telephone. Analysis resulted in three conditions and three consequences. Conditions were dating or not dating, time in a relationship, and physical impact of surgery or breast cancer treatment. Consequences were explaining their choices, experiencing a sense of urgency, and experiencing a sense of loss. Young women who are at risk for HBOC face a complex array of decisions after finding out that they carry a BRCA mutation. Being single and childless adds to this complexity. Nurses can listen to young women with HBOC risk, help them clarify their fears and understanding of their risk, and provide nonthreatening support that goes beyond simply providing more information and includes a nonjudgmental understanding of the young women's experience.

Comprehensive detection of diverse exon 19 deletion mutations of EGFR in lung Cancer by a single probe set.

Science.gov (United States)

Bae, Jin Ho; Jo, Seong-Min; Kim, Hak-Sung

2015-12-15

Detection of exon 19 deletion mutation of EGFR, one of the most frequently occurring mutations in lung cancer, provides the crucial information for diagnosis and treatment guideline in non-small-cell lung cancer (NSCLC). Here, we demonstrate a simple and efficient method to detect various exon 19 deletion mutations of EGFR using a single probe set comprising of an oligo-quencher (oligo-Q) and a molecular beacon (MB). While the MB hybridizes to both the wild and mutant target DNA, the oligo-Q only binds to the wild target DNA, leading to a fluorescent signal in case of deletion mutation. This enables the comprehensive detection of the diverse exon 19 deletion mutations using a single probe set. We demonstrated the utility and efficiency of the approach by detecting the frequent exon 19 deletion mutations of EGFR through a real-time PCR and in situ fluorescence imaging. Our approach enabled the detection of genomic DNA as low as 0.02 ng, showing a detection limit of 2% in a heterogeneous DNA mixture, and could be used for detecting mutations in a single cell level. The present MB and oligo-Q dual probe system can be used for diagnosis and treatment guideline in NSCLC. Copyright © 2015 Elsevier B.V. All rights reserved.

Targeted mutations induced by a single acetylaminofluorene DNA adduct in mammalian cells and bacteria

International Nuclear Information System (INIS)

Moryia, M.; Takeshita, M.; Johnson, F.; Peden, K.; Will, S.; Grollman, A.P.

1988-01-01

Mutagenic specificity of 2-acetylaminofluorene (AAF) has been established in mammalian cells and several strains of bacteria by using a shuttle plasmid vector containing a single N-(deoxyguanosin-8-yl)acetylaminofluorene (C8-dG-AAF) adduct. The nucleotide sequence of the gene conferring tetracycline resistance was modified by conservative codon replacement so as to accommodate the sequence d(CCTTCGCTAC) flanked by two restriction sites, Bsm I and Xho I. The corresponding synthetic oligodeoxynucleotide underwent reaction with 2-(N-acetoxy-N-acetylamino)-fluorene (AAAF), forming a single dG-AAF adduct. This modified oligodeoxynucleotide was hybridized to its complementary strand and ligated between the Bsm I and Xho I sites of the vector. Plasmids containing the C8-dG-AAF adduct were used to transfect simian virus 40-transformed simian kidney (COS-1) cells and to transform several AB strains of Escherichia coli. Colonies containing mutant plasmides were detected by hybridization to 32 P-labeled oligodeoxynucleotides. Presence of the single DNA adduct increased the mutation frequency by 8-fold in both COS cells and E. coli. Over 80% of mutations detected in both systems were targeted and represented G x C → C x G or G x C → T x A transversions or single nucleotide deletions. The authors conclude that modification of a deoxyguanosine residue with AAF preferentially induces mutations targeted at this site when a plasmid containing a single C8-dG-AAF adduct is introduced into mammalian cells or bacteria

A Dual Phenotype of Periventricular Nodular Heterotopia and Frontometaphyseal Dysplasia in One Patient Caused by a Single FLNA Mutation Leading to Two Functionally Different Aberrant Transcripts

Science.gov (United States)

Zenker, Martin; Rauch, Anita; Winterpacht, Andreas; Tagariello, Andreas; Kraus, Cornelia; Rupprecht, Thomas; Sticht, Heinrich; Reis, André

2004-01-01

Two disorders, periventricular nodular heterotopia (PVNH) and a group of skeletal dysplasias belonging to the oto-palato-digital (OPD) spectrum, are caused by FLNA mutations. They are considered mutually exclusive because of the different presumed effects of the respective FLNA gene mutations, leading to loss of function (PVNH) and gain of function (OPD), respectively. We describe here the first patient manifesting PVNH in combination with frontometaphyseal dysplasia, a skeletal dysplasia of the OPD-spectrum. A novel de novo mutation, 7315C→A in exon 45 of the FLNA gene, was identified. It leads to two aberrant transcripts, one full-length transcript with the point mutation causing a substitution of a highly conserved leucine residue (L2439M) and a second shortened transcript lacking 21 bp due to the creation of an ectopic splice donor site in exon 45. We propose that the dual phenotype is caused by two functionally different, aberrant filamin A proteins and therefore represents an exceptional model case of allelic gain-of-function and loss-of-function phenotypes due to a single mutational event. PMID:14988809

Destructive Single-Event Effects in Diodes

Science.gov (United States)

Casey, Megan C.; Lauenstein, Jean-Marie; Campola, Michael J.; Wilcox, Edward P.; Phan, Anthony M.; Label, Kenneth A.

2017-01-01

In this work, we discuss the observed single-event effects in a variety of types of diodes. In addition, we conduct failure analysis on several Schottky diodes that were heavy-ion irradiated. High- and low-magnitude optical microscope images, infrared camera images, and scanning electron microscope images are used to identify and describe the failure locations.

A single nucleotide mutation in Nppc is associated with a long bone abnormality in lbab mice.

Science.gov (United States)

Jiao, Yan; Yan, Jian; Jiao, Feng; Yang, Hongbin; Donahue, Leah Rae; Li, Xinmin; Roe, Bruce A; Stuart, John; Gu, Weikuan

2007-04-17

The long bone abnormality (lbab) mouse is a new autosomal recessive mutant characterized by overall smaller body size with proportionate dwarfing of all organs and shorter long bones. Previous linkage analysis has located the lbab mutation on chromosome 1 between the markers D1Mit9 and D1Mit488. A genome-based positional approach was used to identify a mutation associated with lbab disease. A total of 122 genes and expressed sequence tags at the lbab region were screened for possible mutation by using genomic DNA from lbabl/lbab, lbab/+, and +/+ B6 mice and high throughput temperature gradient capillary electrophoresis. A sequence difference was identified in one of the amplicons of gene Nppc between lbab/lbab and +/+ mice. One-step reverse transcriptase polymerase chain reaction was performed to validate the difference of Nppc in different types of mice at the mRNA level. The mutation of Nppc was unique in lbab/lbab mice among multiple mouse inbred strains. The mutation of Nppc is co-segregated with lbab disease in 200 progenies produced from heterozygous lbab/+ parents. A single nucleotide mutation of Nppc is associated with dwarfism in lbab/lbab mice. Current genome information and technology allow us to efficiently identify single nucleotide mutations from roughly mapped disease loci. The lbab mouse is a useful model for hereditary human achondroplasia.

A single nucleotide mutation in Nppc is associated with a long bone abnormality in lbab mice

Directory of Open Access Journals (Sweden)

Roe Bruce A

2007-04-01

Full Text Available Abstract Background The long bone abnormality (lbab mouse is a new autosomal recessive mutant characterized by overall smaller body size with proportionate dwarfing of all organs and shorter long bones. Previous linkage analysis has located the lbab mutation on chromosome 1 between the markers D1Mit9 and D1Mit488. Results A genome-based positional approach was used to identify a mutation associated with lbab disease. A total of 122 genes and expressed sequence tags at the lbab region were screened for possible mutation by using genomic DNA from lbabl/lbab, lbab/+, and +/+ B6 mice and high throughput temperature gradient capillary electrophoresis. A sequence difference was identified in one of the amplicons of gene Nppc between lbab/lbab and +/+ mice. One-step reverse transcriptase polymerase chain reaction was performed to validate the difference of Nppc in different types of mice at the mRNA level. The mutation of Nppc was unique in lbab/lbab mice among multiple mouse inbred strains. The mutation of Nppc is co-segregated with lbab disease in 200 progenies produced from heterozygous lbab/+ parents. Conclusion A single nucleotide mutation of Nppc is associated with dwarfism in lbab/lbab mice. Current genome information and technology allow us to efficiently identify single nucleotide mutations from roughly mapped disease loci. The lbab mouse is a useful model for hereditary human achondroplasia.

Microbeam mapping of single event latchups and single event upsets in CMOS SRAMs

International Nuclear Information System (INIS)

Barak, J.; Adler, E.; Fischer, B.E.; Schloegl, M.; Metzger, S.

1998-01-01

The first simultaneous microbeam mapping of single event upset (SEU) and latchup (SEL) in the CMOS RAM HM65162 is presented. The authors found that the shapes of the sensitive areas depend on V DD , on the ions being used and on the site on the chip being hit by the ion. In particular, they found SEL sensitive sites close to the main power supply lines between the memory-bit-arrays by detecting the accompanying current surge. All these SELs were also accompanied by bit-flips elsewhere in the memory (which they call indirect SEUs in contrast to the well known SEUs induced in the hit memory cell only). When identical SEL sensitive sites were hit farther away from the supply lines only indirect SEL sensitive sites could be detected. They interpret these events as latent latchups in contrast to the classical ones detected by their induced current surge. These latent SELs were probably decoupled from the main supply lines by the high resistivity of the local supply lines

Single Event Burnout in DC-DC Converters for the LHC Experiments

Energy Technology Data Exchange (ETDEWEB)

Claudio H. Rivetta et al.

2001-09-24

High voltage transistors in DC-DC converters are prone to catastrophic Single Event Burnout in the LHC radiation environment. This paper presents a systematic methodology to analyze single event effects sensitivity in converters and proposes solutions based on de-rating input voltage and output current or voltage.

Quantification of sequence exchange events between PMS2 and PMS2CL provides a basis for improved mutation scanning of Lynch syndrome patients.

NARCIS (Netherlands)

Klift, H.M. van der; Tops, C.M.; Bik, E.C.; Boogaard, M.W.; Borgstein, A.M.; Hansson, K.B.; Ausems, M.G.E.M.; Gomez Garcia, E.; Green, A.; Hes, F.J.; Izatt, L.; Hest, L.P. van; Alonso, A.M.; Vriends, A.H.; Wagner, A.; Zelst-Stams, W.A.G. van; Vasen, H.F.; Morreau, H.; Devilee, P.; Wijnen, J.T.

2010-01-01

Heterozygous mutations in PMS2 are involved in Lynch syndrome, whereas biallelic mutations are found in Constitutional mismatch repair-deficiency syndrome patients. Mutation detection is complicated by the occurrence of sequence exchange events between the duplicated regions of PMS2 and PMS2CL. We

Event-by-event simulation of single-neutron experiments to test uncertainty relations

International Nuclear Information System (INIS)

Raedt, H De; Michielsen, K

2014-01-01

Results from a discrete-event simulation of a recent single-neutron experiment that tests Ozawa's generalization of Heisenberg's uncertainty relation are presented. The event-based simulation algorithm reproduces the results of the quantum theoretical description of the experiment but does not require the knowledge of the solution of a wave equation, nor does it rely on detailed concepts of quantum theory. In particular, the data from these non-quantum simulations satisfy uncertainty relations derived in the context of quantum theory. (paper)

Single Molecule Effects of Osteogenesis Imperfecta Mutations in Tropocollagen Protein Domains

Science.gov (United States)

2008-12-02

Single molecule effects of osteogenesis imperfecta mutations in tropocollagen protein domains Alfonso Gautieri,1,2 Simone Vesentini,2 Alberto...2008 proteinscience.org Abstract: Osteogenesis imperfecta (OI) is a genetic disease characterized by fragile bones, skeletal deformities and, in severe...diagnosis and treatment, an effort referred to as materiomics. Keywords: steered molecular dynamics; osteogenesis imperfecta ; Young’s modulus; collagen

Modeling and simulation of single-event effect in CMOS circuit

International Nuclear Information System (INIS)

Yue Suge; Zhang Xiaolin; Zhao Yuanfu; Liu Lin; Wang Hanning

2015-01-01

This paper reviews the status of research in modeling and simulation of single-event effects (SEE) in digital devices and integrated circuits. After introducing a brief historical overview of SEE simulation, different level simulation approaches of SEE are detailed, including material-level physical simulation where two primary methods by which ionizing radiation releases charge in a semiconductor device (direct ionization and indirect ionization) are introduced, device-level simulation where the main emerging physical phenomena affecting nanometer devices (bipolar transistor effect, charge sharing effect) and the methods envisaged for taking them into account are focused on, and circuit-level simulation where the methods for predicting single-event response about the production and propagation of single-event transients (SETs) in sequential and combinatorial logic are detailed, as well as the soft error rate trends with scaling are particularly addressed. (review)

Adult eyewitness memory for single versus repeated traumatic events

NARCIS (Netherlands)

Theunissen, T.P.M.; Meyer, T.; Memon, A.; Weinsheimer, C.C.

2017-01-01

Reports from individuals who have witnessed multiple, similar emotional events may differ from reports from witnesses of only a single event. To test this, we had participants (N = 65) view a video of a road traffic accident. Half of the participants saw two additional (similar) aversive films.

Single Event Upsets in the ATLAS IBL Front End ASICs

CERN Document Server

Rozanov, Alexandre; The ATLAS collaboration

2018-01-01

During operation at instantaneous luminosities of up to 2.1 1034 cm2 s−1 frontend chips of the ATLAS innermost pixel layer (IBL) experienced single event upsets affecting its global registers as well as the settings for the individual pixels, causing, amongst other things loss of occupancy, noisy pixels, and silent pixels. A quantitative analysis of the single event upsets as well as the operational issues and mitigation techniques are presented.

Development of Guidelines for Use of Proton Single-Event Test Data to Bound Single-Event Effect Susceptibility Due to Light Ions

Data.gov (United States)

National Aeronautics and Space Administration — Conventional methods for Single-Event Effects (SEE) Hardness Assurance have proven difficult to adapt to Explorer, Cubesat and other risk tolerant platforms with...

Near bed suspended sediment flux by single turbulent events

Science.gov (United States)

Amirshahi, Seyed Mohammad; Kwoll, Eva; Winter, Christian

2018-01-01

The role of small scale single turbulent events in the vertical mixing of near bed suspended sediments was explored in a shallow shelf sea environment. High frequency velocity and suspended sediment concentration (SSC; calibrated from the backscatter intensity) were collected using an Acoustic Doppler Velocimeter (ADV). Using quadrant analysis, the despiked velocity time series was divided into turbulent events and small background fluctuations. Reynolds stress and Turbulent Kinetic Energy (TKE) calculated from all velocity samples, were compared to the same turbulent statistics calculated only from velocity samples classified as turbulent events (Reevents and TKEevents). The comparison showed that Reevents and TKEevents was increased 3 and 1.6 times, respectively, when small background fluctuations were removed and that the correlation with SSC for TKE could be improved through removal of the latter. The correlation between instantaneous vertical turbulent flux (w ‧) and SSC fluctuations (SSC ‧) exhibits a tidal pattern with the maximum correlation at peak ebb and flood currents, when strong turbulent events appear. Individual turbulent events were characterized by type, strength, duration and length. Cumulative vertical turbulent sediment fluxes and average SSC associated with individual turbulent events were calculated. Over the tidal cycle, ejections and sweeps were the most dominant events, transporting 50% and 36% of the cumulative vertical turbulent event sediment flux, respectively. Although the contribution of outward interactions to the vertical turbulent event sediment flux was low (11%), single outward interaction events were capable of inducing similar SSC ‧ as sweep events. The results suggest that on time scales of tens of minutes to hours, TKE may be appropriate to quantify turbulence in sediment transport studies, but that event characteristics, particular the upward turbulent flux need to be accounted for when considering sediment transport

Single Event Upsets in the ATLAS IBL Front End ASICs

CERN Document Server

Rozanov, Alexander; The ATLAS collaboration

2018-01-01

During operation at instantaneous luminosities of up to 2.1 10^{34} cm^{-2} s^{-1} the front end chips of the ATLAS innermost pixel layer (IBL) experienced single event upsets affecting its global registers as well as the settings for the individual pixels, causing, among other things loss of occupancy, noisy pixels, and silent pixels. A quantitative analysis of the single event upsets as well as the operational issues and mitigation techniques will be presented.

Single event upset test programs

International Nuclear Information System (INIS)

Russen, L.C.

1984-11-01

It has been shown that the heavy ions in cosmic rays can give rise to single event upsets in VLSI random access memory devices (RAMs). Details are given of the programs written to test 1K, 4K, 16K and 64K memories during their irradiation with heavy charged ions, in order to simulate the effects of cosmic rays in space. The test equipment, which is used to load the memory device to be tested with a known bit pattern, and subsequently interrogate it for upsets, or ''flips'', is fully described. (author)

AIP mutations in Brazilian patients with sporadic pituitary adenomas: a single-center evaluation

Science.gov (United States)

Kasuki, Leandro; de Azeredo Lima, Carlos Henrique; Ogino, Liana; Camacho, Aline H S; Chimelli, Leila; Korbonits, Márta

2017-01-01

Aryl hydrocarbon receptor-interacting protein (AIP) gene mutations (AIPmut) are the most frequent germline mutations found in apparently sporadic pituitary adenomas (SPA). Our aim was to evaluate the frequency of AIPmut among young Brazilian patients with SPA. We performed an observational cohort study between 2013 and 2016 in a single referral center. AIPmut screening was carried out in 132 SPA patients with macroadenomas diagnosed up to 40 years or in adenomas of any size diagnosed until 18 years of age. Twelve tumor samples were also analyzed. Leukocyte DNA and tumor tissue DNA were sequenced for the entire AIP-coding region for evaluation of mutations. Eleven (8.3%) of the 132 patients had AIPmut, comprising 9/74 (12%) somatotropinomas, 1/38 (2.6%) prolactinoma, 1/10 (10%) corticotropinoma and no non-functioning adenomas. In pediatric patients (≤18 years), AIPmut frequency was 13.3% (2/15). Out of the 5 patients with gigantism, two had AIPmut, both truncating mutations. The Y268* mutation was described in Brazilian patients and the K273Rfs*30 mutation is a novel mutation in our patient. No somatic AIP mutations were found in the 12 tumor samples. A tumor sample from an acromegaly patient harboring the A299V AIPmut showed loss of heterozygosity. In conclusion, AIPmut frequency in SPA Brazilian patients is similar to other populations. Our study identified two mutations exclusively found in Brazilians and also shows, for the first time, loss of heterozygosity in tumor DNA from an acromegaly patient harboring the A299V AIPmut. Our findings corroborate previous observations that AIPmut screening should be performed in young patients with SPA. PMID:29074612

Single-Event Transgene Product Levels Predict Levels in Genetically Modified Breeding Stacks.

Science.gov (United States)

Gampala, Satyalinga Srinivas; Fast, Brandon J; Richey, Kimberly A; Gao, Zhifang; Hill, Ryan; Wulfkuhle, Bryant; Shan, Guomin; Bradfisch, Greg A; Herman, Rod A

2017-09-13

The concentration of transgene products (proteins and double-stranded RNA) in genetically modified (GM) crop tissues is measured to support food, feed, and environmental risk assessments. Measurement of transgene product concentrations in breeding stacks of previously assessed and approved GM events is required by many regulatory authorities to evaluate unexpected transgene interactions that might affect expression. Research was conducted to determine how well concentrations of transgene products in single GM events predict levels in breeding stacks composed of these events. The concentrations of transgene products were compared between GM maize, soybean, and cotton breeding stacks (MON-87427 × MON-89034 × DAS-Ø15Ø7-1 × MON-87411 × DAS-59122-7 × DAS-40278-9 corn, DAS-81419-2 × DAS-44406-6 soybean, and DAS-21023-5 × DAS-24236-5 × SYN-IR102-7 × MON-88913-8 × DAS-81910-7 cotton) and their component single events (MON-87427, MON-89034, DAS-Ø15Ø7-1, MON-87411, DAS-59122-7, and DAS-40278-9 corn, DAS-81419-2, and DAS-44406-6 soybean, and DAS-21023-5, DAS-24236-5, SYN-IR102-7, MON-88913-8, and DAS-81910-7 cotton). Comparisons were made within a crop and transgene product across plant tissue types and were also made across transgene products in each breeding stack for grain/seed. Scatter plots were generated comparing expression in the stacks to their component events, and the percent of variability accounted for by the line of identity (y = x) was calculated (coefficient of identity, I 2 ). Results support transgene concentrations in single events predicting similar concentrations in breeding stacks containing the single events. Therefore, food, feed, and environmental risk assessments based on concentrations of transgene products in single GM events are generally applicable to breeding stacks composed of these events.

Variations in tritium levels during single storm events

International Nuclear Information System (INIS)

Smith, L.W.

1979-06-01

Precipitation samples have been taken over a period of one calendar year to determine the variables in environmental tritium during single storm events. Where possible, comment is made on the hydrological implications of these variations

The application of a linear algebra to the analysis of mutation rates.

Science.gov (United States)

Jones, M E; Thomas, S M; Clarke, K

1999-07-07

Cells and bacteria growing in culture are subject to mutation, and as this mutation is the ultimate substrate for selection and evolution, the factors controlling the mutation rate are of some interest. The mutational event is not observed directly, but is inferred from the phenotype of the original mutant or of its descendants; the rate of mutation is inferred from the number of such mutant phenotypes. Such inference presumes a knowledge of the probability distribution for the size of a clone arising from a single mutation. We develop a mathematical formulation that assists in the design and analysis of experiments which investigate mutation rates and mutant clone size distribution, and we use it to analyse data for which the classical Luria-Delbrück clone-size distribution must be rejected. Copyright 1999 Academic Press.

A Single Missense Mutation in 77% of Prostate Cancer Bone Metastases: Novel Opportunity for Genetic Biomarker and Novel Therapeutic Mitochondrial Target

Science.gov (United States)

2017-10-01

goal of this application is to identify targets for the treatment of androgen receptor null castration-resistant prostate cancer in in vitro and pre...AWARD NUMBER: W81XWH-16-1-0584 TITLE : A Single Missense Mutation in 77% of Prostate Cancer Bone Metastases: Novel Opportunity for Genetic...Missense Mutation in 77% of Prostate Cancer Bone Metastases: 5a. CONTRACT NUMBER A Single Missense Mutation in 77% of Prostate Cancer Bone Metastases

Detection of HIV drug resistance mutations in pregnant women receiving single dose Nevirapine in south India

Directory of Open Access Journals (Sweden)

Mini S Jacob

2011-01-01

Full Text Available Background: Single dose of Nevirapine to prevent mother to child transmission of HIV is the commonest preventive regimen in resource-limited countries. Objectives: The objective of this study was to detect drug-resistant virus after single dose of Nevirapine (sdNVP provided to delivering HIV seropositive (HIV+ve women and to evaluate the time taken for its decay. Results: Of the 36 consenting HIV+ve pregnant women enrolled into the study, the mean hemoglobin and total lymphocyte counts were 10.8 g/dl and 1843 cells/mm 3 , respectively. Mean CD4 counts in 64% of women was 363 cells/mm 3 and mean viral load for 16/36 women was 28,143 copies/ml of plasma. Nevirapine-resistance mutations were detected in 28% of women at delivery; using OLA (Oligonucleotide Ligation Assay. K103N mutations were seen in 19.4% of women while the Y181C mutation was seen in 5%. Both the mutations were detected in 2.7% of women. Sequential blood samples collected at delivery, 7-10 days, 6 weeks, 4 months, 6 months and one year postpartum showed that 81% of K103N mutations and 66.7% of Y181C mutations were detected at 6 weeks postpartum . Wild-type virus had replaced the mutants by one year postpartum in all women except one. Conclusion : These observations are relevant for future treatment with antiretroviral therapy in these women for their HIV disease.

Investigation of single event latchup

International Nuclear Information System (INIS)

Xue Yuxiong; Yang Shengsheng; Cao Zhou; Ba Dedong; An Heng; Chen Luojing; Guo Gang

2012-01-01

Radiation effects on avionics microelectronics are important reliability issues for many space applications. In particular, single-event latchup (SEL) phenomenon is a major threat to CMOS integrated circuits in space systems. To effectively circumvent the failure, it is important to know the behavior of such devices during latchup. In this paper, the mechanisms for SEL in CMOS devices are investigated. Several microelectronic devices used in avionics are tested using heavy ion beams, pulsed laser and 252 Cf source. Based on the SEL test results, SEL-hardening and monitoring methods for preventing SEL from the systems design level are proposed. (authors)

Single event effects induced by 15.14 MeV/u 136Xe ions

International Nuclear Information System (INIS)

Hou Mingdong; Zhang Qingxiang; Liu Jie; Wang Zhiguang; Jin Yunfan; Zhu Zhiyong; Zhen Honglou; Liu Changlong; Chen Xiaoxi; Wei Xinguo; Zhang Lin; Fan Youcheng; Zhu Zhourong; Zhang Yiting

2002-01-01

Single event effects induced by 15.14 MeV/u 136 Xe ions in different batches of 32k x 8 bits static random access memory are studied. The incident angle dependences of the cross sections for single event upset and single event latch up are presented. The SEE cross sections are plotted versus energy loss instead of linear energy transfer value in sensitive region. The depth of sensitive volume and thickness of 'dead' layer above the sensitive volume are estimated

Single event effect testing of the Intel 80386 family and the 80486 microprocessor

International Nuclear Information System (INIS)

Moran, A.; LaBel, K.; Gates, M.; Seidleck, C.; McGraw, R.; Broida, M.; Firer, J.; Sprehn, S.

1996-01-01

The authors present single event effect test results for the Intel 80386 microprocessor, the 80387 coprocessor, the 82380 peripheral device, and on the 80486 microprocessor. Both single event upset and latchup conditions were monitored

Single-event effects in analog and mixed-signal integrated circuits

International Nuclear Information System (INIS)

Turflinger, T.L.

1996-01-01

Analog and mixed-signal integrated circuits are also susceptible to single-event effects, but they have rarely been tested. Analog circuit single-particle transients require modified test techniques and data analysis. Existing work is reviewed and future concerns are outlined

Simulating single-event burnout of n-channel power MOSFET's

International Nuclear Information System (INIS)

Johnson, G.H.; Hohl, J.H.; Schrimpf, R.D.; Galloway, K.F.

1993-01-01

Heavy ions are ubiquitous in a space environment. Single-event burnout of power MOSFET's is a sudden catastrophic failure mechanism that is initiated by the passage of a heavy ion through the device structure. The passage of the heavy ion generates a current filament that locally turns on a parasitic n-p-n transistor inherent to the power MOSFET. Subsequent high currents and high voltage in the device induce second breakdown of the parasitic bipolar transistor and hence meltdown of the device. This paper presents a model that can be used for simulating the burnout mechanism in order to gain insight into the significant device parameters that most influence the single-event burnout susceptibility of n-channel power MOSFET's

Single-event burnout of epitaxial bipolar transistors

Energy Technology Data Exchange (ETDEWEB)

Kuboyama, S.; Sugimoto, K.; Shugyo, S.; Matsuda, S. [National Space Development Agency of Japan, Tsukuba, Ibaraki (Japan); Hirao, T. [Japan Atomic Energy Research Inst., Takasaki, Gunma (Japan)

1998-12-01

Single-Event Burnout (SEB) of bipolar junction transistors (BJTs) has been observed nondestructively. It was revealed that all the NPN BJTs, including small signal transistors, with thinner epitaxial layers were inherently susceptible to the SEB phenomenon. It was demonstrated that several design parameters of BJTs were responsible for SEB susceptibility. Additionally, destructive and nondestructive modes of SEB were identified.

Hierarchical mutational events compensate for glutamate auxotrophy of a Bacillus subtilis gltC mutant.

Science.gov (United States)

Dormeyer, Miriam; Lübke, Anastasia L; Müller, Peter; Lentes, Sabine; Reuß, Daniel R; Thürmer, Andrea; Stülke, Jörg; Daniel, Rolf; Brantl, Sabine; Commichau, Fabian M

2017-06-01

Glutamate is the major donor of nitrogen for anabolic reactions. The Gram-positive soil bacterium Bacillus subtilis either utilizes exogenously provided glutamate or synthesizes it using the gltAB-encoded glutamate synthase (GOGAT). In the absence of glutamate, the transcription factor GltC activates expression of the GOGAT genes for glutamate production. Consequently, a gltC mutant strain is auxotrophic for glutamate. Using a genetic selection and screening system, we could isolate and differentiate between gltC suppressor mutants in one step. All mutants had acquired the ability to synthesize glutamate, independent of GltC. We identified (i) gain-of-function mutations in the gltR gene, encoding the transcription factor GltR, (ii) mutations in the promoter of the gltAB operon and (iii) massive amplification of the genomic locus containing the gltAB operon. The mutants belonging to the first two classes constitutively expressed the gltAB genes and produced sufficient glutamate for growth. By contrast, mutants that belong to the third class appeared most frequently and solved glutamate limitation by increasing the copy number of the poorly expressed gltAB genes. Thus, glutamate auxotrophy of a B. subtilis gltC mutant can be relieved in multiple ways. Moreover, recombination-dependent amplification of the gltAB genes is the predominant mutational event indicating a hierarchy of mutations. © 2017 Society for Applied Microbiology and John Wiley & Sons Ltd.

Single base pair mutation analysis by PNA directed PCR clamping

DEFF Research Database (Denmark)

Ørum, H.; Nielsen, P.E.; Egholm, M.

1993-01-01

A novel method that allows direct analysis of single base mutation by the polymerase chain reaction (PCR) is described. The method utilizes the finding that PNAs (peptide nucleic acids) recognize and bind to their complementary nucleic acid sequences with higher thermal stability and specificity...... allows selective amplification/suppression of target sequences that differ by only one base pair. Finally we show that PNAs can be designed in such a way that blockage can be accomplished when the PNA target sequence is located between the PCR primers....

Charge collection and SEU (Single Event Upset) mechanisms

International Nuclear Information System (INIS)

Musseau, O.

1994-01-01

The purpose of this paper is to review the mechanisms of single event upset in microelectronic devices due to interaction with cosmic ions. Experimental and theoretical results are presented, and actual questions and problems are discussed. A brief introduction recalls the creation of the dense plasma of electron-hole pairs along the ion track. The basic processes for charge collection in a simple np junction (drift and diffusion) are presented. The funneling-field effect is discussed and experimental results are compared to numerical simulations and semi-empirical models. Charge collection in actual microelectronic structures is then presented. Single event upset of memory cells is discussed, based on numerical and experimental data. The main parameters for device characterization are presented. From the physical interpretation of charge collection mechanisms, the intrinsic sensitivity of various microelectronic technologies is determined and compared to experimental data. Scaling laws and future trends are discussed. (author)

Retrotransposition and mutation events yield Rap1 GTPases with differential signalling capacity

Directory of Open Access Journals (Sweden)

Penzkofer Tobias

2010-02-01

Full Text Available Abstract Background Retrotransposition of mRNA transcripts gives occasionally rise to functional retrogenes. Through acquiring tempero-spatial expression patterns distinct from their parental genes and/or functional mutations in their coding sequences, such retrogenes may in principle reshape signalling networks. Results Here we present evidence for such a scenario, involving retrogenes of Rap1 belonging to the Ras family of small GTPases. We identified two murine and one human-specific retrogene of Rap1A and Rap1B, which encode proteins that differ by only a few amino acids from their parental Rap1 proteins. Markedly, human hRap1B-retro and mouse mRap1A-retro1 acquired mutations in the 12th and 59th amino acids, respectively, corresponding to residues mutated in constitutively active oncogenic Ras proteins. Statistical and structural analyses support a functional evolution scenario, where Rap1 isoforms of retrogenic origin are functionally distinct from their parental proteins. Indeed, all retrogene-encoded GTPases have an increased GTP/GDP binding ratio in vivo, indicating that their conformations resemble that of active GTP-bound Rap1. We furthermore demonstrate that these three Rap1 isoforms exhibit distinct affinities for the Ras-binding domain of RalGDS. Finally, when tested for their capacity to induce key cellular processes like integrin-mediated cell adhesion or cell spreading, marked differences are seen. Conclusions Together, these data lend strong support for an evolution scenario, where retrotransposition and subsequent mutation events generated species-specific Rap1 isoforms with differential signaling potential. Expression of the constitutively active human Rap1B-retro in cells like those derived from Ramos Burkitt's lymphoma and bone marrow from a patient with myelodysplastic syndrome (MDS warrants further investigation into its role in disease development.

Cosmic and terrestrial single-event radiation effects in dynamic random access memories

International Nuclear Information System (INIS)

Massengill, L.W.

1996-01-01

A review of the literature on single-event radiation effects (SEE) on MOS integrated-circuit dynamic random access memories (DRAM's) is presented. The sources of single-event (SE) radiation particles, causes of circuit information loss, experimental observations of SE information upset, technological developments for error mitigation, and relationships of developmental trends to SE vulnerability are discussed

Frequency and spectrum of mutations induced by gamma irradiation in single, double and triple dwarf wheats

International Nuclear Information System (INIS)

Dhonukshe, B.L.

1981-01-01

Induced mutation studies were carried with three dwarf wheat varieties viz., ''Sonalika'', ''Chhoti Lerma'' and ''Hira'', considered to be single, double and trible dwarfs, respectively. Gamma-rays were used as a source of irradiation. Frequency of chlorophyll mutations were comparatively low and the spectrum was narrow. Chlorophyll mutations were altogether absent in the variety ''Sonalika''. A very wide spectrum of viable mutations affecting stem, leaf, ear growth habit, maturity and fertility characteristics was observed in the M 2 . The cumulative frequency of all the mutants together was quite high, which varied with the varieties. There were varietal differences in the composition and width of the spectrum induced by gamma-rays. The dwarf mutants having desirable leaf and spike characters were isolated in all the three varieties. (author)

Single-event burnout of epitaxial bipolar transistors

Energy Technology Data Exchange (ETDEWEB)

Kuboyama, Satoshi; Sugimoto, Kenji; Matsuda, Sumio [National Space Development Agency of Japan, Ysukuba, Ibaraki (Japan); Hirao, Toshio

1998-10-01

Single-event burnout (SEB) of bipolar junction transistors (BJTs) has been observed nondestructively. It was revealed that all the NPN BJTs including small signal transistors with thinner epitaxial layer were inherently susceptible to the SEB phenomenon. It was demonstrated that several design parameters of BJTs were responsible for SEB susceptibility. Additionally, destructive and nondestructive modes of SEB were identified. (author)

AIP mutations in Brazilian patients with sporadic pituitary adenomas: a single-center evaluation

Directory of Open Access Journals (Sweden)

Paula Bruna Araujo

2017-11-01

Full Text Available Aryl hydrocarbon receptor-interacting protein (AIP gene mutations (AIPmut are the most frequent germline mutations found in apparently sporadic pituitary adenomas (SPA. Our aim was to evaluate the frequency of AIPmut among young Brazilian patients with SPA. We performed an observational cohort study between 2013 and 2016 in a single referral center. AIPmut screening was carried out in 132 SPA patients with macroadenomas diagnosed up to 40 years or in adenomas of any size diagnosed until 18 years of age. Twelve tumor samples were also analyzed. Leukocyte DNA and tumor tissue DNA were sequenced for the entire AIP-coding region for evaluation of mutations. Eleven (8.3% of the 132 patients had AIPmut, comprising 9/74 (12% somatotropinomas, 1/38 (2.6% prolactinoma, 1/10 (10% corticotropinoma and no non-functioning adenomas. In pediatric patients (≤18 years, AIPmut frequency was 13.3% (2/15. Out of the 5 patients with gigantism, two had AIPmut, both truncating mutations. The Y268* mutation was described in Brazilian patients and the K273Rfs*30 mutation is a novel mutation in our patient. No somatic AIP mutations were found in the 12 tumor samples. A tumor sample from an acromegaly patient harboring the A299V AIPmut showed loss of heterozygosity. In conclusion, AIPmut frequency in SPA Brazilian patients is similar to other populations. Our study identified two mutations exclusively found in Brazilians and also shows, for the first time, loss of heterozygosity in tumor DNA from an acromegaly patient harboring the A299V AIPmut. Our findings corroborate previous observations that AIPmut screening should be performed in young patients with SPA.

Low-energy neutron-induced single-event upsets in static random access memory

International Nuclear Information System (INIS)

Guo Xiaoqiang; Guo Hongxia; Wang Guizhen; Ling Dongsheng; Chen Wei; Bai Xiaoyan; Yang Shanchao; Liu Yan

2009-01-01

The visual analysis method of data process was provided for neutron-induced single-event upset(SEU) in static random access memory(SRAM). The SEU effects of six CMOS SRAMs with different feature size(from 0.13 μm to 1.50 μm) were studied. The SEU experiments were performed using the neutron radiation environment at Xi'an pulsed reactor. And the dependence of low-energy neutron-induced SEU cross section on SRAM's feature size was given. The results indicate that the decreased critical charge is the dominant factor for the increase of single event effect sensitivity of SRAM devices with decreased feature size. Small-sized SRAM devices are more sensitive than large-sized ones to single event effect induced by low-energy neutrons. (authors)

Single event effects and total ionizing dose effects of typical VDMOSFET devices

International Nuclear Information System (INIS)

Lou Jianshe; Cai Nan; Liu Jiaxin; Wu Qinzhi; Wang Jia

2012-01-01

In this work, single event effects and total ionizing dose effects of typical VDMOSFET irradiated by 60 Co γ-rays and 252 Cf source were studied. The single event burnout and single event gate rupture (SEB/SEGR) effects were investigated, and the relationship between drain-source breakdown voltage and ionizing dose was obtained. The results showed that the VDMOSFET devices were sensitive to SEB and SEGR, and measures to improve their resistance to SEB and SEGR should be considered seriously for their space applications. The drain-source breakdown voltage was sensitive to total ionizing dose effects as the threshold voltage. In assessing the devices' resistance to the total ionizing dose effects, both the threshold voltage and the drain-source breakdown voltage should be taken into account. (authors)

Analyzing Single-Event Gate Ruptures In Power MOSFET's

Science.gov (United States)

Zoutendyk, John A.

1993-01-01

Susceptibilities of power metal-oxide/semiconductor field-effect transistors (MOSFET's) to single-event gate ruptures analyzed by exposing devices to beams of energetic bromine ions while applying appropriate bias voltages to source, gate, and drain terminals and measuring current flowing into or out of each terminal.

Single Event Effects in FPGA Devices 2015-2016

Science.gov (United States)

Berg, Melanie; LaBel, Kenneth; Pellish, Jonathan

2016-01-01

This presentation provides an overview of single event effects in FPGA devices 2015-2016 including commercial Xilinx V5 heavy ion accelerated testing, Xilinx Kintex-7 heavy ion accelerated testing, mitigation study, and investigation of various types of triple modular redundancy (TMR) for commercial SRAM based FPGAs.

Sequential mutations in Notch1, Fbxw7, and Tp53 in radiation-induced mouse thymic lymphomas.

Science.gov (United States)

Jen, Kuang-Yu; Song, Ihn Young; Banta, Karl Luke; Wu, Di; Mao, Jian-Hua; Balmain, Allan

2012-01-19

T-cell acute lymphoblastic lymphomas commonly demonstrate activating Notch1 mutations as well as mutations or deletions in Fbxw7. However, because Fbxw7 targets Notch1 for degradation, genetic alterations in these genes are expected to be mutually exclusive events in lymphomagenesis. Previously, by using a radiation-induced Tp53-deficient mouse model for T-cell acute lymphoblastic lymphoma, we reported that loss of heterozygosity at the Fbxw7 locus occurs frequently in a Tp53-dependent manner. In the current study, we show that these thymic lymphomas also commonly exhibit activating Notch1 mutations in the proline-glutamic acid-serine-threonine (PEST) domain. Moreover, concurrent activating Notch1 PEST domain mutations and single-copy deletions at the Fbxw7 locus occur with high frequency in the same individual tumors, indicating that these changes are not mutually exclusive events. We further demonstrate that although Notch1 PEST domain mutations are independent of Tp53 status, they are completely abolished in mice with germline Fbxw7 haploinsufficiency. Therefore, Notch1 PEST domain mutations only occur when Fbxw7 expression levels are intact. These data suggest a temporal sequence of mutational events involving these important cancer-related genes, with Notch1 PEST domain mutations occurring first, followed by Fbxw7 deletion, and eventually by complete loss of Tp53.

Quantification of sequence exchange events between PMS2 and PMS2CL provides a basis for improved mutation scanning of Lynch syndrome patients.

Science.gov (United States)

van der Klift, Heleen M; Tops, Carli M J; Bik, Elsa C; Boogaard, Merel W; Borgstein, Anne-Marijke; Hansson, Kerstin B M; Ausems, Margreet G E M; Gomez Garcia, Encarna; Green, Andrew; Hes, Frederik J; Izatt, Louise; van Hest, Liselotte P; Alonso, Angel M; Vriends, Annette H J T; Wagner, Anja; van Zelst-Stams, Wendy A G; Vasen, Hans F A; Morreau, Hans; Devilee, Peter; Wijnen, Juul T

2010-05-01

Heterozygous mutations in PMS2 are involved in Lynch syndrome, whereas biallelic mutations are found in Constitutional mismatch repair-deficiency syndrome patients. Mutation detection is complicated by the occurrence of sequence exchange events between the duplicated regions of PMS2 and PMS2CL. We investigated the frequency of such events with a nonspecific polymerase chain reaction (PCR) strategy, co-amplifying both PMS2 and PMS2CL sequences. This allowed us to score ratios between gene and pseudogene-specific nucleotides at 29 PSV sites from exon 11 to the end of the gene. We found sequence transfer at all investigated PSVs from intron 12 to the 3' end of the gene in 4 to 52% of DNA samples. Overall, sequence exchange between PMS2 and PMS2CL was observed in 69% (83/120) of individuals. We demonstrate that mutation scanning with PMS2-specific PCR primers and MLPA probes, designed on PSVs, in the 3' duplicated region is unreliable, and present an RNA-based mutation detection strategy to improve reliability. Using this strategy, we found 19 different putative pathogenic PMS2 mutations. Four of these (21%) are lying in the region with frequent sequence transfer and are missed or called incorrectly as homozygous with several PSV-based mutation detection methods. (c) 2010 Wiley-Liss, Inc.

Re-Verification of the IRHN57133SE and IRHN57250SE for Single Event Gate Rupture and Single Event Burnout

Science.gov (United States)

Scheick, Leif

2010-01-01

The vertical metal oxide semiconductor field-effect transistor (MOSFET) is a widely used power transistor onboard a spacecraft. The MOSFET is typically employed in power supplies and high current switching applications. Due to the inherent high electric fields in the device, power MOSFETs are sensitive to heavy ion irradiation and can fail catastrophically as a result of single event gate rupture (SEGR) or single event burnout (SEB). Manufacturers have designed radiation-hardened power MOSFETs for space applications. These radiation hardened devices are not immune to SEGR or SEB but, rather, can exhibit them at a much more damaging ion than their non-radiation hardened counterparts. See [1] through [5] for more information.This effort was to investigate the SEGR and SEB responses of two power MOSFETs from IR(the IRHN57133SE and the IRHN57250SE) that have recently been produced on a new fabrication line. These tests will serve as a limited verification of these parts, but it is acknowledged that further testing on the respective parts may be needed for some mission profiles.

Identification of five novel FBN1 mutations by non-radioactive single-strand conformation analysis

Energy Technology Data Exchange (ETDEWEB)

Liu, W.; Qian, C.; Comeau, K.; Francke, U. [Stanford Univ. Medical Center, Stanford, CA (United States)

1994-09-01

Marfan syndrome (MFS), one of the most common genetic disorders of connective tissue, is characterized by variable manifestations in skeletal, cardiovascular and ocular systems. Mutations in the fibrillin gene on chromosome 15 (FBN1) have been shown to cause MFS. To examine the relationship between FBN1 gene mutations, fibrillin protein function and MFS phenotypes, we screened for alternations in the fibrillin coding sequence in fibroblast derived cDNA from MFS patients. To date, abnormally migrating bands in more than 20 unrelated MFS patients have been identified by using non-radioactive single-strand conformation analysis and silver staining. Five altered bands have been directly sequenced. Two missense mutations and three splice site mutations have been identified. Both missense mutations substitute another amino acid for a cysteine residue (C1402W and C1672R) in EGF-like motifs of the fibrillin polypeptide chain. The two splice site mutations are at nucleotide positions 6994+1 (G{yields}A), and 7205-2 (A{yields}G) and result in in-frame skipping of exon 56 and 58, respectively. Skipping of exon 56 occurs in 50% of mutant transcripts. Use of a cryptic splice site 51 bp upstream of the normal donor site results in half of the mutant transcripts containing part of exon 56. Both products contain in-frame deletions. Another splice site mutation, identified by exon screening from patient genomic DNA using intron primers, is at nucleotide position 2293+2 (T{yields}A), but the predicted exon skipping has not been detected at the RT-PCR level. This may be due to instability of the mutant transcript. Including the mutations reported here, a total of 8 out of 36 published FBN1 gene mutations involve exon skipping. It may be inferred that FBN1 exon skipping plays an important pathogenic role in MFS.

Multifragmentation of a very heavy nuclear system (I): selection of single-source events

Energy Technology Data Exchange (ETDEWEB)

Frankland, J.D.; Bacri, Ch.O.; Borderie, B. [Paris-11 Univ., Inst. de Physique Nucleaire, 91 - Orsay (France)] [and others

2000-07-01

A sample of 'single-source' events, compatible with the multifragmentation of very heavy fused systems, are isolated among well-measured {sup 155}Gd + {sup nat}U 36 A.MeV reactions by examining the evolution of the kinematics of fragments with Z {>=} 5 as a function of the dissipated energy and loss of memory of the entrance channel. Single-source events are found to be the result of very central collisions. Such central collisions may also lead to multiple fragment emission due to the decay of excited projectile- and target-like nuclei and so-called 'neck' emission, and for this reason the isolation of single-source events is very difficult. Event-selection criteria based on centrality of collisions, or on the isotropy of the emitted fragments in each event, are found to be inefficient to separate the two mechanisms, unless they take into account the redistribution of fragments' kinetic energies into directions perpendicular to the beam axis. The selected events are good candidates to look for bulk effects in the multifragmentation process. (authors)

Multifragmentation of a very heavy nuclear system (I): selection of single-source events

International Nuclear Information System (INIS)

Frankland, J.D.; Bacri, Ch.O.; Borderie, B.; Rivet, M.F.; Squalli, M.; Auger, G.; Bellaize, N.; Bocage, F.; Bougault, R.; Brou, R.; Buchet, Ph.; Chbihi, A.; Colin, J.; Cussol, D.; Dayras, R.; Demeyer, A.; Dore, D.; Durand, D.; Galichet, E.; Genouin-Duhamel, E.; Gerlic, E.; Guinet, D.; Lautesse, Ph.; Laville, J.L.; Lecolley, J.F.; Legrain, R.; Le Neindre, N.; Lopez, O.; Louvel, M.; Maskay, A.M.; Nalpas, L.; Nguyen, A.D.; Parlog, M.; Peter, J.; Plagnol, E.; Rosato, E.; Saint-Laurent, F.; Salou, S.; Steckmeyer, J.C.; Stern, M.; Tabacaru, G.; Tamain, B.; Tirel, O.; Tassan-Got, L.; Vient, E.; Volant, C.; Wieleczko, J.P.

2001-01-01

A sample of 'single-source' events, compatible with the multifragmentation of very heavy fused systems, are isolated among well-measured 155 Gd+ nat U 36 A MeV reactions by examining the evolution of the kinematics of fragments with Z≥5 as a function of the dissipated energy and loss of memory of the entrance channel. Single-source events are found to be the result of very central collisions. Such central collisions may also lead to multiple fragment emission due to the decay of excited projectile- and target-like nuclei and so-called 'neck' emission, and for this reason the isolation of single-source events is very difficult. Event-selection criteria based on centrality of collisions, or on the isotropy of the emitted fragments in each event, are found to be inefficient to separate the two mechanisms, unless they take into account the redistribution of fragments' kinetic energies into directions perpendicular to the beam axis. The selected events are good candidates to look for bulk effects in the multifragmentation process

Identifying uniformly mutated segments within repeats.

Science.gov (United States)

Sahinalp, S Cenk; Eichler, Evan; Goldberg, Paul; Berenbrink, Petra; Friedetzky, Tom; Ergun, Funda

2004-12-01

Given a long string of characters from a constant size alphabet we present an algorithm to determine whether its characters have been generated by a single i.i.d. random source. More specifically, consider all possible n-coin models for generating a binary string S, where each bit of S is generated via an independent toss of one of the n coins in the model. The choice of which coin to toss is decided by a random walk on the set of coins where the probability of a coin change is much lower than the probability of using the same coin repeatedly. We present a procedure to evaluate the likelihood of a n-coin model for given S, subject a uniform prior distribution over the parameters of the model (that represent mutation rates and probabilities of copying events). In the absence of detailed prior knowledge of these parameters, the algorithm can be used to determine whether the a posteriori probability for n=1 is higher than for any other n>1. Our algorithm runs in time O(l4logl), where l is the length of S, through a dynamic programming approach which exploits the assumed convexity of the a posteriori probability for n. Our test can be used in the analysis of long alignments between pairs of genomic sequences in a number of ways. For example, functional regions in genome sequences exhibit much lower mutation rates than non-functional regions. Because our test provides means for determining variations in the mutation rate, it may be used to distinguish functional regions from non-functional ones. Another application is in determining whether two highly similar, thus evolutionarily related, genome segments are the result of a single copy event or of a complex series of copy events. This is particularly an issue in evolutionary studies of genome regions rich with repeat segments (especially tandemly repeated segments).

NEPP Update of Independent Single Event Upset Field Programmable Gate Array Testing

Science.gov (United States)

Berg, Melanie; Label, Kenneth; Campola, Michael; Pellish, Jonathan

2017-01-01

This presentation provides a NASA Electronic Parts and Packaging (NEPP) Program update of independent Single Event Upset (SEU) Field Programmable Gate Array (FPGA) testing including FPGA test guidelines, Microsemi RTG4 heavy-ion results, Xilinx Kintex-UltraScale heavy-ion results, Xilinx UltraScale+ single event effect (SEE) test plans, development of a new methodology for characterizing SEU system response, and NEPP involvement with FPGA security and trust.

A single mutation in the envelope protein modulates flavivirus antigenicity, stability, and pathogenesis.

Directory of Open Access Journals (Sweden)

Leslie Goo

2017-02-01

Full Text Available The structural flexibility or 'breathing' of the envelope (E protein of flaviviruses allows virions to sample an ensemble of conformations at equilibrium. The molecular basis and functional consequences of virus conformational dynamics are poorly understood. Here, we identified a single mutation at residue 198 (T198F of the West Nile virus (WNV E protein domain I-II hinge that regulates virus breathing. The T198F mutation resulted in a ~70-fold increase in sensitivity to neutralization by a monoclonal antibody targeting a cryptic epitope in the fusion loop. Increased exposure of this otherwise poorly accessible fusion loop epitope was accompanied by reduced virus stability in solution at physiological temperatures. Introduction of a mutation at the analogous residue of dengue virus (DENV, but not Zika virus (ZIKV, E protein also increased accessibility of the cryptic fusion loop epitope and decreased virus stability in solution, suggesting that this residue modulates the structural ensembles sampled by distinct flaviviruses at equilibrium in a context dependent manner. Although the T198F mutation did not substantially impair WNV growth kinetics in vitro, studies in mice revealed attenuation of WNV T198F infection. Overall, our study provides insight into the molecular basis and the in vitro and in vivo consequences of flavivirus breathing.

Single genome retrieval of context-dependent variability in mutation rates for human germline.

Science.gov (United States)

Sahakyan, Aleksandr B; Balasubramanian, Shankar

2017-01-13

Accurate knowledge of the core components of substitution rates is of vital importance to understand genome evolution and dynamics. By performing a single-genome and direct analysis of 39,894 retrotransposon remnants, we reveal sequence context-dependent germline nucleotide substitution rates for the human genome. The rates are characterised through rate constants in a time-domain, and are made available through a dedicated program (Trek) and a stand-alone database. Due to the nature of the method design and the imposed stringency criteria, we expect our rate constants to be good estimates for the rates of spontaneous mutations. Benefiting from such data, we study the short-range nucleotide (up to 7-mer) organisation and the germline basal substitution propensity (BSP) profile of the human genome; characterise novel, CpG-independent, substitution prone and resistant motifs; confirm a decreased tendency of moieties with low BSP to undergo somatic mutations in a number of cancer types; and, produce a Trek-based estimate of the overall mutation rate in human. The extended set of rate constants we report may enrich our resources and help advance our understanding of genome dynamics and evolution, with possible implications for the role of spontaneous mutations in the emergence of pathological genotypes and neutral evolution of proteomes.

The effect of driving force on intramolecular electron transfer in proteins. Studies on single-site mutated azurins

DEFF Research Database (Denmark)

Farver, O; Skov, L K; van de Kamp, M

1992-01-01

-6972]. To further investigate the nature of this long-range electron transfer (LRET) proceeding within the protein matrix, we have now investigated it in two azurins where amino acids have been substituted by single-site mutation of the wild-type Pseudomonas aeruginosa azurin. In one mutated protein, a methionine...... the reorganization energy, lambda and electronic coupling factor, beta. The calculated values fit very well with a through-bond LRET mechanism....

Screening of Duchenne muscular dystrophy (DMD mutations and investigating its mutational mechanism in Chinese patients.

Directory of Open Access Journals (Sweden)

Chen Chen

Full Text Available Duchenne muscular dystrophy (DMD is a common X-linked recessive disease of muscle degeneration and death. In order to provide accurate and reliable genetic counseling and prenatal diagnosis, we screened DMD mutations in a cohort of 119 Chinese patients using multiplex ligation-dependent probe amplification (MLPA and denaturing high performance liquid chromatography (DHPLC followed by Sanger sequencing. In these unrelated DMD patients, we identified 11 patients with DMD small mutations (9.2% and 81 patients with DMD deletions/duplications (del/dup (68.1%, of which 64 (79.0% were deletions, 16 (19.8% were duplications, and one (1.2% was both deletion and duplication. Furthermore, we analyzed the frequency of DMD breakpoint in the 64 deletion cases by calculating exon-deletion events of certain exon interval that revealed a novel mutation hotspot boundary. To explore why DMD rearrangement breakpoints were predisposed to specific regions (hotspot, we precisely characterized junction sequences of breakpoints at the nucleotide level in 21 patients with exon deleted/duplicated in DMD with a high-resolution SNP microarray assay. There were no exactly recurrent breakpoints and there was also no significant difference between single-exon del/dup and multiple-exon del/dup cases. The data from the current study provided a comprehensive strategy to detect DMD mutations for clinical practice, and identified two deletion hotspots at exon 43-55 and exon 10-23 by calculating exon-deletion events of certain exon interval. Furthermore, this is the first study to characterize DMD breakpoint at the nucleotide level in a Chinese population. Our observations provide better understanding of the mechanism for DMD gene rearrangements.

TERT promoter mutation as an early genetic event activating telomerase in follicular thyroid adenoma (FTA) and atypical FTA.

Science.gov (United States)

Wang, Na; Liu, Tiantian; Sofiadis, Anastasios; Juhlin, C Christofer; Zedenius, Jan; Höög, Anders; Larsson, Catharina; Xu, Dawei

2014-10-01

The telomerase reverse transcriptase (TERT) promoter mutations C228T and C250T have been found in many malignancies, including in thyroid carcinomas. However, it is unclear how early these mutations occur in thyroid tumorigenesis. The study included primary tumors from 58 patients initially diagnosed with follicular thyroid adenoma (FTA), a benign entity, 18 with atypical FTA (AFTA) having an uncertain malignant potential, and 52 with follicular thyroid carcinoma (FTC). Sanger sequencing was used to investigate the mutational status of the TERT promoter. Telomere length and TERT messenger RNA (mRNA) expression were determined using quantitative polymerase chain reaction (PCR). Telomerase activity was assessed using a Telomerase PCR enzyme-linked immunosorbent assay kit. The C228T mutation was identified in 1 of 58 FTA (2%) and 3 of 18 AFTA (17%) samples. These 4 tumors all expressed TERT mRNA and telomerase activity, whereas the majority of C228T-negative adenomas lacked TERT expression (C228T versus wild-type, P = .008). The C228T mutation was associated with NRAS gene mutations (P = .016). The patient with C228T-mutated FTA later developed a scar recurrence and died of FTC, whereas none of the remaining 57 patients with FTA had recurrence. No recurrence occurred in 3 patients with AFTA who carried C228T during the follow-up period (36-285 months). Nine of the 52 FTCs (17%) exhibited the TERT mutation (8 of 9 C228T and 1 of 9 C250T), and the presence of the mutation was associated with shorter patient survival. TERT promoter mutations may occur as an early genetic event in thyroid follicular tumors that have not developed malignant features on routine histopathological workup. © 2014 American Cancer Society.

Single Event Effects Test Facility Options at the Oak Ridge National Laboratory

Energy Technology Data Exchange (ETDEWEB)

Riemer, Bernie [ORNL; Gallmeier, Franz X [ORNL; Dominik, Laura J [ORNL

2015-01-01

Increasing use of microelectronics of ever diminishing feature size in avionics systems has led to a growing Single Event Effects (SEE) susceptibility arising from the highly ionizing interactions of cosmic rays and solar particles. Single event effects caused by atmospheric radiation have been recognized in recent years as a design issue for avionics equipment and systems. To ensure a system meets all its safety and reliability requirements, SEE induced upsets and potential system failures need to be considered, including testing of the components and systems in a neutron beam. Testing of integrated circuits (ICs) and systems for use in radiation environments requires the utilization of highly advanced laboratory facilities that can run evaluations on microcircuits for the effects of radiation. This paper provides a background of the atmospheric radiation phenomenon and the resulting single event effects, including single event upset (SEU) and latch up conditions. A study investigating requirements for future single event effect irradiation test facilities and developing options at the Spallation Neutron Source (SNS) is summarized. The relatively new SNS with its 1.0 GeV proton beam, typical operation of 5000 h per year, expertise in spallation neutron sources, user program infrastructure, and decades of useful life ahead is well suited for hosting a world-class SEE test facility in North America. Emphasis was put on testing of large avionics systems while still providing tunable high flux irradiation conditions for component tests. Makers of ground-based systems would also be served well by these facilities. Three options are described; the most capable, flexible, and highest-test-capacity option is a new stand-alone target station using about one kW of proton beam power on a gas-cooled tungsten target, with dual test enclosures. Less expensive options are also described.

Experimental Setups for Single Event Effect Studies

OpenAIRE

N. H. Medina; V. A. P. Aguiar; N. Added; F. Aguirre; E. L. A. Macchione; S. G. Alberton; M. A. G. Silveira; J. Benfica; F. Vargas; B. Porcher

2016-01-01

Experimental setups are being prepared to test and to qualify electronic devices regarding their tolerance to Single Event Effect (SEE). A multiple test setup and a new beam line developed especially for SEE studies at the São Paulo 8 UD Pelletron accelerator were prepared. This accelerator produces proton beams and heavy ion beams up to 107Ag. A Super conducting Linear accelerator, which is under construction, may fulfill all of the European Space Agency requirements to qualify electronic...

JAK2 V617F, MPL, and CALR mutations in essential thrombocythaemia and major thrombotic complications: a single-institute retrospective analysis.

Science.gov (United States)

Pósfai, Éva; Marton, Imelda; Király, Péter Attila; Kotosz, Balázs; Kiss-László, Zsuzsanna; Széll, Márta; Borbényi, Zita

2015-07-01

Thrombo-haemorrhagic events are the main cause of morbidity and mortality in essential thrombocythemia. The aim of this study was to estimate the incidence of thrombotic events and the impact of the JAK2V617F, MPL (W515L, W515K, W515R, W515A and S505N) and CALR (type-1, type-2) mutations on 101 essential thrombocythaemia patients (72 females and 29 males with a mean age of 61 years) diagnosed in a Southern Hungarian regional academic centre. The incidence of major thrombosis was 13.86 %. Sixty percent of the patients carried the JAK2V617F mutation. The MPL mutations were analysed by sequencing and the W515L was the only one we could identify with an incidence of 3.96 %. Type-2 CALR mutation could be identified in 3 cases among the patients who had JAK2/MPL-unmutated ET. Statistical analyses revealed that the JAK2V617F mutation was associated with significantly increased levels of platelet (p = 0.042), haemoglobin (p = 0.000), red blood cell (p = 0.000) and haematocrit (p = 0.000) and hepatomegaly (p = 0.045) at diagnosis compared to JAK2V617F negative counterparts, however there was no significant association between the JAK2V617F mutation status (relative risk: 1.297, 95 % CI 0.395-4.258; p = 0.668) and subsequent thrombotic complications. The impact of JAK2V617F, MPL W515L and CALR mutations on the clinical findings at the diagnosis of ET was obvious, but their statistically significant role in the prediction of thrombotic events could not be proven in this study. Our results indirectly support the concept that, besides the quantitative and qualitative changes in the platelets, the mechanisms leading to thrombosis are more complex and multifactorial.

Compendium of Single Event Effects, Total Ionizing Dose, and Displacement Damage for Candidate Spacecraft Electronics for NASA

Science.gov (United States)

LaBel, Kenneth A.; OBryan, Martha V.; Chen, Dakai; Campola, Michael J.; Casey, Megan C.; Pellish, Jonathan A.; Lauenstein, Jean-Marie; Wilcox, Edward P.; Topper, Alyson D.; Ladbury, Raymond L.;

Anthology of the Development of Radiation Transport Tools as Applied to Single Event Effects

Science.gov (United States)

Reed, R. A.; Weller, R. A.; Akkerman, A.; Barak, J.; Culpepper, W.; Duzellier, S.; Foster, C.; Gaillardin, M.; Hubert, G.; Jordan, T.; Jun, I.; Koontz, S.; Lei, F.; McNulty, P.; Mendenhall, M. H.; Murat, M.; Nieminen, P.; O'Neill, P.; Raine, M.; Reddell, B.; Saigné, F.; Santin, G.; Sihver, L.; Tang, H. H. K.; Truscott, P. R.; Wrobel, F.

2013-06-01

This anthology contains contributions from eleven different groups, each developing and/or applying Monte Carlo-based radiation transport tools to simulate a variety of effects that result from energy transferred to a semiconductor material by a single particle event. The topics span from basic mechanisms for single-particle induced failures to applied tasks like developing websites to predict on-orbit single event failure rates using Monte Carlo radiation transport tools.

Causal relationships between solar proton events and single event upsets for communication satellites

Science.gov (United States)

Lohmeyer, W. Q.; Cahoy, K.; Liu, Shiyang

In this work, we analyze a historical archive of single event upsets (SEUs) maintained by Inmarsat, one of the world's leading providers of global mobile satellite communications services. Inmarsat has operated its geostationary communication satellites and collected extensive satellite anomaly and telemetry data since 1990. Over the course of the past twenty years, the satellites have experienced more than 226 single event upsets (SEUs), a catch-all term for anomalies that occur in a satellite's electronics such as bit-flips, trips in power supplies, and memory changes in attitude control systems. While SEUs are seemingly random and difficult to predict, we correlate their occurrences to space weather phenomena, and specifically show correlations between SEUs and solar proton events (SPEs). SPEs are highly energetic protons that originate from solar coronal mass ejections (CMEs). It is thought that when these particles impact geostationary (GEO) satellites they can cause SEUs as well as solar array degradation. We calculate the associated statistical correlations that each SEU occurs within one day, one week, two weeks, and one month of 10 MeV SPEs between 10 - 10,000 particle flux units (pfu). However, we find that SPEs are most prevalent at solar maximum and that the SEUs on Inmarsat's satellites occur out of phase with the solar maximum. Ultimately, this suggests that SPEs are not the primary cause of the Inmarsat SEUs. A better understanding of the causal relationship between SPEs and SEUs will help the satellite communications industry develop component and operational space weather mitigation techniques as well as help the space weather community to refine radiation models.

Clinical and mutation analysis of 51 probands with anophthalmia and/or severe microphthalmia from a single center

Science.gov (United States)

Gerth-Kahlert, Christina; Williamson, Kathleen; Ansari, Morad; Rainger, Jacqueline K; Hingst, Volker; Zimmermann, Theodor; Tech, Stefani; Guthoff, Rudolf F; van Heyningen, Veronica; FitzPatrick, David R

2013-01-01

Clinical evaluation and mutation analysis was performed in 51 consecutive probands with severe eye malformations – anophthalmia and/or severe microphthalmia – seen in a single specialist ophthalmology center. The mutation analysis consisted of bidirectional sequencing of the coding regions of SOX2, OTX2, PAX6 (paired domain), STRA6, BMP4, SMOC1, FOXE3, and RAX, and genome-wide array-based copy number assessment. Fifteen (29.4%) of the 51 probands had likely causative mutations affecting SOX2 (9/51), OTX2 (5/51), and STRA6 (1/51). Of the cases with bilateral anophthalmia, 9/12 (75%) were found to be mutation positive. Three of these mutations were large genomic deletions encompassing SOX2 (one case) or OTX2 (two cases). Familial inheritance of three intragenic, plausibly pathogenic, and heterozygous mutations was observed. An unaffected carrier parent of an affected child with an identified OTX2 mutation confirmed the previously reported nonpenetrance for this disorder. Two families with SOX2 mutations demonstrated a parent and child both with significant but highly variable eye malformations. Heterozygous loss-of-function mutations in SOX2 and OTX2 are the most common genetic pathology associated with severe eye malformations and bi-allelic loss-of-function in STRA6 is confirmed as an emerging cause of nonsyndromal eye malformations. PMID:24498598

Investigation of photobleaching and saturation of single molecules by fluorophore recrossing events

Energy Technology Data Exchange (ETDEWEB)

Burrows, Sean M.; Reif, Randall D. [Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409-1061 (United States); Pappas, Dimitri [Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409-1061 (United States)], E-mail: d.pappas@ttu.edu

2007-08-15

A method for investigation of photobleaching and saturation of single molecules by fluorophore recrossing events in a laser beam is described. The diffraction-limited probe volumes encountered in single-molecule detection (SMD) produce high excitation irradiance, which can decrease available signal. The single molecules of several dyes were detected and the data was used to extract interpeak times above a defined threshold value. The interpeak times revealed the number of fluorophore recrossing events. The number of molecules detected that were within 2 ms of each other represented a molecular recrossing for this work. Calcein, fluorescein and R-phycoerythrin were analyzed and the saturation irradiance and photobleaching effects were determined as a function of irradiance. This approach is simple and it serves as a method of optimizing experimental conditions for single-molecule detection.

Lack of robustness of life extension associated with several single-gene P element mutations in Drosophila melanogaster.

Science.gov (United States)

Mockett, Robin J; Nobles, Amber C

2013-10-01

The hypothesis tested in this study was that single-gene mutations found previously to extend the life span of Drosophila melanogaster could do so consistently in both long-lived y w and standard w (1118) genetic backgrounds. GAL4 drivers were used to express upstream activation sequence (UAS)-responder transgenes globally or in the nervous system. Transgenes associated with oxidative damage prevention (UAS-hSOD1 and UAS-GCLc) or removal (EP-UAS-Atg8a and UAS-dTOR (FRB) ) failed to increase mean life spans in any expression pattern in either genetic background. Flies containing a UAS-EGFP-bMSRA (C) transgene associated with protein repair were found not to exhibit life extension or detectable enhanced green fluorescent protein (EGFP) activity. The presence of UAS-responder transgenes was confirmed by PCR amplification and sequencing at the 5' and 3' end of each insertion. These results cast doubt on the robustness of life extension in flies carrying single-gene mutations and suggest that the effects of all such mutations should be tested independently in multiple genetic backgrounds and laboratory environments.

Non Invasive Instrumentation For Single Event Effects (NIISEE), Phase I

Data.gov (United States)

National Aeronautics and Space Administration — On this Phase 1 project, Adventium will identify and address key hurdles to achieve Radiation Hardening by Software (RHS) for Single Event Effects (SEEs) for modern...

Single event monitoring system based on Java 3D and XML data binding

International Nuclear Information System (INIS)

Wang Liang; Chinese Academy of Sciences, Beijing; Zhu Kejun; Zhao Jingwei

2007-01-01

Online single event monitoring is important to BESIII DAQ System. Java3D is extension of Java Language in 3D technology, XML data binding is more efficient to handle XML document than SAX and DOM. This paper mainly introduce the implementation of BESIII single event monitoring system with Java3D and XML data binding, and interface for track fitting software with JNI technology. (authors)

Heavy Ion Irradiation Fluence Dependence for Single-Event Upsets in a NAND Flash Memory

Science.gov (United States)

Chen, Dakai; Wilcox, Edward; Ladbury, Raymond L.; Kim, Hak; Phan, Anthony; Seidleck, Christina; Label, Kenneth

2016-01-01

We investigated the single-event effect (SEE) susceptibility of the Micron 16 nm NAND flash, and found that the single-event upset (SEU) cross section varied inversely with cumulative fluence. We attribute the effect to the variable upset sensitivities of the memory cells. Furthermore, the effect impacts only single cell upsets in general. The rate of multiple-bit upsets remained relatively constant with fluence. The current test standards and procedures assume that SEU follow a Poisson process and do not take into account the variability in the error rate with fluence. Therefore, traditional SEE testing techniques may underestimate the on-orbit event rate for a device with variable upset sensitivity.

Single-Cell Analysis of Human Pancreas Reveals Transcriptional Signatures of Aging and Somatic Mutation Patterns.

Science.gov (United States)

Enge, Martin; Arda, H Efsun; Mignardi, Marco; Beausang, John; Bottino, Rita; Kim, Seung K; Quake, Stephen R

2017-10-05

As organisms age, cells accumulate genetic and epigenetic errors that eventually lead to impaired organ function or catastrophic transformation such as cancer. Because aging reflects a stochastic process of increasing disorder, cells in an organ will be individually affected in different ways, thus rendering bulk analyses of postmitotic adult cells difficult to interpret. Here, we directly measure the effects of aging in human tissue by performing single-cell transcriptome analysis of 2,544 human pancreas cells from eight donors spanning six decades of life. We find that islet endocrine cells from older donors display increased levels of transcriptional noise and potential fate drift. By determining the mutational history of individual cells, we uncover a novel mutational signature in healthy aging endocrine cells. Our results demonstrate the feasibility of using single-cell RNA sequencing (RNA-seq) data from primary cells to derive insights into genetic and transcriptional processes that operate on aging human tissue. Copyright © 2017 Elsevier Inc. All rights reserved.

Single-Event Effects in Silicon and Silicon Carbide Power Devices

Science.gov (United States)

Lauenstein, Jean-Marie; Casey, Megan C.; LaBel, Kenneth A.; Topper, Alyson D.; Wilcox, Edward P.; Kim, Hak; Phan, Anthony M.

2014-01-01

NASA Electronics Parts and Packaging program-funded activities over the past year on single-event effects in silicon and silicon carbide power devices are presented, with focus on SiC device failure signatures.

Anthology of the development of radiation transport tools as applied to single event effects

International Nuclear Information System (INIS)

Akkerman, A.; Barak, J.; Murat, M.; Duzellier, S.; Hubert, G.; Gaillardin, M.; Raine, M.; Jordan, T.; Jun, I.; Koontz, S.; Reddell, B.; O'Neill, P.; Foster, C.; Culpepper, W.; Lei, F.; McNulty, P.; Nieminen, P.; Saigne, F.; Wrobel, F.; Santin, G.; Sihver, L.; Tang, H.H.K.; Truscott, P.R.

2013-01-01

This anthology contains contributions from eleven different groups, each developing and/or applying Monte Carlo-based radiation transport tools to simulate a variety of effects that result from energy transferred to a semiconductor material by a single particle event. The topics span from basic mechanisms for single-particle induced failures to applied tasks like developing web sites to predict on-orbit single event failure rates using Monte Carlo radiation transport tools. (authors)

Genetic diagnosis of Duchenne and Becker muscular dystrophy using next-generation sequencing technology: comprehensive mutational search in a single platform.

Science.gov (United States)

Lim, Byung Chan; Lee, Seungbok; Shin, Jong-Yeon; Kim, Jong-Il; Hwang, Hee; Kim, Ki Joong; Hwang, Yong Seung; Seo, Jeong-Sun; Chae, Jong Hee

2011-11-01

Duchenne muscular dystrophy or Becker muscular dystrophy might be a suitable candidate disease for application of next-generation sequencing in the genetic diagnosis because the complex mutational spectrum and the large size of the dystrophin gene require two or more analytical methods and have a high cost. The authors tested whether large deletions/duplications or small mutations, such as point mutations or short insertions/deletions of the dystrophin gene, could be predicted accurately in a single platform using next-generation sequencing technology. A custom solution-based target enrichment kit was designed to capture whole genomic regions of the dystrophin gene and other muscular-dystrophy-related genes. A multiplexing strategy, wherein four differently bar-coded samples were captured and sequenced together in a single lane of the Illumina Genome Analyser, was applied. The study subjects were 25 16 with deficient dystrophin expression without a large deletion/duplication and 9 with a known large deletion/duplication. Nearly 100% of the exonic region of the dystrophin gene was covered by at least eight reads with a mean read depth of 107. Pathogenic small mutations were identified in 15 of the 16 patients without a large deletion/duplication. Using these 16 patients as the standard, the authors' method accurately predicted the deleted or duplicated exons in the 9 patients with known mutations. Inclusion of non-coding regions and paired-end sequence analysis enabled accurate identification by increasing the read depth and providing information about the breakpoint junction. The current method has an advantage for the genetic diagnosis of Duchenne muscular dystrophy and Becker muscular dystrophy wherein a comprehensive mutational search may be feasible using a single platform.

Haplotype analysis suggest that the MLH1 c.2059C > T mutation is a Swedish founder mutation.

Science.gov (United States)

von Salomé, Jenny; Liu, Tao; Keihäs, Markku; Morak, Moni; Holinski-Feder, Elke; Berry, Ian R; Moilanen, Jukka S; Baert-Desurmont, Stéphanie; Lindblom, Annika; Lagerstedt-Robinson, Kristina

2017-12-29

Lynch syndrome (LS) predisposes to a spectrum of cancers and increases the lifetime risk of developing colorectal- or endometrial cancer to over 50%. Lynch syndrome is dominantly inherited and is caused by defects in DNA mismatch-repair genes MLH1, MSH2, MSH6 or PMS2, with the vast majority detected in MLH1 and MSH2. Recurrent LS-associated variants observed in apparently unrelated individuals, have either arisen de novo in different families due to mutation hotspots, or are inherited from a founder (a common ancestor) that lived several generations back. There are variants that recur in some populations while also acting as founders in other ethnic groups. Testing for founder mutations can facilitate molecular diagnosis of Lynch Syndrome more efficiently and more cost effective than screening for all possible mutations. Here we report a study of the missense mutation MLH1 c.2059C > T (p.Arg687Trp), a potential founder mutation identified in eight Swedish families and one Finnish family with Swedish ancestors. Haplotype analysis confirmed that the Finnish and Swedish families shared a haplotype of between 0.9 and 2.8 Mb. While MLH1 c.2059C > T exists worldwide, the Swedish haplotype was not found among mutation carriers from Germany or France, which indicates a common founder in the Swedish population. The geographic distribution of MLH1 c.2059C > T in Sweden suggests a single, ancient mutational event in the northern part of Sweden.

Single event upsets correlated with environment

International Nuclear Information System (INIS)

Vampola, A.L.; Albin, F.; Lauriente, M.; Wilkinson, D.C.; Allen, J.

1994-01-01

Single Event Upset rates on satellites in different Earth orbits are correlated with solar protons and geomagnetic activity and also with the NASA AP8 proton model to extract information about satellite anomalies caused by the space environment. An extensive discussion of the SEU data base from the TOMS solid state recorder and an algorithm for correcting spontaneous upsets in it are included as an Appendix. SAMPEX and TOMS, which have the same memory chips, have similar normalized responses in the South Atlantic Anomaly. SEU rates due to solar protons over the polar caps are within expectations. No geomagnetic activity effects can be discerned in the SEU rates

Heavy Ion Irradiation Fluence Dependence for Single-Event Upsets of NAND Flash Memory

Science.gov (United States)

Chen, Dakai; Wilcox, Edward; Ladbury, Raymond; Kim, Hak; Phan, Anthony; Seidleck, Christina; LaBel, Kenneth

2016-01-01

We investigated the single-event effect (SEE) susceptibility of the Micron 16 nm NAND flash, and found the single-event upset (SEU) cross section varied inversely with fluence. The SEU cross section decreased with increasing fluence. We attribute the effect to the variable upset sensitivities of the memory cells. The current test standards and procedures assume that SEU follow a Poisson process and do not take into account the variability in the error rate with fluence. Therefore, heavy ion irradiation of devices with variable upset sensitivity distribution using typical fluence levels may underestimate the cross section and on-orbit event rate.

Single-Event Effects in Silicon Carbide Power Devices

Science.gov (United States)

Lauenstein, Jean-Marie; Casey, Megan C.; LaBel, Kenneth A.; Ikpe, Stanley; Topper, Alyson D.; Wilcox, Edward P.; Kim, Hak; Phan, Anthony M.

2015-01-01

This report summarizes the NASA Electronic Parts and Packaging Program Silicon Carbide Power Device Subtask efforts in FY15. Benefits of SiC are described and example NASA Programs and Projects desiring this technology are given. The current status of the radiation tolerance of silicon carbide power devices is given and paths forward in the effort to develop heavy-ion single-event effect hardened devices indicated.

Single event effects in pulse width modulation controllers

International Nuclear Information System (INIS)

Penzin, S.H.; Crain, W.R.; Crawford, K.B.; Hansel, S.J.; Kirshman, J.F.; Koga, R.

1996-01-01

SEE testing was performed on pulse width modulation (PWM) controllers which are commonly used in switching mode power supply systems. The devices are designed using both Set-Reset (SR) flip-flops and Toggle (T) flip-flops which are vulnerable to single event upset (SEU) in a radiation environment. Depending on the implementation of the different devices the effect can be significant in spaceflight hardware

Analysis of mutations in the human HPRT gene induced by accelerated heavy-ion irradiation

International Nuclear Information System (INIS)

Kagawa, Yasuhiro; Yatagai, Fumio; Hanaoka, Fumio; Suzuki, Masao; Kase, Youko; Kobayashi, Akiko; Hirano, Masahiko; Kato, Takesi; Watanabe, Masami.

1995-01-01

Multiplex PCR analysis of HPRT(-) mutations in human embryo (HE) cells induced by 230 keV/μm carbon-ion irradiation showed no large deletion around the exon regions of the locus gene in contrast to the irradiations at different LETs. To identify these mutations, the sequence alterations in a cDNA of hprt gene were determined for 18 mutant clones in this study. Missing of exon 6 was the most frequent mutational event (10 clones), and missing of both exons 6 and 8 was next most frequent event (6 clones), then base substitutions (2 clones). These characteristics were not seen in a similar analysis of spontaneous mutations, which showed base substitution (5 clones), frameshift (2 clones), missing of both exons 2 and 3 (2 clones), and a single unidentified clone. Direct sequencing and restriction enzyme digestion of the genomic DNA of the mutants which showed missing of exons 6 and 8 in the cDNA, supports the possibility that they were induced by aberrant mRNA splicing. (author)

Structure Based Thermostability Prediction Models for Protein Single Point Mutations with Machine Learning Tools.

Directory of Open Access Journals (Sweden)

Lei Jia

Full Text Available Thermostability issue of protein point mutations is a common occurrence in protein engineering. An application which predicts the thermostability of mutants can be helpful for guiding decision making process in protein design via mutagenesis. An in silico point mutation scanning method is frequently used to find "hot spots" in proteins for focused mutagenesis. ProTherm (http://gibk26.bio.kyutech.ac.jp/jouhou/Protherm/protherm.html is a public database that consists of thousands of protein mutants' experimentally measured thermostability. Two data sets based on two differently measured thermostability properties of protein single point mutations, namely the unfolding free energy change (ddG and melting temperature change (dTm were obtained from this database. Folding free energy change calculation from Rosetta, structural information of the point mutations as well as amino acid physical properties were obtained for building thermostability prediction models with informatics modeling tools. Five supervised machine learning methods (support vector machine, random forests, artificial neural network, naïve Bayes classifier, K nearest neighbor and partial least squares regression are used for building the prediction models. Binary and ternary classifications as well as regression models were built and evaluated. Data set redundancy and balancing, the reverse mutations technique, feature selection, and comparison to other published methods were discussed. Rosetta calculated folding free energy change ranked as the most influential features in all prediction models. Other descriptors also made significant contributions to increasing the accuracy of the prediction models.

Impact of NBTI Aging on the Single-Event Upset of SRAM Cells

CERN Document Server

Bagatin, M; Gerardin, Simone; Paccagnella, Alessandro; Bagatin, Marta

2010-01-01

We analyzed the impact of negative bias temperature instability (NBTI) on the single-event upset rate of SRAM cells through experiments and SPICE simulations. We performed critical charge simulations introducing different degradation patterns in the cells, in three technology nodes, from 180 to 90 nm. The simulations results were checked with alpha-particle and heavy-ion irradiations on a 130-nm technology. Both simulations and experimental results show that NBTI degradation does not significantly affect the single-event upset SRAM cell rate as long as the parametric drift induced by aging is within 10\\%.

Capillary electrophoretic study of individual exocytotic events in single mast cells

Energy Technology Data Exchange (ETDEWEB)

Ho, Andrea Ming-Wei [Iowa State Univ., Ames, IA (United States)

1999-02-12

The peak profile of individual degranulation events from the on-column release of serotonin from single rat peritoneal mast cells (RPMCs) was monitored using capillary electrophoresis with laser-induced native fluorescence detection (CE-LINF). Serotonin, an important biogenic amine, is contained in granules (0.25 fL) within RPMCs and is extruded by a process termed exocytosis. The secretagogue, Polymyxin B sulfate, was used as the CE running buffer after injection of a single RPMC into the separation capillary to stimulate the release of the granules. Because the release process occurs on a ms time scale, monitoring individual exocytotic events is possible with the coupling of high-speed CE and LINF detection.

Activating mutations in FGFR3 and HRAS reveal a shared genetic origin for congenital disorders and testicular tumors

DEFF Research Database (Denmark)

Goriely, Anne; Hansen, Ruth M S; Taylor, Indira B

2009-01-01

Genes mutated in congenital malformation syndromes are frequently implicated in oncogenesis, but the causative germline and somatic mutations occur in separate cells at different times of an organism's life. Here we unify these processes to a single cellular event for mutations arising in male germ...... cells that show a paternal age effect. Screening of 30 spermatocytic seminomas for oncogenic mutations in 17 genes identified 2 mutations in FGFR3 (both 1948A>G, encoding K650E, which causes thanatophoric dysplasia in the germline) and 5 mutations in HRAS. Massively parallel sequencing of sperm DNA...... a common 'selfish' pathway supporting proliferation in the testis, leading to diverse phenotypes in the next generation including fetal lethality, congenital syndromes and cancer predisposition....

Investigation of the Semicoa 2N7616 and 2N7425 and the Microsemi 2N7480 for Single-Event Gate Rupture and Single-Event Burnout

Science.gov (United States)

Scheick, Leif

2014-01-01

Single-event-effect test results for hi-rel total-dose-hardened power MOSFETs are presented in this report. The 2N7616 and the 2N7425 from Semicoa and the 2N7480 from International Rectifier were tested to NASA test condition standards and requirements. The 2N7480 performed well and the data agree with the manufacture's data. The 2N7616 and 2N7425 were entry parts from Semicoa using a new device architecture. Unfortunately, the device performed poorly and Semicoa is withdrawing power MOSFETs from it line due to these data. Vertical metal-oxide-semiconductor field-effect transistors (MOSFETs) are the most commonly used power transistor. MOSFETs are typically employed in power supplies and high current switching applications. Due to the inherent high electric fields in the device, power MOSFETs are sensitive to heavy ion irradiation and can fail catastrophically as a result of single-event gate rupture (SEGR) or single-event burnout (SEB). Manufacturers have designed radiation-hardened power MOSFETs for space applications. See [1] through [5] for more information. The objective of this effort was to investigate the SEGR and SEB responses of two power MOSFETs recently produced. These tests will serve as a limited verification of these parts. It is acknowledged that further testing on the respective parts may be needed for some mission profiles.

A pan-cancer analysis of transcriptome changes associated with somatic mutations in U2AF1 reveals commonly altered splicing events.

Directory of Open Access Journals (Sweden)

Angela N Brooks

Full Text Available Although recurrent somatic mutations in the splicing factor U2AF1 (also known as U2AF35 have been identified in multiple cancer types, the effects of these mutations on the cancer transcriptome have yet to be fully elucidated. Here, we identified splicing alterations associated with U2AF1 mutations across distinct cancers using DNA and RNA sequencing data from The Cancer Genome Atlas (TCGA. Using RNA-Seq data from 182 lung adenocarcinomas and 167 acute myeloid leukemias (AML, in which U2AF1 is somatically mutated in 3-4% of cases, we identified 131 and 369 splicing alterations, respectively, that were significantly associated with U2AF1 mutation. Of these, 30 splicing alterations were statistically significant in both lung adenocarcinoma and AML, including three genes in the Cancer Gene Census, CTNNB1, CHCHD7, and PICALM. Cell line experiments expressing U2AF1 S34F in HeLa cells and in 293T cells provide further support that these altered splicing events are caused by U2AF1 mutation. Consistent with the function of U2AF1 in 3' splice site recognition, we found that S34F/Y mutations cause preferences for CAG over UAG 3' splice site sequences. This report demonstrates consistent effects of U2AF1 mutation on splicing in distinct cancer cell types.

TALEN-mediated single-base-pair editing identification of an intergenic mutation upstream of BUB1B as causative of PCS (MVA) syndrome

Science.gov (United States)

Ochiai, Hiroshi; Miyamoto, Tatsuo; Kanai, Akinori; Hosoba, Kosuke; Sakuma, Tetsushi; Kudo, Yoshiki; Asami, Keiko; Ogawa, Atsushi; Watanabe, Akihiro; Kajii, Tadashi; Yamamoto, Takashi; Matsuura, Shinya

2014-01-01

Cancer-prone syndrome of premature chromatid separation with mosaic variegated aneuploidy [PCS (MVA) syndrome] is a rare autosomal recessive disorder characterized by constitutional aneuploidy and a high risk of childhood cancer. We previously reported monoallelic mutations in the BUB1B gene (encoding BUBR1) in seven Japanese families with the syndrome. No second mutation was found in the opposite allele of any of the families studied, although a conserved BUB1B haplotype and a decreased transcript were identified. To clarify the molecular pathology of the second allele, we extended our mutational search to a candidate region surrounding BUB1B. A unique single nucleotide substitution, G > A at ss802470619, was identified in an intergenic region 44 kb upstream of a BUB1B transcription start site, which cosegregated with the disorder. To examine whether this is the causal mutation, we designed a transcription activator-like effector nuclease–mediated two-step single-base pair editing strategy and biallelically introduced this substitution into cultured human cells. The cell clones showed reduced BUB1B transcripts, increased PCS frequency, and MVA, which are the hallmarks of the syndrome. We also encountered a case of a Japanese infant with PCS (MVA) syndrome carrying a homozygous single nucleotide substitution at ss802470619. These results suggested that the nucleotide substitution identified was the causal mutation of PCS (MVA) syndrome. PMID:24344301

Screening for mutations in human alpha-globin genes by nonradioactive single-strand conformation polymorphism

Directory of Open Access Journals (Sweden)

Jorge S.B.

2003-01-01

Full Text Available Point mutations and small insertions or deletions in the human alpha-globin genes may produce alpha-chain structural variants and alpha-thalassemia. Mutations can be detected either by direct DNA sequencing or by screening methods, which select the mutated exon for sequencing. Although small (about 1 kb, 3 exons and 2 introns, the alpha-globin genes are duplicate (alpha2 and alpha1 and highy G-C rich, which makes them difficult to denature, reducing sequencing efficiency and causing frequent artifacts. We modified some conditions for PCR and electrophoresis in order to detect mutations in these genes employing nonradioactive single-strand conformation polymorphism (SSCP. Primers previously described by other authors for radioactive SSCP and phast-SSCP plus denaturing gradient gel electrophoresis were here combined and the resultant fragments (6 new besides 6 original per alpha-gene submitted to silver staining SSCP. Nine structural and one thalassemic mutations were tested, under different conditions including two electrophoretic apparatus (PhastSystem(TM and GenePhor(TM, Amersham Biosciences, different polyacrylamide gel concentrations, run temperatures and denaturing agents, and entire and restriction enzyme cut fragments. One hundred percent of sensitivity was achieved with four of the new fragments formed, using the PhastSystem(TM and 20% gels at 15ºC, without the need of restriction enzymes. This nonradioactive PCR-SSCP approach showed to be simple, rapid and sensitive, reducing the costs involved in frequent sequencing repetitions and increasing the reliability of the results. It can be especially useful for laboratories which do not have an automated sequencer.

Research on generation mechanism of single event transient current generated in the semiconductor using ion accelerator

International Nuclear Information System (INIS)

Hirao, Toshio

2007-01-01

Single-event upset (SEU) is triggered when an amount of electric charges induced by energetic ion incidence exceeds a value known as a critical charge in a very short time period. Therefore, accurate evaluation of electric charge and understanding of basic mechanism of SEU are necessary for the improvement of SEU torrance of electronic devices. In this paper, the collected charges for the single event transient current induced on semiconductor by heavy ion microbeams, and application to use microbeam for single event studies are presented. (author)

Stressful Life Event Experiences of Homeless Adults: A Comparison of Single Men, Single Women, and Women with Children

Science.gov (United States)

Zugazaga, Carole

2004-01-01

This article describes stressful life events experienced by a multi-shelter sample of 162 homeless adults in the Central Florida area. Participants included homeless single men (n = 54), homeless single women (n = 54), and homeless women with children (n = 54). Subjects were interviewed with a modified version of the List of Threatening…

Electrical signatures of single-stranded DNA with single base mutations in a nanopore capacitor

International Nuclear Information System (INIS)

Gracheva, Maria E; Aksimentiev, Aleksei; Leburton, Jean-Pierre

2006-01-01

In this paper, we evaluate the magnitude of the electrical signals produced by DNA translocation through a 1 nm diameter nanopore in a capacitor membrane with a numerical multi-scale approach, and assess the possibility of resolving individual nucleotides as well as their types in the absence of conformational disorder. We show that the maximum recorded voltage caused by the DNA translocation is about 35 mV, while the maximum voltage signal due to the DNA backbone is about 30 mV, and the maximum voltage of a DNA base is about 8 mV. Signals from individual nucleotides can be identified in the recorded voltage traces, suggesting a 1 nm diameter pore in a capacitor can be used to accurately count the number of nucleotides in a DNA strand. Furthermore, we study the effect of a single base substitution on the voltage trace, and calculate the differences among the voltage traces due to a single base mutation for the sequences C 3 AC 7 , C 3 CC 7 , C 3 GC 7 and C 3 TC 7 . The calculated voltage differences are in the 5-10 mV range. The calculated maximum voltage caused by the translocation of individual bases varies from 2 to 9 mV, which is experimentally detectable

Diverse growth hormone receptor gene mutations in Laron syndrome.

Science.gov (United States)

Berg, M A; Argente, J; Chernausek, S; Gracia, R; Guevara-Aguirre, J; Hopp, M; Pérez-Jurado, L; Rosenbloom, A; Toledo, S P; Francke, U

1993-01-01

To better understand the molecular genetic basis and genetic epidemiology of Laron syndrome (growth-hormone insensitivity syndrome), we analyzed the growth-hormone receptor (GHR) genes of seven unrelated affected individuals from the United States, South America, Europe, and Africa. We amplified all nine GHR gene exons and splice junctions from these individuals by PCR and screened the products for mutations by using denaturing gradient gel electrophoresis (DGGE). We identified a single GHR gene fragment with abnormal DGGE results for each affected individual, sequenced this fragment, and, in each case, identified a mutation likely to cause Laron syndrome, including two nonsense mutations (R43X and R217X), two splice-junction mutations, (189-1 G to T and 71 + 1 G to A), and two frameshift mutations (46 del TT and 230 del TA or AT). Only one of these mutations, R43X, has been previously reported. Using haplotype analysis, we determined that this mutation, which involves a CpG dinucleotide hot spot, likely arose as a separate event in this case, relative to the two prior reports of R43X. Aside from R43X, the mutations we identified are unique to patients from particular geographic regions. Ten GHR gene mutations have now been described in this disorder. We conclude that Laron syndrome is caused by diverse GHR gene mutations, including deletions, RNA processing defects, translational stop codons, and missense codons. All the identified mutations involve the extracellular domain of the receptor, and most are unique to particular families or geographic areas. Images Figure 1 Figure 2 PMID:8488849

Investigation of the Semicoa SCF9550 and the International Rectifier IRHM57260SE for Single-Event Gate Rapture and Single-Event Burnout : NASA Electronic Parts and Packaging (NEPP) Program Office of Safety and Mission Assurance

Science.gov (United States)

Scheick, Leif

2011-01-01

Single-event-effect test results for hi-rel total-dose-hardened power MOSFETs are presented in this report. TheSCF9550 from Semicoa and the IRHM57260SE from International Rectifier were tested to NASA test condition/standards and requirements.The IRHM57260SE performed much better when compared to previous testing. These initial results confirm that parts from the Temecula line are marginally comparable to the El Segundo line. The SCF9550 from Semicoa was also tested and represents the initial parts offering from this vendor. Both parts experienced single-event gate rupture (SEGR) and single-event burnout (SEB). All of the SEGR was from gate to drain.

Impact of repeated single-metal and multi-metal pollution events on soil quality.

Science.gov (United States)

Burges, Aritz; Epelde, Lur; Garbisu, Carlos

2015-02-01

Most frequently, soil metal pollution results from the occurrence of repeated single-metal and, above all, multi-metal pollution events, with concomitant adverse consequences for soil quality. Therefore, in this study, we evaluated the impact of repeated single-metal and multi-metal (Cd, Pb, Cu, Zn) pollution events on soil quality, as reflected by the values of a variety of soil microbial parameters with potential as bioindicators of soil functioning. Specifically, parameters of microbial activity (potentially mineralizable nitrogen, β-glucosidase and acid phosphatase activity) and biomass (fungal and bacterial gene abundance by RT-qPCR) were determined, in the artificially metal-polluted soil samples, at regular intervals over a period of 26 weeks. Similarly, we studied the evolution over time of CaCl2-extractable metal fractions, in order to estimate metal bioavailability in soil. Different metals showed different values of bioavailability and relative bioavailability ([metal]bio/[metal]tot) in soil throughout the experiment, under both repeated single-metal and multi-metal pollution events. Both repeated Zn-pollution and multi-metal pollution events led to a significant reduction in the values of acid phosphatase activity, and bacterial and fungal gene abundance, reflecting the negative impact of these repeated events on soil microbial activity and biomass, and, hence, soil quality. Copyright © 2014 Elsevier Ltd. All rights reserved.

Can tokamaks PFC survive a single event of any plasma instabilities?

Science.gov (United States)

Hassanein, A.; Sizyuk, V.; Miloshevsky, G.; Sizyuk, T.

2013-07-01

Plasma instability events such as disruptions, edge-localized modes (ELMs), runaway electrons (REs), and vertical displacement events (VDEs) are continued to be serious events and most limiting factors for successful tokamak reactor concept. The plasma-facing components (PFCs), e.g., wall, divertor, and limited surfaces of a tokamak as well as coolant structure materials are subjected to intense particle and heat loads and must maintain a clean and stable surface environment among them and the core/edge plasma. Typical ITER transient events parameters are used for assessing the damage from these four different instability events. HEIGHTS simulation showed that a single event of a disruption, giant ELM, VDE, or RE can cause significant surface erosion (melting and vaporization) damage to PFC, nearby components, and/or structural materials (VDE, RE) melting and possible burnout of coolant tubes that could result in shut down of reactor for extended repair time.

Can tokamaks PFC survive a single event of any plasma instabilities?

International Nuclear Information System (INIS)

Hassanein, A.; Sizyuk, V.; Miloshevsky, G.; Sizyuk, T.

2013-01-01

Plasma instability events such as disruptions, edge-localized modes (ELMs), runaway electrons (REs), and vertical displacement events (VDEs) are continued to be serious events and most limiting factors for successful tokamak reactor concept. The plasma-facing components (PFCs), e.g., wall, divertor, and limited surfaces of a tokamak as well as coolant structure materials are subjected to intense particle and heat loads and must maintain a clean and stable surface environment among them and the core/edge plasma. Typical ITER transient events parameters are used for assessing the damage from these four different instability events. HEIGHTS simulation showed that a single event of a disruption, giant ELM, VDE, or RE can cause significant surface erosion (melting and vaporization) damage to PFC, nearby components, and/or structural materials (VDE, RE) melting and possible burnout of coolant tubes that could result in shut down of reactor for extended repair time

Can tokamaks PFC survive a single event of any plasma instabilities?

Energy Technology Data Exchange (ETDEWEB)

Hassanein, A., E-mail: hassanein@purdue.edu [Center for Materials under Extreme Environment, School of Nuclear Engineering, Purdue University, 400 Central Drive, West Lafayette, IN 47907 (United States); Sizyuk, V.; Miloshevsky, G.; Sizyuk, T. [Center for Materials under Extreme Environment, School of Nuclear Engineering, Purdue University, 400 Central Drive, West Lafayette, IN 47907 (United States)

2013-07-15

Plasma instability events such as disruptions, edge-localized modes (ELMs), runaway electrons (REs), and vertical displacement events (VDEs) are continued to be serious events and most limiting factors for successful tokamak reactor concept. The plasma-facing components (PFCs), e.g., wall, divertor, and limited surfaces of a tokamak as well as coolant structure materials are subjected to intense particle and heat loads and must maintain a clean and stable surface environment among them and the core/edge plasma. Typical ITER transient events parameters are used for assessing the damage from these four different instability events. HEIGHTS simulation showed that a single event of a disruption, giant ELM, VDE, or RE can cause significant surface erosion (melting and vaporization) damage to PFC, nearby components, and/or structural materials (VDE, RE) melting and possible burnout of coolant tubes that could result in shut down of reactor for extended repair time.

Single-event transients (SET) in analog circuits

International Nuclear Information System (INIS)

Chen Panxun; Zhou Kaiming

2006-01-01

A new phenomenon of single- event upset is introduced. The transient signal is produced in the output of analog circuits after a heavy ion strikes. The transient upset can influence the circuit connected with the output of analog circuits. For example, the output of operational amplifier can be connected with the input of a digital counter, and the pulse of sufficiently high transient output induced by an ion can increase counts of the counter. On the other hand, the transient voltage signal at the output of analog circuits can change the stage of other circuits. (authors)

Experimental study on heavy-ion single event effect on nanometer DDR SRAM

International Nuclear Information System (INIS)

Luo Yinhong; Zhang Fengqi; Guo Hongxia; Zhou Hui; Wang Yanping; Zhang Keying

2013-01-01

Single event effect experimental study on 90 nm and 65 nm DDR SRAM were carried out, single event upset (SEU) cross section was discussed as a function of several parameters such as feature size, test pattern, incidence angle, supply voltage. Key influence factors and effect rule were analyzed. Feasibility of the current test method was discussed. Results indicate that, SEU cross section reduces as technologies scale down; the influence of test pattern and power supply on SEU cross section is small; tilt angle increases SEU cross section due to multiple upset increasement. The applicability of cosine tilt test method is correlative to ion species and linear energy transfer (LET) values. (authors)

Physical mechanisms of single-event effects in advanced microelectronics

Energy Technology Data Exchange (ETDEWEB)

Schrimpf, Ronald D. [Electrical Engineering and Computer Science, Vanderbilt University, 5635 Stevenson Center, Nashville, TN 37235 (United States)]. E-mail: ron.schrimpf@vanderbilt.edu; Weller, Robert A. [Electrical Engineering and Computer Science, Vanderbilt University, 5635 Stevenson Center, Nashville, TN 37235 (United States); Mendenhall, Marcus H. [Free Electron Laser Center, Vanderbilt University, Station B 351816, Nashville, TN 37235 (United States); Reed, Robert A. [Electrical Engineering and Computer Science, Vanderbilt University, 5635 Stevenson Center, Nashville, TN 37235 (United States); Massengill, Lloyd W. [Electrical Engineering and Computer Science, Vanderbilt University, 5635 Stevenson Center, Nashville, TN 37235 (United States)

2007-08-15

The single-event error rate in advanced semiconductor technologies can be estimated more accurately than conventional methods by using simulation based on accurate descriptions of a large number of individual particle interactions. The results can be used to select the ion types and energies for accelerator testing and to identify situations in which nuclear reactions will contribute to the error rate.

Physical mechanisms of single-event effects in advanced microelectronics

International Nuclear Information System (INIS)

Schrimpf, Ronald D.; Weller, Robert A.; Mendenhall, Marcus H.; Reed, Robert A.; Massengill, Lloyd W.

2007-01-01

The single-event error rate in advanced semiconductor technologies can be estimated more accurately than conventional methods by using simulation based on accurate descriptions of a large number of individual particle interactions. The results can be used to select the ion types and energies for accelerator testing and to identify situations in which nuclear reactions will contribute to the error rate

Current Single Event Effects Results for Candidate Spacecraft Electronics for NASA

Science.gov (United States)

OBryan, Martha V.; Seidleck, Christina M.; Carts, Martin A.; LaBel, Kenneth A.; Marshall, Cheryl J.; Reed, Robert A.; Sanders, Anthony B.; Hawkins, Donald K.; Cox, Stephen R.; Kniffin, Scott D.

2004-01-01

We present data on the vulnerability of a variety of candidate spacecraft electronics to proton and heavy ion induced single event effects. Devices tested include digital, analog, linear bipolar, and hybrid devices, among others.

Multiple origins of knockdown resistance mutations in the Afrotropical mosquito vector Anopheles gambiae.

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João Pinto

2007-11-01

Full Text Available How often insecticide resistance mutations arise in natural insect populations is a fundamental question for understanding the evolution of resistance and also for modeling its spread. Moreover, the development of resistance is regarded as a favored model to study the molecular evolution of adaptive traits. In the malaria vector Anopheles gambiae two point mutations (L1014F and L1014S in the voltage-gated sodium channel gene, that confer knockdown resistance (kdr to DDT and pyrethroid insecticides, have been described. In order to determine whether resistance alleles result from single or multiple mutation events, genotyping of the kdr locus and partial sequencing of the upstream intron-1 was performed on a total of 288 A. gambiae S-form collected from 28 localities in 15 countries. Knockdown resistance alleles were found to be widespread in West Africa with co-occurrence of both 1014S and 1014F in West-Central localities. Differences in intron-1 haplotype composition suggest that kdr alleles may have arisen from at least four independent mutation events. Neutrality tests provided evidence for a selective sweep acting on this genomic region, particularly in West Africa. The frequency and distribution of these kdr haplotypes varied geographically, being influenced by an interplay between different mutational occurrences, gene flow and local selection. This has important practical implications for the management and sustainability of malaria vector control programs.

Single event effects and performance predictions for space applications of RISC processors

International Nuclear Information System (INIS)

Kimbrough, J.R.; Colella, N.J.; Denton, S.M.; Shaeffer, D.L.; Shih, D.; Wilburn, J.W.; Coakley, P.G.; Casteneda, C.; Koga, R.; Clark, D.A.; Ullmann, J.L.

1994-01-01

Proton and ion Single Event Phenomena (SEP) tests were performed on 32-b processors including R3000A's from all commercial manufacturers along with the Performance PR3400 family, Integrated Device Technology Inc. 79R3081, LSI Logic Corporation LR33000HC, and Intel i80960MX parts. The microprocessors had acceptable upset rates for operation in a low earth orbit or a lunar mission such as CLEMENTINE with a wide range in proton total dose failure. Even though R3000A devices are 60% smaller in physical area than R3000 devices, there was a 340% increase in device Single Event Upset (SEU) cross section. Software tests of varying complexity demonstrate that registers and other functional blocks using register architecture dominate the cross section. The current approach of giving a single upset cross section can lead to erroneous upset rates depending on the application software

Sentinel and other mutational effects in offspring of cancer survivors

International Nuclear Information System (INIS)

Mulvihill, J.J.

1990-01-01

To date, no agent has been documented to cause germ cell mutation in human beings, with the possible exception of radiation causing abnormal meiotic chromosomes in testes. For studies in humans, mutation epidemiologists prefer the cohort approach, starting with an exposed population and looking for mutations that may be expressed in offspring as variants in health, chromosomes, proteins, or nucleic acids. Currently patients with cancer are the cohort exposed to the largest doses of potential mutagens, i.e., radiotherapy and drugs. In 12 large studies with over 825 patients and 1573 pregnancies, 46 (4%) of 1240 liveborns had a major birth defect, a rate comparable to that in the general population. One of these was a classic sentinel phenotype, i.e., a new sporadic case of a dominant mendelian syndrome. In collaboration with 5 U.S. cancer registries, we interviewed a retrospective cohort of 2383 patients diagnosed with cancer under age 20 years, from 1945 through 1975. Records were sought to verify major genetic disease, defined as a cytogenetic or single gene disorder or 1 of 15 isolated birth defects. In 2308 offspring of survivors, 5 had a chromosomal syndrome, 11 had a single gene disorder, and 62 had at least one major malformation. Among 4722 offspring of sibling controls, the respective numbers were 7, 12, and 127, nonsignificant differences. 7% of the parents of the offspring with possibly new mutations received potentially mutagenic therapy, compared with 12% of parents of normal children. Since pregnancy in or by cancer survivors is still a rare event, future efforts to document germ cell mutation may be best studied through international cooperation coupled with diverse laboratory measures of mutation

Toehold-mediated strand displacement reaction triggered isothermal DNA amplification for highly sensitive and selective fluorescent detection of single-base mutation.

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Zhu, Jing; Ding, Yongshun; Liu, Xingti; Wang, Lei; Jiang, Wei

2014-09-15

Highly sensitive and selective detection strategy for single-base mutations is essential for risk assessment of malignancy and disease prognosis. In this work, a fluorescent detection method for single-base mutation was proposed based on high selectivity of toehold-mediated strand displacement reaction (TSDR) and powerful signal amplification capability of isothermal DNA amplification. A discrimination probe was specially designed with a stem-loop structure and an overhanging toehold domain. Hybridization between the toehold domain and the perfect matched target initiated the TSDR along with the unfolding of the discrimination probe. Subsequently, the target sequence acted as a primer to initiate the polymerization and nicking reactions, which released a great abundant of short sequences. Finally, the released strands were annealed with the reporter probe, launching another polymerization and nicking reaction to produce lots of G-quadruplex DNA, which could bind the N-methyl mesoporphyrin IX to yield an enhanced fluorescence response. However, when there was even a single base mismatch in the target DNA, the TSDR was suppressed and so subsequent isothermal DNA amplification and fluorescence response process could not occur. The proposed approach has been successfully implemented for the identification of the single-base mutant sequences in the human KRAS gene with a detection limit of 1.8 pM. Furthermore, a recovery of 90% was obtained when detecting the target sequence in spiked HeLa cells lysate, demonstrating the feasibility of this detection strategy for single-base mutations in biological samples. Copyright © 2014 Elsevier B.V. All rights reserved.

Variable myopathic presentation in a single family with novel skeletal RYR1 mutation.

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Ruben Attali

Full Text Available We describe an autosomal recessive heterogeneous congenital myopathy in a large consanguineous family. The disease is characterized by variable severity, progressive course in 3 of 4 patients, myopathic face without ophthalmoplegia and proximal muscle weakness. Absence of cores was noted in all patients. Genome wide linkage analysis revealed a single locus on chromosome 19q13 with Zmax = 3.86 at θ = 0.0 and homozygosity of the polymorphic markers at this locus in patients. Direct sequencing of the main candidate gene within the candidate region, RYR1, was performed. A novel homozygous A to G nucleotide substitution (p.Y3016C within exon 60 of the RYR1 gene was found in patients. ARMS PCR was used to screen for the mutation in all available family members and in an additional 150 healthy individuals. This procedure confirmed sequence analysis and did not reveal the A to G mutation (p.Y3016C in 300 chromosomes from healthy individuals. Functional analysis on EBV immortalized cell lines showed no effect of the mutation on RyR1 pharmacological activation or the content of intracellular Ca(2+ stores. Western blot analysis demonstrated a significant reduction of the RyR1 protein in the patient's muscle concomitant with a reduction of the DHPRα1.1 protein. This novel mutation resulting in RyR1 protein decrease causes heterogeneous clinical presentation, including slow progression course and absence of centrally localized cores on muscle biopsy. We suggest that RYR1 related myopathy should be considered in a wide variety of clinical and pathological presentation in childhood myopathies.

Tuning and Switching Enantioselectivity of Asymmetric Carboligation in an Enzyme through Mutational Analysis of a Single Hot Spot.

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Wechsler, Cindy; Meyer, Danilo; Loschonsky, Sabrina; Funk, Lisa-Marie; Neumann, Piotr; Ficner, Ralf; Brodhun, Florian; Müller, Michael; Tittmann, Kai

2015-12-01

Enantioselective bond making and breaking is a hallmark of enzyme action, yet switching the enantioselectivity of the reaction is a difficult undertaking, and typically requires extensive screening of mutant libraries and multiple mutations. Here, we demonstrate that mutational diversification of a single catalytic hot spot in the enzyme pyruvate decarboxylase gives access to both enantiomers of acyloins acetoin and phenylacetylcarbinol, important pharmaceutical precursors, in the case of acetoin even starting from the unselective wild-type protein. Protein crystallography was used to rationalize these findings and to propose a mechanistic model of how enantioselectivity is controlled. In a broader context, our studies highlight the efficiency of mechanism-inspired and structure-guided rational protein design for enhancing and switching enantioselectivity of enzymatic reactions, by systematically exploring the biocatalytic potential of a single hot spot. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Domain-restricted mutation analysis to identify novel driver events in human cancer

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Sanket Desai

2017-10-01

Full Text Available Analysis of mutational spectra across various cancer types has given valuable insights into tumorigenesis. Different approaches have been used to identify novel drivers from the set of somatic mutations, including the methods which use sequence conservation, geometric localization and pathway information. Recent computational methods suggest use of protein domain information for analysis and understanding of the functional consequence of non-synonymous mutations. Similarly, evidence suggests recurrence at specific position in proteins is robust indicators of its functional impact. Building on this, we performed a systematic analysis of TCGA exome derived somatic mutations across 6089 PFAM domains and significantly mutated domains were identified using randomization approach. Multiple alignment of individual domain allowed us to prioritize for conserved residues mutated at analogous positions across different proteins in a statistically disciplined manner. In addition to the known frequently mutated genes, this analysis independently identifies low frequency Meprin and TRAF-Homology (MATH domain in Speckle Type BTB/POZ (SPOP protein, in prostate adenocarcinoma. Results from this analysis will help generate hypotheses about the downstream molecular mechanism resulting in cancer phenotypes.

Novel inborn error of folate metabolism: identification by exome capture and sequencing of mutations in the MTHFD1 gene in a single proband.

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Watkins, David; Schwartzentruber, Jeremy A; Ganesh, Jaya; Orange, Jordan S; Kaplan, Bernard S; Nunez, Laura Dempsey; Majewski, Jacek; Rosenblatt, David S

2011-09-01

An infant was investigated because of megaloblastic anaemia, atypical hemolytic uraemic syndrome, severe combined immune deficiency, elevated blood levels of homocysteine and methylmalonic acid, and a selective decreased synthesis of methylcobalamin in cultured fibroblasts. Exome sequencing was performed on patient genomic DNA. Two mutations were identified in the MTHFD1 gene, which encodes a protein that catalyses three reactions involved in cellular folate metabolism. This protein is essential for the generation of formyltetrahydrofolate and methylenetetrahydrofolate and important for nucleotide and homocysteine metabolism. One mutation (c.727+1G>A) affects the splice acceptor site of intron 8. The second mutation, c.517C>T (p.R173C), changes a critical arginine residue in the NADP-binding site of the protein. Mutations affecting this arginine have previously been shown to affect enzyme activity. Both parents carry a single mutation and an unaffected sibling carries neither mutation. The combination of two mutations in the MTHFRD1 gene, predicted to have severe consequences, in the patient and their absence in the unaffected sibling, supports causality. This patient represents the first case of an inborn error of folate metabolism affecting the trifunctional MTHFD1 protein. This report reinforces the power of exome capture and sequencing for the discovery of novel genes, even when only a single proband is available for study.

Single-event burnout of power bipolar junction transistors

International Nuclear Information System (INIS)

Titus, J.L.; Johnson, G.H.; Schrimpf, R.D.; Galloway, K.F.

1991-01-01

Experimental evidence of single-event burnout of power bipolar junctions transistors (BJTs) is reported for the first time. Several commercial power BJTs were characterized in a simulated cosmic ray environment using mono-energetic ions at the tandem Van de Graaff accelerator facility at Brookhaven National Laboratory. Most of the device types exposed to this simulated environment exhibited burnout behavior. In this paper the experimental technique, data, and results are presented, while a qualitative model is used to help explain those results and trends observed in this experiment

Detection of MPLW515L/K mutations and determination of allele frequencies with a single-tube PCR assay.

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Takei, Hiraku; Morishita, Soji; Araki, Marito; Edahiro, Yoko; Sunami, Yoshitaka; Hironaka, Yumi; Noda, Naohiro; Sekiguchi, Yuji; Tsuneda, Satoshi; Ohsaka, Akimichi; Komatsu, Norio

2014-01-01

A gain-of-function mutation in the myeloproliferative leukemia virus (MPL) gene, which encodes the thrombopoietin receptor, has been identified in patients with essential thrombocythemia and primary myelofibrosis, subgroups of classic myeloproliferative neoplasms (MPNs). The presence of MPL gene mutations is a critical diagnostic criterion for these diseases. Here, we developed a rapid, simple, and cost-effective method of detecting two major MPL mutations, MPLW515L/K, in a single PCR assay; we termed this method DARMS (dual amplification refractory mutation system)-PCR. DARMS-PCR is designed to produce three different PCR products corresponding to MPLW515L, MPLW515K, and all MPL alleles. The amplicons are later detected and quantified using a capillary sequencer to determine the relative frequencies of the mutant and wild-type alleles. Applying DARMS-PCR to human specimens, we successfully identified MPL mutations in MPN patients, with the exception of patients bearing mutant allele frequencies below the detection limit (5%) of this method. The MPL mutant allele frequencies determined using DARMS-PCR correlated strongly with the values determined using deep sequencing. Thus, we demonstrated the potential of DARMS-PCR to detect MPL mutations and determine the allele frequencies in a timely and cost-effective manner.

Detection of MPLW515L/K mutations and determination of allele frequencies with a single-tube PCR assay.

Directory of Open Access Journals (Sweden)

Hiraku Takei

Full Text Available A gain-of-function mutation in the myeloproliferative leukemia virus (MPL gene, which encodes the thrombopoietin receptor, has been identified in patients with essential thrombocythemia and primary myelofibrosis, subgroups of classic myeloproliferative neoplasms (MPNs. The presence of MPL gene mutations is a critical diagnostic criterion for these diseases. Here, we developed a rapid, simple, and cost-effective method of detecting two major MPL mutations, MPLW515L/K, in a single PCR assay; we termed this method DARMS (dual amplification refractory mutation system-PCR. DARMS-PCR is designed to produce three different PCR products corresponding to MPLW515L, MPLW515K, and all MPL alleles. The amplicons are later detected and quantified using a capillary sequencer to determine the relative frequencies of the mutant and wild-type alleles. Applying DARMS-PCR to human specimens, we successfully identified MPL mutations in MPN patients, with the exception of patients bearing mutant allele frequencies below the detection limit (5% of this method. The MPL mutant allele frequencies determined using DARMS-PCR correlated strongly with the values determined using deep sequencing. Thus, we demonstrated the potential of DARMS-PCR to detect MPL mutations and determine the allele frequencies in a timely and cost-effective manner.

Oncogenetic tree model of somatic mutations and DNA methylation in colon tumors.

Science.gov (United States)

Sweeney, Carol; Boucher, Kenneth M; Samowitz, Wade S; Wolff, Roger K; Albertsen, Hans; Curtin, Karen; Caan, Bette J; Slattery, Martha L

2009-01-01

Our understanding of somatic alterations in colon cancer has evolved from a concept of a series of events taking place in a single sequence to a recognition of multiple pathways. An oncogenetic tree is a model intended to describe the pathways and sequence of somatic alterations in carcinogenesis without assuming that tumors will fall in mutually exclusive categories. We applied this model to data on colon tumor somatic alterations. An oncogenetic tree model was built using data on mutations of TP53, KRAS2, APC, and BRAF genes, methylation at CpG sites of MLH1 and TP16 genes, methylation in tumor (MINT) markers, and microsatellite instability (MSI) for 971 colon tumors from a population-based series. Oncogenetic tree analysis resulted in a reproducible tree with three branches. The model represents methylation of MINT markers as initiating a branch and predisposing to MSI, methylation of MHL1 and TP16, and BRAF mutation. APC mutation is the first alteration in an independent branch and is followed by TP53 mutation. KRAS2 mutation was placed a third independent branch, implying that it neither depends on, nor predisposes to, the other alterations. Individual tumors were observed to have alteration patterns representing every combination of one, two, or all three branches. The oncogenetic tree model assumptions are appropriate for the observed heterogeneity of colon tumors, and the model produces a useful visual schematic of the sequence of events in pathways of colon carcinogenesis.

Kinetics of mutation induction by ultraviolet light in excision-deficient yeast.

Science.gov (United States)

Eckardt, F; Haynes, R H

1977-02-01

We have measured the frequency of UV-induced reversions (locus plus suppressor) for the ochre alleles ade2-1 and lys2-1 and forward mutations (ade2 adex double auxotrophs) in an excision-deficient strain of Saccharomyces cerevisiae (rad2-20). For very low UV doses, both mutational systems exhibit linear induction kinetics. However, as the dose increases, a strikingly different response is observed: in the selective reversion system a transition to higher order induction kinetics occurs near 9 ergs/mm2 (25% survival), whereas in the nonselective forward system the mutation frequency passes through a maximum near 14 ergs/mm2 (4.4% survival) and then declines. This contrast in kinetics cannot be explained in any straightforward way by current models of induced mutagenesis, which have been developed primarily on the basis of bacterial data. The bacterial models are designed to accommodate the quadratic induction kinetics that are frequently observed in these systems. We have derived a mathematical expression for mutation frequency that enables us to fit both the forward and reversion data on the assumptions that mutagenesis is basically a "single event" Poisson process, and that mutation and killing are not necessarily independent of one another. In particular, the dose-response relations are consistent with the idea that the sensitivity of the revertants is about 25% less than that of the original cell population, whereas the sensitivity of the forward mutants is about 29% greater than the population average. We argue that this relatively small differential sensitivity of mutant and nonmutant cells is associated with events that take place during mutation expression and clonal growth.

Kinetics of mutation induction by ultraviolet light in excision-deficient yeast

International Nuclear Information System (INIS)

Eckardt, F.; Haynes, R.H.

1977-01-01

We have measured the frequency of uv-induced reversions (locus plus suppressor) for the ochre alleles ade 2-1 and lys 2-1 and forward mutations (ade2 adex double auxotrophs) in an excision-deficient strain of Saccharomyces cerevisiae (rad 2-20). For very low uv doses, both mutational systems exhibit linear induction kinetics. However, as the dose increases, a strikingly different response is observed: in the selective reversion system a transition to higher order induction kinetics occurs near 9 ergs/mm 2 (25 percent survival), whereas in the nonselective forward system the mutation frequency passes through a maximum near 14 ergs/mm 2 (4.4 percent survival) and then declines. This contrast in kinetics cannot be explained in any straightforward way by current models of induced mutagenesis, which have been developed primarily on the basis of bacterial data. The bacterial models are designed to accommodate the quadratic induction kinetics that are frequently observed in these systems. We have derived a mathematical expression for mutation frequency that enables us to fit both the forward and reversion data on the assumptions that mutagenesis is basically a ''single event'' Poisson process, and that mutation and killing are not necessarily independent of one another. In particular, the dose-response relations are consistent with the idea that the sensitivity of the revertants is about 25 percent less than that of the original cell population, whereas the sensitivity of the forward mutants is about 29 percent greater than the population average. We argue that this relatively small differential sensitivity of mutant and nonmutant cells is associated with events that take place during mutation expression and clonal growth

Deep sequencing of natural and experimental populations of Drosophila melanogaster reveals biases in the spectrum of new mutations.

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Assaf, Zoe June; Tilk, Susanne; Park, Jane; Siegal, Mark L; Petrov, Dmitri A

2017-12-01

Mutations provide the raw material of evolution, and thus our ability to study evolution depends fundamentally on having precise measurements of mutational rates and patterns. We generate a data set for this purpose using (1) de novo mutations from mutation accumulation experiments and (2) extremely rare polymorphisms from natural populations. The first, mutation accumulation (MA) lines are the product of maintaining flies in tiny populations for many generations, therefore rendering natural selection ineffective and allowing new mutations to accrue in the genome. The second, rare genetic variation from natural populations allows the study of mutation because extremely rare polymorphisms are relatively unaffected by the filter of natural selection. We use both methods in Drosophila melanogaster , first generating our own novel data set of sequenced MA lines and performing a meta-analysis of all published MA mutations (∼2000 events) and then identifying a high quality set of ∼70,000 extremely rare (≤0.1%) polymorphisms that are fully validated with resequencing. We use these data sets to precisely measure mutational rates and patterns. Highlights of our results include: a high rate of multinucleotide mutation events at both short (∼5 bp) and long (∼1 kb) genomic distances, showing that mutation drives GC content lower in already GC-poor regions, and using our precise context-dependent mutation rates to predict long-term evolutionary patterns at synonymous sites. We also show that de novo mutations from independent MA experiments display similar patterns of single nucleotide mutation and well match the patterns of mutation found in natural populations. © 2017 Assaf et al.; Published by Cold Spring Harbor Laboratory Press.

Validation of an "Intelligent Mouthguard" Single Event Head Impact Dosimeter.

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Bartsch, Adam; Samorezov, Sergey; Benzel, Edward; Miele, Vincent; Brett, Daniel

2014-11-01

Dating to Colonel John Paul Stapp MD in 1975, scientists have desired to measure live human head impacts with accuracy and precision. But no instrument exists to accurately and precisely quantify single head impact events. Our goal is to develop a practical single event head impact dosimeter known as "Intelligent Mouthguard" and quantify its performance on the benchtop, in vitro and in vivo. In the Intelligent Mouthguard hardware, limited gyroscope bandwidth requires an algorithm-based correction as a function of impact duration. After we apply gyroscope correction algorithm, Intelligent Mouthguard results at time of CG linear acceleration peak correlate to the Reference Hybrid III within our tested range of pulse durations and impact acceleration profiles in American football and Boxing in vitro tests: American football, IMG=1.00REF-1.1g, R2=0.99; maximum time of peak XYZ component imprecision 3.6g and 370 rad/s2; maximum time of peak azimuth and elevation imprecision 4.8° and 2.9°; maximum average XYZ component temporal imprecision 3.3g and 390 rad/s2. Boxing, IMG=1.00REF-0.9 g, R2=0.99, R2=0.98; maximum time of peak XYZ component imprecision 3.9 g and 390 rad/s2, maximum time of peak azimuth and elevation imprecision 2.9° and 2.1°; average XYZ component temporal imprecision 4.0 g and 440 rad/s2. In vivo Intelligent Mouthguard true positive head impacts from American football players and amateur boxers have temporal characteristics (first harmonic frequency from 35 Hz to 79 Hz) within our tested benchtop (first harmonic frequencyIntelligent Mouthguard qualifies as a single event dosimeter in American football and Boxing.

Single-event burnout of power MOSFET devices for satellite application

International Nuclear Information System (INIS)

Xue Yuxiong; Tian Kai; Cao Zhou; Yang Shiyu; Liu Gang; Cai Xiaowu; Lu Jiang

2008-01-01

Single-event burnout (SEB) sensitivity was tested for power MOSFET devices, JTMCS081 and JTMCS062, which were made in Institute of Microelectronics, Chinese Academy of Sciences, using californium-252 simulation source. SEB voltage threshold was found for devices under test (DUT). It is helpful for engineers to choose devices used in satellites. (authors)

3-D topological signatures and a new discrimination method for single-electron events and 0νββ events in CdZnTe: A Monte Carlo simulation study

Energy Technology Data Exchange (ETDEWEB)

Zeng, Ming; Li, Teng-Lin; Cang, Ji-Rong [Key Laboratory of Particle & Radiation Imaging (Tsinghua University), Ministry of Education (China); Department of Engineering Physics, Tsinghua University, Beijing 100084 (China); Zeng, Zhi, E-mail: zengzhi@tsinghua.edu.cn [Key Laboratory of Particle & Radiation Imaging (Tsinghua University), Ministry of Education (China); Department of Engineering Physics, Tsinghua University, Beijing 100084 (China); Fu, Jian-Qiang; Zeng, Wei-He; Cheng, Jian-Ping; Ma, Hao; Liu, Yi-Nong [Key Laboratory of Particle & Radiation Imaging (Tsinghua University), Ministry of Education (China); Department of Engineering Physics, Tsinghua University, Beijing 100084 (China)

2017-06-21

In neutrinoless double beta (0νββ) decay experiments, the diversity of topological signatures of different particles provides an important tool to distinguish double beta events from background events and reduce background rates. Aiming at suppressing the single-electron backgrounds which are most challenging, several groups have established Monte Carlo simulation packages to study the topological characteristics of single-electron events and 0νββ events and develop methods to differentiate them. In this paper, applying the knowledge of graph theory, a new topological signature called REF track (Refined Energy-Filtered track) is proposed and proven to be an accurate approximation of the real particle trajectory. Based on the analysis of the energy depositions along the REF track of single-electron events and 0νββ events, the REF energy deposition models for both events are proposed to indicate the significant differences between them. With these differences, this paper presents a new discrimination method, which, in the Monte Carlo simulation, achieved a single-electron rejection factor of 93.8±0.3 (stat.)% as well as a 0νββ efficiency of 85.6±0.4 (stat.)% with optimized parameters in CdZnTe.

Molecular analysis of HEXA gene in Argentinean patients affected with Tay-Sachs disease: possible common origin of the prevalent c.459+5A>G mutation.

Science.gov (United States)

Zampieri, Stefania; Montalvo, Annalisa; Blanco, Mariana; Zanin, Irene; Amartino, Hernan; Vlahovicek, Kristian; Szlago, Marina; Schenone, Andrea; Pittis, Gabriela; Bembi, Bruno; Dardis, Andrea

2012-05-15

Tay-Sachs disease (TSD) is a recessively inherited disorder caused by the deficient activity of hexosaminidase A due to mutations in the HEXA gene. Up to date there is no information regarding the molecular genetics of TSD in Argentinean patients. In the present study we have studied 17 Argentinean families affected by TSD, including 20 patients with the acute infantile form and 3 with the sub-acute form. Overall, we identified 14 different mutations accounting for 100% of the studied alleles. Eight mutations were novel: 5 were single base changes leading to drastic residue changes or truncated proteins, 2 were small deletions and one was an intronic mutation that may cause a splicing defect. Although the spectrum of mutations was highly heterogeneous, a high frequency of the c.459+5G>A mutation, previously described in different populations was found among the studied cohort. Haplotype analysis suggested that in these families the c.459+5G>A mutation might have arisen by a single mutational event. Copyright © 2012 Elsevier B.V. All rights reserved.

Single nucleotide polymorphism array lesions, TET2, DNMT3A, ASXL1 and CBL mutations are present in systemic mastocytosis.

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Fabiola Traina

Full Text Available We hypothesized that analysis of single nucleotide polymorphism arrays (SNP-A and new molecular defects may provide new insight in the pathogenesis of systemic mastocytosis (SM. SNP-A karyotyping was applied to identify recurrent areas of loss of heterozygosity and bidirectional sequencing was performed to evaluate the mutational status of TET2, DNMT3A, ASXL1, EZH2, IDH1/IDH2 and the CBL gene family. Overall survival (OS was analyzed using the Kaplan-Meier method. We studied a total of 26 patients with SM. In 67% of SM patients, SNP-A karyotyping showed new chromosomal abnormalities including uniparental disomy of 4q and 2p spanning TET2/KIT and DNMT3A. Mutations in TET2, DNMT3A, ASXL1 and CBL were found in 23%, 12%, 12%, and 4% of SM patients, respectively. No mutations were observed in EZH2 and IDH1/IDH2. Significant differences in OS were observed for SM mutated patients grouped based on the presence of combined TET2/DNMT3A/ASXL1 mutations independent of KIT (P = 0.04 and sole TET2 mutations (P<0.001. In conclusion, TET2, DNMT3A and ASXL1 mutations are also present in mastocytosis and these mutations may affect prognosis, as demonstrated by worse OS in mutated patients.

Mutation-Specific Mechanisms of Hyperactivation of Noonan Syndrome SOS Molecules Detected with Single-molecule Imaging in Living Cells.

Science.gov (United States)

Nakamura, Yuki; Umeki, Nobuhisa; Abe, Mitsuhiro; Sako, Yasushi

2017-10-26

Noonan syndrome (NS) is a congenital hereditary disorder associated with developmental and cardiac defects. Some patients with NS carry mutations in SOS, a guanine nucleotide exchange factor (GEF) for the small GTPase RAS. NS mutations have been identified not only in the GEF domain, but also in various domains of SOS, suggesting that multiple mechanisms disrupt SOS function. In this study, we examined three NS mutations in different domains of SOS to clarify the abnormality in its translocation to the plasma membrane, where SOS activates RAS. The association and dissociation kinetics between SOS tagged with a fluorescent protein and the living cell surface were observed in single molecules. All three mutants showed increased affinity for the plasma membrane, inducing excessive RAS signalling. However, the mechanisms by which their affinity was increased were specific to each mutant. Conformational disorder in the resting state, increased probability of a conformational change on the plasma membrane, and an increased association rate constant with the membrane receptor are the suggested mechanisms. These different properties cause the specific phenotypes of the mutants, which should be rescuable with different therapeutic strategies. Therefore, single-molecule kinetic analyses of living cells are useful for the pathological analysis of genetic diseases.

Mutator activity in Schizophyllum commune

Energy Technology Data Exchange (ETDEWEB)

Shneyour, Y.; Koltin, Y. (Tel Aviv Univ. (Israel). Dept. of Microbiology)

1983-01-01

A strain with an elevated level of spontaneous mutations and an especially high rate of reversion at a specific locus (pab/sup -/) was identified. The mutator trait is recessive. UV sensitivity and the absence of a UV-specific endonucleolytic activity were associated with the enhancement of the mutation rate in mutator strains. The endonuclease associated with the regulation of the mutation rate also acted on single-stranded DNA. The molecular weight of this enzyme is about 38,000 daltons.

Design of thermostable rhamnogalacturonan lyase mutants from Bacillus licheniformis by combination of targeted single point mutations

DEFF Research Database (Denmark)

da Silva, Ines Isabel Cardoso Rodrigues; Jers, Carsten; Otten, Harm

2014-01-01

Rhamnogalacturonan I lyases (RGI lyases) (EC 4.2.2.-) catalyze cleavage of α-1,4 bonds between rhamnose and galacturonic acid in the backbone of pectins by β-elimination. In the present study, targeted improvement of the thermostability of a PL family 11 RGI lyase from Bacillus licheniformis (DSM......, were obtained due to additive stabilizing effects of single amino acid mutations (E434L, G55V, and G326E) compared to the wild type. The crystal structure of the B. licheniformis wild-type RGI lyase was also determined; the structural analysis corroborated that especially mutation of charged amino...

Pervasive within-Mitochondrion Single-Nucleotide Variant Heteroplasmy as Revealed by Single-Mitochondrion Sequencing

Directory of Open Access Journals (Sweden)

Jacqueline Morris

2017-12-01

Full Text Available Summary: A number of mitochondrial diseases arise from single-nucleotide variant (SNV accumulation in multiple mitochondria. Here, we present a method for identification of variants present at the single-mitochondrion level in individual mouse and human neuronal cells, allowing for extremely high-resolution study of mitochondrial mutation dynamics. We identified extensive heteroplasmy between individual mitochondrion, along with three high-confidence variants in mouse and one in human that were present in multiple mitochondria across cells. The pattern of variation revealed by single-mitochondrion data shows surprisingly pervasive levels of heteroplasmy in inbred mice. Distribution of SNV loci suggests inheritance of variants across generations, resulting in Poisson jackpot lines with large SNV load. Comparison of human and mouse variants suggests that the two species might employ distinct modes of somatic segregation. Single-mitochondrion resolution revealed mitochondria mutational dynamics that we hypothesize to affect risk probabilities for mutations reaching disease thresholds. : Morris et al. use independent sequencing of multiple individual mitochondria from mouse and human brain cells to show high pervasiveness of mutations. The mutations are heteroplasmic within single mitochondria and within and between cells. These findings suggest mechanisms by which mutations accumulate over time, resulting in mitochondrial dysfunction and disease. Keywords: single mitochondrion, single cell, human neuron, mouse neuron, single-nucleotide variation

Single event effects induced by 15.14 MeV/u sup 1 sup 3 sup 6 Xe ions

CERN Document Server

Hou Ming Dong; LiuJie; Wang Zhi Guang; Jin Yun Fan; Zhu Zhi Yong; Zhen Hong Lou; Liu Chang Long; Chen Xiao Xi; Wei Xin Guo; Zhang Li; Fan You Cheng; Zhu Zhou Rong; Zhang Yiting

2002-01-01

Single event effects induced by 15.14 MeV/u sup 1 sup 3 sup 6 Xe ions in different batches of 32k x 8 bits static random access memory are studied. The incident angle dependences of the cross sections for single event upset and single event latch up are presented. The SEE cross sections are plotted versus energy loss instead of linear energy transfer value in sensitive region. The depth of sensitive volume and thickness of 'dead' layer above the sensitive volume are estimated

Combining Single Strand Oligodeoxynucleotides and CRISPR/Cas9 to Correct Gene Mutations in β-Thalassemia-induced Pluripotent Stem Cells.

Science.gov (United States)

Niu, Xiaohua; He, Wenyin; Song, Bing; Ou, Zhanhui; Fan, Di; Chen, Yuchang; Fan, Yong; Sun, Xiaofang

2016-08-05

β-Thalassemia (β-Thal) is one of the most common genetic diseases in the world. The generation of patient-specific β-Thal-induced pluripotent stem cells (iPSCs), correction of the disease-causing mutations in those cells, and then differentiation into hematopoietic stem cells offers a new therapeutic strategy for this disease. Here, we designed a CRISPR/Cas9 to specifically target the Homo sapiens hemoglobin β (HBB) gene CD41/42(-CTTT) mutation. We demonstrated that the combination of single strand oligodeoxynucleotides with CRISPR/Cas9 was capable of correcting the HBB gene CD41/42 mutation in β-Thal iPSCs. After applying a correction-specific PCR assay to purify the corrected clones followed by sequencing to confirm mutation correction, we verified that the purified clones retained full pluripotency and exhibited normal karyotyping. Additionally, whole-exome sequencing showed that the mutation load to the exomes was minimal after CRISPR/Cas9 targeting. Furthermore, the corrected iPSCs were selected for erythroblast differentiation and restored the expression of HBB protein compared with the parental iPSCs. This method provides an efficient and safe strategy to correct the HBB gene mutation in β-Thal iPSCs. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Single Event Upset Studies Using the ATLAS SCT

CERN Document Server

Dafinca, A; The ATLAS collaboration; Weidberg, A R

2014-01-01

Single Event Upsets (SEU) are expected to occur during high luminosity running of the ATLAS SemiConductor Tracker (SCT). The SEU cross sections were measured in pion beams with momenta in the range 200 to 465 MeV/c and proton test beams at 24 GeV/c but the extrapolation to LHC conditions is non-trivial because of the range of particle types and momenta. The SEUs studied occur in the p-i-n photodiode and the registers in the ABCD chip. Comparisons between predicted SEU rates and those measured from ATLAS data are presented. The implications for ATLAS operation are discussed

Modeling of Single Event Transients With Dual Double-Exponential Current Sources: Implications for Logic Cell Characterization

Science.gov (United States)

Black, Dolores A.; Robinson, William H.; Wilcox, Ian Z.; Limbrick, Daniel B.; Black, Jeffrey D.

2015-08-01

Single event effects (SEE) are a reliability concern for modern microelectronics. Bit corruptions can be caused by single event upsets (SEUs) in the storage cells or by sampling single event transients (SETs) from a logic path. An accurate prediction of soft error susceptibility from SETs requires good models to convert collected charge into compact descriptions of the current injection process. This paper describes a simple, yet effective, method to model the current waveform resulting from a charge collection event for SET circuit simulations. The model uses two double-exponential current sources in parallel, and the results illustrate why a conventional model based on one double-exponential source can be incomplete. A small set of logic cells with varying input conditions, drive strength, and output loading are simulated to extract the parameters for the dual double-exponential current sources. The parameters are based upon both the node capacitance and the restoring current (i.e., drive strength) of the logic cell.

Single-Event Effect Testing of the Vishay Si7414DN n-Type TrenchFET(Registered Trademark) Power MOSFET

Science.gov (United States)

Lauenstein, J.-M.; Casey, M. C.; Campola, M. A.; Phan, A. M.; Wilcox, E. P.; Topper, A. D.; Ladbury, R. L.

2017-01-01

This study was being undertaken to determine the single event effect susceptibility of the commercial Vishay 60-V TrenchFET power MOSFET. Heavy-ion testing was conducted at the Texas AM University Cyclotron Single Event Effects Test Facility (TAMU) and the Lawrence Berkeley National Laboratory BASE Cyclotron Facility (LBNL). In addition, initial 200-MeV proton testing was conducted at Massachusetts General Hospital (MGH) Francis H. Burr Proton Beam Therapy Center. Testing was performed to evaluate this device for single-event effects from lower-LET, lighter ions relevant to higher risk tolerant space missions.

Single-Event Effect Performance of a Conductive-Bridge Memory EEPROM

Science.gov (United States)

Chen, Dakai; Wilcox, Edward; Berg, Melanie; Kim, Hak; Phan, Anthony; Figueiredo, Marco; Seidleck, Christina; LaBel, Kenneth

2015-01-01

We investigated the heavy ion single-event effect (SEE) susceptibility of the industry’s first stand-alone memory based on conductive-bridge memory (CBRAM) technology. The device is available as an electrically erasable programmable read-only memory (EEPROM). We found that single-event functional interrupt (SEFI) is the dominant SEE type for each operational mode (standby, dynamic read, and dynamic write/read). SEFIs occurred even while the device is statically biased in standby mode. Worst case SEFIs resulted in errors that filled the entire memory space. Power cycle did not always clear the errors. Thus the corrupted cells had to be reprogrammed in some cases. The device is also vulnerable to bit upsets during dynamic write/read tests, although the frequency of the upsets are relatively low. The linear energy transfer threshold for cell upset is between 10 and 20 megaelectron volts per square centimeter per milligram, with an upper limit cross section of 1.6 times 10(sup -11) square centimeters per bit (95 percent confidence level) at 10 megaelectronvolts per square centimeter per milligram. In standby mode, the CBRAM array appears invulnerable to bit upsets.

Characterization of a mutation commonly associated with persistent stuttering: evidence for a founder mutation

Science.gov (United States)

Fedyna, Alison; Drayna, Dennis; Kang, Changsoo

2010-01-01

Stuttering is a disorder which affects the fluency of speech. It has been shown to have high heritability, and has recently been linked to mutations in the GNPTAB gene. One such mutation, Glu1200Lys, has been repeatedly observed in unrelated families and individual cases. Eight unrelated individuals carrying this mutation were analyzed in an effort to distinguish whether these arise from repeated mutation at the same site, or whether they represent a founder mutation with a single origin. Results show that all 12 chromosomes carrying this mutation share a common haplotype in this region, indicating it is a founder mutation. Further analysis estimated the age of this allele to be ~572 generations. Construction of a cladogram tracing the mutation through our study sample also supports the founder mutation hypothesis. PMID:20944643

The p16INK4alpha/p19ARF gene mutations are infrequent and are mutually exclusive to p53 mutations in Indian oral squamous cell carcinomas.

Science.gov (United States)

Kannan, K; Munirajan, A K; Krishnamurthy, J; Bhuvarahamurthy, V; Mohanprasad, B K; Panishankar, K H; Tsuchida, N; Shanmugam, G

2000-03-01

Eighty-seven untreated primary oral squamous cell carcinomas (SCCs) associated with betel quid and tobacco chewing from Indian patients were analysed for the presence of mutations in the commonly shared exon 2 of p16INK4alpha/p19ARF genes. Polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and sequencing analysis were used to detect mutations. SSCP analysis indicated that only 9% (8/87) of the tumours had mutation in p16INK4alpha/p19ARF genes. Seventy-two tumours studied here were previously analysed for p53 mutations and 21% (15/72) of them were found to have mutations in p53 gene. Only one tumour was found to have mutation at both p53 and p16INK4alpha/p19ARF genes. Thus, the mutation rates observed were 21% for p53, 9% for p16INK4alpha/p19ARF, and 1% for both. Sequencing analysis revealed two types of mutations; i) G to C (GCAG to CCAG) transversion type mutation at intron 1-exon 2 splice junction and ii) another C to T transition type mutation resulting in CGA to TGA changing arginine to a termination codon at p16INK4alpha gene codon 80 and the same mutation will alter codon 94 of p19ARF gene from CCG to CTG (proline to leucine). These results suggest that p16INK4alpha/p19ARF mutations are less frequent than p53 mutations in Indian oral SCCs. The p53 and p16INK4alpha/p19ARF mutational events are independent and are mutually exclusive suggesting that mutational inactivation of either p53 or p16INK4alpha/p19ARF may alleviate the need for the inactivation of the other gene.

BRAF, KRAS and PIK3CA mutations in colorectal serrated polyps and cancer: Primary or secondary genetic events in colorectal carcinogenesis?

Directory of Open Access Journals (Sweden)

Schmitt Fernando

2008-09-01

Full Text Available Abstract Background BRAF, KRAS and PIK3CA mutations are frequently found in sporadic colorectal cancer (CRC. In contrast to KRAS and PIK3CA mutations, BRAF mutations are associated with tumours harbouring CpG Island methylation phenotype (CIMP, MLH1 methylation and microsatellite instability (MSI. We aimed at determine the frequency of KRAS, BRAF and PIK3CA mutations in the process of colorectal tumourigenesis using a series of colorectal polyps and carcinomas. In the series of polyps CIMP, MLH1 methylation and MSI were also studied. Methods Mutation analyses were performed by PCR/sequencing. Bisulfite treated DNA was used to study CIMP and MLH1 methylation. MSI was detected by pentaplex PCR and Genescan analysis of quasimonomorphic mononucleotide repeats. Chi Square test and Fisher's Exact test were used to perform association studies. Results KRAS, PIK3CA or BRAF occur in 71% of polyps and were mutually exclusive. KRAS mutations occur in 35% of polyps. PIK3CA was found in one of the polyps. V600E BRAF mutations occur in 29% of cases, all of them classified as serrated adenoma. CIMP phenotype occurred in 25% of the polyps and all were mutated for BRAF. MLH1 methylation was not detected and all the polyps were microsatellite stable. The comparison between the frequency of oncogenic mutations in polyps and CRC (MSI and MSS lead us to demonstrate that KRAS and PIK3CA are likely to precede both types of CRC. BRAF mutations are likely to precede MSI carcinomas since the frequency found in serrated polyps is similar to what is found in MSI CRC (P = 0.9112, but statistically different from what is found in microsatellite stable (MSS tumours (P = 0.0191. Conclusion Our results show that BRAF, KRAS and PIK3CA mutations occur prior to malignant transformation demonstrating that these oncogenic alterations are primary genetic events in colorectal carcinogenesis. Further, we show that BRAF mutations occur in association with CIMP phenotype in colorectal

BRAF, KRAS and PIK3CA mutations in colorectal serrated polyps and cancer: Primary or secondary genetic events in colorectal carcinogenesis?

International Nuclear Information System (INIS)

Velho, Sérgia; Moutinho, Cátia; Cirnes, Luís; Albuquerque, Cristina; Hamelin, Richard; Schmitt, Fernando; Carneiro, Fátima; Oliveira, Carla; Seruca, Raquel

2008-01-01

BRAF, KRAS and PIK3CA mutations are frequently found in sporadic colorectal cancer (CRC). In contrast to KRAS and PIK3CA mutations, BRAF mutations are associated with tumours harbouring CpG Island methylation phenotype (CIMP), MLH1 methylation and microsatellite instability (MSI). We aimed at determine the frequency of KRAS, BRAF and PIK3CA mutations in the process of colorectal tumourigenesis using a series of colorectal polyps and carcinomas. In the series of polyps CIMP, MLH1 methylation and MSI were also studied. Mutation analyses were performed by PCR/sequencing. Bisulfite treated DNA was used to study CIMP and MLH1 methylation. MSI was detected by pentaplex PCR and Genescan analysis of quasimonomorphic mononucleotide repeats. Chi Square test and Fisher's Exact test were used to perform association studies. KRAS, PIK3CA or BRAF occur in 71% of polyps and were mutually exclusive. KRAS mutations occur in 35% of polyps. PIK3CA was found in one of the polyps. V600E BRAF mutations occur in 29% of cases, all of them classified as serrated adenoma. CIMP phenotype occurred in 25% of the polyps and all were mutated for BRAF. MLH1 methylation was not detected and all the polyps were microsatellite stable. The comparison between the frequency of oncogenic mutations in polyps and CRC (MSI and MSS) lead us to demonstrate that KRAS and PIK3CA are likely to precede both types of CRC. BRAF mutations are likely to precede MSI carcinomas since the frequency found in serrated polyps is similar to what is found in MSI CRC (P = 0.9112), but statistically different from what is found in microsatellite stable (MSS) tumours (P = 0.0191). Our results show that BRAF, KRAS and PIK3CA mutations occur prior to malignant transformation demonstrating that these oncogenic alterations are primary genetic events in colorectal carcinogenesis. Further, we show that BRAF mutations occur in association with CIMP phenotype in colorectal serrated polyps and verified that colorectal serrated

Results of single-event multilevel orthopedic surgery in children with cerebral palsy

Directory of Open Access Journals (Sweden)

Akhmed Tomov

2015-11-01

Full Text Available Background: Single-event multilevel orthopedic surgery is a modern approach in the operative treatment of children with cerebral palsy. Methods: Single-event multilevel orthopedic surgery was carried out in 108 patients with cerebral palsy. Patients’ average age was 11.3±1.7 years. Surgical results were analyzed at follow-up after 18 to 24 months, by way of detailed physical examination, functional assessment, imaging, the Edinburgh Visual Gait Score and Gillette Functional Assessment Questionnaire. Results: In our series, 647 procedures were performed during 141 surgeries. Patients had an average of 4.59 procedures per surgery. Observational gait analysis showed an improvement in stance and swing gait phases in ambulatory children. According to the Gillette Functional Assessment Questionnaire, an increase of functional level was noted in 50 patients but did not change in 32 patients. Conclusions: For children with cerebral palsy, single-event multilevel surgery is defined as two or more surgical procedures of the soft tissue or bone at two or more anatomical levels during one operative procedure. In cases where a large volume of surgery is required, two separate operations with a short break in between, but requiring only one hospital admission and one rehabilitation period, are also included. This approach requires adapted methods of surgical intervention, and appropriate methods of anesthesia and pain control in the postoperative period to the start of rehabilitation. Compliance with the above principles allowed the necessary correction of orthopedic complications to be achieved in all cases.

Application of Single Strand Conformational Polymorphism (PCR-SSCP) in Identification of Some Beta-Globin Gene Mutations in A Group of Egyptian Beta-Thalassemia Patients and Carriers

International Nuclear Information System (INIS)

Somaya, E.T.; Soliman, M.D

2010-01-01

The present study investigated whether the single-strand conformational polymorphism (SSCP) method could be employed to identify (rather than simply detect) four of the most common beta-globin gene mutations in the Egyptian population: IVS-I-110, IVS-I-6, the IVS-I-1, and Codon 39. Using DNA from 90 beta-thalassemia patients and carriers, by PCR the appropriate 238-bp region of the human beta-globin gene was amplified, the reaction products (Single-stranded DNA) were analyzed by none denaturing polyacrylamide gel electrophoresis, and the bands visualized by silver staining. Single-stranded DNA (ssDNA) fragments showed reproducible pattern of bands that were characteristic of the mutations present. With the use of control samples containing six of the 10 possible combinations of the four beta-globin gene mutations under study, we were able to predict the mutations present in 23 out of 90 (26.4%) of the patients studied. These predictions were confirmed independently by the amplification refractory mutation system (ARMS) method. It is concluded that this non-radioactive PCR-SSCP method can be used to reliably identify mutations in beta-thalassemia patients, provided that suitable controls are available. However, usefulness of this method for determining the genotype of beta-thalassaemic individuals is obviously limited by the great number of controls required. Moreover, the ability to detect mutations by SSCP is in general lower compared to other methods, ARMS, DGGE or DHPLC, which are reported to detect 49.5% to 73% of the mutations present. The SSCP method is nevertheless much easier to employ than other methods and is especially successful for beta-thalassemia carriers. This method would thus be particularly useful for an initial screening of target groups (prenatal diagnosis)

Identification of Constrained Cancer Driver Genes Based on Mutation Timing

Science.gov (United States)

Sakoparnig, Thomas; Fried, Patrick; Beerenwinkel, Niko

2015-01-01

Cancer drivers are genomic alterations that provide cells containing them with a selective advantage over their local competitors, whereas neutral passengers do not change the somatic fitness of cells. Cancer-driving mutations are usually discriminated from passenger mutations by their higher degree of recurrence in tumor samples. However, there is increasing evidence that many additional driver mutations may exist that occur at very low frequencies among tumors. This observation has prompted alternative methods for driver detection, including finding groups of mutually exclusive mutations and incorporating prior biological knowledge about gene function or network structure. Dependencies among drivers due to epistatic interactions can also result in low mutation frequencies, but this effect has been ignored in driver detection so far. Here, we present a new computational approach for identifying genomic alterations that occur at low frequencies because they depend on other events. Unlike passengers, these constrained mutations display punctuated patterns of occurrence in time. We test this driver–passenger discrimination approach based on mutation timing in extensive simulation studies, and we apply it to cross-sectional copy number alteration (CNA) data from ovarian cancer, CNA and single-nucleotide variant (SNV) data from breast tumors and SNV data from colorectal cancer. Among the top ranked predicted drivers, we find low-frequency genes that have already been shown to be involved in carcinogenesis, as well as many new candidate drivers. The mutation timing approach is orthogonal and complementary to existing driver prediction methods. It will help identifying from cancer genome data the alterations that drive tumor progression. PMID:25569148

High-energy heavy ion testing of VLSI devices for single event ...

Indian Academy of Sciences (India)

Unknown

per describes the high-energy heavy ion radiation testing of VLSI devices for single event upset (SEU) ... The experimental set up employed to produce low flux of heavy ions viz. silicon ... through which they pass, leaving behind a wake of elec- ... for use in Bus Management Unit (BMU) and bulk CMOS ... was scheduled.

Applicability of LET to single events in microelectronic structures

Science.gov (United States)

Xapsos, Michael A.

1992-12-01

LET is often used as a single parameter to determine the energy deposited in a microelectronic structure by a single event. The accuracy of this assumption is examined for ranges of ion energies and volumes of silicon appropriate for modern microelectronics. It is shown to be accurate only under very restricted conditions. Significant differences arise because (1) LET is related to energy lost by the ion, not energy deposited in the volume; and (2) LET is an average value and does not account for statistical variations in energy deposition. Criteria are suggested for determining when factors other than LET should be considered, and new analytical approaches are presented to account for them. One implication of these results is that improvements can be made in space upset rate predictions by incorporating the new methods into currently used codes such as CREME and CRUP.

Single Event Upset Studies Using the ATLAS SCT

CERN Document Server

Weidberg, A R; The ATLAS collaboration

2013-01-01

Single Event Upsets (SEU) are expected to occur during high luminosity running of the ATLAS SemiConductor Tracker (SCT). The SEU cross sections were measured in pion beams with momenta in the range 200 to 465 MeV/c and proton test beams at 24 GeV/c but the extrapolation to LHC conditions is non-trivial because of the range of particle types and momenta. The SEUs studied occur in the \\emph{p-i-n} photodiode and the registers in the ABCD chip. Comparisons between predicted SEU rates and those measured from ATLAS data are presented. The implications for ATLAS operation are discussed.

Applications of heavy ion microprobe for single event effects analysis

International Nuclear Information System (INIS)

Reed, Robert A.; Vizkelethy, Gyorgy; Pellish, Jonathan A.; Sierawski, Brian; Warren, Kevin M.; Porter, Mark; Wilkinson, Jeff; Marshall, Paul W.; Niu, Guofu; Cressler, John D.; Schrimpf, Ronald D.; Tipton, Alan; Weller, Robert A.

2007-01-01

The motion of ionizing-radiation-induced rogue charge carriers in a semiconductor can create unwanted voltage and current conditions within a microelectronic circuit. If sufficient unwanted charge or current occurs on a sensitive node, a variety of single event effects (SEEs) can occur with consequences ranging from trivial to catastrophic. This paper describes the application of heavy ion microprobes to assist with calibration and validation of SEE modeling approaches

Recurrent LDL-receptor mutation causes familial ...

African Journals Online (AJOL)

1995-05-05

May 5, 1995 ... 3. eaudet . New. Recurrent LDL-receptor mutation causes familial hypercholesterolaemia in ... amplification refractory mutation system (ARMS)" and single- strand conformation .... Location. Afrikaner. Mixed race. ApaLl.

Limited importance of the dominant-negative effect of TP53 missense mutations

International Nuclear Information System (INIS)

Stoczynska-Fidelus, Ewelina; Liberski, Pawel P; Rieske, Piotr; Szybka, Malgorzata; Piaskowski, Sylwester; Bienkowski, Michal; Hulas-Bigoszewska, Krystyna; Banaszczyk, Mateusz; Zawlik, Izabela; Jesionek-Kupnicka, Dorota; Kordek, Radzislaw

2011-01-01

Heterozygosity of TP53 missense mutations is related to the phenomenon of the dominant-negative effect (DNE). To estimate the importance of the DNE of TP53 mutations, we analysed the percentage of cancer cases showing a single heterozygous mutation of TP53 and searched for a cell line with a single heterozygous mutation of this gene. This approach was based on the knowledge that genes with evident DNE, such as EGFR and IDH1, represent nearly 100% of single heterozygous mutations in tumour specimens and cell lines. Genetic analyses (LOH and sequencing) performed for early and late passages of several cell lines originally described as showing single heterozygous TP53 mutations (H-318, G-16, PF-382, MOLT-13, ST-486 and LS-123). Statistical analysis of IARC TP53 and SANGER databases. Genetic analyses of N-RAS, FBXW7, PTEN and STR markers to test cross-contamination and cell line identity. Cell cloning, fluorescence-activated cell sorting and SSCP performed for the PF-382 cell line. A database study revealed TP53 single heterozygous mutations in 35% of in vivo (surgical and biopsy) samples and only 10% of cultured cells (in vitro), although those numbers appeared to be overestimated. We deem that published in vivo TP53 mutation analyses are not as rigorous as studies in vitro, and we did not find any cell line showing a stable, single heterozygous mutation. G16, PF-382 and MOLT-13 cells harboured single heterozygous mutations temporarily. ST-486, H-318 and LS-123 cell lines were misclassified. Specific mutations, such as R175H, R273H, R273L or R273P, which are reported in the literature to exert a DNE, showed the lowest percentage of single heterozygous mutations in vitro (about 5%). We suggest that the currently reported percentage of TP53 single heterozygous mutations in tumour samples and cancer cell lines is overestimated. Thus, the magnitude of the DNE of TP53 mutations is questionable. This scepticism is supported by database investigations showing that retention

Hit-size effectiveness theory applied to high doses of low LET radiation for pink mutations in Tradescantia

International Nuclear Information System (INIS)

Varma, M.N.; Bond, V.P.; Matthews, G.

1985-01-01

A hit-size effectiveness function which represents the probability of inducing a pink mutation in Tradescantia as a function of lineal energy density has been obtained (1) using observed pink mutation data for seven different radiation qualities and their respective single event microdosimetric spectra. In obtaining this function only the linear portions of dose-response curves were used. A significant improvement of the concepts embodied in the proposed hit-size effectiveness theory would be the demonstration of its applicability at high doses (where multiple hits are produced) and high dose rates (at which no significant biological repair takes place). In this article details are given on preliminary calculations of the pink mutation frequency in Tradescantia at 1, 5, 10, 20, and 60 rads for 250 kVp x rays, using the multi-hit spectra and the hit-size effectiveness function obtained on the basis of single hit microdosimetric spectra as outline in (1). A comparison of the calculated and observed pink mutation frequencies indicate excellent agreement and suggests the possibility of obtaining the hit-size effectiveness function from high dose biological-effect data obtained using low-LET radiations. 6 refs., 3 figs., 3 tabs

Thermomechanical Stresses Analysis of a Single Event Burnout Process

Science.gov (United States)

Tais, Carlos E.; Romero, Eduardo; Demarco, Gustavo L.

2009-06-01

This work analyzes the thermal and mechanical effects arising in a power Diffusion Metal Oxide Semiconductor (DMOS) during a Single Event Burnout (SEB) process. For studying these effects we propose a more detailed simulation structure than the previously used by other authors, solving the mathematical models by means of the Finite Element Method. We use a cylindrical heat generation region, with 5 W, 10 W, 50 W and 100 W for emulating the thermal phenomena occurring during SEB processes, avoiding the complexity of the mathematical treatment of the ion-semiconductor interaction.

Repair-resistant mutation in Neurospora

International Nuclear Information System (INIS)

Stadler, D.; Macleod, H.; Loo, M.

1987-01-01

Chronic UV treatment produces severalfold fewer mutations in Neurospora conidia than does the same total dose of acute UV. Experiments were designed to determine the conditions required for chronic UV mutagenesis. Measurement of the coincidence frequency for two independent mutations revealed the existence of a subset of cells which are mutable by chronic UV. Analysis of forward mutation at the mtr locus showed that the genetic alterations produced by chronic UV were virtually all point mutants, even though the assay system could detect alterations or deletions extending into neighboring genes. A significant fraction of the mutants produced by acute UV were multigenic deletions. The size of the dose-rate effect (acute UV mutation frequency divided by chronic UV mutation frequency) was compared for several different mutation assay systems. Forward mutations (recessive lethals and mtr) gave values ranging from four to nine. For events which were restricted to specific molecular sites (specific reversions and nonsense suppressor mutations), there was a wider range of dose-rate ratios. This suggests that chronic UV mutation may be restricted to certain molecular sequences or configurations

Fundus albipunctatus associated with compound heterozygous mutations in RPE65

DEFF Research Database (Denmark)

Schatz, Patrik; Preising, Markus; Lorenz, Birgit

2011-01-01

To describe a family with an 18-year-old woman with fundus albipunctatus and compound heterozygous mutations in RPE65 whose unaffected parents and 1 female sibling harbored single heterozygous RPE65 mutations.......To describe a family with an 18-year-old woman with fundus albipunctatus and compound heterozygous mutations in RPE65 whose unaffected parents and 1 female sibling harbored single heterozygous RPE65 mutations....

Bleeding complications in BCR-ABL negative myeloproliferative neoplasms: prevalence, type, and risk factors in a single-center cohort.

Science.gov (United States)

Kander, Elizabeth M; Raza, Sania; Zhou, Zheng; Gao, Juehua; Zakarija, Anaadriana; McMahon, Brandon J; Stein, Brady L

2015-11-01

The BCR-ABL1-negative myeloproliferative neoplasms (MPN) share an increased risk of thrombotic and hemorrhagic complications. Risk factors for hemorrhage are less well defined than those for thrombosis. Because patients with CALR mutations have higher platelet counts compared to JAK2 V617F-mutated patients, bleeding rates may be increased in this group. Our aim was to retrospectively evaluate whether acquired von Willebrand disease (AvWD), thrombocytosis, mutational status, or treatment history are associated with bleeding in a cohort of MPN patients. Using an electronic database, MPN patients seen between 2005 and 2013 were retrospectively identified using ICD-9 codes and billing records. A bleeding event was defined as one that was identified in the medical record and graded based on the Common Terminology Criteria for Adverse Event (CTCAE) version 4.0. Among 351 MPN patients, 15.6 % experienced 64 bleeding event types. There was no association of bleeding with mutational status, gender, MPN subtype, aspirin use, prior thrombosis, or platelet count at presentation. There was an association between bleeding and older age at diagnosis. aVWD was identified in six patients. In this single-center retrospective study, bleeding events were identified in 15 % of patients, and associated with older age at diagnosis. aVWD was rarely tested for in this cohort.

Multi-region and single-cell sequencing reveal variable genomic heterogeneity in rectal cancer.

Science.gov (United States)

Liu, Mingshan; Liu, Yang; Di, Jiabo; Su, Zhe; Yang, Hong; Jiang, Beihai; Wang, Zaozao; Zhuang, Meng; Bai, Fan; Su, Xiangqian

2017-11-23

Colorectal cancer is a heterogeneous group of malignancies with complex molecular subtypes. While colon cancer has been widely investigated, studies on rectal cancer are very limited. Here, we performed multi-region whole-exome sequencing and single-cell whole-genome sequencing to examine the genomic intratumor heterogeneity (ITH) of rectal tumors. We sequenced nine tumor regions and 88 single cells from two rectal cancer patients with tumors of the same molecular classification and characterized their mutation profiles and somatic copy number alterations (SCNAs) at the multi-region and the single-cell levels. A variable extent of genomic heterogeneity was observed between the two patients, and the degree of ITH increased when analyzed on the single-cell level. We found that major SCNAs were early events in cancer development and inherited steadily. Single-cell sequencing revealed mutations and SCNAs which were hidden in bulk sequencing. In summary, we studied the ITH of rectal cancer at regional and single-cell resolution and demonstrated that variable heterogeneity existed in two patients. The mutational scenarios and SCNA profiles of two patients with treatment naïve from the same molecular subtype are quite different. Our results suggest each tumor possesses its own architecture, which may result in different diagnosis, prognosis, and drug responses. Remarkable ITH exists in the two patients we have studied, providing a preliminary impression of ITH in rectal cancer.

Relationship between single-event upset immunity and fabrication processes of recent memories

International Nuclear Information System (INIS)

Nemoto, N.; Shindou, H.; Kuboyama, S.; Matsuda, S.; Itoh, H.; Okada, S.; Nashiyama, I.

1999-01-01

Single-Event upset (SEU) immunity for commercial devices were evaluated by irradiation tests using high-energy heavy ions. We show test results and describe the relationship between observed SEU and structures/fabrication processes. We have evaluated single-even upset (SEU) tolerance of recent commercial memory devices using high energy heavy ions in order to find relationship between SEU rate and their fabrication process. It was revealed that the change of the process parameter gives much effect for the SEU rate of the devices. (authors)

First nondestructive measurements of power MOSFET single event burnout cross sections

International Nuclear Information System (INIS)

Oberg, D.L.; Wert, J.L.

1987-01-01

A new technique to nondestructively measure single event burnout cross sections for N-channel power MOSFETs is presented. Previous measurements of power MOSFET burnout susceptibility have been destructive and thus not conducive to providing statistically meaningful burnout probabilities. The nondestructive technique and data for various device types taken at several accelerators, including the LBL Bevalac, are documented. Several new phenomena are observed

The chlorophyll-deficient golden leaf mutation in cucumber is due to a single nucleotide substitution in CsChlI for magnesium chelatase I subunit.

Science.gov (United States)

Gao, Meiling; Hu, Liangliang; Li, Yuhong; Weng, Yiqun

2016-10-01

The cucumber chlorophyll-deficient golden leaf mutation is due to a single nucleotide substitution in the CsChlI gene for magnesium chelatase I subunit which plays important roles in the chlorophyll biosynthesis pathway. The Mg-chelatase catalyzes the insertion of Mg(2+) into the protoporphyrin IX in the chlorophyll biosynthesis pathway, which is a protein complex encompassing three subunits CHLI, CHLD, and CHLH. Chlorophyll-deficient mutations in genes encoding the three subunits have played important roles in understanding the structure, function and regulation of this important enzyme. In an EMS mutagenesis population, we identified a chlorophyll-deficient mutant C528 with golden leaf color throughout its development which was viable and able to set fruits and seeds. Segregation analysis in multiple populations indicated that this leaf color mutation was recessively inherited and the green color showed complete dominance over golden color. Map-based cloning identified CsChlI as the candidate gene for this mutation which encoded the CHLI subunit of cucumber Mg-chelatase. The 1757-bp CsChlI gene had three exons and a single nucleotide change (G to A) in its third exon resulted in an amino acid substitution (G269R) and the golden leaf color in C528. This mutation occurred in the highly conserved nucleotide-binding domain of the CHLI protein in which chlorophyll-deficient mutations have been frequently identified. The mutant phenotype, CsChlI expression pattern and the mutated residue in the CHLI protein suggested the mutant allele in C528 is unique among mutations identified so far in different species. This golden leaf mutant not only has its potential in cucumber breeding, but also provides a useful tool in understanding the CHLI function and its regulation in the chlorophyll biosynthesis pathway as well as chloroplast development.

Rates of Mutation and Host Transmission for an Escherichia coli Clone over 3 Years

Science.gov (United States)

Reeves, Peter R.; Liu, Bin; Zhou, Zhemin; Li, Dan; Guo, Dan; Ren, Yan; Clabots, Connie; Lan, Ruiting; Johnson, James R.; Wang, Lei

2011-01-01

Although over 50 complete Escherichia coli/Shigella genome sequences are available, it is only for closely related strains, for example the O55:H7 and O157:H7 clones of E. coli, that we can assign differences to individual evolutionary events along specific lineages. Here we sequence the genomes of 14 isolates of a uropathogenic E. coli clone that persisted for 3 years within a household, including a dog, causing a urinary tract infection (UTI) in the dog after 2 years. The 20 mutations observed fit a single tree that allows us to estimate the mutation rate to be about 1.1 per genome per year, with minimal evidence for adaptive change, including in relation to the UTI episode. The host data also imply at least 6 host transfer events over the 3 years, with 2 lineages present over much of that period. To our knowledge, these are the first direct measurements for a clone in a well-defined host community that includes rates of mutation and host transmission. There is a concentration of non-synonymous mutations associated with 2 transfers to the dog, suggesting some selection pressure from the change of host. However, there are no changes to which we can attribute the UTI event in the dog, which suggests that this occurrence after 2 years of the clone being in the household may have been due to chance, or some unknown change in the host or environment. The ability of a UTI strain to persist for 2 years and also to transfer readily within a household has implications for epidemiology, diagnosis, and clinical intervention. PMID:22046404

Rapid detection of single nucleotide mutation in p53 gene based on ...

Indian Academy of Sciences (India)

mutation.27 Nevertheless, more than 50% of all human tumors contain p53 mutation; ... gene mutation detection in various fields of biology and medicine persuaded us to find ..... Yola M L, Eren T and Atar N 2014 Electrochim. Acta. 125 38. 26.

Soft error rate analysis methodology of multi-Pulse-single-event transients

International Nuclear Information System (INIS)

Zhou Bin; Huo Mingxue; Xiao Liyi

2012-01-01

As transistor feature size scales down, soft errors in combinational logic because of high-energy particle radiation is gaining more and more concerns. In this paper, a combinational logic soft error analysis methodology considering multi-pulse-single-event transients (MPSETs) and re-convergence with multi transient pulses is proposed. In the proposed approach, the voltage pulse produced at the standard cell output is approximated by a triangle waveform, and characterized by three parameters: pulse width, the transition time of the first edge, and the transition time of the second edge. As for the pulse with the amplitude being smaller than the supply voltage, the edge extension technique is proposed. Moreover, an efficient electrical masking model comprehensively considering transition time, delay, width and amplitude is proposed, and an approach using the transition times of two edges and pulse width to compute the amplitude of pulse is proposed. Finally, our proposed firstly-independently-propagating-secondly-mutually-interacting (FIP-SMI) is used to deal with more practical re-convergence gate with multi transient pulses. As for MPSETs, a random generation model of MPSETs is exploratively proposed. Compared to the estimates obtained using circuit level simulations by HSpice, our proposed soft error rate analysis algorithm has 10% errors in SER estimation with speed up of 300 when the single-pulse-single-event transient (SPSET) is considered. We have also demonstrated the runtime and SER decrease with the increment of P0 using designs from the ISCAS-85 benchmarks. (authors)

New method for selection and characterization of single-source events in Ni+Ni collisions at 32 A.MeV

International Nuclear Information System (INIS)

Maskay-Wallez, Anne-Marie

1999-01-01

The study of heavy ion collisions, with the help of such efficient multi-detectors as INDRA, has shown the persistence of reactions leading to single-source events, up to bombarding energies higher than the Fermi one. These events could help characterizing an expected phase transition in nuclear matter. Whatever interesting they may be, the single-source events correspond to a small part of the total cross section, which makes them difficult to isolate and therefore to analyze. That is why different selection means have been tested - thanks to the 'Simon' event generator - on a simulated Ni + Ni at 32 A·MeV sample, before any application to the INDRA experimental data. As the known methods based on global variables did not prove effective, a set of new 4-dimensional quantities has been built, whose main advantage lies in a better description of physical events. From a Discriminant Analysis performed on 625 of these new 'moments' proceeds a highly discriminant variable, called D 625 . The experimental cross section associated with D 625 -selected single-source events amounts to 170 mb at 32 A·MeV. Such quasi-fusion events are shown to disappear at about 60 A·MeV. As regards the deexcitation mode of the 32 A·MeV Ni + Ni single-source events, an extensive experimental study and comparisons of the data with two reference models seem to confirm the hypothesis of a transition between fusion-evaporation and simultaneous multifragmentation mechanisms. (author)

Analysis of cosmic ray neutron-induced single-event phenomena

International Nuclear Information System (INIS)

Tukamoto, Yasuyuki; Watanabe, Yukinobu; Nakashima, Hideki

2003-01-01

We have developed a database of cross sections for the n+ 28 Si reaction in the energy range between 2 MeV and 3 GeV in order to analyze single-event upset (SEU) phenomena induced by cosmic-ray neutrons in semiconductor memory devices. The data are applied to calculations of SEU cross sections using the Burst Generation Rate (BGR) model including two parameters, critical charge and effective depth. The calculated results are compared with measured SEU cross-sections for energies up to 160 MeV, and the reaction products that provide important effects on SEU are mainly investigated. (author)

Device simulation of charge collection and single-event upset

International Nuclear Information System (INIS)

Dodd, P.E.

1996-01-01

In this paper the author reviews the current status of device simulation of ionizing-radiation-induced charge collection and single-event upset (SEU), with an emphasis on significant results of recent years. The author presents an overview of device-modeling techniques applicable to the SEU problem and the unique challenges this task presents to the device modeler. He examines unloaded simulations of radiation-induced charge collection in simple p/n diodes, SEU in dynamic random access memories (DRAM's), and SEU in static random access memories (SRAM's). The author concludes with a few thoughts on future issues likely to confront the SEU device modeler

Calculation of cosmic ray induced single event upsets: Program CRUP (Cosmic Ray Upset Program)

Science.gov (United States)

Shapiro, P.

1983-09-01

This report documents PROGRAM CRUP, COSMIC RAY UPSET PROGRAM. The computer program calculates cosmic ray induced single-event error rates in microelectronic circuits exposed to several representative cosmic-ray environments.

Kernel PLS Estimation of Single-trial Event-related Potentials

Science.gov (United States)

Rosipal, Roman; Trejo, Leonard J.

2004-01-01

Nonlinear kernel partial least squaes (KPLS) regressior, is a novel smoothing approach to nonparametric regression curve fitting. We have developed a KPLS approach to the estimation of single-trial event related potentials (ERPs). For improved accuracy of estimation, we also developed a local KPLS method for situations in which there exists prior knowledge about the approximate latency of individual ERP components. To assess the utility of the KPLS approach, we compared non-local KPLS and local KPLS smoothing with other nonparametric signal processing and smoothing methods. In particular, we examined wavelet denoising, smoothing splines, and localized smoothing splines. We applied these methods to the estimation of simulated mixtures of human ERPs and ongoing electroencephalogram (EEG) activity using a dipole simulator (BESA). In this scenario we considered ongoing EEG to represent spatially and temporally correlated noise added to the ERPs. This simulation provided a reasonable but simplified model of real-world ERP measurements. For estimation of the simulated single-trial ERPs, local KPLS provided a level of accuracy that was comparable with or better than the other methods. We also applied the local KPLS method to the estimation of human ERPs recorded in an experiment on co,onitive fatigue. For these data, the local KPLS method provided a clear improvement in visualization of single-trial ERPs as well as their averages. The local KPLS method may serve as a new alternative to the estimation of single-trial ERPs and improvement of ERP averages.

Dietary factors and Truncating APC Mutations in Sporadic Colorectal Adenomas

NARCIS (Netherlands)

Diergaarde, B.; Tiemersma, E.W.; Braam, H.; Muijen, van G.N.P.; Nagengast, F.M.; Kok, F.J.; Kampman, E.

2005-01-01

Inactivating mutations in APC are thought to be early, initiating events in colorectal carcinogenesis. To gain insight into the relationship between diet and inactivating APC mutations, we evaluated associations between dietary factors and the occurrence of these mutations in a Dutch case-control

Dietary factors and truncating APC mutations in sporadic colorectal adenomas.

NARCIS (Netherlands)

Diergaarde, B.; Tiemersma, E.W.; Braam, H.; Muijen, G.N.P. van; Nagengast, F.M.; Kok, F.J.; Kampman, E.

2005-01-01

Inactivating mutations in APC are thought to be early, initiating events in colorectal carcinogenesis. To gain insight into the relationship between diet and inactivating APC mutations, we evaluated associations between dietary factors and the occurrence of these mutations in a Dutch case-control

Parasitic bipolar amplification in a single event transient and its temperature dependence

International Nuclear Information System (INIS)

Liu Zheng; Chen Shu-Ming; Chen Jian-Jun; Qin Jun-Rui; Liu Rong-Rong

2012-01-01

Using three-dimensional technology computer-aided design (TCAD) simulation, parasitic bipolar amplification in a single event transient (SET) current of a single transistor and its temperature dependence are studied. We quantify the contributions of different current components in a SET current pulse, and it is found that the proportion of parasitic bipolar amplification in total collected charge is about 30% in both 130-nm and 90-nm technologies. The temperature dependence of parasitic bipolar amplification and the mechanism of the SET pulse are also investigated and quantified. The results show that the proportion of charge induced by parasitic bipolar increases with rising temperature, which illustrates that the parasitic bipolar amplification plays an important role in the charge collection of a single transistor

Influence of the MDM2 single nucleotide polymorphism SNP309 on tumour development in BRCA1 mutation carriers

Directory of Open Access Journals (Sweden)

Johnson Peter W

2006-03-01

Full Text Available Abstract Background The MDM2 gene encodes a negative regulator of the p53 tumour suppressor protein. A single nucleotide polymorphism (SNP in the MDM2 promoter (a T to G exchange at nucleotide 309 has been reported to produce accelerated tumour formation in individuals with inherited p53 mutations. We have investigated the effect of the MDM2 SNP309 on clinical outcome in a cohort of patients with germline mutations of BRCA1. Methods Genomic DNA was obtained for 102 healthy controls and 116 patients with established pathogenic mutations of BRCA1 and Pyrosequencing technology™ was used to determine the genotype at the MDM2 SNP309 locus. Results The polymorphism was present in 52.9% of the controls (G/T in 37.3% and G/G in 15.6% and 58.6% of the BRCA1 mutation carriers (47.4% G/T and 11.2% G/G. Incidence of malignancy in female BRCA1 carriers was not significantly higher in SNP309 carriers than in wildtype (T/T individuals (72.7% vs. 75.6%, p = 1.00. Mean age of diagnosis of first breast cancer was 41.2 years in the SNP309 G/G genotype carriers, 38.6 years in those with the SNP309 G/T genotype and 39.0 years in wildtype subjects (p = 0.80. Conclusion We found no evidence that the MDM2 SNP309 accelerates tumour development in carriers of known pathogenic germline mutations of BRCA1.

A nonadaptive origin of a beneficial trait: in silico selection for free energy of folding leads to the neutral emergence of mutational robustness in single domain proteins.

Science.gov (United States)

Pagan, Rafael F; Massey, Steven E

2014-02-01

Proteins are regarded as being robust to the deleterious effects of mutations. Here, the neutral emergence of mutational robustness in a population of single domain proteins is explored using computer simulations. A pairwise contact model was used to calculate the ΔG of folding (ΔG folding) using the three dimensional protein structure of leech eglin C. A random amino acid sequence with low mutational robustness, defined as the average ΔΔG resulting from a point mutation (ΔΔG average), was threaded onto the structure. A population of 1,000 threaded sequences was evolved under selection for stability, using an upper and lower energy threshold. Under these conditions, mutational robustness increased over time in the most common sequence in the population. In contrast, when the wild type sequence was used it did not show an increase in robustness. This implies that the emergence of mutational robustness is sequence specific and that wild type sequences may be close to maximal robustness. In addition, an inverse relationship between ∆∆G average and protein stability is shown, resulting partly from a larger average effect of point mutations in more stable proteins. The emergence of mutational robustness was also observed in the Escherichia coli colE1 Rop and human CD59 proteins, implying that the property may be common in single domain proteins under certain simulation conditions. The results indicate that at least a portion of mutational robustness in small globular proteins might have arisen by a process of neutral emergence, and could be an example of a beneficial trait that has not been directly selected for, termed a "pseudaptation."

Characterization of phospholipase C gamma enzymes with gain-of-function mutations.

Science.gov (United States)

Everett, Katy L; Bunney, Tom D; Yoon, Youngdae; Rodrigues-Lima, Fernando; Harris, Richard; Driscoll, Paul C; Abe, Koichiro; Fuchs, Helmut; de Angelis, Martin Hrabé; Yu, Philipp; Cho, Wohnwa; Katan, Matilda

2009-08-21

Phospholipase C gamma isozymes (PLC gamma 1 and PLC gamma 2) have a crucial role in the regulation of a variety of cellular functions. Both enzymes have also been implicated in signaling events underlying aberrant cellular responses. Using N-ethyl-N-nitrosourea (ENU) mutagenesis, we have recently identified single point mutations in murine PLC gamma 2 that lead to spontaneous inflammation and autoimmunity. Here we describe further, mechanistic characterization of two gain-of-function mutations, D993G and Y495C, designated as ALI5 and ALI14. The residue Asp-993, mutated in ALI5, is a conserved residue in the catalytic domain of PLC enzymes. Analysis of PLC gamma 1 and PLC gamma 2 with point mutations of this residue showed that removal of the negative charge enhanced PLC activity in response to EGF stimulation or activation by Rac. Measurements of PLC activity in vitro and analysis of membrane binding have suggested that ALI5-type mutations facilitate membrane interactions without compromising substrate binding and hydrolysis. The residue mutated in ALI14 (Tyr-495) is within the spPH domain. Replacement of this residue had no effect on folding of the domain and enhanced Rac activation of PLC gamma 2 without increasing Rac binding. Importantly, the activation of the ALI14-PLC gamma 2 and corresponding PLC gamma 1 variants was enhanced in response to EGF stimulation and bypassed the requirement for phosphorylation of critical tyrosine residues. ALI5- and ALI14-type mutations affected basal activity only slightly; however, their combination resulted in a constitutively active PLC. Based on these data, we suggest that each mutation could compromise auto-inhibition in the inactive PLC, facilitating the activation process; in addition, ALI5-type mutations could enhance membrane interaction in the activated state.

Mutations altering the gammaretrovirus endoproteolytic motif affect glycosylation of the envelope glycoprotein and early events of the virus life cycle

Energy Technology Data Exchange (ETDEWEB)

Argaw, Takele; Wilson, Carolyn A., E-mail: carolyn.wilson@fda.hhs.gov

2015-01-15

Previously, we found that mutation of glutamine to proline in the endoproteolytic cleavage signal of the PERV-C envelope (RQKK to RPKK) resulted in non-infectious vectors. Here, we show that RPKK results in a non-infectious vector when placed in not only a PERV envelope, but also the envelope of a related gammaretrovirus, FeLV-B. The amino acid substitutions do not prevent envelope precursor cleavage, viral core and genome assembly, or receptor binding. Rather, the mutations result in the formation of hyperglycosylated glycoprotein and a reduction in the reverse transcribed minus strand synthesis and undetectable 2-LTR circular DNA in cells exposed to vectors with these mutated envelopes. Our findings suggest novel functions associated with the cleavage signal sequence that may affect trafficking through the glycosylation machinery of the cell. Further, the glycosylation status of the envelope appears to impact post-binding events of the viral life cycle, either membrane fusion, internalization, or reverse transcription. - Highlights: • Env cleavage signal impacts infectivity of gammaretroviruses. • Non-infectious mutants have hyper-glycosylated envelope that bind target cells. • Non-infectious mutants have defects in the formation of the double-stranded DNA. • Env cleavage motif has functions beyond cleavage of the env precursor.

Molecular Clock of Neutral Mutations in a Fitness-Increasing Evolutionary Process.

Science.gov (United States)

Kishimoto, Toshihiko; Ying, Bei-Wen; Tsuru, Saburo; Iijima, Leo; Suzuki, Shingo; Hashimoto, Tomomi; Oyake, Ayana; Kobayashi, Hisaka; Someya, Yuki; Narisawa, Dai; Yomo, Tetsuya

2015-07-01

The molecular clock of neutral mutations, which represents linear mutation fixation over generations, is theoretically explained by genetic drift in fitness-steady evolution or hitchhiking in adaptive evolution. The present study is the first experimental demonstration for the molecular clock of neutral mutations in a fitness-increasing evolutionary process. The dynamics of genome mutation fixation in the thermal adaptive evolution of Escherichia coli were evaluated in a prolonged evolution experiment in duplicated lineages. The cells from the continuously fitness-increasing evolutionary process were subjected to genome sequencing and analyzed at both the population and single-colony levels. Although the dynamics of genome mutation fixation were complicated by the combination of the stochastic appearance of adaptive mutations and clonal interference, the mutation fixation in the population was simply linear over generations. Each genome in the population accumulated 1.6 synonymous and 3.1 non-synonymous neutral mutations, on average, by the spontaneous mutation accumulation rate, while only a single genome in the population occasionally acquired an adaptive mutation. The neutral mutations that preexisted on the single genome hitchhiked on the domination of the adaptive mutation. The successive fixation processes of the 128 mutations demonstrated that hitchhiking and not genetic drift were responsible for the coincidence of the spontaneous mutation accumulation rate in the genome with the fixation rate of neutral mutations in the population. The molecular clock of neutral mutations to the fitness-increasing evolution suggests that the numerous neutral mutations observed in molecular phylogenetic trees may not always have been fixed in fitness-steady evolution but in adaptive evolution.

Molecular Clock of Neutral Mutations in a Fitness-Increasing Evolutionary Process.

Directory of Open Access Journals (Sweden)

Toshihiko Kishimoto

2015-07-01

Full Text Available The molecular clock of neutral mutations, which represents linear mutation fixation over generations, is theoretically explained by genetic drift in fitness-steady evolution or hitchhiking in adaptive evolution. The present study is the first experimental demonstration for the molecular clock of neutral mutations in a fitness-increasing evolutionary process. The dynamics of genome mutation fixation in the thermal adaptive evolution of Escherichia coli were evaluated in a prolonged evolution experiment in duplicated lineages. The cells from the continuously fitness-increasing evolutionary process were subjected to genome sequencing and analyzed at both the population and single-colony levels. Although the dynamics of genome mutation fixation were complicated by the combination of the stochastic appearance of adaptive mutations and clonal interference, the mutation fixation in the population was simply linear over generations. Each genome in the population accumulated 1.6 synonymous and 3.1 non-synonymous neutral mutations, on average, by the spontaneous mutation accumulation rate, while only a single genome in the population occasionally acquired an adaptive mutation. The neutral mutations that preexisted on the single genome hitchhiked on the domination of the adaptive mutation. The successive fixation processes of the 128 mutations demonstrated that hitchhiking and not genetic drift were responsible for the coincidence of the spontaneous mutation accumulation rate in the genome with the fixation rate of neutral mutations in the population. The molecular clock of neutral mutations to the fitness-increasing evolution suggests that the numerous neutral mutations observed in molecular phylogenetic trees may not always have been fixed in fitness-steady evolution but in adaptive evolution.

Single Event Effects (SEE) for Power Metal-Oxide-Semiconductor Field-Effect Transistors (MOSFETs)

Science.gov (United States)

Lauenstein, Jean-Marie

2011-01-01

Single-event gate rupture (SEGR) continues to be a key failure mode in power MOSFETs. (1) SEGR is complex, making rate prediction difficult SEGR mechanism has two main components: (1) Oxide damage-- Reduces field required for rupture (2) Epilayer response -- Creates transient high field across the oxide.

Single Event Upset Energy Dependence In a Buck-Converter Power Supply Design

CERN Document Server

Drake, G; The ATLAS collaboration; Gopalakrishnan, A; Mahadik, S; Mellado, B; Proudfoot, J; Reed, R; Senthilkumaran, A; Stanek, R

2012-01-01

We present a study of Single Event Upsets (SEU) performed on a commercial pulse-width modulator controller chip for switching power supplies. We performed tests to study the probability of an SEU occurring as a function of incident particle (hadron) energy. We discuss the performance of the circuit, and present a solution using external circuitry to effectively eliminate the effect.

IFITM5 mutations and osteogenesis imperfecta.

Science.gov (United States)

Hanagata, Nobutaka

2016-03-01

Interferon-induced transmembrane protein 5 (IFITM5) is an osteoblast-specific membrane protein that has been shown to be a positive regulatory factor for mineralization in vitro. However, Ifitm5 knockout mice do not exhibit serious bone abnormalities, and thus the function of IFITM5 in vivo remains unclear. Recently, a single point mutation (c.-14C>T) in the 5' untranslated region of IFITM5 was identified in patients with osteogenesis imperfecta type V (OI-V). Furthermore, a single point mutation (c.119C>T) in the coding region of IFITM5 was identified in OI patients with more severe symptoms than patients with OI-V. Although IFITM5 is not directly involved in the formation of bone in vivo, the reason why IFITM5 mutations cause OI remains a major mystery. In this review, the current state of knowledge of OI pathological mechanisms due to IFITM5 mutations will be reviewed.

Single-Event Effect Testing of the Cree C4D40120D Commercial 1200V Silicon Carbide Schottky Diode

Science.gov (United States)

Lauenstein, J.-M.; Casey, M. C.; Wilcox, E. P.; Kim, Hak; Topper, A. D.

2014-01-01

This study was undertaken to determine the single event effect (SEE) susceptibility of the commercial silicon carbide 1200V Schottky diode manufactured by Cree, Inc. Heavy-ion testing was conducted at the Texas A&M University Cyclotron Single Event Effects Test Facility (TAMU). Its purpose was to evaluate this device as a candidate for use in the Solar-Electric Propulsion flight project.

Monitoring of seismic events from a specific source region using a single regional array: A case study

Science.gov (United States)

Gibbons, S. J.; Kværna, T.; Ringdal, F.

2005-07-01

In the monitoring of earthquakes and nuclear explosions using a sparse worldwide network of seismic stations, it is frequently necessary to make reliable location estimates using a single seismic array. It is also desirable to screen out routine industrial explosions automatically in order that analyst resources are not wasted upon detections which can, with a high level of confidence, be associated with such a source. The Kovdor mine on the Kola Peninsula of NW Russia is the site of frequent industrial blasts which are well recorded by the ARCES regional seismic array at a distance of approximately 300 km. We describe here an automatic procedure for identifying signals which are likely to result from blasts at the Kovdor mine and, wherever possible, for obtaining single array locations for such events. Carefully calibrated processing parameters were chosen using measurements from confirmed events at the mine over a one-year period for which the operators supplied Ground Truth information. Phase arrival times are estimated using an autoregressive method and slowness and azimuth are estimated using broadband f{-} k analysis in fixed frequency bands and time-windows fixed relative to the initial P-onset time. We demonstrate the improvement to slowness estimates resulting from the use of fixed frequency bands. Events can be located using a single array if, in addition to the P-phase, at least one secondary phase is found with both an acceptable slowness estimate and valid onset-time estimate. We evaluate the on-line system over a twelve month period; every event known to have occured at the mine is detected by the process and 32 out of 53 confirmed events were located automatically. The remaining events were classified as “very likely” Kovdor events and were subsequently located by an analyst. The false alarm rate is low; only 84 very likely Kovdor events were identified during the whole of 2003 and none of these were subsequently located at a large distance from

Radiation-induced mutation at minisatellite loci

International Nuclear Information System (INIS)

Dubrova, Y.E.; Nesterov, V.N.; Krouchinsky, N.G.

1997-01-01

We are studying the radiation-induced increase of mutation rate in minisatellite loci in mice and humans. Minisatellite mutations were scored by multilocus DNA fingerprint analysis in the progeny of γ-irradiated and non-irradiated mice. The frequency of mutation in offspring of irradiated males was 1.7 higher that in the control group. Germline mutation at human minisatellite loci was studied among children born in heavily polluted areas of the Mogilev district of Belarus after the Chernobyl accident and in a control population. The frequency of mutation assayed both by DNA fingerprinting and by eight single locus probes was found to be two times higher in the exposed families than in the control group. Furthermore, mutation rate was correlated with the parental radiation dose for chronic exposure 137 Cs, consistent with radiation-induction of germline mutation. The potential use of minisatellites in monitoring germline mutation in humans will be discussed

Germ-line origins of mutation in families with hemophilia B: The sex ratio varies with the type of mutation

Energy Technology Data Exchange (ETDEWEB)

Ketterling, R.P.; Vielhaber, E.; Bottema, C.D.K.; Schaid, D.J.; Sommer, S.S. (Mayo Clinic/Foundation, Rochester, MN (United States)); Cohen, M.P. (Vanderbilt Univ., Nashville, TN (United States)); Sexauer, C.L. (Children' s Hospital, Oklahoma City, OK (United States))

1993-01-01

Previous epidemiological and biochemical studies have generated conflicting estimates of the sex ratio of mutation. Direct genomic sequencing in combination with haplotype analysis extends previous analyses by allowing the precise mutation to be determined in a given family. From analysis of the factor IX gene of 260 consecutive families with hemophilia B, the authors report the germ-line origin of mutation in 25 families. When combined with 14 origins of mutation reported by others and with 4 origins previously reported by them, a total of 25 occur in the female germ line, and 18 occur in the male germ line. The excess of germ-line origins in females does not imply an overall excess mutation rate per base pair in the female germ line. Bayesian analysis of the data indicates that the sex ratio varies with the type of mutation. The aggregate of single-base substitutions shows a male predominance of germ-line mutations (P < .002). The maximum-likelihood estimate of the male predominance is 3.5-fold. Of the single-base substitutions, deletions display a sex ratio of unity. Analysis of the parental age at transmission of a new mutation suggests that germ-line mutations are associated with a small increase in parental age in females but little, if any, increase in males. Although direct genomic sequencing offers a general method for defining the origin of mutation in specific families, accurate estimates of the sex ratios of different mutational classes require large sample sizes and careful correction for multiple biases of ascertainment. The biases in the present data result in an underestimate of the enhancement of mutation in males. 62 refs., 1 fig., 5 tabs.

Effectiveness Analysis of a Non-Destructive Single Event Burnout Test Methodology

CERN Document Server

Oser, P; Spiezia, G; Fadakis, E; Foucard, G; Peronnard, P; Masi, A; Gaillard, R

2014-01-01

It is essential to characterize power MosFETs regarding their tolerance to destructive Single Event Burnouts (SEB). Therefore, several non-destructive test methods have been developed to evaluate the SEB cross-section of power devices. A power MosFET has been evaluated using a test circuit, designed according to standard non-destructive test methods discussed in the literature. Guidelines suggest a prior adaptation of auxiliary components to the device sensitivity before the radiation test. With the first value chosen for the de-coupling capacitor, the external component initiated destructive events and affected the evaluation of the cross-section. As a result, the influence of auxiliary components on the device cross-section was studied. This paper presents the obtained experimental results, supported by SPICE simulations, to evaluate and discuss how the circuit effectiveness depends on the external components.

Introduction of a point mutation into an HLA class I single-chain trimer induces enhancement of CTL priming and antitumor immunity

Directory of Open Access Journals (Sweden)

Masanori Matsui

2014-01-01

Full Text Available We previously discovered one particular HLA-A*02:01 mutant that enhanced peptide-specific cytotoxic T lymphocyte (CTL recognition in vitro compared to wild-type HLA-A*02:01. This mutant contains a single amino acid substitution from histidine to leucine at position 74 (H74L that is located in the peptide-binding groove. To investigate the effect of the H74L mutation on the in vivo CTL priming, we took advantage of the technology of the HLA class I single-chain trimer (SCT in which three components involving a peptide, β2 microglobulin and the HLA class I heavy chain are joined together via flexible linkers. We generated recombinant adenovirus expressing SCT comprised influenza A matrix protein (FMP-derived peptide, β2 microglobulin and the H74L heavy chain. HLA-A*02:01 transgenic mice were immunized with the adenovirus, and the induction of peptide-specific CTLs and antitumor immunity was investigated. It was clearly shown that the H74L mutation enabled the HLA-A*02:01 SCT molecule to dramatically enhance both in vivo priming of FMP-specific CTLs and protection against a lethal challenge of tumor cells expressing FMP. These data present the first evidence that a simple point mutation in the HLA class I heavy chain of SCT is beneficial for improving CTL-based immunotherapy and prophylaxis to control tumors.

HER2 mutated breast cancer responds to treatment with single agent neratinib, a second generation HER2/EGFR tyrosine kinase inhibitor

Science.gov (United States)

Ben–Baruch, Noa Efrat; Bose, Ron; Kavuri, Shyam M.; Ma, Cynthia X.; Ellis, Matthew J.

2015-01-01

Activating mutations in the HER2 tyrosine kinase have been identified in human breast cancers that lack HER2 gene amplification. These patients are not candidates for HER2 targeted drugs under current standards of care, but preclinical data strongly suggest that these patients will benefit from anti-HER2 drugs. In this case report, we describe a young woman with metastatic breast cancer whose tumor was found to carry a HER2 L755S mutation, which is in the kinase domain of HER2. Treatment with the second generation HER2/EGFR tyrosine kinase inhibitor, neratinib, resulted in partial response and dramatic improvement in the patient’s function status. This partial response lasted 11 months and when the patient’s cancer progressed, she was treated with neratinib plus capecitabine and her cancer again responded. This second response parallels the benefit seen with continuing trastuzumab in HER2 amplified breast cancer after disease progression. This case is the first report, to our knowledge, of successful single agent treatment of HER2 mutated breast cancer. Two clinical trials of neratinib for HER2 mutated, metastatic breast cancer are currently enrolling patients. Further, data from The Cancer Genome Atlas project have identified HER2 mutations in a wide range of solid tumors, including bladder, colorectal, and non-small cell lung cancer, suggesting that clinical trials of neratinib or neratinib-based combinations for HER2 mutated solid tumors is warranted. PMID:26358790

HER2-Mutated Breast Cancer Responds to Treatment With Single-Agent Neratinib, a Second-Generation HER2/EGFR Tyrosine Kinase Inhibitor.

Science.gov (United States)

Ben-Baruch, Noa Efrat; Bose, Ron; Kavuri, Shyam M; Ma, Cynthia X; Ellis, Matthew J

2015-09-01

Activating mutations in the HER2 tyrosine kinase have been identified in human breast cancers that lack HER2 gene amplification. These patients are not candidates for HER2-targeted drugs under current standards of care, but preclinical data strongly suggest that these patients will benefit from anti-HER2 drugs. This case report describes a young woman with metastatic breast cancer whose tumor was found to carry a HER2 L755S mutation, which is in the kinase domain of HER2. Treatment with the second-generation HER2/EGFR tyrosine kinase inhibitor neratinib resulted in partial response and dramatic improvement in the patient's functional status. This partial response lasted 11 months, and when the patient's cancer progressed, she was treated with neratinib plus capecitabine and her cancer again responded. This second response parallels the benefit seen with continuing trastuzumab in HER2-amplified breast cancer after disease progression. This case represents the first report, to our knowledge, of successful single-agent treatment of HER2-mutated breast cancer. Two clinical trials of neratinib for HER2-mutated metastatic breast cancer are currently enrolling patients. Further, data from The Cancer Genome Atlas project have identified HER2 mutations in a wide range of solid tumors, including bladder, colorectal, and non-small cell lung cancers, suggesting that clinical trials of neratinib or neratinib-based combinations for HER2-mutated solid tumors is warranted. Copyright © 2015 by the National Comprehensive Cancer Network.

Mutations in the Norrie disease gene.

Science.gov (United States)

Schuback, D E; Chen, Z Y; Craig, I W; Breakefield, X O; Sims, K B

1995-01-01

We report our experience to date in mutation identification in the Norrie disease (ND) gene. We carried out mutational analysis in 26 kindreds in an attempt to identify regions presumed critical to protein function and potentially correlated with generation of the disease phenotype. All coding exons, as well as noncoding regions of exons 1 and 2, 636 nucleotides in the noncoding region of exon 3, and 197 nucleotides of 5' flanking sequence, were analyzed for single-strand conformation polymorphisms (SSCP) by polymerase chain reaction (PCR) amplification of genomic DNA. DNA fragments that showed altered SSCP band mobilities were sequenced to locate the specific mutations. In addition to three previously described submicroscopic deletions encompassing the entire ND gene, we have now identified 6 intragenic deletions, 8 missense (seven point mutations, one 9-bp deletion), 6 nonsense (three point mutations, three single bp deletions/frameshift) and one 10-bp insertion, creating an expanded repeat in the 5' noncoding region of exon 1. Thus, mutations have been identified in a total of 24 of 26 (92%) of the kindreds we have studied to date. With the exception of two different mutations, each found in two apparently unrelated kindreds, these mutations are unique and expand the genotype database. Localization of the majority of point mutations at or near cysteine residues, potentially critical in protein tertiary structure, supports a previous protein model for norrin as member of a cystine knot growth factor family (Meitinger et al., 1993). Genotype-phenotype correlations were not evident with the limited clinical data available, except in the cases of larger submicroscopic deletions associated with a more severe neurologic syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)

TDRS-1 single event upsets and the effect of the space environment

International Nuclear Information System (INIS)

Wilkinson, D.C.; Daughtridge, S.C.; Stone, J.L.; Sauer, H.H.; Darling, P.

1991-01-01

The systematic recording of Single Event Upsets on TDRS-1 from 1984 to 1990 allows correlations to be drawn between those upsets and the space environment. In this paper, ground based neutron monitor data are used to illustrate the long-term relationship between galactic cosmic rays and TDRS-1 upsets. The short-term effects of energetic solar particles are illustrated with space environment data from GOES-7

Approaches to proton single-event rate calculations

International Nuclear Information System (INIS)

Petersen, E.L.

1996-01-01

This article discusses the fundamentals of proton-induced single-event upsets and of the various methods that have been developed to calculate upset rates. Two types of approaches are used based on nuclear-reaction analysis. Several aspects can be analyzed using analytic methods, but a complete description is not available. The paper presents an analytic description for the component due to elastic-scattering recoils. There have been a number of studies made using Monte Carlo methods. These can completely describe the reaction processes, including the effect of nuclear reactions occurring outside the device-sensitive volume. They have not included the elastic-scattering processes. The article describes the semiempirical approaches that are most widely used. The quality of previous upset predictions relative to space observations is discussed and leads to comments about the desired quality of future predictions. Brief sections treat the possible testing limitation due to total ionizing dose effects, the relationship of proton and heavy-ion upsets, upsets due to direct proton ionization, and relative proton and cosmic-ray upset rates

Discussions On Worst-Case Test Condition For Single Event Burnout

Science.gov (United States)

Liu, Sandra; Zafrani, Max; Sherman, Phillip

2011-10-01

This paper discusses the failure characteristics of single- event burnout (SEB) on power MOSFETs based on analyzing the quasi-stationary avalanche simulation curves. The analyses show the worst-case test condition for SEB would be using the ion that has the highest mass that would result in the highest transient current due to charge deposition and displacement damage. The analyses also show it is possible to build power MOSFETs that will not exhibit SEB even when tested with the heaviest ion, which have been verified by heavy ion test data on SEB sensitive and SEB immune devices.

Identification of somatic mutations in postmortem human brains by whole genome sequencing and their implications for psychiatric disorders.

Science.gov (United States)

Nishioka, Masaki; Bundo, Miki; Ueda, Junko; Katsuoka, Fumiki; Sato, Yukuto; Kuroki, Yoko; Ishii, Takao; Ukai, Wataru; Murayama, Shigeo; Hashimoto, Eri; Nagasaki, Masao; Yasuda, Jun; Kasai, Kiyoto; Kato, Tadafumi; Iwamoto, Kazuya

2018-04-01

Somatic mutations in the human brain are hypothesized to contribute to the functional diversity of brain cells as well as the pathophysiology of neuropsychiatric diseases. However, there are still few reports on somatic mutations in non-neoplastic human brain tissues. This study attempted to unveil the landscape of somatic mutations in the human brain. We explored the landscape of somatic mutations in human brain tissues derived from three individuals with no neuropsychiatric diseases by whole-genome deep sequencing at a depth of around 100. The candidate mutations underwent multi-layered filtering, and were validated by ultra-deep target amplicon sequencing at a depth of around 200 000. Thirty-one somatic mutations were identified in the human brain, demonstrating the utility of whole-genome sequencing of bulk brain tissue. The mutations were enriched in neuron-expressed genes, and two-thirds of the identified somatic single nucleotide variants in the brain tissues were cytosine-to-thymine transitions, half of which were in CpG dinucleotides. Our developed filtering and validation approaches will be useful to identify somatic mutations in the human brain. The vulnerability of neuron-expressed genes to mutational events suggests their potential relevance to neuropsychiatric diseases. © 2017 The Authors. Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.

Potential impact of single-risk-factor versus total risk management for the prevention of cardiovascular events in Seychelles.

Science.gov (United States)

Ndindjock, Roger; Gedeon, Jude; Mendis, Shanthi; Paccaud, Fred; Bovet, Pascal

2011-04-01

To assess the prevalence of cardiovascular (CV) risk factors in Seychelles, a middle-income African country, and compare the cost-effectiveness of single-risk-factor management (treating individuals with arterial blood pressure ≥ 140/90 mmHg and/or total serum cholesterol ≥ 6.2 mmol/l) with that of management based on total CV risk (treating individuals with a total CV risk ≥ 10% or ≥ 20%). CV risk factor prevalence and a CV risk prediction chart for Africa were used to estimate the 10-year risk of suffering a fatal or non-fatal CV event among individuals aged 40-64 years. These figures were used to compare single-risk-factor management with total risk management in terms of the number of people requiring treatment to avert one CV event and the number of events potentially averted over 10 years. Treatment for patients with high total CV risk (≥ 20%) was assumed to consist of a fixed-dose combination of several drugs (polypill). Cost analyses were limited to medication. A total CV risk of ≥ 10% and ≥ 20% was found among 10.8% and 5.1% of individuals, respectively. With single-risk-factor management, 60% of adults would need to be treated and 157 cardiovascular events per 100000 population would be averted per year, as opposed to 5% of adults and 92 events with total CV risk management. Management based on high total CV risk optimizes the balance between the number requiring treatment and the number of CV events averted. Total CV risk management is much more cost-effective than single-risk-factor management. These findings are relevant for all countries, but especially for those economically and demographically similar to Seychelles.

Evaluation of single-event upset tolerance on 64Mbit DRAM and 16Mbit DRAM

Energy Technology Data Exchange (ETDEWEB)

Nemoto, N; Shindou, H; Matsuzaki, K; Akutsu, T; Matsuda, S [National Space Development Agency of Japan, Tokyo (Japan); Hirao, T; Itoh, H; Nashiyama, I

1997-11-01

In recent years, reduction in the mission cost is regarded as one of the most important matters, and thus much effort has been made to reduce the cost of electronic components used in spacecrafts without diminishing their performance. On this policy, there has been a growing interest in space application of commercial devices such as highly integrated memory ICs because of low prices and high performance of such devices. To ensure success in this application, it is indispensable to investigate radiation effects, e.g., single-event and total-dose effects, on commercial devices precisely. In the present study, we have evaluated single-event upset (SEU) tolerance for 1Mbit, 4Mbit SRAM and 16Mbit, 64Mbit DRAM by irradiation of high energy heavy ions such as 175MeV-Ar{sup 8+} and 450MeV-Xe{sup 23+}. We observed these SEU tolerance in space. (author)

The Mutational Robustness of Influenza A Virus.

Directory of Open Access Journals (Sweden)

Elisa Visher

2016-08-01

Full Text Available A virus' mutational robustness is described in terms of the strength and distribution of the mutational fitness effects, or MFE. The distribution of MFE is central to many questions in evolutionary theory and is a key parameter in models of molecular evolution. Here we define the mutational fitness effects in influenza A virus by generating 128 viruses, each with a single nucleotide mutation. In contrast to mutational scanning approaches, this strategy allowed us to unambiguously assign fitness values to individual mutations. The presence of each desired mutation and the absence of additional mutations were verified by next generation sequencing of each stock. A mutation was considered lethal only after we failed to rescue virus in three independent transfections. We measured the fitness of each viable mutant relative to the wild type by quantitative RT-PCR following direct competition on A549 cells. We found that 31.6% of the mutations in the genome-wide dataset were lethal and that the lethal fraction did not differ appreciably between the HA- and NA-encoding segments and the rest of the genome. Of the viable mutants, the fitness mean and standard deviation were 0.80 and 0.22 in the genome-wide dataset and best modeled as a beta distribution. The fitness impact of mutation was marginally lower in the segments coding for HA and NA (0.88 ± 0.16 than in the other 6 segments (0.78 ± 0.24, and their respective beta distributions had slightly different shape parameters. The results for influenza A virus are remarkably similar to our own analysis of CirSeq-derived fitness values from poliovirus and previously published data from other small, single stranded DNA and RNA viruses. These data suggest that genome size, and not nucleic acid type or mode of replication, is the main determinant of viral mutational fitness effects.

Heavy ion microbeam system for study of single event effects

International Nuclear Information System (INIS)

Kamiya, Tomihiro; Utsunomiya, Nobuhiro; Minehara, Eiichi; Tanaka, Ryuichi; Ohmura, Miyoshi; Kohno, Kazuhiro; Iwamoto, Eiji.

1992-01-01

A high-energy heavy ion microbeam system has been developed and installed on a beam line of a 3 MV tandem electrostatic accelerator mainly for analysis of basic mechanism of single event upset (SEU) of semiconductor devices in spacecraft. The SEU is now the most serious problem for highly reliable spacecraft electronics system with long space mission. However, the mechanism has not been understood on the basis of microscopic process of SEU. The SEU phenomena depends not only upon hitting particles, but also upon the hit position on the microcircuit. To observe the transient charge pulse from a SEU, a single ion particle must hit exactly the desired position of the microcircuit. Such an experiment requires the microbeam spot size within 1 μm, the beam positioning accuracy within ±1 μm, and single ion hitting. The microbeam system has been designed to meet the above technical requirements. The system is equipped with two lens systems: one to control the target beam current in a wide range down to extremely low current without any change of the beam optics, and the other to focus heavy ion beams within a spot size of 1 μm. The final goal is to hit a microscopic target area with a single 15 MeV nickel ion. The beam spot size has been evaluated by Gaussian fitting of secondary electron profiles with microbeam scanning across the fine Cu mesh. The single ion detection has been also tested to generate a trigger signal for closing beam shutter to prevent further hits. This paper outlines the new microbeam system and describes methods to realize these techniques. (author)

Are There Mutator Polymerases?

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Miguel Garcia-Diaz

2003-01-01

Full Text Available DNA polymerases are involved in different cellular events, including genome replication and DNA repair. In the last few years, a large number of novel DNA polymerases have been discovered, and the biochemical analysis of their properties has revealed a long list of intriguing features. Some of these polymerases have a very low fidelity and have been suggested to play mutator roles in different processes, like translesion synthesis or somatic hypermutation. The current view of these processes is reviewed, and the current understanding of DNA polymerases and their role as mutator enzymes is discussed.

Circulating mutational portrait of cancer: manifestation of aggressive clonal events in both early and late stages

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Meng Yang

2017-05-01

Full Text Available Abstract Background Solid tumors residing in tissues and organs leave footprints in circulation through circulating tumor cells (CTCs and circulating tumor DNAs (ctDNA. Characterization of the ctDNA portraits and comparison with tumor DNA mutational portraits may reveal clinically actionable information on solid tumors that is traditionally achieved through more invasive approaches. Methods We isolated ctDNAs from plasma of patients of 103 lung cancer and 74 other solid tumors of different tissue origins. Deep sequencing using the Guardant360 test was performed to identify mutations in 73 clinically actionable genes, and the results were associated with clinical characteristics of the patient. The mutation profiles of 37 lung cancer cases with paired ctDNA and tumor genomic DNA sequencing were used to evaluate clonal representation of tumor in circulation. Five lung cancer cases with longitudinal ctDNA sampling were monitored for cancer progression or response to treatments. Results Mutations in TP53, EGFR, and KRAS genes are most prevalent in our cohort. Mutation rates of ctDNA are similar in early (I and II and late stage (III and IV cancers. Mutation in DNA repair genes BRCA1, BRCA2, and ATM are found in 18.1% (32/177 of cases. Patients with higher mutation rates had significantly higher mortality rates. Lung cancer of never smokers exhibited significantly higher ctDNA mutation rates as well as higher EGFR and ERBB2 mutations than ever smokers. Comparative analysis of ctDNA and tumor DNA mutation data from the same patients showed that key driver mutations could be detected in plasma even when they were present at a minor clonal population in the tumor. Mutations of key genes found in the tumor tissue could remain in circulation even after frontline radiotherapy and chemotherapy suggesting these mutations represented resistance mechanisms. Longitudinal sampling of five lung cancer cases showed distinct changes in ctDNA mutation portraits that

A Biofunctional Molecular Beacon for Detecting Single Base Mutations in Cancer Cells

Directory of Open Access Journals (Sweden)

Haiyan Dong

2016-01-01

Full Text Available The development of a convenient and sensitive biosensing system to detect specific DNA sequences is an important issue in the field of genetic disease therapy. As a classic DNA detection technique, molecular beacon (MB is often used in the biosensing system. However, it has intrinsic drawbacks, including high assay cost, complicated chemical modification, and operational complexity. In this study, we developed a simple and cost-effective label-free multifunctional MB (LMMB by integrating elements of polymerization primer, template, target recognition, and G-quadruplex into one entity to detect target DNA. The core technique was accomplished by introducing a G-hairpin that features fragments of both G-quadruplex and target DNA recognition in the G-hairpin stem. Hybridization between LMMB and target DNA triggered conformational change between the G-hairpin and the common C-hairpin, resulting in significant SYBR-green signal amplification. The hybridization continues to the isothermal circular strand-displacement polymerization and accumulation of the double-stranded fragments, causing the uninterrupted extension of the LMMB without a need of chemical modification and other assistant DNA sequences. The novel and programmable LMMB could detect target DNA with sensitivity at 250 pmol/l with a linear range from 2 to 100 nmol/l and the relative standard deviation of 7.98%. The LMMB could sense a single base mutation from the normal DNA, and polymerase chain reaction (PCR amplicons of the mutant-type cell line from the wild-type one. The total time required for preparation and assaying was only 25 minutes. Apparently, the LMMB shows great potential for detecting DNA and its mutations in biosamples, and therefore it opens up a new prospect for genetic disease therapy.

Revertant mutation releases confined lethal mutation, opening Pandora's box: a novel genetic pathogenesis.

Directory of Open Access Journals (Sweden)

Yasushi Ogawa

2014-05-01

Full Text Available When two mutations, one dominant pathogenic and the other "confining" nonsense, coexist in the same allele, theoretically, reversion of the latter may elicit a disease, like the opening of Pandora's box. However, cases of this hypothetical pathogenic mechanism have never been reported. We describe a lethal form of keratitis-ichthyosis-deafness (KID syndrome caused by the reversion of the GJB2 nonsense mutation p.Tyr136X that would otherwise have confined the effect of another dominant lethal mutation, p.Gly45Glu, in the same allele. The patient's mother had the identical misssense mutation which was confined by the nonsense mutation. The biological relationship between the parents and the child was confirmed by genotyping of 15 short tandem repeat loci. Haplotype analysis using 40 SNPs spanning the >39 kbp region surrounding the GJB2 gene and an extended SNP microarray analysis spanning 83,483 SNPs throughout chromosome 13 in the family showed that an allelic recombination event involving the maternal allele carrying the mutations generated the pathogenic allele unique to the patient, although the possibility of coincidental accumulation of spontaneous point mutations cannot be completely excluded. Previous reports and our mutation screening support that p.Gly45Glu is in complete linkage disequilibrium with p.Tyr136X in the Japanese population. Estimated from statisitics in the literature, there may be approximately 11,000 p.Gly45Glu carriers in the Japanese population who have this second-site confining mutation, which acts as natural genetic protection from the lethal disease. The reversion-triggered onset of the disesase shown in this study is a previously unreported genetic pathogenesis based on Mendelian inheritance.

Mitochondrial DNA deletion mutations in adult mouse cardiac side population cells

International Nuclear Information System (INIS)

Lushaj, Entela B.; Lozonschi, Lucian; Barnes, Maria; Anstadt, Emily; Kohmoto, Takushi

2012-01-01

We investigated the presence and potential role of mitochondrial DNA (mtDNA) deletion mutations in adult cardiac stem cells. Cardiac side population (SP) cells were isolated from 12-week-old mice. Standard polymerase chain reaction (PCR) was used to screen for the presence of mtDNA deletion mutations in (a) freshly isolated SP cells and (b) SP cells cultured to passage 10. When present, the abundance of mtDNA deletion mutation was analyzed in single cell colonies. The effect of different levels of deletion mutations on SP cell growth and differentiation was determined. MtDNA deletion mutations were found in both freshly isolated and cultured cells from 12-week-old mice. While there was no significant difference in the number of single cell colonies with mtDNA deletion mutations from any of the groups mentioned above, the abundance of mtDNA deletion mutations was significantly higher in the cultured cells, as determined by quantitative PCR. Within a single clonal cell population, the detectable mtDNA deletion mutations were the same in all cells and unique when compared to deletions of other colonies. We also found that cells harboring high levels of mtDNA deletion mutations (i.e. where deleted mtDNA comprised more than 60% of total mtDNA) had slower proliferation rates and decreased differentiation capacities. Screening cultured adult stem cells for mtDNA deletion mutations as a routine assessment will benefit the biomedical application of adult stem cells.

Development of heavy-ion irradiation technique for single-event in semiconductor devices

Energy Technology Data Exchange (ETDEWEB)

Nemoto, Norio; Akutsu, Takao; Matsuda, Sumio [National Space Development Agency of Japan, Tsukuba, Ibaraki (Japan). Tsukuba Space Center; Naitoh, Ichiro; Itoh, Hisayoshi; Agematsu, Takashi; Kamiya, Tomihiro; Nashiyama, Isamu

1997-03-01

Heavy-ion irradiation technique has been developed for the evaluation of single-event effects on semiconductor devices. For the uniform irradiation of high energy heavy ions to device samples, we have designed and installed a magnetic beam-scanning system in a JAERI cyclotron beam course. It was found that scanned area was approximately 4 x 2 centimeters and that the deviation of ion fluence from the average value was less than 7%. (author)

Prediction Methodology for Proton Single Event Burnout: Application to a STRIPFET Device

CERN Document Server

Siconolfi, Sara; Oser, Pascal; Spiezia, Giovanni; Hubert, Guillaume; David, Jean-Pierre

2015-01-01

This paper presents a single event burnout (SEB) sensitivity characterization for power MOSFETs, independent from tests, through a prediction model issued from TCAD analysis and the knowledge of device topology. The methodology is applied to a STRIPFET device and compared to proton data obtained at PSI, showing a good agreement in the order of magnitude of proton SEB cross section, and thus validating the prediction model as an alternative device characterization with respect to SEB.

NASA Electronic Parts and Packaging Field Programmable Gate Array Single Event Effects Test Guideline Update

Science.gov (United States)

Berg, Melanie D.; LaBel, Kenneth A.

2018-01-01

The following are updated or new subjects added to the FPGA SEE Test Guidelines manual: academic versus mission specific device evaluation, single event latch-up (SEL) test and analysis, SEE response visibility enhancement during radiation testing, mitigation evaluation (embedded and user-implemented), unreliable design and its affects to SEE Data, testing flushable architectures versus non-flushable architectures, intellectual property core (IP Core) test and evaluation (addresses embedded and user-inserted), heavy-ion energy and linear energy transfer (LET) selection, proton versus heavy-ion testing, fault injection, mean fluence to failure analysis, and mission specific system-level single event upset (SEU) response prediction. Most sections within the guidelines manual provide information regarding best practices for test structure and test system development. The scope of this manual addresses academic versus mission specific device evaluation and visibility enhancement in IP Core testing.

Frequency of Antiretroviral Resistance Mutations among Infants Exposed to Single-Dose Nevirapine and Short Course Maternal Antiretroviral Regimens: ACTG A5207.

Science.gov (United States)

Hitti, Jane; Halvas, Elias K; Zheng, Lu; Panousis, Constantinos G; Kabanda, Joseph; Taulo, Frank; Kumarasamy, Nagalingeswaran; Pape, Jean William; Lalloo, Umesh; Sprenger, Heather; Klingman, Karin L; Chan, Ellen S; McMahon, Deborah; Mellors, John W

2014-11-01

Intrapartum single-dose nevirapine (sdNVP) reduces HIV-1 perinatal transmission but selects NVP resistance among mothers and infants. We evaluated the frequency of antiretroviral resistance among infants with intrauterine HIV-1 infection exposed to sdNVP and maternal antenatal or breastfeeding antiretroviral therapy. This analysis included 429 infants from sub-Saharan Africa, India and Haiti whose 422 mothers received sdNVP plus maternal study treatment. At entry mothers had CD4>250/μL and were ART-naïve except for antenatal ZDV per local standard of care. Maternal study treatment started intrapartum and included ZDV/3TC, TDF/FTC or LPV/r for 7 or 21 days in a randomized factorial design. Infants received sdNVP study treatment and ZDV if local standard of care. Infant HIV RNA or DNA PCR and samples for genotype were obtained at birth and weeks 2, 4 and 12; infants who ever breast-fed were also tested at weeks 16, 24, 48 and 96. Samples from HIV-1-infected infants were tested for drug resistance by population genotype (ViroSeq). NVP or NRTI resistance mutations were assessed using the IAS-USA mutation list. Perinatal HIV-1 transmission occurred in 17 (4.0%) infants including 12 intrauterine infections. Resistance mutations were detected among 5 (42%) intrauterine-infected infants; of these, 3 had mutations conferring resistance to NVP alone, 1 had resistance to NRTI alone, and 1 had dual-class resistance mutations. Among the 2 infants with NRTI mutations, one (K70R) was likely maternally transmitted and one (K65R) occurred in the context of breastfeeding exposure to maternal antiretroviral therapy. Infants with intrauterine HIV infection are at risk of acquiring resistance mutations from exposure to maternal antiretroviral medications intrapartum and/or during breastfeeding. New approaches are needed to lower the risk of antiretroviral resistance in these infants.

An analog cell to detect single event transients in voltage references

Energy Technology Data Exchange (ETDEWEB)

Franco, F.J., E-mail: fjfranco@fis.ucm.es [Departamento de Física Aplicada III, Facultad de Físicas, Universidad Complutense de Madrid (UCM), 28040 Madrid (Spain); Palomar, C. [Departamento de Física Aplicada III, Facultad de Físicas, Universidad Complutense de Madrid (UCM), 28040 Madrid (Spain); Izquierdo, J.G. [Centro de Láseres Ultrarrápidos, Facultad de Químicas, Universidad Complutense de Madrid (UCM), 28040 Madrid (Spain); Agapito, J.A. [Departamento de Física Aplicada III, Facultad de Físicas, Universidad Complutense de Madrid (UCM), 28040 Madrid (Spain)

2015-01-11

A reliable voltage reference is mandatory in mixed-signal systems. However, this family of components can undergo very long single event transients when operating in radiation environments such as space and nuclear facilities due to the impact of heavy ions. The purpose of the present paper is to demonstrate how a simple cell can be used to detect these transients. The cell was implemented with typical COTS components and its behavior was verified by SPICE simulations and in a laser facility. Different applications of the cell are explored as well.

Penetrance of Hypertrophic Cardiomyopathy in Children Who Are Mutation Positive

NARCIS (Netherlands)

Vermeer, Alexa M. C.; Clur, Sally-Ann B.; Blom, Nico A.; Wilde, Arthur A. M.; Christiaans, Imke

2017-01-01

Objectives To investigate the presence of hypertrophic cardiomyopathy (HCM) at first cardiac evaluation and during follow-up and cardiac events in predictively tested children who are mutation positive. Study design The study included 119 predictively tested children who were mutation positive, with

Single mutation confers vanadate resistance to the plasma membrane H+-ATPase from the yeast Schizosaccharomyces pombe

International Nuclear Information System (INIS)

Ulaszewski, S.; Van Herck, J.C.; Dufour, J.P.; Kulpa, J.; Nieuwenhuis, B.; Goffeau, A.

1987-01-01

A single-gene nuclear mutant has been selected from the yeast Schizosaccharomyces pombe for growth resistance to Dio-9, a plasma membrane H+-ATPase inhibitor. From this mutant, called pma1, an ATPase activity has been purified. It contains a Mr = 100,000 major polypeptide which is phosphorylated by [gamma- 32 P] ATP. Proton pumping is not impaired since the isolated mutant ATPase is able, in reconstituted proteoliposomes, to quench the fluorescence of the delta pH probe 9-amino-6-chloro-2-methoxy acridine. The isolated mutant ATPase is sensitive to Dio-9 as well as to seven other plasma membrane H+-ATPase inhibitors. The mutant H+-ATPase activity tested in vitro is, however, insensitive to vanadate. Its Km for MgATP is modified and its ATPase specific activity is decreased. The pma1 mutation decreases the rate of extracellular acidification induced by glucose when cells are incubated at pH 4.5 under nongrowing conditions. During growth, the intracellular mutant pH is more acid than the wild type one. The derepression by ammonia starvation of methionine transport is decreased in the mutant. The growth rate of pma1 mutants is reduced in minimal medium compared to rich medium, especially when combined to an auxotrophic mutation. It is concluded that the H+-ATPase activity from yeast plasma membranes controls the intracellular pH as well as the derepression of amino acid, purine, and pyrimidine uptakes. The pma1 mutation modifies several transport properties of the cells including those responsible for the uptake of Dio-9 and other inhibitors

Single Versus Multiple Events Error Potential Detection in a BCI-Controlled Car Game With Continuous and Discrete Feedback.

Science.gov (United States)

Kreilinger, Alex; Hiebel, Hannah; Müller-Putz, Gernot R

2016-03-01

This work aimed to find and evaluate a new method for detecting errors in continuous brain-computer interface (BCI) applications. Instead of classifying errors on a single-trial basis, the new method was based on multiple events (MEs) analysis to increase the accuracy of error detection. In a BCI-driven car game, based on motor imagery (MI), discrete events were triggered whenever subjects collided with coins and/or barriers. Coins counted as correct events, whereas barriers were errors. This new method, termed ME method, combined and averaged the classification results of single events (SEs) and determined the correctness of MI trials, which consisted of event sequences instead of SEs. The benefit of this method was evaluated in an offline simulation. In an online experiment, the new method was used to detect erroneous MI trials. Such MI trials were discarded and could be repeated by the users. We found that, even with low SE error potential (ErrP) detection rates, feasible accuracies can be achieved when combining MEs to distinguish erroneous from correct MI trials. Online, all subjects reached higher scores with error detection than without, at the cost of longer times needed for completing the game. Findings suggest that ErrP detection may become a reliable tool for monitoring continuous states in BCI applications when combining MEs. This paper demonstrates a novel technique for detecting errors in online continuous BCI applications, which yields promising results even with low single-trial detection rates.

Guanine holes are prominent targets for mutation in cancer and inherited disease.

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Albino Bacolla

Full Text Available Single base substitutions constitute the most frequent type of human gene mutation and are a leading cause of cancer and inherited disease. These alterations occur non-randomly in DNA, being strongly influenced by the local nucleotide sequence context. However, the molecular mechanisms underlying such sequence context-dependent mutagenesis are not fully understood. Using bioinformatics, computational and molecular modeling analyses, we have determined the frequencies of mutation at G • C bp in the context of all 64 5'-NGNN-3' motifs that contain the mutation at the second position. Twenty-four datasets were employed, comprising >530,000 somatic single base substitutions from 21 cancer genomes, >77,000 germline single-base substitutions causing or associated with human inherited disease and 16.7 million benign germline single-nucleotide variants. In several cancer types, the number of mutated motifs correlated both with the free energies of base stacking and the energies required for abstracting an electron from the target guanines (ionization potentials. Similar correlations were also evident for the pathological missense and nonsense germline mutations, but only when the target guanines were located on the non-transcribed DNA strand. Likewise, pathogenic splicing mutations predominantly affected positions in which a purine was located on the non-transcribed DNA strand. Novel candidate driver mutations and tissue-specific mutational patterns were also identified in the cancer datasets. We conclude that electron transfer reactions within the DNA molecule contribute to sequence context-dependent mutagenesis, involving both somatic driver and passenger mutations in cancer, as well as germline alterations causing or associated with inherited disease.

Preimplantation genetic diagnosis for mitochondrial DNA mutations: analysis of one blastomere suffices.

Science.gov (United States)

Sallevelt, Suzanne C E H; Dreesen, Joseph C F M; Coonen, Edith; Paulussen, Aimee D C; Hellebrekers, Debby M E I; de Die-Smulders, Christine E M; Smeets, Hubert J M; Lindsey, Patrick

2017-10-01

Preimplantation genetic diagnosis (PGD) is a reproductive strategy for mitochondrial DNA (mtDNA) mutation carriers, strongly reducing their risk of affected offspring. Embryos either without the mutation or with mutation load below the phenotypic threshold are transferred to the uterus. Because of incidental heteroplasmy deviations in single blastomere and the relatively limited data available, we so far preferred relying on two blastomeres rather than one. Considering the negative effect of a two-blastomere biopsy protocol compared with a single-blastomere biopsy protocol on live birth delivery rate, we re-evaluated the error rate in our current dataset. For the m.3243A>G mutation, sufficient embryos/blastomeres were available for a powerful analysis. The diagnostic error rate, defined as a potential false-negative result, based on a threshold of 15%, was determined in 294 single blastomeres analysed in 73 embryos of 9 female m.3243A>G mutation carriers. Only one out of 294 single blastomeres (0.34%) would have resulted in a false-negative diagnosis. False-positive diagnoses were not detected. Our findings support a single-blastomere biopsy PGD protocol for the m.3243A>G mutation as the diagnostic error rate is very low. As in the early preimplantation embryo no mtDNA replication seems to occur and the mtDNA is divided randomly among the daughter cells, we conclude this result to be independent of the specific mutation and therefore applicable to all mtDNA mutations. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Mutation induction by ion beams in plants

International Nuclear Information System (INIS)

Tanaka, Atsushi

2001-01-01

The effect of ion beams such as C, He, and Ne ions was investigated on the mutation induction in plants with the expectation that ion beams of high linear energy transfer (LET) can frequently produce large DNA alternation such as inversion, translocation and large deletion rather than point mutation. Mutation frequency was investigated using Arabidopsis visible phenotype loci and was 8 to 33 fold higher for 220 MeV carbon ions than for electrons. Mutation spectrum was investigated on the flower color of chrysanthemum cv to find that flower mutants induced by ion beams show complex and stripe types rather than single color. Polymerase chain reaction analysis was performed to investigate DNA alteration of mutations. In conclusion, the characteristics of ion beams for the mutation induction are 1) high frequency, 2) broad mutation spectrum, and 3) novel mutants. (S. Ohno)

Mutation induction by ion beams in plants

Energy Technology Data Exchange (ETDEWEB)

Tanaka, Atsushi [Japan Atomic Energy Research Inst., Takasaki, Gunma (Japan). Takasaki Radiation Chemistry Research Establishment

2001-03-01

The effect of ion beams such as C, He, and Ne ions was investigated on the mutation induction in plants with the expectation that ion beams of high linear energy transfer (LET) can frequently produce large DNA alternation such as inversion, translocation and large deletion rather than point mutation. Mutation frequency was investigated using Arabidopsis visible phenotype loci and was 8 to 33 fold higher for 220 MeV carbon ions than for electrons. Mutation spectrum was investigated on the flower color of chrysanthemum cv to find that flower mutants induced by ion beams show complex and stripe types rather than single color. Polymerase chain reaction analysis was performed to investigate DNA alteration of mutations. In conclusion, the characteristics of ion beams for the mutation induction are 1) high frequency, 2) broad mutation spectrum, and 3) novel mutants. (S. Ohno)

Automatic Single Event Effects Sensitivity Analysis of a 13-Bit Successive Approximation ADC

Science.gov (United States)

Márquez, F.; Muñoz, F.; Palomo, F. R.; Sanz, L.; López-Morillo, E.; Aguirre, M. A.; Jiménez, A.

2015-08-01

This paper presents Analog Fault Tolerant University of Seville Debugging System (AFTU), a tool to evaluate the Single-Event Effect (SEE) sensitivity of analog/mixed signal microelectronic circuits at transistor level. As analog cells can behave in an unpredictable way when critical areas interact with the particle hitting, there is a need for designers to have a software tool that allows an automatic and exhaustive analysis of Single-Event Effects influence. AFTU takes the test-bench SPECTRE design, emulates radiation conditions and automatically evaluates vulnerabilities using user-defined heuristics. To illustrate the utility of the tool, the SEE sensitivity of a 13-bits Successive Approximation Analog-to-Digital Converter (ADC) has been analysed. This circuit was selected not only because it was designed for space applications, but also due to the fact that a manual SEE sensitivity analysis would be too time-consuming. After a user-defined test campaign, it was detected that some voltage transients were propagated to a node where a parasitic diode was activated, affecting the offset cancelation, and therefore the whole resolution of the ADC. A simple modification of the scheme solved the problem, as it was verified with another automatic SEE sensitivity analysis.

Minisequencing mitochondrial DNA pathogenic mutations

Directory of Open Access Journals (Sweden)

Carracedo Ángel

2008-04-01

Full Text Available Abstract Background There are a number of well-known mutations responsible of common mitochondrial DNA (mtDNA diseases. In order to overcome technical problems related to the analysis of complete mtDNA genomes, a variety of different techniques have been proposed that allow the screening of coding region pathogenic mutations. Methods We here propose a minisequencing assay for the analysis of mtDNA mutations. In a single reaction, we interrogate a total of 25 pathogenic mutations distributed all around the whole mtDNA genome in a sample of patients suspected for mtDNA disease. Results We have detected 11 causal homoplasmic mutations in patients suspected for Leber disease, which were further confirmed by standard automatic sequencing. Mutations m.11778G>A and m.14484T>C occur at higher frequency than expected by change in the Galician (northwest Spain patients carrying haplogroup J lineages (Fisher's Exact test, P-value Conclusion We here developed a minisequencing genotyping method for the screening of the most common pathogenic mtDNA mutations which is simple, fast, and low-cost. The technique is robust and reproducible and can easily be implemented in standard clinical laboratories.

MPL mutations in myeloproliferative disorders

DEFF Research Database (Denmark)

Beer, Philip A.; Campbell, Peter J.; Scott, Linda M.

2008-01-01

Activating mutations of MPL exon 10 have been described in a minority of patients with idiopathic myelofibrosis (IMF) or essential thrombocythemia (ET), but their prevalence and clinical significance are unclear. Here we demonstrate that MPL mutations outside exon 10 are uncommon in platelet c......DNA and identify 4 different exon 10 mutations in granulocyte DNA from a retrospective cohort of 200 patients with ET or IMF. Allele-specific polymerase chain reaction was then used to genotype 776 samples from patients with ET entered into the PT-1 studies. MPL mutations were identified in 8.5% of JAK2 V617F......(-) patients and a single V617F(+) patient. Patients carrying the W515K allele had a significantly higher allele burden than did those with the W515L allele, suggesting a functional difference between the 2 variants. Compared with V617F(+) ET patients, those with MPL mutations displayed lower hemoglobin...

Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations.

Science.gov (United States)

Rebbeck, Timothy R; Friebel, Tara M; Friedman, Eitan; Hamann, Ute; Huo, Dezheng; Kwong, Ava; Olah, Edith; Olopade, Olufunmilayo I; Solano, Angela R; Teo, Soo-Hwang; Thomassen, Mads; Weitzel, Jeffrey N; Chan, T L; Couch, Fergus J; Goldgar, David E; Kruse, Torben A; Palmero, Edenir Inêz; Park, Sue Kyung; Torres, Diana; van Rensburg, Elizabeth J; McGuffog, Lesley; Parsons, Michael T; Leslie, Goska; Aalfs, Cora M; Abugattas, Julio; Adlard, Julian; Agata, Simona; Aittomäki, Kristiina; Andrews, Lesley; Andrulis, Irene L; Arason, Adalgeir; Arnold, Norbert; Arun, Banu K; Asseryanis, Ella; Auerbach, Leo; Azzollini, Jacopo; Balmaña, Judith; Barile, Monica; Barkardottir, Rosa B; Barrowdale, Daniel; Benitez, Javier; Berger, Andreas; Berger, Raanan; Blanco, Amie M; Blazer, Kathleen R; Blok, Marinus J; Bonadona, Valérie; Bonanni, Bernardo; Bradbury, Angela R; Brewer, Carole; Buecher, Bruno; Buys, Saundra S; Caldes, Trinidad; Caliebe, Almuth; Caligo, Maria A; Campbell, Ian; Caputo, Sandrine M; Chiquette, Jocelyne; Chung, Wendy K; Claes, Kathleen B M; Collée, J Margriet; Cook, Jackie; Davidson, Rosemarie; de la Hoya, Miguel; De Leeneer, Kim; de Pauw, Antoine; Delnatte, Capucine; Diez, Orland; Ding, Yuan Chun; Ditsch, Nina; Domchek, Susan M; Dorfling, Cecilia M; Velazquez, Carolina; Dworniczak, Bernd; Eason, Jacqueline; Easton, Douglas F; Eeles, Ros; Ehrencrona, Hans; Ejlertsen, Bent; Engel, Christoph; Engert, Stefanie; Evans, D Gareth; Faivre, Laurence; Feliubadaló, Lidia; Ferrer, Sandra Fert; Foretova, Lenka; Fowler, Jeffrey; Frost, Debra; Galvão, Henrique C R; Ganz, Patricia A; Garber, Judy; Gauthier-Villars, Marion; Gehrig, Andrea; Gerdes, Anne-Marie; Gesta, Paul; Giannini, Giuseppe; Giraud, Sophie; Glendon, Gord; Godwin, Andrew K; Greene, Mark H; Gronwald, Jacek; Gutierrez-Barrera, Angelica; Hahnen, Eric; Hauke, Jan; Henderson, Alex; Hentschel, Julia; Hogervorst, Frans B L; Honisch, Ellen; Imyanitov, Evgeny N; Isaacs, Claudine; Izatt, Louise; Izquierdo, Angel; Jakubowska, Anna; James, Paul; Janavicius, Ramunas; Jensen, Uffe Birk; John, Esther M; Vijai, Joseph; Kaczmarek, Katarzyna; Karlan, Beth Y; Kast, Karin; Investigators, KConFab; Kim, Sung-Won; Konstantopoulou, Irene; Korach, Jacob; Laitman, Yael; Lasa, Adriana; Lasset, Christine; Lázaro, Conxi; Lee, Annette; Lee, Min Hyuk; Lester, Jenny; Lesueur, Fabienne; Liljegren, Annelie; Lindor, Noralane M; Longy, Michel; Loud, Jennifer T; Lu, Karen H; Lubinski, Jan; Machackova, Eva; Manoukian, Siranoush; Mari, Véronique; Martínez-Bouzas, Cristina; Matrai, Zoltan; Mebirouk, Noura; Meijers-Heijboer, Hanne E J; Meindl, Alfons; Mensenkamp, Arjen R; Mickys, Ugnius; Miller, Austin; Montagna, Marco; Moysich, Kirsten B; Mulligan, Anna Marie; Musinsky, Jacob; Neuhausen, Susan L; Nevanlinna, Heli; Ngeow, Joanne; Nguyen, Huu Phuc; Niederacher, Dieter; Nielsen, Henriette Roed; Nielsen, Finn Cilius; Nussbaum, Robert L; Offit, Kenneth; Öfverholm, Anna; Ong, Kai-Ren; Osorio, Ana; Papi, Laura; Papp, Janos; Pasini, Barbara; Pedersen, Inge Sokilde; Peixoto, Ana; Peruga, Nina; Peterlongo, Paolo; Pohl, Esther; Pradhan, Nisha; Prajzendanc, Karolina; Prieur, Fabienne; Pujol, Pascal; Radice, Paolo; Ramus, Susan J; Rantala, Johanna; Rashid, Muhammad Usman; Rhiem, Kerstin; Robson, Mark; Rodriguez, Gustavo C; Rogers, Mark T; Rudaitis, Vilius; Schmidt, Ane Y; Schmutzler, Rita Katharina; Senter, Leigha; Shah, Payal D; Sharma, Priyanka; Side, Lucy E; Simard, Jacques; Singer, Christian F; Skytte, Anne-Bine; Slavin, Thomas P; Snape, Katie; Sobol, Hagay; Southey, Melissa; Steele, Linda; Steinemann, Doris; Sukiennicki, Grzegorz; Sutter, Christian; Szabo, Csilla I; Tan, Yen Y; Teixeira, Manuel R; Terry, Mary Beth; Teulé, Alex; Thomas, Abigail; Thull, Darcy L; Tischkowitz, Marc; Tognazzo, Silvia; Toland, Amanda Ewart; Topka, Sabine; Trainer, Alison H; Tung, Nadine; van Asperen, Christi J; van der Hout, Annemieke H; van der Kolk, Lizet E; van der Luijt, Rob B; Van Heetvelde, Mattias; Varesco, Liliana; Varon-Mateeva, Raymonda; Vega, Ana; Villarreal-Garza, Cynthia; von Wachenfeldt, Anna; Walker, Lisa; Wang-Gohrke, Shan; Wappenschmidt, Barbara; Weber, Bernhard H F; Yannoukakos, Drakoulis; Yoon, Sook-Yee; Zanzottera, Cristina; Zidan, Jamal; Zorn, Kristin K; Hutten Selkirk, Christina G; Hulick, Peter J; Chenevix-Trench, Georgia; Spurdle, Amanda B; Antoniou, Antonis C; Nathanson, Katherine L

2018-05-01

The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations. © 2018 Wiley Periodicals, Inc.

Molecular screening of pituitary adenomas for gene mutations and rearrangements

Energy Technology Data Exchange (ETDEWEB)

Herman, V.; Drazin, N.Z.; Gonskey, R.; Melmed, S. (Cedars-Sinai Medical Center, Los Angeles, CA (United States))

1993-07-01

Although pituitary tumors arise as benign monoclonal neoplasms, genetic alterations have not readily been identified in these adenomas. The authors studied restriction fragment abnormalities involving the GH gene locus, and mutations in the p53 and H-, K-, and N-ras genes in 22 human GH cell adenomas. Twenty two nonsecretory adenomas were also examined for p53 and ras gene mutations. Seven prolactinoma DNA samples were tested for deletions in the multiple endocrine neoplasia-1 (MEN-1) locus, as well as for rearrangements in the hst gene, a member of the fibroblast growth factor family. In DNA from GH-cell adenomas, identical GH restriction patterns were detected in both pituitary and lymphocyte DNA in all patients and in one patient with a mixed GH-TSH cell adenoma. Using polymerase chain reaction (PCR)-single stranded conformation polymorphism analysis, no mutations were detected in exons 5, 6, 7 and 8 of the p53 gene in GH cell adenomas nor in 22 nonsecretory adenomas. Codons 12/13 and 61 of H-ras, K-ras, and N-ras genes were also intact on GH cell adenomas and in nonsecretory adenomas. Site-specific probes for chromosome 11q13 including, PYGM, D11S146, and INT2 were used in 7 sporadic PRL-secreting adenomas to detect deletions of the MEN-1 locus on chromosome 11. One patient was identified with a loss of 11p, and the remaining 6 patients did not demonstrate loss of heterozygosity in the pituitary 11q13 locus, compared to lymphocyte DNA. None of these patients demonstrated hst gene rearrangements which also maps to this locus. These results show that p53 and ras gene mutations are not common events in the pathogenesis of acromegaly and nonsecretory tumors. Although hst gene rearrangements and deletions of 11q13 are not associated with sporadic PRl-cell adenoma formation, a single patient was detected with a partial loss of chromosome 11, including the putative MEN-1 site. 31 refs., 5 figs., 2 tabs.

Rapid formation of a modern bedrock canyon by a single flood event

Science.gov (United States)

Lamb, Michael P.; Fonstad, Mark A.

2010-07-01

Deep river canyons are thought to form slowly over geological time (see, for example, ref. 1), cut by moderate flows that reoccur every few years. In contrast, some of the most spectacular canyons on Earth and Mars were probably carved rapidly during ancient megaflood events. Quantification of the flood discharge, duration and erosion mechanics that operated during such events is hampered because we lack modern analogues. Canyon Lake Gorge, Texas, was carved in 2002 during a single catastrophic flood. The event offers a rare opportunity to analyse canyon formation and test palaeo-hydraulic-reconstruction techniques under known topographic and hydraulic conditions. Here we use digital topographic models and visible/near-infrared aerial images from before and after the flood, discharge measured during the event, field measurements and sediment-transport modelling to show that the flood moved metre-sized boulders, excavated ~7m of limestone and transformed a soil-mantled valley into a bedrock canyon in just ~3days. We find that canyon morphology is strongly dependent on rock type: plucking of limestone blocks produced waterfalls, inner channels and bedrock strath terraces, whereas abrasion of cemented alluvium sculpted walls, plunge pools and streamlined islands. Canyon formation was so rapid that erosion might have been limited by the ability of the flow to transport sediment. We suggest that our results might improve hydraulic reconstructions of similar megafloods on Earth and Mars.

The Influence of Age at Single-Event Multilevel Surgery on Outcome in Children with Cerebral Palsy Who Walk with Flexed Knee Gait

Science.gov (United States)

Svehlik, Martin; Steinwender, Gerhard; Kraus, Tanja; Saraph, Vinay; Lehmann, Thomas; Linhart, Wolfgang E.; Zwick, Ernst B.

2011-01-01

Aim: Information on the timing and long-term outcome of single-event multilevel surgery in children with bilateral spastic cerebral palsy (CP) walking with flexed knee gait is limited. Based on our clinical experience, we hypothesized that older children with bilateral spastic CP would benefit more from single-event multilevel surgery than younger…

Discrete event model-based simulation for train movement on a single-line railway

International Nuclear Information System (INIS)

Xu Xiao-Ming; Li Ke-Ping; Yang Li-Xing

2014-01-01

The aim of this paper is to present a discrete event model-based approach to simulate train movement with the considered energy-saving factor. We conduct extensive case studies to show the dynamic characteristics of the traffic flow and demonstrate the effectiveness of the proposed approach. The simulation results indicate that the proposed discrete event model-based simulation approach is suitable for characterizing the movements of a group of trains on a single railway line with less iterations and CPU time. Additionally, some other qualitative and quantitative characteristics are investigated. In particular, because of the cumulative influence from the previous trains, the following trains should be accelerated or braked frequently to control the headway distance, leading to more energy consumption. (general)

Prevalent mutations in fatty acid oxidation disorders

DEFF Research Database (Denmark)

Gregersen, N; Andresen, B S; Bross, P

2000-01-01

UNLABELLED: The mutational spectrum in a given disease-associated gene is often comprised of a large number of different mutations, of which a single or a few are present in a large proportion of diseased individuals. Such prevalent mutations are known in four genes of the fatty acid oxidation...... of the disease in question and determination of the carrier frequency in the general population may help in elucidating the penetrance of the genotype. This is exemplified in disorders of mitochondrial fatty acid oxidation....

Same β-globin gene mutation is present on nine different β-thalassemia chromosomes in a Sardinian population

International Nuclear Information System (INIS)

Pirastu, M.; Galanello, R.; Doherty, M.A.; Tuveri, T.; Cao, A.; Kan, Y.W.

1987-01-01

The predominant β-thalassemia in Sardinia is the β 0 type in which no β-globin chains are synthesized in the homozygous state. The authors determined the β-thalassemia mutations in this population by the oligonucleotide-probe method and defined the chromosome haplotypes on which the mutation resides. The same β/sup 39(CAG→TAG)/ nonsense mutation was found on nine different chromosome haplotypes. Although this mutation may have arisen more than once, the multiple haplotypes could also be generated by crossing over and gene conversion events. These findings underscore the frequency of mutational events in the β-globin gene region

Exonization of an Intronic LINE-1 Element Causing Becker Muscular Dystrophy as a Novel Mutational Mechanism in Dystrophin Gene.

Science.gov (United States)

Gonçalves, Ana; Oliveira, Jorge; Coelho, Teresa; Taipa, Ricardo; Melo-Pires, Manuel; Sousa, Mário; Santos, Rosário

2017-10-03

A broad mutational spectrum in the dystrophin ( DMD ) gene, from large deletions/duplications to point mutations, causes Duchenne/Becker muscular dystrophy (D/BMD). Comprehensive genotyping is particularly relevant considering the mutation-centered therapies for dystrophinopathies. We report the genetic characterization of a patient with disease onset at age 13 years, elevated creatine kinase levels and reduced dystrophin labeling, where multiplex-ligation probe amplification (MLPA) and genomic sequencing failed to detect pathogenic variants. Bioinformatic, transcriptomic (real time PCR, RT-PCR), and genomic approaches (Southern blot, long-range PCR, and single molecule real-time sequencing) were used to characterize the mutation. An aberrant transcript was identified, containing a 103-nucleotide insertion between exons 51 and 52, with no similarity with the DMD gene. This corresponded to the partial exonization of a long interspersed nuclear element (LINE-1), disrupting the open reading frame. Further characterization identified a complete LINE-1 (~6 kb with typical hallmarks) deeply inserted in intron 51. Haplotyping and segregation analysis demonstrated that the mutation had a de novo origin. Besides underscoring the importance of mRNA studies in genetically unsolved cases, this is the first report of a disease-causing fully intronic LINE-1 element in DMD , adding to the diversity of mutational events that give rise to D/BMD.

Exonization of an Intronic LINE-1 Element Causing Becker Muscular Dystrophy as a Novel Mutational Mechanism in Dystrophin Gene

Science.gov (United States)

Gonçalves, Ana; Coelho, Teresa; Melo-Pires, Manuel; Sousa, Mário

2017-01-01

A broad mutational spectrum in the dystrophin (DMD) gene, from large deletions/duplications to point mutations, causes Duchenne/Becker muscular dystrophy (D/BMD). Comprehensive genotyping is particularly relevant considering the mutation-centered therapies for dystrophinopathies. We report the genetic characterization of a patient with disease onset at age 13 years, elevated creatine kinase levels and reduced dystrophin labeling, where multiplex-ligation probe amplification (MLPA) and genomic sequencing failed to detect pathogenic variants. Bioinformatic, transcriptomic (real time PCR, RT-PCR), and genomic approaches (Southern blot, long-range PCR, and single molecule real-time sequencing) were used to characterize the mutation. An aberrant transcript was identified, containing a 103-nucleotide insertion between exons 51 and 52, with no similarity with the DMD gene. This corresponded to the partial exonization of a long interspersed nuclear element (LINE-1), disrupting the open reading frame. Further characterization identified a complete LINE-1 (~6 kb with typical hallmarks) deeply inserted in intron 51. Haplotyping and segregation analysis demonstrated that the mutation had a de novo origin. Besides underscoring the importance of mRNA studies in genetically unsolved cases, this is the first report of a disease-causing fully intronic LINE-1 element in DMD, adding to the diversity of mutational events that give rise to D/BMD. PMID:28972564

Mutation effect of ion implantation on tomato breeding

International Nuclear Information System (INIS)

Wu Baoshan; Ling Haiqiu; Mao Peihong; Jin Xiang; Zeng Xianxian

2003-01-01

The mutation effects of N + ion implantation on cultivated tomato, Catchup type and Eatable type were studied. The result show that the mutation ranges of single-fruit weight and fruit number per plant were increased and their mutation frequencies were high, however the effect of ion implantation on germination rate of seed and quality of fruit was very weak. Using doses of 4 x 10 16 and 6 x 10 16 N + /cm 2 , the yield was greatly improved. The optimum mutation dosage was slightly different for seed of 2 tomato lines

Event-by-event simulation of quantum phenomena

NARCIS (Netherlands)

Raedt, H. De; Raedt, K. De; Michielsen, K.; Landau, DP; Lewis, SP; Schuttler, HB

2006-01-01

In various basic experiments in quantum physics, observations are recorded event-by-event. The final outcome of such experiments can be computed according to the rules of quantum theory but quantum theory does not describe single events. In this paper, we describe a stimulation approach that does

Homozygosity for a single base-pair mutation in the oocyte-specific GDF9 gene results in sterility in Thoka sheep

DEFF Research Database (Denmark)

Nicel, Linda; Bishop, Stephen; Pong-Wong, Richardo

2009-01-01

and infertility in homozygotes. Analysis of homozygote ovarian morphology and a number of genes normally activated in growing follicles showed that GDF9 was not involved in oocyte activation, but in subsequent development of the follicle. This study highlights the importance of oocyte factors in regulating...... ovulation rate, although in some cases homozygous ewes are infertile. In the present study we present a detailed characterisation of a novel mutation in growth differentiation factor 9 (GDF9), found in Icelandic Thoka sheep. This mutation is a single base change (A1279C) resulting in a non-conservative...... fertility and provides new information for structural analysis and investigation of the potentially important sites of dimerization or translational modifications required to produce biologically active GDF9. It also provides the basis for the utilisation of these animals to enhance sheep production...

Single-Event Effects in Power MOSFETs During Heavy Ion Irradiations Performed After Gamma-Ray Degradation

Science.gov (United States)

Busatto, G.; De Luca, V.; Iannuzzo, F.; Sanseverino, A.; Velardi, F.

2013-10-01

The robustness of commercial power metal-oxide semiconductor field-effect transistors to combined gamma-heavy ion irradiation has been investigated, evidence that the degradation of the gate oxide caused by the γ irradiation can severely corrupt the robustness to single-event effects and drastically modify the physical behavior of the device under test after the impact of a heavy ion. A decrease of the critical voltages at which destructive burnouts and gate ruptures for heavy ion impact appear, has been detected in the devices under test, which were previously irradiated with γ rays. In addition, the amount of critical voltage reduction is strictly related to the amount of the absorbed γ-ray dose. Furthermore, at the failure voltage, the behavior of the device is affected by the conduction of a current through the gate oxide. Moreover, the single-event gate rupture” of the device appears at lower voltages because of the reduction of the Fowler-Nordheim limit in the γ-irradiated devices.

Mutational analyses of molecularly cloned satellite tobacco mosaic virus during serial passage in plants: Evidence for hotspots of genetic change

Science.gov (United States)

Kurath, G.; Dodds, J.A.

1995-01-01

The high level of genetic diversity and rapid evolution of viral RNA genomes are well documented, but few studies have characterized the rate and nature of ongoing genetic change over time under controlled experimental conditions, especially in plant hosts. The RNA genome of satellite tobacco mosaic virus (STMV) was used as an effective model for such studies because of advantageous features of its genome structure and because the extant genetic heterogeneity of STMV has been characterized previously. In the present study, the process of genetic change over time was studied by monitoring multiple serial passage lines of STMV populations for changes in their consensus sequences. A total of 42 passage lines were initiated by inoculation of tobacco plants with a helper tobamovirus and one of four STMV RNA inocula that were transcribed from full-length infectious STMV clones or extracted from purified STMV type strain virions. Ten serial passages were carried out for each line and the consensus genotypes of progeny STMV populations were assessed for genetic change by RNase protection analyses of the entire 1,059-nt STMV genome. Three different types of genetic change were observed, including the fixation of novel mutations in 9 of 42 lines, mutation at the major heterogeneity site near nt 751 in 5 of the 19 lines inoculated with a single genotype, and selection of a single major genotype in 6 of the 23 lines inoculated with mixed genotypes. Sequence analyses showed that the majority of mutations were single base substitutions. The distribution of mutation sites included three clusters in which mutations occurred at or very near the same site, suggesting hot spots of genetic change in the STMV genome. The diversity of genetic changes in sibling lines is clear evidence for the important role of chance and random sampling events in the process of genetic diversification of STMV virus populations.

Hyperfunctioning thyroid nodules in toxic multinodular goiter share activating thyrotropin receptor mutations with solitary toxic adenoma.

Science.gov (United States)

Tonacchera, M; Chiovato, L; Pinchera, A; Agretti, P; Fiore, E; Cetani, F; Rocchi, R; Viacava, P; Miccoli, P; Vitti, P

1998-02-01

Toxic multinodular goiter is a cause of nonautoimmune hyperthyroidism and is believed to differ in its nature and pathogenesis from toxic adenoma. Gain-of-function mutations of the TSH receptor gene have been identified as a cause of toxic adenoma. The pathogenesis at the molecular level of hyperfunctioning nodules in toxic multinodular goiter has yet not been reported. Six patients with a single hot nodule within a multinodular goiter and 11 patients with toxic thyroid adenoma were enrolled in our study. At histology five hyperfunctioning nodules in multinodular goiters showed the features of adenomas, and one was identified as a hyperplastic nodule. The entire exon 10 of the TSH receptor gene was directly sequenced after PCR amplification from genomic DNA obtained from surgical specimens. Functional studies of mutated receptors were performed in COS-7 cells. Five out of 6 (83%) hyperfunctioning nodules within toxic multinodular goiters harbored a TSH receptor mutation. A TSH receptor mutation was also evident in the hyperfunctioning nodule that at histology had the features of noncapsulated hyperplastic nodule. Among toxic adenomas, 8 out of 11 (72%) nodules harbored a TSH receptor mutation. All the mutations were heterozygotic and somatic. Nonfunctioning nodules, whether adenomas or hyperplastic nodules present in association with hyperfunctioning nodules in the same multinodular goiters, had no TSH receptor mutation. All the mutations identified had constitutive activity as assessed by cAMP production after expression in COS-7 cells. Hyperfunctioning thyroid nodules in multinodular goiters recognize the same pathogenetic event (TSH receptor mutation) as toxic adenoma. Other mechanisms are implicated in the growth of nonfunctioning thyroid nodules coexistent in the same gland.

Mutation spectrum of the rhodopsin gene among patients with autosomal dominant retinitis pigmentosa

International Nuclear Information System (INIS)

Dryja, T.P.; Han, L.B.; Cowley, G.S.; McGee, T.L.; Berson, E.L.

1991-01-01

The authors searched for point mutations in every exon of the rhodopsin gene in 150 patients from separate families with autosomal dominant retinitis pigmentosa. Including the 4 mutations the authors reported previously, they found a total of 17 different mutations that correlate with the disease. Each of these mutations is a single-base substitution corresponding to a single amino acid substitution. Based on current models for the structure of rhodopsin, 3 of the 17 mutant amino acids are normally located on the cytoplasmic side of the protein, 6 in transmembrane domains, and 8 on the intradiscal side. Forty-three of the 150 patients (29%) carry 1 of these mutations, and no patient has more than 1 mutation. In every family with a mutation so far analyzed, the mutation cosegregates with the disease. They found one instance of a mutation in an affected patient that was absent in both unaffected parents (i.e., a new germ-line mutation), indicating that some isolate cases of retinitis pigmentosa carry a mutation of the rhodopsin gene

Somatic point mutation calling in low cellularity tumors.

Directory of Open Access Journals (Sweden)

Karin S Kassahn

Full Text Available Somatic mutation calling from next-generation sequencing data remains a challenge due to the difficulties of distinguishing true somatic events from artifacts arising from PCR, sequencing errors or mis-mapping. Tumor cellularity or purity, sub-clonality and copy number changes also confound the identification of true somatic events against a background of germline variants. We have developed a heuristic strategy and software (http://www.qcmg.org/bioinformatics/qsnp/ for somatic mutation calling in samples with low tumor content and we show the superior sensitivity and precision of our approach using a previously sequenced cell line, a series of tumor/normal admixtures, and 3,253 putative somatic SNVs verified on an orthogonal platform.

The relationship of the factor V Leiden mutation or the deletion-deletion polymorphism of the angiotensin converting enzyme to postoperative thromboembolic events following total joint arthroplasty

Directory of Open Access Journals (Sweden)

Fang Carrie

2001-04-01

Full Text Available Abstract Background Although all patients undergoing total joint arthroplasty are subjected to similar risk factors that predispose to thromboembolism, only a subset of patients develop this complication. The objective of this study was to determine whether a specific genetic profile is associated with a higher risk of developing a postoperative thromboembolic complication. Specifically, we examined if the Factor V Leiden (FVL mutation or the deletion polymorphism of the angiotensin-converting enzyme (ACE gene increased a patient's risk for postoperative thromboembolic events. The FVL mutation has been associated with an increased risk of idiopathic thromboembolism and the deletion polymorphism of the ACE gene has been associated with increased vascular tone, attenuated fibrinolysis and increased platelet aggregation. Methods The presence of these genetic profiles was determined for 38 patients who had a postoperative symptomatic pulmonary embolus or proximal deep venous thrombosis and 241 control patients without thrombosis using molecular biological techniques. Results The Factor V Leiden mutation was present in none of the 38 experimental patients and in 3% or 8 of the 241 controls (p = 0.26. Similarly there was no difference detected in the distribution of polymorphisms for the ACE gene with the deletion-deletion genotype present in 36% or 13 of the 38 experimental patients and in 31% or 74 of the 241 controls (p = 0.32. Conclusions Our results suggest that neither of these potentially hypercoaguable states are associated with an increased risk of symptomatic thromboembolic events following total hip or knee arthroplasty in patients receiving pharmacological thromboprophylaxis.

Systematic reconstruction of autism biology from massive genetic mutation profiles.

Science.gov (United States)

Luo, Weijun; Zhang, Chaolin; Jiang, Yong-Hui; Brouwer, Cory R

2018-04-01

Autism spectrum disorder (ASD) affects 1% of world population and has become a pressing medical and social problem worldwide. As a paradigmatic complex genetic disease, ASD has been intensively studied and thousands of gene mutations have been reported. Because these mutations rarely recur, it is difficult to (i) pinpoint the fewer disease-causing versus majority random events and (ii) replicate or verify independent studies. A coherent and systematic understanding of autism biology has not been achieved. We analyzed 3392 and 4792 autism-related mutations from two large-scale whole-exome studies across multiple resolution levels, that is, variants (single-nucleotide), genes (protein-coding unit), and pathways (molecular module). These mutations do not recur or replicate at the variant level, but significantly and increasingly do so at gene and pathway levels. Genetic association reveals a novel gene + pathway dual-hit model, where the mutation burden becomes less relevant. In multiple independent analyses, hundreds of variants or genes repeatedly converge to several canonical pathways, either novel or literature-supported. These pathways define recurrent and systematic ASD biology, distinct from previously reported gene groups or networks. They also present a catalog of novel ASD risk factors including 118 variants and 72 genes. At a subpathway level, most variants disrupt the pathway-related gene functions, and in the same gene, they tend to hit residues extremely close to each other and in the same domain. Multiple interacting variants spotlight key modules, including the cAMP (adenosine 3',5'-monophosphate) second-messenger system and mGluR (metabotropic glutamate receptor) signaling regulation by GRKs (G protein-coupled receptor kinases). At a superpathway level, distinct pathways further interconnect and converge to three biology themes: synaptic function, morphology, and plasticity.

Number of infection events per cell during HIV-1 cell-free infection.

Science.gov (United States)

Ito, Yusuke; Remion, Azaria; Tauzin, Alexandra; Ejima, Keisuke; Nakaoka, Shinji; Iwasa, Yoh; Iwami, Shingo; Mammano, Fabrizio

2017-07-26

HIV-1 accumulates changes in its genome through both recombination and mutation during the course of infection. For recombination to occur, a single cell must be infected by two HIV strains. These coinfection events were experimentally demonstrated to occur more frequently than would be expected for independent infection events and do not follow a random distribution. Previous mathematical modeling approaches demonstrated that differences in target cell susceptibility can explain the non-randomness, both in the context of direct cell-to-cell transmission, and in the context of free virus transmission (Q. Dang et al., Proc. Natl. Acad. Sci. USA 101:632-7, 2004: K. M. Law et al., Cell reports 15:2711-83, 2016). Here, we build on these notions and provide a more detailed and extensive quantitative framework. We developed a novel mathematical model explicitly considering the heterogeneity of target cells and analysed datasets of cell-free HIV-1 single and double infection experiments in cell culture. Particularly, in contrast to the previous studies, we took into account the different susceptibility of the target cells as a continuous distribution. Interestingly, we showed that the number of infection events per cell during cell-free HIV-1 infection follows a negative-binomial distribution, and our model reproduces these datasets.

In-flight and ground testing of single event upset sensitivity in static RAMs

International Nuclear Information System (INIS)

Johansson, K.; Dyreklev, P.; Granbom, B.; Calvet, C.; Fourtine, S.; Feuillatre, O.

1998-01-01

This paper presents the results from in-flight measurements of single event upsets (SEU) in static random access memories (SRAM) caused by the atmospheric radiation environment at aircraft altitudes. The memory devices were carried on commercial airlines at high altitude and mainly high latitudes. The SEUs were monitored by a Component Upset Test Equipment (CUTE), designed for this experiment. The in flight results are compared to ground based testing with neutrons from three different sources

Impact of JAK2V617F Mutational Status on Phenotypic Features in Essential Thrombocythemia and Primary Myelofibrosis

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İpek Yönal

2016-05-01

Full Text Available Objective: The JAK2V617F mutation is present in the majority of patients with essential thrombocythemia (ET and primary myelofibrosis (PMF. The impact of this mutation on disease phenotype in ET and PMF is still a matter of discussion. This study aims to determine whether there are differences in clinical presentation and disease outcome between ET and PMF patients with and without the JAK2V617F mutation. Materials and Methods: In this single-center study, a total of 184 consecutive Philadelphia-negative chronic myeloproliferative neoplasms, 107 cases of ET and 77 cases of PMF, were genotyped for JAK2V617F mutation using the JAK2 Ipsogen MutaScreen assay, which involves allele-specific polymerase chain reaction. Results: ET patients positive for JAK2V617F mutation had higher hemoglobin (Hb and hematocrit (Hct levels, lower platelet counts, and more prevalent splenomegaly at diagnosis compared to patients negative for the JAK2V617F mutation, but rates of major thrombotic events, arterial thrombosis, and venous thrombosis were comparable between the groups. At presentation, PMF patients with JAK2V617F mutation had significantly higher Hb and Hct levels and leukocyte counts than patients without the mutation. Similar to the findings of ET patients, thromboembolic rates were similar in PMF patients with and without theJAK2V617F mutation. For ET and PMF patients, no difference was observed in rates of death with respect to JAK2V617F mutational status. Moreover, leukemic transformation rate was not different in our PMF patients with and without JAK2V617F mutation. Conclusion: We conclude that JAK2V617F-mutated ET patients express a polycythemia vera-like phenotype and JAK2V617F mutation in PMF patients is associated with a more pronounced myeloproliferative phenotype.

Intercellular distribution of mutations induced in oopcytes of Drosophila melanogaster by chemical and physical mutagens

International Nuclear Information System (INIS)

Traut, H.

1979-01-01

When females of Drosophila melanogaster are treated with chemical or physical mutagens, not only in one but also in both of the two homologous X chromosomes of a given oocyte, a recessive sex-linked lethal mutation may be induced. A method is described that discriminates between such single and double mutations. A theory is developed to show how a comparison betweeen the expected and the observer frequency of double mutations yields an indication of the intercellular distribution (random or nonrandom) of recessive lethal mutations induced by mutagenic agents in oocytes and, consequently, of the distribution (homogenous or nonhomogeneous) of those agents. Three agents were tested: FUdR (12.5, 50.0 and 81.0 μg/ml), mitomycin C (130.0 μg/ml) and x rays (2000 R, 150 kV). After FUdR feeding, no increase in the mutation frequency usually observed in D. melanogaster without mutagenic treatment was obtained (u = 0.13%, namely three single mutations among 2332 chromosomes tested). After mitomycin C feeding 104 single and three double mutations were obtained. All of the 50 mutations observed after x irradiation were single mutations. The results obtained in the mitomycin C and radiation experiments favor the assumption of a random intercellular distribution of recessive lethal mutations induced by these two agents in oocytes of D. melanogaster. Reasons are discussed why for other types of mutagenic agents nonrandom distributions may be observed with our technique

Reduction of spontaneous somatic mutation frequency by a low-dose X irradiation of Drosophila larvae and possible involvement of DNA single-strand damage repair.

Science.gov (United States)

Koana, Takao; Takahashi, Takashi; Tsujimura, Hidenobu

2012-03-01

The third instar larvae of Drosophila were irradiated with X rays, and the somatic mutation frequency in their wings was measured after their eclosion. In the flies with normal DNA repair and apoptosis functions, 0.2 Gy irradiation at 0.05 Gy/min reduced the frequency of the so-called small spot (mutant cell clone with reduced reproductive activity) compared with that in the sham-irradiated flies. When apoptosis was suppressed using the baculovirus p35 gene, the small spot frequency increased four times in the sham-irradiated control group, but the reduction by the 0.2-Gy irradiation was still evident. In a non-homologous end joining-deficient mutant, the small spot frequency was also reduced by 0.2 Gy radiation. In a mutant deficient in single-strand break repair, no reduction in the small spot frequency by 0.2 Gy radiation was observed, and the small spot frequency increased with the radiation dose. Large spot (mutant cell clone with normal reproductive activity) frequency was not affected by suppression of apoptosis and increased monotonically with radiation dose in wild-type larvae and in mutants for single- or double-strand break repair. It is hypothesized that some of the small spots resulted from single-strand damage and, in wild-type larvae, 0.2 Gy radiation activated the normal single-strand break repair gene, which reduced the background somatic mutation frequency.

A Novel Approach to Estimating Nitrous Oxide Emissions during Wetting Events from Single-Timepoint Flux Measurements.

Science.gov (United States)

Davis, Brian W; Needelman, Brian A; Cavigelli, Michel A; Yarwood, Stephanie A; Maul, Jude E; Bagley, Gwendolyn A; Mirsky, Steven B

2017-03-01

Precipitation and irrigation induce pulses of NO emissions in agricultural soils, but the magnitude, duration, and timing of these pulses remain uncertain. This uncertainty makes it difficult to accurately extrapolate emissions from unmeasured time periods between chamber sampling events. Therefore, we developed a modeling protocol to predict NO emissions from data collected daily for 7 d after wetting events. Within a cover crop-based corn ( L.) production system in Beltsville, MD, we conducted the 7-d time series during four time periods representing a range of corn growth stages in 2013 and 2014. Treatments included mixtures and monocultures of grass and legume cover crops that were fertilized with pelletized poultry litter or urea-ammonium nitrate solution (9-276 kg N ha). Most fluxes did not exhibit the expected exponential decay over time (82%); therefore, cumulative emissions were calculated using trapezoidal integration over 7 d after the wetting event. Cumulative 7-d emissions were well correlated with single point gas fluxes on the second day after a wetting event using a generalized linear mixed model (ln[emissions] = 0.809∙ln[flux] + 2.47). Soil chemical covariates before or after a wetting event were weakly associated with cumulative emissions. The ratio of dissolved organic C to total inorganic N was negatively correlated with cumulative emissions ( = 0.23-0.29), whereas nitrate was positively correlated with cumulative emissions ( = 0.23-0.33). Our model is an innovative approach that is calibrated using site-specific time series data, which may then be used to estimate short-term NO emissions after wetting events using only a single flux measurement. Copyright © by the American Society of Agronomy, Crop Science Society of America, and Soil Science Society of America, Inc.

Mutation of NRAS but not KRAS significantly reduces myeloma sensitivity to single-agent bortezomib therapy

NARCIS (Netherlands)

G. Mulligan (George); D.I. Lichter (David); A.D. Bacco (Alessandra Di); S.J. Blakemore (Stephen); A. Berger (Allison); E. Koenig (Erik); H. Bernard (Hugues); W.L. Trepicchio (William); B. Li (Bin); R. Neuwirth (Rachel); N. Chattopadhyay (Nibedita); J.B. Bolen (Joseph); A.J. Dorner (Andrew); H. van de Velde (Helgi); D. Ricci (Deborah); S. Jagannath (Sundar); J.R. Berenson (James); P.G. Richardson (Paul Gerard); E.A. Stadtmauer (Edward); R.Z. Orlowski (Robert); S. Lonial (Sagar); K.C. Anderson (Kenneth); P. Sonneveld (Pieter); J.F. San Miguel (Jesús Fernando); D.-L. Esseltine (Dixie-Lee); M. Schu (Matthew)

2014-01-01

textabstractVarious translocations and mutations have been identified in myeloma, and certain aberrations, such as t(4;14) and del17, are linked with disease prognosis. To investigate mutational prevalence in myeloma and associations between mutations and patient outcomes, we tested a panel of 41

Two-dimensional numerical simulation of the effect of single event burnout for n-channel VDMOSFET

International Nuclear Information System (INIS)

Guo Hongxia; Chen Yusheng; Wang Wei; Zhao Jinlong; Zhang Yimen; Zhou Hui

2004-01-01

2D MEDICI simulator is used to investigate the effect of Single Event Burnout (SEB) for n-channel power VDMOSFETs. The simulation results are consistent with experimental results which have been published. The simulation results are of great interest for a better understanding of the occurrence of events. The effects of the minority carrier lifetime in the base region, the base width and the emitter doping density on SEB susceptibility are verified. Some hardening solutions to SEB are provided. The work shows that the 2D simulator MEDICI is an useful tool for burnout prediction and for the evaluation of hardening solutions. (authors)

Single event upsets in semiconductor devices induced by highly ionising particles.

Science.gov (United States)

Sannikov, A V

2004-01-01

A new model of single event upsets (SEUs), created in memory cells by heavy ions and high energy hadrons, has been developed. The model takes into account the spatial distribution of charge collection efficiency over the cell area not considered in previous approaches. Three-dimensional calculations made by the HADRON code have shown good agreement with experimental data for the energy dependence of proton SEU cross sections, sensitive depths and other SEU observables. The model is promising for prediction of SEU rates for memory chips exposed in space and in high-energy experiments as well as for the development of a high-energy neutron dosemeter based on the SEU effect.

A novel deleterious PTEN mutation in a patient with early-onset bilateral breast cancer

International Nuclear Information System (INIS)

Pradella, Laura Maria; Gasparre, Giuseppe; Turchetti, Daniela; Evangelisti, Cecilia; Ligorio, Claudia; Ceccarelli, Claudio; Neri, Iria; Zuntini, Roberta; Amato, Laura Benedetta; Ferrari, Simona; Martelli, Alberto Maria

2014-01-01

An early age at Breast Cancer (BC) onset may be a hallmark of inherited predisposition, but BRCA1/2 mutations are only found in a minority of younger BC patients. Among the others, a fraction may carry mutations in rarer BC genes, such as TP53, STK11, CDH1 and PTEN. As the identification of women harboring such mutations allows for targeted risk-management, the knowledge of associated manifestations and an accurate clinical and family history evaluation are warranted. We describe the case of a woman who developed an infiltrating ductal carcinoma of the right breast at the age of 32, a contralateral BC at age 36 and another BC of the right breast at 40. When she was 39 years-old, during a dermatological examination, mucocutaneous features suggestive of Cowden Syndrome, a disorder associated to germ-line PTEN mutations, were noticed. PTEN genetic testing revealed the novel c.71A > T (p.Asp24Val) mutation, whose deleterious effect, suggested by conservation data and in silico tools, was definitely demonstrated by the incapacity of mutant PTEN to inhibit Akt phosphorylation when used to complement PTEN-null cells. In BC tissue, despite the absence of LOH or somatic mutations of PTEN, Akt phosphorylation was markedly increased in comparison to normal tissue, thus implying additional somatic events into the deregulation of the PI3K/Akt/mTOR pathway and, presumably, into carcinogenesis. Hence, known oncogenic mutations in PIK3CA (exons 10 and 21) and AKT1 (exon 2) were screened in tumor DNA with negative results, which suggests that the responsible somatic event(s) is a different, uncommon one. This case stresses the importance of clinical/genetic assessment of early-onset BC patients in order to identify mutation carriers, who are at high risk of new events, so requiring tailored management. Moreover, it revealed a novel PTEN mutation with pathogenic effect, pointing out, however, the need for further efforts to elucidate the molecular steps of PTEN

Single Event Upset Energy Dependence In a Buck-Converter Power Supply Design

CERN Document Server

Drake, G; The ATLAS collaboration; De Lurgio, P; Stanek, R; Mellado, B; Gopalakrishnan, A; Mahadik, S; Reed, R; Senthilkumaran, A

2012-01-01

We present a study of Single Event Upsets performed on a commercial pulse-width modulator controller chip that we are using for a switching power supply design for the Atlas Tile Calorimeter at the LHC. We performed tests to study the probability of an SEU occurring as a function of incident particle (hadron) energy. We compare the results with prediction from theory. We discuss the performance of the circuit, and perform an analysis using Bendel parameters. We also present a solution that we found using external circuitry that eliminates the effect.

A multiplex single nucleotide polymorphism typing assay for detecting mutations that result in decreased fluoroquinolone susceptibility in Salmonella enterica serovars Typhi and Paratyphi A.

LENUS (Irish Health Repository)

Song, Yajun

2010-08-01

OBJECTIVES: Decreased susceptibility to fluoroquinolones has become a major problem for the successful therapy of human infections caused by Salmonella enterica, especially the life-threatening typhoid and paratyphoid fevers. METHODS: By using Luminex xTAG beads, we developed a rapid, reliable and cost-effective multiplexed genotyping assay for simultaneously detecting 11 mutations in gyrA, gyrB and parE of S. enterica serovars Typhi and Paratyphi A that result in nalidixic acid resistance (Nal(R)) and\\/or decreased susceptibility to fluoroquinolones. RESULTS: This assay yielded unambiguous single nucleotide polymorphism calls on extracted DNA from 292 isolates of Salmonella Typhi (Nal(R) = 223 and Nal(S) = 69) and 106 isolates of Salmonella Paratyphi A (Nal(R) = 24 and Nal(S) = 82). All of the 247 Nal(R) Salmonella Typhi and Salmonella Paratyphi A isolates were found to harbour at least one of the target mutations, with GyrA Phe-83 as the most common one (143\\/223 for Salmonella Typhi and 18\\/24 for Salmonella Paratyphi A). We also identified three GyrB mutations in eight Nal(S) Salmonella Typhi isolates (six for GyrB Phe-464, one for GyrB Leu-465 and one for GyrB Asp-466), and mutations GyrB Phe-464 and GyrB Asp-466 seem to be related to the decreased ciprofloxacin susceptibility phenotype in Salmonella Typhi. This assay can also be used directly on boiled single colonies. CONCLUSIONS: The assay presented here would be useful for clinical and reference laboratories to rapidly screen quinolone-resistant isolates of Salmonella Typhi and Salmonella Paratyphi A, and decipher the underlying genetic changes for epidemiological purposes.

Coexistence of K-ras mutations and HPV infection in colon cancer

Directory of Open Access Journals (Sweden)

Tezol Ayda

2006-05-01

Full Text Available Abstract Background Activation of the ras genes or association with human papillomavirus infection have been extensively studied in colorectal cancer. However, the correlation between K-ras mutations and HPV in colorectal cancer has not been investigated yet. In this study we aimed to investigate the presence of K-ras mutations and their correlation with HPV infection in colon cancer. Methods K-ras mutations were analyzed by a mutagenic PCR assay and digestion with specific restriction enzymes to distinguish the wild-type and mutant codons. HPV infection was analyzed by PCR amplification and hybridization with specific probes by Southern blotting. Stattistical analyses were performed by the chi-square and Fisher's exact tests Results HPV gene fragments were detected in 43 tumors and 17 normal tissue samples. HPV 18 was the prevalent type in the tumor tissue. A mutation at codon 12 of the K-ras gene was present in 31 patients. 56% of the HPV-positive tumors also harbored a K-ras mutation. Codon 13 mutations were not observed. These data indicate that infection with high risk HPV types and mutational activation of the K-ras gene are frequent events in colorectal carcinogenesis. Conclusion Our findings suggest that mutational activation of the K-ras gene is a common event in colon carcinogenesis and that HPV infection may represent an important factor in the development of the premalignant lesions leading to the neoplastic phenotype.

Short barb: a feather structure mutation in Japanese quail.

Science.gov (United States)

Fulton, J E; Roberts, C W; Nichols, C R; Cheng, K M

1982-12-01

A type of feather structure abnormality in Japanese quail resulting in shortened barbs on contour feathers was found to be controlled by a single autosomal recessive gene, sh (short barb). The mutation was first identified in a full-sib family from the University of British Columbia wild type line. Unlike other feather structure mutations in Japanese quail reported previously in literature, the short barb mutation is not associated with poor reproduction.

Distinct pattern of p53 mutations in bladder cancer

DEFF Research Database (Denmark)

Spruck, C H; Rideout, W M; Olumi, A F

1993-01-01

A distinct mutational spectrum for the p53 tumor suppressor gene in bladder carcinomas was established in patients with known exposures to cigarette smoke. Single-strand conformational polymorphism analysis of exons 5 through 8 of the p53 gene showed inactivating mutations in 16 of 40 (40%) bladder...... tumors from smokers and 13 of 40 (33%) tumors from lifetime nonsmokers. Overall, 13 of the 50 (26%) total point mutations discovered in this and previous work were G:C-->C:G transversions, a relatively rare mutational type in human tumors. In six tumors, identical AGA (Arg)-->ACA (Thr) point mutations...... double mutations, four of which were tandem mutations on the same allele. No double mutations were found in tumors from nonsmoking patients. None of the mutations in smokers were G:C-->T:A transversions, which would be anticipated for exposure to the suspected cigarette smoke carcinogen 4-aminobiphenyl...

Single event upset threshold estimation based on local laser irradiation

International Nuclear Information System (INIS)

Chumakov, A.I.; Egorov, A.N.; Mavritsky, O.B.; Yanenko, A.V.

1999-01-01

An approach for estimation of ion-induced SEU threshold based on local laser irradiation is presented. Comparative experiment and software simulation research were performed at various pulse duration and spot size. Correlation of single event threshold LET to upset threshold laser energy under local irradiation was found. The computer analysis of local laser irradiation of IC structures was developed for SEU threshold LET estimation. The correlation of local laser threshold energy with SEU threshold LET was shown. Two estimation techniques were suggested. The first one is based on the determination of local laser threshold dose taking into account the relation of sensitive area to local irradiated area. The second technique uses the photocurrent peak value instead of this relation. The agreement between the predicted and experimental results demonstrates the applicability of this approach. (authors)

Nonlinear dynamics of the rock-paper-scissors game with mutations.

Science.gov (United States)

Toupo, Danielle F P; Strogatz, Steven H

2015-05-01

We analyze the replicator-mutator equations for the rock-paper-scissors game. Various graph-theoretic patterns of mutation are considered, ranging from a single unidirectional mutation pathway between two of the species, to global bidirectional mutation among all the species. Our main result is that the coexistence state, in which all three species exist in equilibrium, can be destabilized by arbitrarily small mutation rates. After it loses stability, the coexistence state gives birth to a stable limit cycle solution created in a supercritical Hopf bifurcation. This attracting periodic solution exists for all the mutation patterns considered, and persists arbitrarily close to the limit of zero mutation rate and a zero-sum game.

Studies of human mutation rates, December 1, 1985--November 30, 1986

International Nuclear Information System (INIS)

Neel, J.V.

1985-01-01

This program seeks to quantify native human mutation rates and to determine how man's activities may affect these rates. The program is divided into six tasks, i.e. The American Indian mutation rate, monitoring populations for frequency of mutation by electrophoresis of blood proteins, application of molecular biological approaches to the detection and study of mutational events in human populations, development of two-dimensional electrophoresis for identification of mutant proteins, co-operative program with the Radiation Effects Research Foundation in Hiroshima and Nagasaki, Japan, and statistical problems associated with the estimation of mutation rates. Progress of each of the above tasks is related in detail. (DT)

Single-Trial Event-Related Potential Based Rapid Image Triage System

Directory of Open Access Journals (Sweden)

Ke Yu

2011-06-01

Full Text Available Searching for points of interest (POI in large-volume imagery is a challenging problem with few good solutions. In this work, a neural engineering approach called rapid image triage (RIT which could offer about a ten-fold speed up in POI searching is developed. It is essentially a cortically-coupled computer vision technique, whereby the user is presented bursts of images at a speed of 6–15 images per second and then neural signals called event-related potential (ERP is used as the ‘cue’ for user seeing images of high relevance likelihood. Compared to past efforts, the implemented system has several unique features: (1 it applies overlapping frames in image chip preparation, to ensure rapid image triage performance; (2 a novel common spatial-temporal pattern (CSTP algorithm that makes use of both spatial and temporal patterns of ERP topography is proposed for high-accuracy single-trial ERP detection; (3 a weighted version of probabilistic support-vector-machine (SVM is used to address the inherent unbalanced nature of single-trial ERP detection for RIT. High accuracy, fast learning, and real-time capability of the developed system shown on 20 subjects demonstrate the feasibility of a brainmachine integrated rapid image triage system for fast detection of POI from large-volume imagery.

Comparison between Radioisotopic and Non-radioisotopic Polymerase Chain Reaction-Single Strand Conformation Polymorphism (PCR-SSCP) Procedures in the Detection of Mutations at the rpoB Gene Associated with Rifampicin Resistance in Mycobacterium tuberculosis

International Nuclear Information System (INIS)

Lee, H.; Bang, H.E.; Johnson, R.; Jordaan, A.M.; Victor, T.C. . E-mail : tv@sun.ac.za; Dar, L.; Khan, B.K.; Cho, S.N. . E-mail : raycho@yonsei.ac.kr

2006-01-01

Rapid and sensitive detection of mutations at the rpoB gene of Mycobacterium tuberculosis would be of great importance for proper management of tuberculosis (TB) patients and control of multi-drug resistant TB. Polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) using both radioisotopic and non-radioisotopic methods have been widely used for detecting such mutations. However, the silver staining method, which is the most frequently employed in PCR-SSCP, has been reported to be producing results of varying sensitivity. Radioisotope-based methods have shown greater sensitivity in detecting the rpoB mutations than the silver staining method. The primary objective of this study was therefore to compare the radioisotopic method with the silver staining method detection of mutations of rpoB gene by PCR-SSCP in the same laboratory. Purified DNAs from M. tuberculosis H37Rv were serially diluted and used for PCR amplification with and without radionuclides. The PCR products were then detected by silver staining and autoradiography methods. In addition, clinical isolates were analyzed by PCR-SSCP. The radioisotopic method showed about four-fold increase in the detection of PCR products over ethidium bromide staining in agarose gel. When compared with silver staining, the radioisotopic method gave a sensitivity of more than 10-fold in detecting PCR products and about 8-fold in PCR-SSCP. Radioisotope-based detection methods provided a clearer resolution in PCR-SSCP than the silver staining method when applied to clinical isolates of M. tuberculosis. Radioisotope-based detection method was shown to be more sensitive than non-isotope-based method in detecting PCR products and mutations at the rpoB gene of M. tuberculosis by PCR-SSCP. It may be noted that mutations in the rpoB gene as a marker have significant clinical importance because of the increasing number of MDR-TB cases in the world. It is especially relevant to MDR and Extreme Drug Resistance TB

Molecular evaluation of a novel missense mutation & an insertional truncating mutation in SUMF1 gene

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Udhaya H Kotecha

2014-01-01

Full Text Available Background & objectives: Multiple suphphatase deficiency (MSD is an autosomal recessive disorder affecting the post translational activation of all enzymes of the sulphatase family. To date, approximately 30 different mutations have been identified in the causative gene, sulfatase modifying factor 1 (SUMF1. We describe here the mutation analysis of a case of MSD. Methods: The proband was a four year old boy with developmental delay followed by neuroregression. He had coarse facies, appendicular hypertonia, truncal ataxia and ichthyosis limited to both lower limbs. Radiographs showed dysostosis multiplex. Clinical suspicion of MSD was confirmed by enzyme analysis of four enzymes of the sulphatase group. Results: The patient was compound heterozygote for a c.451A>G (p.K151E substitution in exon 3 and a single base insertion mutation (c.690_691 InsT in exon 5 in the SUMF1 gene. The bioinformatic analysis of the missense mutation revealed no apparent effect on the overall structure. However, the mutated 151-amino acid residue was found to be adjacent to the substrate binding and the active site residues, thereby affecting the substrate binding and/or catalytic activity, resulting in almost complete loss of enzyme function. Conclusions: The two mutations identified in the present case were novel. This is perhaps the first report of an insertion mutation in SUMF1 causing premature truncation of the protein.

Abrupt onset of mutations in a developmentally regulated gene during terminal differentiation of post-mitotic photoreceptor neurons in mice.

Directory of Open Access Journals (Sweden)

Ivette M Sandoval

Full Text Available For sensitive detection of rare gene repair events in terminally differentiated photoreceptors, we generated a knockin mouse model by replacing one mouse rhodopsin allele with a form of the human rhodopsin gene that causes a severe, early-onset form of retinitis pigmentosa. The human gene contains a premature stop codon at position 344 (Q344X, cDNA encoding the enhanced green fluorescent protein (EGFP at its 3' end, and a modified 5' untranslated region to reduce translation rate so that the mutant protein does not induce retinal degeneration. Mutations that eliminate the stop codon express a human rhodopsin-EGFP fusion protein (hRho-GFP, which can be readily detected by fluorescence microscopy. Spontaneous mutations were observed at a frequency of about one per retina; in every case, they gave rise to single fluorescent rod cells, indicating that each mutation occurred during or after the last mitotic division. Additionally, the number of fluorescent rods did not increase with age, suggesting that the rhodopsin gene in mature rod cells is less sensitive to mutation than it is in developing rods. Thus, there is a brief developmental window, coinciding with the transcriptional activation of the rhodopsin locus, in which somatic mutations of the rhodopsin gene abruptly begin to appear.

Amelogenesis Imperfecta and Screening of Mutation in Amelogenin Gene

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Fernanda Veronese Oliveira

2014-01-01

Full Text Available The aim of this study was to report the clinical findings and the screening of mutations of amelogenin gene of a 7-year-old boy with amelogenesis imperfecta (AI. The genomic DNA was extracted from saliva of patient and his family, followed by PCR and direct DNA sequencing. The c.261C>T mutation was found in samples of mother, father, and brother, but the mutation was not found in the sequence of the patient. This mutation is a silent mutation and a single-nucleotide polymorphism (rs2106416. Thus, it is suggested that the mutation found was not related to the clinical presence of AI. Further research is necessary to examine larger number of patients and genes related to AI.

A new method for explicit modelling of single failure event within different common cause failure groups

International Nuclear Information System (INIS)

Kančev, Duško; Čepin, Marko

2012-01-01

Redundancy and diversity are the main principles of the safety systems in the nuclear industry. Implementation of safety components redundancy has been acknowledged as an effective approach for assuring high levels of system reliability. The existence of redundant components, identical in most of the cases, implicates a probability of their simultaneous failure due to a shared cause—a common cause failure. This paper presents a new method for explicit modelling of single component failure event within multiple common cause failure groups simultaneously. The method is based on a modification of the frequently utilised Beta Factor parametric model. The motivation for development of this method lays in the fact that one of the most widespread softwares for fault tree and event tree modelling as part of the probabilistic safety assessment does not comprise the option for simultaneous assignment of single failure event to multiple common cause failure groups. In that sense, the proposed method can be seen as an advantage of the explicit modelling of common cause failures. A standard standby safety system is selected as a case study for application and study of the proposed methodology. The results and insights implicate improved, more transparent and more comprehensive models within probabilistic safety assessment.

Investigations on heavy ion induced Single-Event Transients (SETs) in highly-scaled FinFETs

Energy Technology Data Exchange (ETDEWEB)

Gaillardin, M., E-mail: marc.gaillardin@cea.fr [CEA, DAM, DIF, F-91297 Arpajon (France); Raine, M.; Paillet, P. [CEA, DAM, DIF, F-91297 Arpajon (France); Adell, P.C. [Jet Propulsion Laboratory, Pasadena, CA 91101 (United States); Girard, S. [Université de Saint-Etienne, Laboratoire H. Curien, UMR-5516, 42000 Saint-Etienne (France); Duhamel, O. [CEA, DAM, DIF, F-91297 Arpajon (France); Andrieu, F.; Barraud, S.; Faynot, O. [CEA, LETI-Minatec, 17 avenue des Martyrs, 38000 Grenoble (France)

2015-12-15

We investigate Single-Event Transients (SET) in different designs of multiple-gate devices made of FinFETs with various geometries. Heavy ion experimental results are explained by using a thorough charge collection analysis of fast transients measured on dedicated test structures. Multi-level simulations are performed to get new insights into the charge collection mechanisms in multiple-gate devices. Implications for multiple-gate device design hardening are finally discussed.

DNA sequence analysis of the mutational specificity of u.v. light in the SUP4-o gene of yeast

International Nuclear Information System (INIS)

Kunz, B.A.; Mis, J.R.A.; Pierce, M.K.; Giroux, C.N.

1987-01-01

Mutations induced in the SUP4-o gene of Saccharomyces cerevisiae by u.v. irradiation have been characterized. DNA sequence analysis of 120 mutants revealed that u.v. induced all types of base substitutions, although transitions, in particular G:C → A:T events predominated. In addition, a small number of single base pair deletions and double mutations, occurring in tandem or separated by a few base pairs, were recovered. The base pair substitutions were not distributed randomly in the SUP4-o gene and, with one exception, were all located at sites of adjacent pyrimidines, suggesting they were targeted by u.v. photolesions. A substantial fraction of the mutations were detected at hotspots for u.v. mutagenesis. The majority of changes occurred at the 3' base of dipyrimidine sequences where both cyclobutane dimers and [6-4]-photoproducts could form. Approximately one-third of the induced base substitutions were found at potential pyrimidine dimer sites where [6-4]-photoproducts would be expected to occur rarely. Possible origins of the induced mutations and the role of cyclobutane dimers as premutational u.v. lesions in yeast are considered. (author)

Prognostic implications of mutation-specific QTc standard deviation in congenital long QT syndrome.

Science.gov (United States)

Mathias, Andrew; Moss, Arthur J; Lopes, Coeli M; Barsheshet, Alon; McNitt, Scott; Zareba, Wojciech; Robinson, Jennifer L; Locati, Emanuela H; Ackerman, Michael J; Benhorin, Jesaia; Kaufman, Elizabeth S; Platonov, Pyotr G; Qi, Ming; Shimizu, Wataru; Towbin, Jeffrey A; Michael Vincent, G; Wilde, Arthur A M; Zhang, Li; Goldenberg, Ilan

2013-05-01

Individual corrected QT interval (QTc) may vary widely among carriers of the same long QT syndrome (LQTS) mutation. Currently, neither the mechanism nor the implications of this variable penetrance are well understood. To hypothesize that the assessment of QTc variance in patients with congenital LQTS who carry the same mutation provides incremental prognostic information on the patient-specific QTc. The study population comprised 1206 patients with LQTS with 95 different mutations and ≥ 5 individuals who carry the same mutation. Multivariate Cox proportional hazards regression analysis was used to assess the effect of mutation-specific standard deviation of QTc (QTcSD) on the risk of cardiac events (comprising syncope, aborted cardiac arrest, and sudden cardiac death) from birth through age 40 years in the total population and by genotype. Assessment of mutation-specific QTcSD showed large differences among carriers of the same mutations (median QTcSD 45 ms). Multivariate analysis showed that each 20 ms increment in QTcSD was associated with a significant 33% (P = .002) increase in the risk of cardiac events after adjustment for the patient-specific QTc duration and the family effect on QTc. The risk associated with QTcSD was pronounced among patients with long QT syndrome type 1 (hazard ratio 1.55 per 20 ms increment; P<.001), whereas among patients with long QT syndrome type 2, the risk associated with QTcSD was not statistically significant (hazard ratio 0.99; P = .95; P value for QTcSD-by-genotype interaction = .002). Our findings suggest that mutations with a wider variation in QTc duration are associated with increased risk of cardiac events. These findings appear to be genotype-specific, with a pronounced effect among patients with the long QT syndrome type 1 genotype. Copyright © 2013. Published by Elsevier Inc.

Novel NTRK1 mutations cause hereditary sensory and autonomic neuropathy type IV: demonstration of a founder mutation in the Turkish population.

Science.gov (United States)

Tüysüz, Beyhan; Bayrakli, Fatih; DiLuna, Michael L; Bilguvar, Kaya; Bayri, Yasar; Yalcinkaya, Cengiz; Bursali, Aysegul; Ozdamar, Elif; Korkmaz, Baris; Mason, Christopher E; Ozturk, Ali K; Lifton, Richard P; State, Matthew W; Gunel, Murat

2008-05-01

Hereditary sensory and autonomic neuropathy type IV (HSAN IV), or congenital insensitivity to pain with anhidrosis, is an autosomal recessive disorder characterized by insensitivity to noxious stimuli, anhidrosis from deinnervated sweat glands, and delayed mental and motor development. Mutations in the neurotrophic tyrosine kinase receptor type 1 (NTRK1), a receptor in the neurotrophin signaling pathway phosphorylated in response to nerve growth factor, are associated with this disorder. We identified six families from Northern Central Turkey with HSAN IV. We screened the NTRK1 gene for mutations in these families. Microsatellite and single nucleotide polymorphism (SNP) markers on the Affymetrix 250K chip platform were used to determine the haplotypes for three families harboring the same mutation. Screening for mutations in the NTRK1 gene demonstrated one novel frameshift mutation, two novel nonsense mutations, and three unrelated kindreds with the same splice-site mutation. Genotyping of the three families with the identical splice-site mutation revealed that they share the same haplotype. This report broadens the spectrum of mutations in NTRK1 that cause HSAN IV and demonstrates a founder mutation in the Turkish population.

Mutational specificity of γ-rays

International Nuclear Information System (INIS)

Hoebee, Barbara.

1990-01-01

The aim of the study described in this thesis was to get more information on the mutagenic properties of radiation-induced DNA modifications and the possible mechanisms involved in radiation-induced mutagenesis, principally by investigating the kinds of mutations by DNA sequence analysis. The mutations were analyzed after γ-irradiation of recombinant bacteriophage M13 and plasmide pUC DNA in diluted aqueous solutions, followed by transfection or transformation to E. coli cells, in which the damaged DNA molecules are repaired and replicated. Error-prone repair, misrepair or bypass of lesions during replication may lead to the introduction of mutations. Both the M13 and the plasmid DNA used in our mutation studies contain a mutation target sequence, which makes an easy selection and sequence analysis of mutant DNA molecules possible. Under the radiation conditions used, e.g. irradiation of diluted aqueous DNA solutions, only DNA damage occurs introduced by the water derived OH* and H* radicals and the hydrated electrons. By using different gas conditions during irradiation the relative yields of these reaction species can be manipulated, which opens up the opportunity to determine their effects separately. The mutation spectrum obtained in double-stranded (ds) M13DNA after irradiation under oxic conditions and the mutation spectrum obtained under the same conditions and in the same mutation target but cloned in plasmid DNA, are described. The mutation specificity under anoxic conditions in ds M13DNA is given. Results obtained after irradiation of ds M13DNA under N 2 conditions are discussed together with experiments with single-stranded DNA. Similarities and differences between radiation-induced mutation spectra obtained by other groups and those presented in this thesis are discussed. (author). 155 refs.; 134 figs.; 16 tabs

A review of the number and severity of injuries sustained following a single motocross event.

Science.gov (United States)

Dick, Charles G; White, Simon; Bopf, Daniel

2014-03-01

Competitive and recreational motocross is an increasingly popular sport in Australia and worldwide. Children as young as 4-year-old can participate in this activity. It is recognised that this is a high risk sport despite the use of protective equipment and developments in course design. Injuries sustained range from minor contusions and fractures to severe life threatening spine and head injuries in adults and the paediatric population. In addition organised events can generate a surge of trauma that can burden small local hospitals, resulting in an unpredicted increase in the workload with subsequent delays to treatment. We present the trauma workload generated in a district hospital following a single motocross event. All patients attending a district hospital emergency department with injuries sustained during a single motocross event were identified through hospital and ambulance records. The nature of their injuries and the treatment required, the length of hospital stay and operative theatre time generated by their injuries were obtained from hospital and theatre records. 14 patients attended the emergency department over a 24-hour period, requiring 5 ambulances from the scene. 7 patients required hospital admission with 7 operations performed, consuming 12.2 h of operating theatre time and 21 days of hospital beds. 2 patients sustained head injuries requiring observation, one of which was transferred to a spinal unit for management of their spinal injuries. Motocross is a popular sport and at times has unacceptable risks of injury in organised competitions, especially with regards to paediatric injuries. Better course design, restrictions on participant age and limitations in vehicle speeds may help reduce the number of severe injuries. These events can also generate a sudden trauma burden to local hospital facilities with knock on effects on waiting times for theatre and potentially compromising not only treatment of the injured participants but also

The rad2 mutation affects the molecular nature of UV and acridine-mustard-induced mutations in the ADE2 gene of Saccharomyces cerevisiae

International Nuclear Information System (INIS)

Ivanov, E.L.; Kovaltzova, S.V.; Kassinova, G.V.; Gracheva, L.M.; Korolev, V.G.; Zakharov, I.A.

1986-01-01

The authors have studied the molecular nature of ade2 mutations induced by UV light and bifunctional acridine-mustard (BAM) in wild-type (RAD) and in excision-deficient (rad2) strains of the yeast, Saccharomyces cerevisiae. In the RAD strain, UV causes 45% GC → AT transitions among all mutations; in the rad2 strain this value is 77%. BAM was shown to be highly specific for frameshift mutagenesis: 60% frameshifts in the RAD strain, and as many as 84% frameshifts in the rad2 strain were induced. Therefore, the rad2 mutation affects the specificity of UV- and BAM-induced mutagenesis in yeast. Experimental data agree with the view that the majority of mutations in the RAD strain are induced by a prereplicative mechanism, whereas mutations in the rad2 strain are predominantly postreplicative events. (Auth.)

Age-related cancer mutations associated with clonal hematopoietic expansion

Science.gov (United States)

Xie, Mingchao; Lu, Charles; Wang, Jiayin; McLellan, Michael D.; Johnson, Kimberly J.; Wendl, Michael C.; McMichael, Joshua F.; Schmidt, Heather K.; Yellapantula, Venkata; Miller, Christopher A.; Ozenberger, Bradley A.; Welch, John S.; Link, Daniel C.; Walter, Matthew J.; Mardis, Elaine R.; Dipersio, John F.; Chen, Feng; Wilson, Richard K.; Ley, Timothy J.; Ding, Li

2015-01-01

Several genetic alterations characteristic of leukemia and lymphoma have been detected in the blood of individuals without apparent hematological malignancies. We analyzed blood-derived sequence data from 2,728 individuals within The Cancer Genome Atlas, and discovered 77 blood-specific mutations in cancer-associated genes, the majority being associated with advanced age. Remarkably, 83% of these mutations were from 19 leukemia/lymphoma-associated genes, and nine were recurrently mutated (DNMT3A, TET2, JAK2, ASXL1, TP53, GNAS, PPM1D, BCORL1 and SF3B1). We identified 14 additional mutations in a very small fraction of blood cells, possibly representing the earliest stages of clonal expansion in hematopoietic stem cells. Comparison of these findings to mutations in hematological malignancies identified several recurrently mutated genes that may be disease initiators. Our analyses show that the blood cells of more than 2% of individuals (5–6% of people older than 70 years) contain mutations that may represent premalignant, initiating events that cause clonal hematopoietic expansion. PMID:25326804

Identification of seven novel mutations including the first two genomic rearrangements in SLC26A3 mutated in congenital chloride diarrhea.

Science.gov (United States)

Höglund, P; Sormaala, M; Haila, S; Socha, J; Rajaram, U; Scheurlen, W; Sinaasappel, M; de Jonge, H; Holmberg, C; Yoshikawa, H; Kere, J

2001-09-01

Congenital chloride diarrhea (CLD) is an autosomal recessive disorder characterized by defective intestinal electrolyte absorption, resulting in voluminous osmotic diarrhea with high chloride content. A variety of mutations in the solute carrier family 26, member 3 gene (SLC26A3, previously known as CLD or DRA) are responsible for the disease. Since the identification of the SLC26A3 gene and the determination of its genomic structure, altogether three founder and 17 private mutations have been characterized within miscellaneous ethnic groups. We screened for mutations in seven unrelated families with CLD. The diagnoses were confirmed by fecal chloride measurements. The combined PCR-SSCP and sequencing analyses revealed altogether seven novel mutations including two missense mutations (S206P, D468V), two splicing defects (IVS12-1G>C, IVS13-2delA), one nonsense mutation (Q436X), one insertion/deletion mutation (2104-2105delGGins29-bp), and an intragenic deletion of SLC26A3 exons 7 and 8. Two previously identified mutations were also found. This is the first report of rearrangement mutations in SLC26A3. Molecular features predisposing SLC26A3 for the two rearrangements may include repetitive elements and palindromic-like sequences. The increasingly wide diversity of SLC26A3 mutations suggests that mutations in the SLC26A3 gene may not be rare events. Copyright 2001 Wiley-Liss, Inc.

A meta-analysis of the relationship between FGFR3 and TP53 mutations in bladder cancer.

Science.gov (United States)

Neuzillet, Yann; Paoletti, Xavier; Ouerhani, Slah; Mongiat-Artus, Pierre; Soliman, Hany; de The, Hugues; Sibony, Mathilde; Denoux, Yves; Molinie, Vincent; Herault, Aurélie; Lepage, May-Linda; Maille, Pascale; Renou, Audrey; Vordos, Dimitri; Abbou, Claude-Clément; Bakkar, Ashraf; Asselain, Bernard; Kourda, Nadia; El Gaaied, Amel; Leroy, Karen; Laplanche, Agnès; Benhamou, Simone; Lebret, Thierry; Allory, Yves; Radvanyi, François

2012-01-01

TP53 and FGFR3 mutations are the most common mutations in bladder cancers. FGFR3 mutations are most frequent in low-grade low-stage tumours, whereas TP53 mutations are most frequent in high-grade high-stage tumours. Several studies have reported FGFR3 and TP53 mutations to be mutually exclusive events, whereas others have reported them to be independent. We carried out a meta-analysis of published findings for FGFR3 and TP53 mutations in bladder cancer (535 tumours, 6 publications) and additional unpublished data for 382 tumours. TP53 and FGFR3 mutations were not independent events for all tumours considered together (OR = 0.25 [0.18-0.37], p = 0.0001) or for pT1 tumours alone (OR = 0.47 [0.28-0.79], p = 0.0009). However, if the analysis was restricted to pTa tumours or to muscle-invasive tumours alone, FGFR3 and TP53 mutations were independent events (OR = 0.56 [0.23-1.36] (p = 0.12) and OR = 0.99 [0.37-2.7] (p = 0.35), respectively). After stratification of the tumours by stage and grade, no dependence was detected in the five tumour groups considered (pTaG1 and pTaG2 together, pTaG3, pT1G2, pT1G3, pT2-4). These differences in findings can be attributed to the putative existence of two different pathways of tumour progression in bladder cancer: the CIS pathway, in which FGFR3 mutations are rare, and the Ta pathway, in which FGFR3 mutations are frequent. TP53 mutations occur at the earliest stage of the CIS pathway, whereas they occur would much later in the Ta pathway, at the T1G3 or muscle-invasive stage.

Top quark polarization in t-channel single top-quark events with the ATLAS detector

CERN Document Server

Chitishvili, Mariam

2017-01-01

This summary presents the measurement of the top‐quark polarization in t-channel single top quarks with the ATLAS detector at the LHC. Monte Carlo simulated events are used. Selected events contain one lepton, large missing transverse momentum and exactly two jets, with one of them identified as b-jet. Selection cuts are used to identify the t-channel topology at reconstruction level. The polarization is measured, from an asymmetry in an angular distribution, at parton level by correcting the reconstructed angular distribution for detector effects. This project provides an overview on how a "standard" physics analysis is performed within ATLAS. The analysis is performed in ROOT. Simulation data is reconstructed to perform an unfolded measurement of a given property of a fundamental particle within the Standard Model. Finally results are compared with theoretical predictions.

Advantages of a single-cycle production assay to study cell culture-adaptive mutations of hepatitis C virus

DEFF Research Database (Denmark)

Russell, Rodney S; Meunier, Jean-Christophe; Takikawa, Shingo

2008-01-01

mutations that were selected during serial passage in Huh-7.5 cells were studied. Recombinant genomes containing all five mutations produced 3-4 logs more infectious virions than did wild type. Neither a coding mutation in NS5A nor a silent mutation in E2 was adaptive, whereas coding mutations in E2, p7......The JFH1 strain of hepatitis C virus (HCV) is unique among HCV isolates, in that the wild-type virus can traverse the entire replication cycle in cultured cells. However, without adaptive mutations, only low levels of infectious virus are produced. In the present study, the effects of five...

Properties of Coronal Shocks at the Origin of SEP events Observed by Only One Single Spacecraft

Science.gov (United States)

Lario, D.; Kwon, R.

2017-12-01

The simultaneous observation of solar energetic particle (SEP) events by multiple spacecraft distributed in the interplanetary medium depends not only on the spatial separation among the different spacecraft, but also on the properties of the particle sources and the characteristics of the SEP transport in interplanetary space. Among the SEP events observed by STEREO-A, STEREO-B and/or near-Earth spacecraft during solar cycle 24, we select SEP events observed by a single spacecraft (specifically, the SEP events observed only by near-Earth spacecraft on 2012 April 5, 2011 September 4, and 2013 August 17). We analyze whether the properties of the coronal shock associated with the origin of the events (as seen in extreme-ultraviolet and white-light coronal images) differ from those associated with SEP events observed by two or three spacecraft. For the selected events we find that the associated CMEs are, in general, narrower than those associated with SEP events observed by two or three spacecraft. The confined extension of the parent coronal shock and the absence of magnetic connection between distant spacecraft and the regions of the expanding coronal shock able to efficiently accelerate SEPs seem to be the conditions leading to intense SEP events observed only over narrow regions of interplanetary space by spacecraft magnetically connected to regions close to the parent eruption site. Weak and gradual intensity increases observed in extended regions of space might involve transport processes and/or later connections established with interplanetary shocks. Systematic analyses of a larger number of events are required before drawing firm conclusions.

Mechanisms of mutations in myeloproliferative neoplasms.

Science.gov (United States)

Levine, Ross L

2009-12-01

In recent years, a series of studies have provided genetic insight into the pathogenesis of myeloproliferative neoplasms (MPNs). It is now known that JAK2V617F mutations are present in 90% of patients with polycythaemia vera (PV), 60% of patients with essential thrombocytosis (ET) and 50% of patients with myelofibrosis (MF). Despite the high prevalence of JAK2V617F mutations in these three myeloid malignancies, several questions remain. For example, how does one mutation contribute to the pathogenesis of three clinically distinct diseases, and how do some patients develop these diseases in the absence of a JAK2V617F mutation? Single nucleotide polymorphisms at various loci and somatic mutations, such as those in MPLW515L/K, TET2 and in exon 12 of JAK2, may also contribute to the pathogenesis of these MPNs. There are likely additional germline and somatic genetic factors important to the MPN phenotype. Additional studies of large MPN and control cohorts with new techniques will help identify these factors.

Observation of Single Isolated Electrons of High Transverse Momentum in Events with Missing Transverse Energy at the CERN pp Collider

DEFF Research Database (Denmark)

Banner, M.; Kofoed-Hansen, O.

1983-01-01

We report the results of a search for single isolated electrons of high transverse momentum at the CERN collider. Above 15 GeV/c, four events are found having large missing transverse energy along a direction opposite in azimuth to that of the high-pT electron. Both the configuration of the events...

Automated Detection of Obstructive Sleep Apnea Events from a Single-Lead Electrocardiogram Using a Convolutional Neural Network.

Science.gov (United States)

Urtnasan, Erdenebayar; Park, Jong-Uk; Joo, Eun-Yeon; Lee, Kyoung-Joung

2018-04-23

In this study, we propose a method for the automated detection of obstructive sleep apnea (OSA) from a single-lead electrocardiogram (ECG) using a convolutional neural network (CNN). A CNN model was designed with six optimized convolution layers including activation, pooling, and dropout layers. One-dimensional (1D) convolution, rectified linear units (ReLU), and max pooling were applied to the convolution, activation, and pooling layers, respectively. For training and evaluation of the CNN model, a single-lead ECG dataset was collected from 82 subjects with OSA and was divided into training (including data from 63 patients with 34,281 events) and testing (including data from 19 patients with 8571 events) datasets. Using this CNN model, a precision of 0.99%, a recall of 0.99%, and an F 1 -score of 0.99% were attained with the training dataset; these values were all 0.96% when the CNN was applied to the testing dataset. These results show that the proposed CNN model can be used to detect OSA accurately on the basis of a single-lead ECG. Ultimately, this CNN model may be used as a screening tool for those suspected to suffer from OSA.

Quantifying the risk of pandemic influenza virus evolution by mutation and re-assortment.

Science.gov (United States)

Reperant, Leslie A; Grenfell, Bryan T; Osterhaus, Albert D M E

2015-12-08

Large outbreaks of zoonotic influenza A virus (IAV) infections may presage an influenza pandemic. However, the likelihood that an airborne-transmissible variant evolves upon zoonotic infection or co-infection with zoonotic and seasonal IAVs remains poorly understood, as does the relative importance of accumulating mutations versus re-assortment in this process. Using discrete-time probabilistic models, we determined quantitative probability ranges that transmissible variants with 1-5 mutations and transmissible re-assortants evolve after a given number of zoonotic IAV infections. The systematic exploration of a large population of model parameter values was designed to account for uncertainty and variability in influenza virus infection, epidemiological and evolutionary processes. The models suggested that immunocompromised individuals are at high risk of generating IAV variants with pandemic potential by accumulation of mutations. Yet, both immunocompetent and immunocompromised individuals could generate high viral loads of single and double mutants, which may facilitate their onward transmission and the subsequent accumulation of additional 1-2 mutations in newly-infected individuals. This may result in the evolution of a full transmissible genotype along short chains of contact transmission. Although co-infection with zoonotic and seasonal IAVs was shown to be a rare event, it consistently resulted in high viral loads of re-assortants, which may facilitate their onward transmission among humans. The prevention or limitation of zoonotic IAV infection in immunocompromised and contact individuals, including health care workers, as well as vaccination against seasonal IAVs-limiting the risk of co-infection-should be considered fundamental tools to thwart the evolution of a novel pandemic IAV by accumulation of mutations and re-assortment. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

A single mutation in Taiwanese H6N1 influenza hemagglutinin switches binding to human-type receptors

Energy Technology Data Exchange (ETDEWEB)

de Vries, Robert P.; Tzarum, Netanel; Peng, Wenjie; Thompson, Andrew J.; Ambepitiya Wickramasinghe, Iresha N.; de la Pena, Alba T. Torrents; van Breemen, Marielle J.; Bouwman, Kim M.; Zhu, Xueyong; McBride, Ryan; Yu, Wenli; Sanders, Rogier W.; Verheije, Monique H.; Wilson, Ian A.; Paulson, James C.

2017-07-10

In June 2013, the first case of human infection with an avian H6N1 virus was reported in a Taiwanese woman. Although this was a single non-fatal case, the virus continues to circulate in Taiwanese poultry. As with any emerging avian virus that infects humans, there is concern that acquisition of human-type receptor specificity could enable transmission in the human population. Despite mutations in the receptor-binding pocket of the human H6N1 isolate, it has retained avian-type (NeuAcα2-3Gal) receptor specificity. However, we show here that a single nucleotide substitution, resulting in a change from Gly to Asp at position 225 (G225D), completely switches specificity to human-type (NeuAcα2-6Gal) receptors. Significantly, G225D H6 loses binding to chicken trachea epithelium and is now able to bind to human tracheal tissue. Structural analysis reveals that Asp225 directly interacts with the penultimate Gal of the human-type receptor, stabilizing human receptor binding.

Delineation of Ehlers-Danlos syndrome phenotype due to the c.934C>T, p.(Arg312Cys) mutation in COL1A1: Report on a three-generation family without cardiovascular events, and literature review.

Science.gov (United States)

Colombi, Marina; Dordoni, Chiara; Venturini, Marina; Zanca, Arianna; Calzavara-Pinton, Piergiacomo; Ritelli, Marco

2017-02-01

Classical Ehlers-Danlos syndrome (cEDS) is a rare connective tissue disorder primarily characterized by hyperextensible skin, defective wound healing, abnormal scars, easy bruising, and generalized joint hypermobility; arterial dissections are rarely observed. Mutations in COL5A1 and COL5A2 encoding type V collagen account for more than 90% of the patients so far characterized. In addition, cEDS phenotype was reported in a small number of patients carrying the c.934C>T mutation in COL1A1 that results in an uncommon substitution of a non-glycine residue in one Gly-Xaa-Yaa repeat of the pro-α1(I)-chain p.(Arg312Cys), which leads to disturbed collagen fibrillogenesis due to delayed removal of the type I procollagen N-propeptide. This specific mutation has been associated with propensity to arterial rupture in early adulthood; indeed, in literature the individuals harboring this mutation are also referred to as "(classic) vascular-like" EDS patients. Herein, we describe a three-generation cEDS family with six adults carrying the p.(Arg312Cys) substitution, which show a variable and prevalent cutaneous involvement without any major vascular event. These data, together with those available in literature, suggest that vascular events are not a diagnostic handle to differentiate patients with the p.(Arg312Cys) COL1A1 mutation from those with COL5A1 and COL5A2 defects, and highlight that during the diagnostic process the presence of at least the p.(Arg312Cys) substitution in COL1A1 should be investigated in cEDS patients without type V collagen mutations. Nevertheless, for these patients, as well as for those affected with cEDS, a periodical vascular surveillance should be carried out together with cardiovascular risk factors monitoring. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Mutations of the KRAS oncogene in endometrial hyperplasia and carcinoma.

Directory of Open Access Journals (Sweden)

Wiesława Niklińska

2009-05-01

Full Text Available The aim of this study was to examine the prevalence and clinicopathological significance of KRAS point mutation in endometrial hyperplasia and carcinoma. We analysed KRAS in 11 cases of complex atypical hyperplasia and in 49 endometrial carcinomas using polymerase chain reaction associated with restriction fragment length polymorphism (PCR-RFPL. Point mutations at codon 12 of KRAS oncogene were identified in 7 of 49 (14,3% tumor specimens and in 2 of 11 (18,2% hyperplasias. No correlation was found between KRAS gene mutation and age at onset, histology, grade of differentiation and clinical stage. We conclude that KRAS mutation is a relatively common event in endometrial carcinogenesis, but with no prognostic value.

Single-Point Mutation with a Rotamer Library Toolkit: Toward Protein Engineering.

Science.gov (United States)

Pottel, Joshua; Moitessier, Nicolas

2015-12-28

Protein engineers have long been hard at work to harness biocatalysts as a natural source of regio-, stereo-, and chemoselectivity in order to carry out chemistry (reactions and/or substrates) not previously achieved with these enzymes. The extreme labor demands and exponential number of mutation combinations have induced computational advances in this domain. The first step in our virtual approach is to predict the correct conformations upon mutation of residues (i.e., rebuilding side chains). For this purpose, we opted for a combination of molecular mechanics and statistical data. In this work, we have developed automated computational tools to extract protein structural information and created conformational libraries for each amino acid dependent on a variable number of parameters (e.g., resolution, flexibility, secondary structure). We have also developed the necessary tool to apply the mutation and optimize the conformation accordingly. For side-chain conformation prediction, we obtained overall average root-mean-square deviations (RMSDs) of 0.91 and 1.01 Å for the 18 flexible natural amino acids within two distinct sets of over 3000 and 1500 side-chain residues, respectively. The commonly used dihedral angle differences were also evaluated and performed worse than the state of the art. These two metrics are also compared. Furthermore, we generated a family-specific library for kinases that produced an average 2% lower RMSD upon side-chain reconstruction and a residue-specific library that yielded a 17% improvement. Ultimately, since our protein engineering outlook involves using our docking software, Fitted/Impacts, we applied our mutation protocol to a benchmarked data set for self- and cross-docking. Our side-chain reconstruction does not hinder our docking software, demonstrating differences in pose prediction accuracy of approximately 2% (RMSD cutoff metric) for a set of over 200 protein/ligand structures. Similarly, when docking to a set of over 100

Epidermal growth factor receptor mutation in gastric cancer.

Science.gov (United States)

Liu, Zhimin; Liu, Lina; Li, Mei; Wang, Zhaohui; Feng, Lu; Zhang, Qiuping; Cheng, Shihua; Lu, Shen

2011-04-01

Epidermal growth factor receptor (EGFR) and Kirsten-RAS (KRAS) mutations have been identified as predictors of response to EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer. We aimed to screen the mutations of both genes in gastric carcinoma to detect the suitability of EGFR TKIs for patients with gastric carcinoma. We screened EGFR mutation in exons 19-21 and KRAS mutation in exon 2 in 58 gastric adenocarcinomas from China using high resolution melting analysis (HRMA). Positive samples were confirmed by DNA sequencing. Three EGFR missense mutations (5.2%) and 22 single nucleotide polymorphisms (SNP, Q787Q, 37.9%) were identified. To our knowledge, we report for the first time three mutation patterns of EGFR, Y801C, L858R and G863D, in gastric carcinoma. Two samples with EGFR mutation were mucinous adenocarcinoma. These three samples were collected from male patients aged over 75 years old. The frequency of KRAS mutation was 10.3% (6/58). The exclusiveness of EGFR and KRAS mutations was proven for the first time in gastric cancer. Gastric carcinoma of the mucinous adenocarcinoma type collected from older male patients may harbour EGFR mutations. The small subset of gastric adenocarcinoma patients may respond to EGFR TKIs.

Versatile single-chip event sequencer for atomic physics experiments

Science.gov (United States)

Eyler, Edward

2010-03-01

A very inexpensive dsPIC microcontroller with internal 32-bit counters is used to produce a flexible timing signal generator with up to 16 TTL-compatible digital outputs, with a time resolution and accuracy of 50 ns. This time resolution is easily sufficient for event sequencing in typical experiments involving cold atoms or laser spectroscopy. This single-chip device is capable of triggered operation and can also function as a sweeping delay generator. With one additional chip it can also concurrently produce accurately timed analog ramps, and another one-chip addition allows real-time control from an external computer. Compared to an FPGA-based digital pattern generator, this design is slower but simpler and more flexible, and it can be reprogrammed using ordinary `C' code without special knowledge. I will also describe the use of the same microcontroller with additional hardware to implement a digital lock-in amplifier and PID controller for laser locking, including a simple graphics-based control unit. This work is supported in part by the NSF.

Calculation of neutron-induced single-event upset cross sections for semiconductor memory devices

International Nuclear Information System (INIS)

Ikeuchi, Taketo; Watanabe, Yukinobu; Nakashima, Hideki; Sun, Weili

2001-01-01

Neutron-induced single-event upset (SEU) cross sections for semiconductor memory devices are calculated by the Burst Generation Rate (BGR) method using LA150 data and QMD calculation in the neutron energy range between 20 MeV and 10 GeV. The calculated results are compared with the measured SEU cross sections for energies up to 160 MeV, and the validity of the calculation method and the nuclear data used is verified. The kind of reaction products and the neutron energy range that have the most effect on SEU are discussed. (author)

Effect of the achondroplasia mutation on FGFR3 dimerization and FGFR3 structural response to fgf1 and fgf2: A quantitative FRET study in osmotically derived plasma membrane vesicles.

Science.gov (United States)

Sarabipour, Sarvenaz; Hristova, Kalina

2016-07-01

The G380R mutation in the transmembrane domain of FGFR3 is a germline mutation responsible for most cases of Achondroplasia, a common form of human dwarfism. Here we use quantitative Fӧster Resonance Energy Transfer (FRET) and osmotically derived plasma membrane vesicles to study the effect of the achondroplasia mutation on the early stages of FGFR3 signaling in response to the ligands fgf1 and fgf2. Using a methodology that allows us to capture structural changes on the cytoplasmic side of the membrane in response to ligand binding to the extracellular domain of FGFR3, we observe no measurable effects of the G380R mutation on FGFR3 ligand-bound dimer configurations. Instead, the most notable effect of the achondroplasia mutation is increased propensity for FGFR3 dimerization in the absence of ligand. This work reveals new information about the molecular events that underlie the achondroplasia phenotype, and highlights differences in FGFR3 activation due to different single amino-acid pathogenic mutations. Copyright © 2016 Elsevier B.V. All rights reserved.

Diploid yeast cells yield homozygous spontaneous mutations

Science.gov (United States)

Esposito, M. S.; Bruschi, C. V.; Brushi, C. V. (Principal Investigator)

1993-01-01

A leucine-requiring hybrid of Saccharomyces cerevisiae, homoallelic at the LEU1 locus (leu1-12/leu1-12) and heterozygous for three chromosome-VII genetic markers distal to the LEU1 locus, was employed to inquire: (1) whether spontaneous gene mutation and mitotic segregation of heterozygous markers occur in positive nonrandom association and (2) whether homozygous LEU1/LEU1 mutant diploids are generated. The results demonstrate that gene mutation of leu1-12 to LEU1 and mitotic segregation of heterozygous chromosome-VII markers occur in strong positive nonrandom association, suggesting that the stimulatory DNA lesion is both mutagenic and recombinogenic. In addition, genetic analysis of diploid Leu+ revertants revealed that approximately 3% of mutations of leu1-12 to LEU1 result in LEU1/LEU1 homozygotes. Red-white sectored Leu+ colonies exhibit genotypes that implicate post-replicational chromatid breakage and exchange near the site of leu1-12 reversion, chromosome loss, and subsequent restitution of diploidy, in the sequence of events leading to mutational homozygosis. By analogy, diploid cell populations can yield variants homozygous for novel recessive gene mutations at biologically significant rates. Mutational homozygosis may be relevant to both carcinogenesis and the evolution of asexual diploid organisms.

Search for anomalous Wtb couplings and top FCNC in t-channel single-top-quark events in the CMS experiment

CERN Document Server

Tsirova, Natalia

2015-01-01

Single-top-quark events in the t-channel are used to probe Wtb anomalous couplings and to search for top-quark Flavor-Changing Neutral Current (FCNC) interactions in proton-proton collisions with the CMS experiment. A Bayesian neural network is used to discriminate between signal and backgrounds. The observed event yields are consistent with SM prediction, and exclusion limits at 95\\% C.L. are determined.

Phase I, Dose-Escalation, Two-Part Trial of the PARP Inhibitor Talazoparib in Patients with Advanced Germline BRCA1/2 Mutations and Selected Sporadic Cancers.

Science.gov (United States)

de Bono, Johann; Ramanathan, Ramesh K; Mina, Lida; Chugh, Rashmi; Glaspy, John; Rafii, Saeed; Kaye, Stan; Sachdev, Jasgit; Heymach, John; Smith, David C; Henshaw, Joshua W; Herriott, Ashleigh; Patterson, Miranda; Curtin, Nicola J; Byers, Lauren Averett; Wainberg, Zev A

2017-06-01

Talazoparib inhibits PARP catalytic activity, trapping PARP1 on damaged DNA and causing cell death in BRCA1/2 -mutated cells. We evaluated talazoparib therapy in this two-part, phase I, first-in-human trial. Antitumor activity, MTD, pharmacokinetics, and pharmacodynamics of once-daily talazoparib were determined in an open-label, multicenter, dose-escalation study (NCT01286987). The MTD was 1.0 mg/day, with an elimination half-life of 50 hours. Treatment-related adverse events included fatigue (26/71 patients; 37%) and anemia (25/71 patients; 35%). Grade 3 to 4 adverse events included anemia (17/71 patients; 24%) and thrombocytopenia (13/71 patients; 18%). Sustained PARP inhibition was observed at doses ≥0.60 mg/day. At 1.0 mg/day, confirmed responses were observed in 7 of 14 (50%) and 5 of 12 (42%) patients with BRCA mutation-associated breast and ovarian cancers, respectively, and in patients with pancreatic and small cell lung cancer. Talazoparib demonstrated single-agent antitumor activity and was well tolerated in patients at the recommended dose of 1.0 mg/day. Significance: In this clinical trial, we show that talazoparib has single-agent antitumor activity and a tolerable safety profile. At its recommended phase II dose of 1.0 mg/day, confirmed responses were observed in patients with BRCA mutation-associated breast and ovarian cancers and in patients with pancreatic and small cell lung cancer. Cancer Discov; 7(6); 620-9. ©2017 AACR. This article is highlighted in the In This Issue feature, p. 539 . ©2017 American Association for Cancer Research.

Update of the androgen receptor gene mutations database.

Science.gov (United States)

Gottlieb, B; Beitel, L K; Lumbroso, R; Pinsky, L; Trifiro, M

1999-01-01

The current version of the androgen receptor (AR) gene mutations database is described. The total number of reported mutations has risen from 309 to 374 during the past year. We have expanded the database by adding information on AR-interacting proteins; and we have improved the database by identifying those mutation entries that have been updated. Mutations of unknown significance have now been reported in both the 5' and 3' untranslated regions of the AR gene, and in individuals who are somatic mosaics constitutionally. In addition, single nucleotide polymorphisms, including silent mutations, have been discovered in normal individuals and in individuals with male infertility. A mutation hotspot associated with prostatic cancer has been identified in exon 5. The database is available on the internet (http://www.mcgill.ca/androgendb/), from EMBL-European Bioinformatics Institute (ftp.ebi.ac.uk/pub/databases/androgen), or as a Macintosh FilemakerPro or Word file (MC33@musica.mcgill.ca). Copyright 1999 Wiley-Liss, Inc.

Formalin fixation increases deamination mutation signature but should not lead to false positive mutations in clinical practice.

Directory of Open Access Journals (Sweden)

Leah M Prentice

Full Text Available Genomic analysis of cancer tissues is an essential aspect of personalized oncology treatment. Though it has been suggested that formalin fixation of patient tissues may be suboptimal for molecular studies, this tissue processing approach remains the industry standard. Therefore clinical molecular laboratories must be able to work with formalin fixed, paraffin embedded (FFPE material. This study examines the effects of pre-analytic variables introduced by routine pathology processing on specimens used for clinical reports produced by next-generation sequencing technology. Tissue resected from three colorectal cancer patients was subjected to 2, 15, 24, and 48 hour fixation times in neutral buffered formalin. DNA was extracted from all tissues twice, once with uracil-N-glycosylase (UNG treatment to counter deamination effects, and once without. Of note, deamination events at methylated cytosine, as found at CpG sites, remains unaffected by UNG. After extraction a two-step PCR targeted sequencing method was performed using the Illumina MiSeq and the data was analyzed via a custom-built bioinformatics pipeline, including filtration of reads with mapping quality T/A mutations that is not represented in DNA treated with UNG. This suggests these errors may be due to deamination events triggered by a longer fixation time. However the allelic frequency of these events remained below the limit of detection for reportable mutations in this assay (<2%. We do however recommend that suspected intratumoral heterogeneity events be verified by re-sequencing the same FFPE block.

Base substitution spectra of nalidixylate resistant mutations induced by monochromatic soft X and 60Co γ-rays in bacillus subtilis spores

International Nuclear Information System (INIS)

Takahashi, Nobuhiro; Hieda, Kotaro; Morohoshi, Fumiko; Munakata, Nobuo

1999-01-01

Bacillus subtilis spores were exposed to three types of photons, monochromatic soft X-rays with the energy corresponding to the absorption peak of phosphorus K-shell electron (2,153 eV) and with the slightly lower energy (2,147 eV), and 60 Co γ-rays. From the irradiated spores, 233 mutants exhibiting nalidixic acid resistance were isolated, and together with 94 spontaneous mutants, the sequence changes in the 5'-terminal region of the gyrA gene coding for DNA gyrase subunit A were determined. Among eighteen alleles of the gyrA mutations, eight were single-base substitutions, nine were tandem double-base substitutions, and one was a double substitution skipping a middle base pair. About 6% of the radiation-induced mutations were tandem double-base substitutions, whereas none was observed among the spontaneous ones. Among spontaneous mutations, A:T and G:C pairs were equally subjected to mutations, whereas the substitutions from G:C pairs and those to A:T pairs predominated among those induced with soft X-rays. The peak-energy X-rays were more effective in killing and causing mutations than the low-energy X-rays, however, there seemed no base-change events uniquely attributable to phosphorus K-shell absorption. (author)

Mitochondrial Mutation Rate, Spectrum and Heteroplasmy in Caenorhabditis elegans Spontaneous Mutation Accumulation Lines of Differing Population Size.

Science.gov (United States)

Konrad, Anke; Thompson, Owen; Waterston, Robert H; Moerman, Donald G; Keightley, Peter D; Bergthorsson, Ulfar; Katju, Vaishali

2017-06-01

Mitochondrial genomes of metazoans, given their elevated rates of evolution, have served as pivotal markers for phylogeographic studies and recent phylogenetic events. In order to determine the dynamics of spontaneous mitochondrial mutations in small populations in the absence and presence of selection, we evolved mutation accumulation (MA) lines of Caenorhabditis elegans in parallel over 409 consecutive generations at three varying population sizes of N = 1, 10, and 100 hermaphrodites. The N =1 populations should have a minimal influence of natural selection to provide the spontaneous mutation rate and the expected rate of neutral evolution, whereas larger population sizes should experience increasing intensity of selection. New mutations were identified by Illumina paired-end sequencing of 86 mtDNA genomes across 35 experimental lines and compared with published genomes of natural isolates. The spontaneous mitochondrial mutation rate was estimated at 1.05 × 10-7/site/generation. A strong G/C→A/T mutational bias was observed in both the MA lines and the natural isolates. This suggests that the low G + C content at synonymous sites is the product of mutation bias rather than selection as previously proposed. The mitochondrial effective population size per worm generation was estimated to be 62. Although it was previously concluded that heteroplasmy was rare in C. elegans, the vast majority of mutations in this study were heteroplasmic despite an experimental regime exceeding 400 generations. The frequencies of frameshift and nonsynonymous mutations were negatively correlated with population size, which suggests their deleterious effects on fitness and a potent role for selection in their eradication. © The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Effect of vitamin E on cytotoxicity, DNA single strand breaks, chromosomal aberrations, and mutation in Chinese hamster V-79 cells exposed to ultraviolet-B light

International Nuclear Information System (INIS)

Sugiyama, M.; Tsuzuki, K.; Matsumoto, K.; Ogura, R.

1992-01-01

The effect of pretreatment with vitamin E on cytotoxicity, DNA single strand breaks, and chromosomal aberrations as well as on mutation induced by ultraviolet-B light (UV-B) was investigated in Chinese hamster V-79 cells. Cellular pretreatment with non-toxic levels of 25 μM α-tocopherol succinate (vitamin E) for 24h prior to exposure resulted in a 10-fold increase in cellular levels of α-tocopherol. Using a colony-forming assay, this pretreatment decreased the cytotoxicity of UV-B light. However, alkaline elution assays demonstrated that pretreatment with vitamin E did not affect the number of DNA single strand breaks caused by UV-B light. UV-B exposure produced a dose-dependent induction of chromosomal aberrations and mutations at the HGPRT locus, and neither of these actions of UV-B was influenced by pretreatment with the vitamin. These results suggest that vitamin E protects cells from UV-B-induced cytotoxicity, possibly through its ability to scavenge free radicals. The genotoxicity induced by UV-B light may not correlate directly with the cytotoxic action of this wavelength region in sunlight. (author)

Single event upsets calculated from new ENDF/B-VI proton and neutron data up to 150 MeV

International Nuclear Information System (INIS)

Chadwick, M.B.

1999-01-01

Single-event upsets (SEU) in microelectronics are calculated from newly-developed silicon nuclear reaction recoil data that extend up to 150 MeV, for incident protons and neutrons. Calculated SEU cross sections are compared with measured data

Single-cell analysis of pyroptosis dynamics reveals conserved GSDMD-mediated subcellular events that precede plasma membrane rupture.

Science.gov (United States)

de Vasconcelos, Nathalia M; Van Opdenbosch, Nina; Van Gorp, Hanne; Parthoens, Eef; Lamkanfi, Mohamed

2018-04-17

Pyroptosis is rapidly emerging as a mechanism of anti-microbial host defense, and of extracellular release of the inflammasome-dependent cytokines interleukin (IL)-1β and IL-18, which contributes to autoinflammatory pathology. Caspases 1, 4, 5 and 11 trigger this regulated form of necrosis by cleaving the pyroptosis effector gasdermin D (GSDMD), causing its pore-forming amino-terminal domain to oligomerize and perforate the plasma membrane. However, the subcellular events that precede pyroptotic cell lysis are ill defined. In this study, we triggered primary macrophages to undergo pyroptosis from three inflammasome types and recorded their dynamics and morphology using high-resolution live-cell spinning disk confocal laser microscopy. Based on quantitative analysis of single-cell subcellular events, we propose a model of pyroptotic cell disintegration that is initiated by opening of GSDMD-dependent ion channels or pores that are more restrictive than recently proposed GSDMD pores, followed by osmotic cell swelling, commitment of mitochondria and other membrane-bound organelles prior to sudden rupture of the plasma membrane and full permeability to intracellular proteins. This study provides a dynamic framework for understanding cellular changes that occur during pyroptosis, and charts a chronological sequence of GSDMD-mediated subcellular events that define pyroptotic cell death at the single-cell level.

Comparative research on “high currents” induced by single event latch-up and transient-induced latch-up

International Nuclear Information System (INIS)

Chen Rui; Han Jian-Wei; Zheng Han-Sheng; Yu Yong-Tao; Shangguang Shi-Peng; Feng Guo-Qiang; Ma Ying-Qi

2015-01-01

By using the pulsed laser single event effect facility and electro-static discharge (ESD) test system, the characteristics of the “high current”, relation with external stimulus and relevance to impacted modes of single event latch-up (SEL) and transient-induced latch-up (TLU) are studied, respectively, for a 12-bit complementary metal–oxide semiconductor (CMOS) analog-to-digital converter. Furthermore, the sameness and difference in physical mechanism between “high current” induced by SEL and that by TLU are disclosed in this paper. The results show that the minority carrier diffusion in the PNPN structure of the CMOS device which initiates the active parasitic NPN and PNP transistors is the common reason for the “high current” induced by SEL and for that by TLU. However, for SEL, the minority carrier diffusion is induced by the ionizing radiation, and an underdamped sinusoidal voltage on the supply node (the ground node) is the cause of the minority carrier diffusion for TLU. (paper)

Motor pathway excitability in ATP13A2 mutation carriers

DEFF Research Database (Denmark)

Zittel, S; Kroeger, J; van der Vegt, J P M

2012-01-01

OBJECTIVE: To describe excitability of motor pathways in Kufor-Rakeb syndrome (PARK9), an autosomal recessive nigro-striatal-pallidal-pyramidal neurodegeneration caused by a mutation in the ATP13A2 gene, using transcranial magnetic stimulation (TMS). METHODS: Five members of a Chilean family...... with an ATP13A2 mutation (one affected mutation carrier (MC) with a compound heterozygous mutation, 4 asymptomatic MC with a single heterozygous mutation) and 11 healthy subjects without mutations were studied. We measured motor evoked potentials (MEP), the contralateral silent period (cSP), short interval....... RESULTS: CSP duration was increased in the symptomatic ATP13A2 MC. The iSP measurements revealed increased interhemispheric inhibition in both the compound heterozygous and the heterozygous MC. CONCLUSION: A compound heterozygous mutation in the ATP13A2 gene is associated with increased intracortical...

Application of RADSAFE to Model Single Event Upset Response of a 0.25 micron CMOS SRAM

Science.gov (United States)

Warren, Kevin M.; Weller, Robert A.; Sierawski, Brian; Reed, Robert A.; Mendenhall, Marcus H.; Schrimpf, Ronald D.; Massengill, Lloyd; Porter, Mark; Wilkerson, Jeff; LaBel, Kenneth A.;

NASA Electronic Parts and Packaging (NEPP) Field Programmable Gate Array (FPGA) Single Event Effects (SEE) Test Guideline Update

Science.gov (United States)

Berg, Melanie D.; LaBel, Kenneth A.

2018-01-01

The following are updated or new subjects added to the FPGA SEE Test Guidelines manual: academic versus mission specific device evaluation, single event latch-up (SEL) test and analysis, SEE response visibility enhancement during radiation testing, mitigation evaluation (embedded and user-implemented), unreliable design and its affects to SEE Data, testing flushable architectures versus non-flushable architectures, intellectual property core (IP Core) test and evaluation (addresses embedded and user-inserted), heavy-ion energy and linear energy transfer (LET) selection, proton versus heavy-ion testing, fault injection, mean fluence to failure analysis, and mission specific system-level single event upset (SEU) response prediction. Most sections within the guidelines manual provide information regarding best practices for test structure and test system development. The scope of this manual addresses academic versus mission specific device evaluation and visibility enhancement in IP Core testing.

OBSCN Mutations Associated with Dilated Cardiomyopathy and Haploinsufficiency.

Directory of Open Access Journals (Sweden)

Steven Marston

Full Text Available Studies of the functional consequences of DCM-causing mutations have been limited to a few cases where patients with known mutations had heart transplants. To increase the number of potential tissue samples for direct investigation we performed whole exon sequencing of explanted heart muscle samples from 30 patients that had a diagnosis of familial dilated cardiomyopathy and screened for potentially disease-causing mutations in 58 HCM or DCM-related genes.We identified 5 potentially disease-causing OBSCN mutations in 4 samples; one sample had two OBSCN mutations and one mutation was judged to be not disease-related. Also identified were 6 truncating mutations in TTN, 3 mutations in MYH7, 2 in DSP and one each in TNNC1, TNNI3, MYOM1, VCL, GLA, PLB, TCAP, PKP2 and LAMA4. The mean level of obscurin mRNA was significantly greater and more variable in healthy donor samples than the DCM samples but did not correlate with OBSCN mutations. A single obscurin protein band was observed in human heart myofibrils with apparent mass 960 ± 60 kDa. The three samples with OBSCN mutations had significantly lower levels of obscurin immunoreactive material than DCM samples without OBSCN mutations (45±7, 48±3, and 72±6% of control level.Obscurin levels in DCM controls, donor heart and myectomy samples were the same.OBSCN mutations may result in the development of a DCM phenotype via haploinsufficiency. Mutations in the obscurin gene should be considered as a significant causal factor of DCM, alone or in concert with other mutations.

Nanolock-Nanopore Facilitated Digital Diagnostics of Cancer Driver Mutation in Tumor Tissue.

Science.gov (United States)

Wang, Yong; Tian, Kai; Shi, Ruicheng; Gu, Amy; Pennella, Michael; Alberts, Lindsey; Gates, Kent S; Li, Guangfu; Fan, Hongxin; Wang, Michael X; Gu, Li-Qun

2017-07-28

Cancer driver mutations are clinically significant biomarkers. In precision medicine, accurate detection of these oncogenic changes in patients would enable early diagnostics of cancer, individually tailored targeted therapy, and precise monitoring of treatment response. Here we investigated a novel nanolock-nanopore method for single-molecule detection of a serine/threonine protein kinase gene BRAF V600E mutation in tumor tissues of thyroid cancer patients. The method lies in a noncovalent, mutation sequence-specific nanolock. We found that the nanolock formed on the mutant allele/probe duplex can separate the duplex dehybridization procedure into two sequential steps in the nanopore. Remarkably, this stepwise unzipping kinetics can produce a unique nanopore electric marker, with which a single DNA molecule of the cancer mutant allele can be unmistakably identified in various backgrounds of the normal wild-type allele. The single-molecule sensitivity for mutant allele enables both binary diagnostics and quantitative analysis of mutation occurrence. In the current configuration, the method can detect the BRAF V600E mutant DNA lower than 1% in the tumor tissues. The nanolock-nanopore method can be adapted to detect a broad spectrum of both transversion and transition DNA mutations, with applications from diagnostics to targeted therapy.

A full-angle Monte-Carlo scattering technique including cumulative and single-event Rutherford scattering in plasmas

Science.gov (United States)

Higginson, Drew P.

2017-11-01

We describe and justify a full-angle scattering (FAS) method to faithfully reproduce the accumulated differential angular Rutherford scattering probability distribution function (pdf) of particles in a plasma. The FAS method splits the scattering events into two regions. At small angles it is described by cumulative scattering events resulting, via the central limit theorem, in a Gaussian-like pdf; at larger angles it is described by single-event scatters and retains a pdf that follows the form of the Rutherford differential cross-section. The FAS method is verified using discrete Monte-Carlo scattering simulations run at small timesteps to include each individual scattering event. We identify the FAS regime of interest as where the ratio of temporal/spatial scale-of-interest to slowing-down time/length is from 10-3 to 0.3-0.7; the upper limit corresponds to Coulomb logarithm of 20-2, respectively. Two test problems, high-velocity interpenetrating plasma flows and keV-temperature ion equilibration, are used to highlight systems where including FAS is important to capture relevant physics.

Test Standard Revision Update: JESD57, "Procedures for the Measurement of Single-Event Effects in Semiconductor Devices from Heavy-Ion Irradiation"

Science.gov (United States)

Lauenstein, Jean-Marie

2015-01-01

The JEDEC JESD57 test standard, Procedures for the Measurement of Single-Event Effects in Semiconductor Devices from Heavy-Ion Irradiation, is undergoing its first revision since 1996. In this talk, we place this test standard into context with other relevant radiation test standards to show its importance for single-event effect radiation testing for space applications. We show the range of industry, government, and end-user party involvement in the revision. Finally, we highlight some of the key changes being made and discuss the trade-space in which setting standards must be made to be both useful and broadly adopted.

Single-Event Effects in High-Frequency Linear Amplifiers: Experiment and Analysis

Science.gov (United States)

Zeinolabedinzadeh, Saeed; Ying, Hanbin; Fleetwood, Zachary E.; Roche, Nicolas J.-H.; Khachatrian, Ani; McMorrow, Dale; Buchner, Stephen P.; Warner, Jeffrey H.; Paki-Amouzou, Pauline; Cressler, John D.

2017-01-01

The single-event transient (SET) response of two different silicon-germanium (SiGe) X-band (8-12 GHz) low noise amplifier (LNA) topologies is fully investigated in this paper. The two LNAs were designed and implemented in 130nm SiGe HBT BiCMOS process technology. Two-photon absorption (TPA) laser pulses were utilized to induce transients within various devices in these LNAs. Impulse response theory is identified as a useful tool for predicting the settling behavior of the LNAs subjected to heavy ion strikes. Comprehensive device and circuit level modeling and simulations were performed to accurately simulate the behavior of the circuits under ion strikes. The simulations agree well with TPA measurements. The simulation, modeling and analysis presented in this paper can be applied for any other circuit topologies for SET modeling and prediction.

Cortical atrophy and hypofibrinogenemia due to FGG and TBCD mutations in a single family: a case report.

Science.gov (United States)

Stephen, Joshi; Nampoothiri, Sheela; Vinayan, K P; Yesodharan, Dhanya; Remesh, Preetha; Gahl, William A; Malicdan, May Christine V

2018-05-16

Blended phenotypes or co-occurrence of independent phenotypically distinct conditions are extremely rare and are due to coincidence of multiple pathogenic mutations, especially due to consanguinity. Hereditary fibrinogen deficiencies result from mutations in the genes FGA, FGB, and FGG, encoding the three different polypeptide chains that comprise fibrinogen. Neurodevelopmental abnormalities have not been associated with fibrinogen deficiencies. In this study, we report an unusual patient with a combination of two independently inherited genetic conditions; fibrinogen deficiency and early onset cortical atrophy. The study describes a male child from consanguineous family presented with hypofibrinogenemia, diffuse cortical atrophy, microcephaly, hypertonia and axonal motor neuropathy. Through a combination of homozygosity mapping and exome sequencing, we identified bi-allelic pathogenic mutations in two genes: a homozygous novel truncating mutation in FGG (c.554del; p.Lys185Argfs*14) and a homozygous missense mutation in TBCD (c.1423G > A;p.Ala475Thr). Loss of function mutations in FGG have been associated with fibrinogen deficiency, while the c.1423G > A mutation in TBCD causes a novel syndrome of neurodegeneration and early onset encephalopathy. Our study highlights the importance of homozygosity mapping and exome sequencing in molecular prenatal diagnosis, especially when multiple gene mutations are responsible for the phenotype.

Acquired RhD mosaicism identifies fibrotic transformation of thrombopoietin receptor-mutated essential thrombocythemia.

Science.gov (United States)

Montemayor-Garcia, Celina; Coward, Rebecca; Albitar, Maher; Udani, Rupa; Jain, Prachi; Koklanaris, Eleftheria; Battiwalla, Minoo; Keel, Siobán; Klein, Harvey G; Barrett, A John; Ito, Sawa

2017-09-01

Acquired copy-neutral loss of heterozygosity has been described in myeloid malignant progression with an otherwise normal karyotype. A 65-year-old woman with MPL-mutated essential thrombocythemia and progression to myelofibrosis was noted upon routine pretransplant testing to have mixed field reactivity with anti-D and an historic discrepancy in RhD type. The patient had never received transfusions or transplantation. Gel immunoagglutination revealed group A red blood cells and a mixed-field reaction for the D phenotype, with a predominant D-negative population and a small subset of circulating red blood cells carrying the D antigen. Subsequent genomic microarray single nucleotide polymorphism profiling revealed copy-neutral loss of heterozygosity of chromosome 1 p36.33-p34.2, a known molecular mechanism underlying fibrotic progression of MPL-mutated essential thrombocythemia. The chromosomal region affected by this copy-neutral loss of heterozygosity encompassed the RHD, RHCE, and MPL genes. We propose a model of chronological molecular events that is supported by RHD zygosity assays in peripheral lymphoid and myeloid-derived cells. Copy-neutral loss of heterozygosity events that lead to clonal selection and myeloid malignant progression may also affect the expression of adjacent unrelated genes, including those encoding for blood group antigens. Detection of mixed-field reactions and investigation of discrepant blood typing results are important for proper transfusion support of these patients and can provide useful surrogate markers of myeloproliferative disease progression. © 2017 AABB.

The shapes of the radiation dose-mutation response curves in drosophila: Mechanisms and implications

International Nuclear Information System (INIS)

Abrahamson, S.; DeJongh, C.; Meyer, H.U.

1981-01-01

This chapter proposes that radiation induced mutations, namely sex-linked recessive lethals in Drosophila and forward mutations at specific loci in Drosophila, mammals and lower eucaryotes, are the result of two sub-lesions or hits, induced by either single ionization tracks or by the interaction of two independent tracks for low LET radiations, when the dose is delivered in an acute fashion. Utilizes the well recognized linear quadratic expression Y=C+αD+βD 2 , where C is the spontaneous frequency of events scored and α and β represent the coefficients of the dose. Concludes that for low LET radiations, X or gamma rays, the linear-quadratic model can be used to predict the genetic response of germ cells and somatic cells to a variety of radiation regimes. Points out that the point of inflection in the curve, α/β value, can be determined specifically by target dimensions which vary with respect to DNA content. Considers the difference in RBE values observed for different species to be a reflection of their different target sizes

Allogeneic Transplant in ELANE and MEFV Mutation Positive Severe Cyclic Neutropenia: Review of Prognostic Factors for Secondary Severe Events

Directory of Open Access Journals (Sweden)

Onyemaechi N. Okolo

2017-01-01

Full Text Available Objective and Importance. Cyclic neutropenia (CyN is a rare autosomal dominant inherited disorder due to the mutation ELANE primarily affecting bone marrow stem cells and is characterized by recurrent neutropenia every 2 to 4 weeks. Symptoms vary from benign to severe, including death. Postulations on the cause of wide spectrum in symptom presentation include the possibility of other genetic mutations, such as MEFV. Recommended treatment for CyN is G-CSF to keep ANC higher to minimize risk of infection. Case. A 25-year-old male diagnosed with CyN, on G-CSF but worsening quality of life. Pretransplant investigations revealed ELANE mutation positive severe CyN along with familial Mediterranean fever (MEFV mutation. Intervention. Bone marrow transplantation as treatment for dual mutation (ELANE and MEFV mutation positive severe CyN. Conclusion. BMT may be considered as an alternative treatment for severe CyN in patients who are refractory to G-CSF. It is postulated that in our patient the combined mutations (CyN and MEFV may have contributed to the severity of this individual’s symptoms. We suggest CyN patients who present with severe symptoms have evaluation with ELANE mutation testing, Periodic Fever Syndromes Panel, and routine marrow assessment with FISH, conventional cytogenetics, and morphological evaluation for MDS/AML.

JAK2 mutation in a patient with CLL with coexistent myeloproliferative neoplasm (MPN).

Science.gov (United States)

Kodali, Srinivas; Chen, Chi; Rathnasabapathy, Chenthilmurugan; Wang, Jen Chin

2009-12-01

JAK2 mutation has not been described in patients with chronic lymphocytic leukemia (CLL). We found JAK2 mutation in a patient with CLL and coexisting myeloproliferative neoplasm (MPN). In this patient, we demonstrated the presence of the JAK2 mutation in CD34(+) progenitor cells, myeloid lineage cells, megakaryocytes, B lymphocytes but not in T lymphocytes. This case represents the first case report of JAK2 mutation in CLL and may also suggest that, JAK2 mutation most likely represents a secondary event from primary gene mutations involving the primitive stem cells which give rise to MPN and CLL. Furthermore, in this case, we believe that we are the first to demonstrate that JAK2 mutation in myeloid and B lymphoid cells but not T lymphocytes in a case of coexisting CLL and MPN.

Sequence analysis of LACI mutations obtained from lung cells of control and radon-exposed Big Blue trademark transgenic mice

International Nuclear Information System (INIS)

Jostes, R.F.; Cross, F.T.; Stillwell, L.

1995-01-01

We have exposed Stratagene Big Blue trademark transgenic mice by inhalation to 310, 640 and 960 Working Level Months (WLM) of radon progency. Twelve LacI mutations have been isolated from the lung tissue of a mouse from the 960-WLM group and the LacI gene sequenced. Mutations are scored only if they occur unambiguously in both strands of the mutant gene; the entire gene is evaluated. In addition, sixteen LacI mutations were isolated from the lung tissue of a mouse from the 640-WLM group; seven have been completely sequenced. Nine LacI mutations from the lung tissue of unirradiated control mice have been sequenced. Sequence data from the unirradiated mice are similar to that found in lung tissue at Stratagene; predominately G:C to A:T transitions in the protein associated region. The mutation spectrum from radon-irradiated mice is markedly different from that obtained with the control, unirradiated mice. Small deletions and insertions compromise 53% of the mutations in the irradiated mice. No multiple events have been noted in the spontaneous mutations; six of the mutations obtained from radon-irradiated mice (26%) have multiple events within the gene. In some, deletions, insertions are base changes occur together. The mutational events in the irradiated mice are approximately equally distributed throughout the gene. The breakpoint rejoining regions of large deletions obtained from the radon-irradiated mice are being studied at the University of California, San Francisco

Age-related mutations associated with clonal hematopoietic expansion and malignancies.

Science.gov (United States)

Xie, Mingchao; Lu, Charles; Wang, Jiayin; McLellan, Michael D; Johnson, Kimberly J; Wendl, Michael C; McMichael, Joshua F; Schmidt, Heather K; Yellapantula, Venkata; Miller, Christopher A; Ozenberger, Bradley A; Welch, John S; Link, Daniel C; Walter, Matthew J; Mardis, Elaine R; Dipersio, John F; Chen, Feng; Wilson, Richard K; Ley, Timothy J; Ding, Li

2014-12-01

Several genetic alterations characteristic of leukemia and lymphoma have been detected in the blood of individuals without apparent hematological malignancies. The Cancer Genome Atlas (TCGA) provides a unique resource for comprehensive discovery of mutations and genes in blood that may contribute to the clonal expansion of hematopoietic stem/progenitor cells. Here, we analyzed blood-derived sequence data from 2,728 individuals from TCGA and discovered 77 blood-specific mutations in cancer-associated genes, the majority being associated with advanced age. Remarkably, 83% of these mutations were from 19 leukemia and/or lymphoma-associated genes, and nine were recurrently mutated (DNMT3A, TET2, JAK2, ASXL1, TP53, GNAS, PPM1D, BCORL1 and SF3B1). We identified 14 additional mutations in a very small fraction of blood cells, possibly representing the earliest stages of clonal expansion in hematopoietic stem cells. Comparison of these findings to mutations in hematological malignancies identified several recurrently mutated genes that may be disease initiators. Our analyses show that the blood cells of more than 2% of individuals (5-6% of people older than 70 years) contain mutations that may represent premalignant events that cause clonal hematopoietic expansion.

Screening for duplications, deletions and a common intronic mutation detects 35% of second mutations in patients with USH2A monoallelic mutations on Sanger sequencing.

Science.gov (United States)

Steele-Stallard, Heather B; Le Quesne Stabej, Polona; Lenassi, Eva; Luxon, Linda M; Claustres, Mireille; Roux, Anne-Francoise; Webster, Andrew R; Bitner-Glindzicz, Maria

2013-08-08

23 (35%) of 'missing' mutations in Usher type 2 probands with only a single heterozygous USH2A mutation detected with Sanger sequencing could be attributed to deletions, duplications or a pathogenic deep intronic variant. Future mutation detection strategies and genetic counselling will need to take into account the prevalence of these types of mutations in order to provide a more comprehensive diagnostic service.

Age-Related Hearing Impairment (ARHI) associated with GJB2 single mutation IVS1+1G>A in the Yakut population isolate in Eastern Siberia.

Science.gov (United States)

Barashkov, Nikolay A; Teryutin, Fedor M; Pshennikova, Vera G; Solovyev, Aisen V; Klarov, Leonid A; Solovyeva, Natalya A; Kozhevnikov, Andrei A; Vasilyeva, Lena M; Fedotova, Elvira E; Pak, Maria V; Lekhanova, Sargylana N; Zakharova, Elena V; Savvinova, Kyunney E; Gotovtsev, Nyurgun N; Rafailo, Adyum M; Luginov, Nikolay V; Alexeev, Anatoliy N; Posukh, Olga L; Dzhemileva, Lilya U; Khusnutdinova, Elza K; Fedorova, Sardana A

2014-01-01

Age-Related Hearing Impairment (ARHI) is one of the frequent sensory disorders registered in 50% of individuals over 80 years. ARHI is a multifactorial disorder due to environmental and poor-known genetic components. In this study, we present the data on age-related hearing impairment of 48 heterozygous carriers of mutation IVS1+1G>A (GJB2 gene) and 97 subjects with GJB2 genotype wt/wt in the Republic of Sakha/Yakutia (Eastern Siberia, Russia). This subarctic territory was found as the region with the most extensive accumulation of mutation IVS1+1G>A in the world as a result of founder effect in the unique Yakut population isolate. The GJB2 gene resequencing and detailed audiological analysis in the frequency range 0.25, 0.5, 1.0, 2.0, 4.0, 8.0 kHz were performed in all examined subjects that allowed to investigate genotype-phenotype correlations between the presence of single mutation IVS1+1G>A and hearing of subjects from examined groups. We revealed the linear correlation between increase of average hearing thresholds at speech frequencies (PTA0.5,1.0,2.0,4.0 kHz) and age of individuals with GJB2 genotype IVS1+1G>A/wt (rs = 0.499, p = 0.006860 for males and rs = 0.427, p = 0.000277 for females). Moreover, the average hearing thresholds on high frequency (8.0 kHz) in individuals with genotype IVS1+1G>A/wt (both sexes) were significantly worse than in individuals with genotype wt/wt (pA/wt was estimated to be ∼40 years (rs = 0.504, p = 0.003). These findings demonstrate that the single IVS1+1G>A mutation (GJB2) is associated with age-related hearing impairment (ARHI) of the IVS1+1G>A carriers in the Yakuts.

Age-Related Hearing Impairment (ARHI associated with GJB2 single mutation IVS1+1G>A in the Yakut population isolate in Eastern Siberia.

Directory of Open Access Journals (Sweden)

Nikolay A Barashkov

Full Text Available Age-Related Hearing Impairment (ARHI is one of the frequent sensory disorders registered in 50% of individuals over 80 years. ARHI is a multifactorial disorder due to environmental and poor-known genetic components. In this study, we present the data on age-related hearing impairment of 48 heterozygous carriers of mutation IVS1+1G>A (GJB2 gene and 97 subjects with GJB2 genotype wt/wt in the Republic of Sakha/Yakutia (Eastern Siberia, Russia. This subarctic territory was found as the region with the most extensive accumulation of mutation IVS1+1G>A in the world as a result of founder effect in the unique Yakut population isolate. The GJB2 gene resequencing and detailed audiological analysis in the frequency range 0.25, 0.5, 1.0, 2.0, 4.0, 8.0 kHz were performed in all examined subjects that allowed to investigate genotype-phenotype correlations between the presence of single mutation IVS1+1G>A and hearing of subjects from examined groups. We revealed the linear correlation between increase of average hearing thresholds at speech frequencies (PTA0.5,1.0,2.0,4.0 kHz and age of individuals with GJB2 genotype IVS1+1G>A/wt (rs = 0.499, p = 0.006860 for males and rs = 0.427, p = 0.000277 for females. Moreover, the average hearing thresholds on high frequency (8.0 kHz in individuals with genotype IVS1+1G>A/wt (both sexes were significantly worse than in individuals with genotype wt/wt (pA/wt was estimated to be ∼40 years (rs = 0.504, p = 0.003. These findings demonstrate that the single IVS1+1G>A mutation (GJB2 is associated with age-related hearing impairment (ARHI of the IVS1+1G>A carriers in the Yakuts.

Mutation at the Human D1S80 Minisatellite Locus

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Kuppareddi Balamurugan

2012-01-01

Full Text Available Little is known about the general biology of minisatellites. The purpose of this study is to examine repeat mutations from the D1S80 minisatellite locus by sequence analysis to elucidate the mutational process at this locus. This is a highly polymorphic minisatellite locus, located in the subtelomeric region of chromosome 1. We have analyzed 90,000 human germline transmission events and found seven (7 mutations at this locus. The D1S80 alleles of the parentage trio, the child, mother, and the alleged father were sequenced and the origin of the mutation was determined. Using American Association of Blood Banks (AABB guidelines, we found a male mutation rate of 1.04×10-4 and a female mutation rate of 5.18×10-5 with an overall mutation rate of approximately 7.77×10-5. Also, in this study, we found that the identified mutations are in close proximity to the center of the repeat array rather than at the ends of the repeat array. Several studies have examined the mutational mechanisms of the minisatellites according to infinite allele model (IAM and the one-step stepwise mutation model (SMM. In this study, we found that this locus fits into the one-step mutation model (SMM mechanism in six out of seven instances similar to STR loci.

Mutations in 23S rRNA at the Peptidyl Transferase Center and Their Relationship to Linezolid Binding and Cross-Resistance

DEFF Research Database (Denmark)

Long, Katherine; Munck, Christian

2010-01-01

The oxazolidinone antibiotic linezolid targets the peptidyl transferase center (PTC) on the bacterial ribosome. Thirteen single and four double 23S rRNA mutations were introduced into a Mycobacterium smegmatis strain with a single rRNA operon. Converting bacterial base identity by single mutations...... at positions 2032, 2453, and 2499 to human cytosolic base identity did not confer significantly reduced susceptibility to linezolid. The largest decrease in linezolid susceptibility for any of the introduced single mutations was observed with the G2576U mutation at a position that is 7.9 Å from linezolid....... Smaller decreases were observed with the A2503G, U2504G, and G2505A mutations at nucleotides proximal to linezolid, showing that the degree of resistance conferred is not simply inversely proportional to the nucleotide-drug distance. The double mutations G2032A-C2499A, G2032A-U2504G, C2055A-U2504G, and C...

Measurement of top quark and W boson polarisation observables with t-channel single-top-quark events in the ATLAS experiment.

CERN Document Server

AUTHOR|(INSPIRE)INSPIRE-00288626

This thesis presents two studies, one related with the alignment of the ATLAS Inner Detector tracking system and other with the measurement of top quark and W boson polarisation observables using t-channel single-top-quark events. The first topic describes the implementation of a monitoring tool, which is used to monitor the Level 1 alignment corrections obtained in the calibration loop, as well as the use of constraints on the momentum and impact parameters biases using $Z \\rightarrow\\mu\\mu$ events on the alignment algorithms. These techniques were developed during 2012 data taking campaign and provide the most accurate description of the ATLAS Inner Detector. The second topic presents a detailed measurement of top quark and W boson polarisation observables using the 20.3 $fb^{-1}$ of data collected by the ATLAS detector at $\\sqrt{s}$ = 8 TeV. The measurement is performed using $t$-channel single top quark events and exploits the feature that the produced top quark is highly polarised along the direction of ...

The use of radiations to induce useful mutations in fruit trees

International Nuclear Information System (INIS)

Donini, B.

1976-01-01

The researches carried out at Casaccia in this field had covered the problems of technique of mutagenic treatment, mechanism of mutation induction and methodology of somatic mutation isolation. To enhance the efficiency of somatic mutation induction several conditions during and after the treatment have been studied. More experience has been gained with regard to the induction of somatic mutation which raises from genetical event or by tissue arrangement of a chimaeric shoot apex. To increase the size of mutated sector treatment have been carried out on the primordia in a very early stages and to improve the methodology of somatic mutation special techniques have been adapted of handling the material in the propagation. Possibility for early detection of mutants has been explored in cherry by establishing a correlation between mutants and hormonal content. By using the above mentioned techniques, useful mutants have been isolated in cherries, grapes, olives and peaches. (author)

A meta-analysis of the relationship between FGFR3 and TP53 mutations in bladder cancer.

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Yann Neuzillet

Full Text Available TP53 and FGFR3 mutations are the most common mutations in bladder cancers. FGFR3 mutations are most frequent in low-grade low-stage tumours, whereas TP53 mutations are most frequent in high-grade high-stage tumours. Several studies have reported FGFR3 and TP53 mutations to be mutually exclusive events, whereas others have reported them to be independent. We carried out a meta-analysis of published findings for FGFR3 and TP53 mutations in bladder cancer (535 tumours, 6 publications and additional unpublished data for 382 tumours. TP53 and FGFR3 mutations were not independent events for all tumours considered together (OR = 0.25 [0.18-0.37], p = 0.0001 or for pT1 tumours alone (OR = 0.47 [0.28-0.79], p = 0.0009. However, if the analysis was restricted to pTa tumours or to muscle-invasive tumours alone, FGFR3 and TP53 mutations were independent events (OR = 0.56 [0.23-1.36] (p = 0.12 and OR = 0.99 [0.37-2.7] (p = 0.35, respectively. After stratification of the tumours by stage and grade, no dependence was detected in the five tumour groups considered (pTaG1 and pTaG2 together, pTaG3, pT1G2, pT1G3, pT2-4. These differences in findings can be attributed to the putative existence of two different pathways of tumour progression in bladder cancer: the CIS pathway, in which FGFR3 mutations are rare, and the Ta pathway, in which FGFR3 mutations are frequent. TP53 mutations occur at the earliest stage of the CIS pathway, whereas they occur would much later in the Ta pathway, at the T1G3 or muscle-invasive stage.

Measurement of the associated production of a single top quark and a W boson in single-lepton events with the ATLAS detector

Energy Technology Data Exchange (ETDEWEB)

Mergelmeyer, Sebastian

2016-06-15

The production of a single top quark in association with a W boson (Wt) is measured with the ATLAS detector using proton-proton collision events with one lepton, three jets and missing transverse energy at √(s)=8 TeV. Signal events are identified using an artificial neural network in an unconventional manner, addressing the large uncertainties due to the major background, which has an about 10 times larger cross section and a very similar signature compared with the Wt signal. State-of-the-art statistical methods are used to validate the modelling of the signal and the background, and to extract the cross section for Wt production. The cross section is found to be consistent with related measurements as well as the Standard Model prediction. In addition, a direct measurement of the CKM matrix element V{sub tb} is performed.

Measurement of the associated production of a single top quark and a W boson in single-lepton events with the ATLAS detector

International Nuclear Information System (INIS)

Mergelmeyer, Sebastian

2016-06-01

The production of a single top quark in association with a W boson (Wt) is measured with the ATLAS detector using proton-proton collision events with one lepton, three jets and missing transverse energy at √(s)=8 TeV. Signal events are identified using an artificial neural network in an unconventional manner, addressing the large uncertainties due to the major background, which has an about 10 times larger cross section and a very similar signature compared with the Wt signal. State-of-the-art statistical methods are used to validate the modelling of the signal and the background, and to extract the cross section for Wt production. The cross section is found to be consistent with related measurements as well as the Standard Model prediction. In addition, a direct measurement of the CKM matrix element V_t_b is performed.

NetNorM: Capturing cancer-relevant information in somatic exome mutation data with gene networks for cancer stratification and prognosis.

Science.gov (United States)

Le Morvan, Marine; Zinovyev, Andrei; Vert, Jean-Philippe

2017-06-01

Genome-wide somatic mutation profiles of tumours can now be assessed efficiently and promise to move precision medicine forward. Statistical analysis of mutation profiles is however challenging due to the low frequency of most mutations, the varying mutation rates across tumours, and the presence of a majority of passenger events that hide the contribution of driver events. Here we propose a method, NetNorM, to represent whole-exome somatic mutation data in a form that enhances cancer-relevant information using a gene network as background knowledge. We evaluate its relevance for two tasks: survival prediction and unsupervised patient stratification. Using data from 8 cancer types from The Cancer Genome Atlas (TCGA), we show that it improves over the raw binary mutation data and network diffusion for these two tasks. In doing so, we also provide a thorough assessment of somatic mutations prognostic power which has been overlooked by previous studies because of the sparse and binary nature of mutations.

Computing in the presence of soft bit errors. [caused by single event upset on spacecraft

Science.gov (United States)

Rasmussen, R. D.

1984-01-01

It is shown that single-event-upsets (SEUs) due to cosmic rays are a significant source of single bit error in spacecraft computers. The physical mechanism of SEU, electron hole generation by means of Linear Energy Transfer (LET), it discussed with reference made to the results of a study of the environmental effects on computer systems of the Galileo spacecraft. Techniques for making software more tolerant of cosmic ray effects are considered, including: reducing the number of registers used by the software; continuity testing of variables; redundant execution of major procedures for error detection; and encoding state variables to detect single-bit changes. Attention is also given to design modifications which may reduce the cosmic ray exposure of on-board hardware. These modifications include: shielding components operating in LEO; removing low-power Schottky parts; and the use of CMOS diodes. The SEU parameters of different electronic components are listed in a table.

Soft sweeps III: the signature of positive selection from recurrent mutation.

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Pleuni S Pennings

2006-12-01

Full Text Available Polymorphism data can be used to identify loci at which a beneficial allele has recently gone to fixation, given that an accurate description of the signature of selection is available. In the classical model that is used, a favored allele derives from a single mutational origin. This ignores the fact that beneficial alleles can enter a population recurrently by mutation during the selective phase. In this study, we present a combination of analytical and simulation results to demonstrate the effect of adaptation from recurrent mutation on summary statistics for polymorphism data from a linked neutral locus. We also analyze the power of standard neutrality tests based on the frequency spectrum or on linkage disequilibrium (LD under this scenario. For recurrent beneficial mutation at biologically realistic rates, we find substantial deviations from the classical pattern of a selective sweep from a single new mutation. Deviations from neutrality in the level of polymorphism and in the frequency spectrum are much less pronounced than in the classical sweep pattern. In contrast, for levels of LD, the signature is even stronger if recurrent beneficial mutation plays a role. We suggest a variant of existing LD tests that increases their power to detect this signature.

Search for anomalous Wtb couplings and top FCNC in t-channel single-top-quark events

CERN Document Server

CMS Collaboration

2014-01-01

Single-top-quark events in the $t$-channel are used to probe Wtb anomalous couplings and to search for top quark Flavor Changing Neutral Current (FCNC) interactions in proton-proton collisions at $\\sqrt{s}=7$ TeV. The analyzed data correspond to an integrated luminosity of 5~fb$^{-1}$. Events with the top quark decaying into a muon, neutrino and b-quark are selected. A Bayesian neural network is used to discriminate between signal and backgrounds. The observed event yields are consistent with SM prediction, and exclusion limits at 95\\% C.L. are determined. The exclusion limits on anomalous right vector and left tensor couplings of the Wtb vertex are found to be $|f_{V}^{R}|< 0.34$ and $|f_{T}^{L}|<0.09$. In the scenarios with FCNC tcg and tug couplings, limits on the coupling strengths are found to be $\\kappa_{tug}/\\Lambda < 1.8 \\cdot 10^{-2}~ \\mathrm{TeV^{-1}},\\ \\kappa_{tcg}/\\Lambda < 5.6 \\cdot 10^{-2} ~ \\mathrm{TeV^{-1}}$ which corresponds to limits on the branching ratios $Br(t~\\rightarrow~u+g)...

The presence of two different infantile Tay-Sachs disease mutations in a Cajun population

Energy Technology Data Exchange (ETDEWEB)

McDowell, G.A.; Blitzer, M.G. (Univ. of Maryland School of Medicine, Baltimore, MD (United States)); Mules, E.H. (Kennedy Krieger Institute, Baltimore, MD (United States)); Fabacher, P. (Office of Public Health, Shreveport, LA (United States)); Shapira, E. (Tulane Univ. of School of Medicine, New Orleans, LA (United States))

1992-11-01

A study was undertaken to characterize the mutation(s) responsible for Tay-Sachs disease (TSD) in a Cajun population in southwest Louisiana and to identify the origins of these mutations. Eleven of 12 infantile TSD alleles examined in six families had the [beta]-hexosaminidase A (Hex A) [alpha]-subunit exon 11 insertion mutation that is present in approximately 70% of Ashkenazi Jewish TSD heterozygotes. The mutation in the remaining allele was a single-base transition in the donor splice site of the [alpha]-subunit intron 9. To determine the origins of these two mutations in the Cajun population, the TSD carrier status was enzymatically determined for 90 members of four of the six families, and extensive pedigrees were constructed for all carriers. A single ancestral couple from France was found to be common to most of the carriers of the exon 11 insertion. Pedigree data suggest that this mutation has been in the Cajun population since its founding over 2 centuries ago and that it may be widely distributed within the population. In contrast, the intron 9 mutation apparently was introduced within the last century and probably is limited to a few Louisiana families. 29 refs., 4 figs.

Survival analysis of cancer risk reduction strategies for BRCA1/2 mutation carriers.

Science.gov (United States)

Kurian, Allison W; Sigal, Bronislava M; Plevritis, Sylvia K

2010-01-10

Women with BRCA1/2 mutations inherit high risks of breast and ovarian cancer; options to reduce cancer mortality include prophylactic surgery or breast screening, but their efficacy has never been empirically compared. We used decision analysis to simulate risk-reducing strategies in BRCA1/2 mutation carriers and to compare resulting survival probability and causes of death. We developed a Monte Carlo model of breast screening with annual mammography plus magnetic resonance imaging (MRI) from ages 25 to 69 years, prophylactic mastectomy (PM) at various ages, and/or prophylactic oophorectomy (PO) at ages 40 or 50 years in 25-year-old BRCA1/2 mutation carriers. With no intervention, survival probability by age 70 is 53% for BRCA1 and 71% for BRCA2 mutation carriers. The most effective single intervention for BRCA1 mutation carriers is PO at age 40, yielding a 15% absolute survival gain; for BRCA2 mutation carriers, the most effective single intervention is PM, yielding a 7% survival gain if performed at age 40 years. The combination of PM and PO at age 40 improves survival more than any single intervention, yielding 24% survival gain for BRCA1 and 11% for BRCA2 mutation carriers. PM at age 25 instead of age 40 offers minimal incremental benefit (1% to 2%); substituting screening for PM yields a similarly minimal decrement in survival (2% to 3%). Although PM at age 25 plus PO at age 40 years maximizes survival probability, substituting mammography plus MRI screening for PM seems to offer comparable survival. These results may guide women with BRCA1/2 mutations in their choices between prophylactic surgery and breast screening.

Genetic improvement of 'NPq' rice with induced mutations

International Nuclear Information System (INIS)

Ram, Mahabal

1974-01-01

Exposure of the seeds of rice to different doses of gamma-rays increased the total mutation frequency with an increase in the dose rate, and the most economic mutations occurred around 30 kr. Induced mutants with dwarf plant type, early maturity, fine grain, high-yielding ability, and resistance to lodging and major diseases were isolated in the M, and M generations. Genetical studies indicated that height is controlled by 4 pairs of additive genes, grass-clumps by 2 pairs of non-allelic interacting genes (inhibitory), and chlorophyll mutations such as albina by 2 pairs of duplicate genes and xantha by a single gene pair. (author)

Adaptive synonymous mutations in an experimentally evolved Pseudomonas fluorescens population

DEFF Research Database (Denmark)

Bailey, Susan; Hinz, Aaron; Kassen, Rees

2014-01-01

Conventional wisdom holds that synonymous mutations, nucleotide changes that do not alter the encoded amino acid, have no detectable effect on phenotype or fitness. However, a growing body of evidence from both comparative and experimental studies suggests otherwise. Synonymous mutations have been...... shown to impact gene expression, protein folding and fitness, however, direct evidence that they can be positively selected, and so contribute to adaptation, is lacking. Here we report the recovery of two beneficial synonymous single base pair changes that arose spontaneously and independently...... in an experimentally evolved population of Pseudomonas fluorescens. We show experimentally that these mutations increase fitness by an amount comparable to non-synonymous mutations and that the fitness increases stem from increased gene expression. These results provide unequivocal evidence that synonymous mutations...

Observed differences in event structures of high-p/sub T/ π0 and single photon events produced in pp collisions at the CERN ISR

International Nuclear Information System (INIS)

Rahm, D.C.

1980-01-01

The direct photon production in pp collisions for c.m. energies 31 less than or equal to 63 GeV and transverse momenta of up to 9 GeV/c were measured at the ISR by use of a segmented lead/liquid argon calorimeter. The observed γ/π 0 ratio was found to be a significantly larger than zero at 4 GeV/c in p/sub T/, increasing to 0.4 at 9 GeV/c. The average multiplicity on the trigger side for the single-photon events was found to be significantly lower than for π 0 events. The correlations in Δy and Δphi between the trigger particle and an additional particle were found to differe mainly at small Δy and Δphi. 3 figures

Contribution of silent mutations to thermal adaptation of RNA bacteriophage Qβ.

Science.gov (United States)

Kashiwagi, Akiko; Sugawara, Ryu; Sano Tsushima, Fumie; Kumagai, Tomofumi; Yomo, Tetsuya

2014-10-01

Changes in protein function and other biological properties, such as RNA structure, are crucial for adaptation of organisms to novel or inhibitory environments. To investigate how mutations that do not alter amino acid sequence may be positively selected, we performed a thermal adaptation experiment using the single-stranded RNA bacteriophage Qβ in which the culture temperature was increased from 37.2°C to 41.2°C and finally to an inhibitory temperature of 43.6°C in a stepwise manner in three independent lines. Whole-genome analysis revealed 31 mutations, including 14 mutations that did not result in amino acid sequence alterations, in this thermal adaptation. Eight of the 31 mutations were observed in all three lines. Reconstruction and fitness analyses of Qβ strains containing only mutations observed in all three lines indicated that five mutations that did not result in amino acid sequence changes but increased the amplification ratio appeared in the course of adaptation to growth at 41.2°C. Moreover, these mutations provided a suitable genetic background for subsequent mutations, altering the fitness contribution from deleterious to beneficial. These results clearly showed that mutations that do not alter the amino acid sequence play important roles in adaptation of this single-stranded RNA virus to elevated temperature. Recent studies using whole-genome analysis technology suggested the importance of mutations that do not alter the amino acid sequence for adaptation of organisms to novel environmental conditions. It is necessary to investigate how these mutations may be positively selected and to determine to what degree such mutations that do not alter amino acid sequences contribute to adaptive evolution. Here, we report the roles of these silent mutations in thermal adaptation of RNA bacteriophage Qβ based on experimental evolution during which Qβ showed adaptation to growth at an inhibitory temperature. Intriguingly, four synonymous mutations and

Phenotypic diversity associated with the mitochondrial m.8313G>A point mutation.

LENUS (Irish Health Repository)

O'Rourke, Killian

2012-02-01

We report the clinical, histochemical, and molecular genetic findings in a patient with progressive mitochondrial cytopathy due to the m.8313G>A point mutation in the mitochondrial tRNA(Lys) (MTTK) gene. The clinical features in this case are severe, including short stature, myopathy, peripheral neuropathy, and osteoporosis, while extensive analysis of maternal relatives indicate that the mutation has arisen de novo and was not maternally inherited. This report of a second case, together with single muscle fiber mutation analysis that shows clear segregation of mutation load with cytochrome c oxidase deficiency, confirms that the mutation is pathologic.

FANCA Gene Mutations with 8 Novel Molecular Changes in Indian Fanconi Anemia Patients.

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Avani Solanki

Full Text Available Fanconi anemia (FA, a rare heterogeneous genetic disorder, is known to be associated with 19 genes and a spectrum of clinical features. We studied FANCA molecular changes in 34 unrelated and 2 siblings of Indian patients with FA and have identified 26 different molecular changes of FANCA gene, of which 8 were novel mutations (a small deletion c.2500delC, 4 non-sense mutations c.2182C>T, c.2630C>G, c.3677C>G, c.3189G>A; and 3 missense mutations; c.1273G>C, c.3679 G>C, and c.3992 T>C. Among these only 16 patients could be assigned FA-A complementation group, because we could not confirm single exon deletions detected by MLPA or cDNA amplification by secondary confirmation method and due to presence of heterozygous non-pathogenic variations or heterozygous pathogenic mutations. An effective molecular screening strategy should be developed for confirmation of these mutations and determining the breakpoints for single exon deletions.

FANCA Gene Mutations with 8 Novel Molecular Changes in Indian Fanconi Anemia Patients.

Science.gov (United States)

Solanki, Avani; Mohanty, Purvi; Shukla, Pallavi; Rao, Anita; Ghosh, Kanjaksha; Vundinti, Babu Rao

2016-01-01

Fanconi anemia (FA), a rare heterogeneous genetic disorder, is known to be associated with 19 genes and a spectrum of clinical features. We studied FANCA molecular changes in 34 unrelated and 2 siblings of Indian patients with FA and have identified 26 different molecular changes of FANCA gene, of which 8 were novel mutations (a small deletion c.2500delC, 4 non-sense mutations c.2182C>T, c.2630C>G, c.3677C>G, c.3189G>A; and 3 missense mutations; c.1273G>C, c.3679 G>C, and c.3992 T>C). Among these only 16 patients could be assigned FA-A complementation group, because we could not confirm single exon deletions detected by MLPA or cDNA amplification by secondary confirmation method and due to presence of heterozygous non-pathogenic variations or heterozygous pathogenic mutations. An effective molecular screening strategy should be developed for confirmation of these mutations and determining the breakpoints for single exon deletions.

Embryo genome profiling by single-cell sequencing for successful preimplantation genetic diagnosis in a family harboring COL4A1 c.1537G>A; p.G513S mutation

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Nayana H Patel

2016-01-01

Full Text Available CONTEXT: Genetic profiling of embryos (also known as preimplantation genetic diagnosis before implantation has dramatically enhanced the success quotient of in vitro fertilization (IVF in recent times. The technology helps in avoiding selective pregnancy termination since the baby is likely to be free of the disease under consideration. AIM: Screening of embryos free from c.1537G>A; p.G513S mutation within the COL4A1 gene for which the father was known in before be in heterozygous condition. SUBJECTS AND METHODS: Processing of trophectoderm biopsies was done from twelve embryos for c.1537G>A; p.G513S mutation within the COL4A1 gene. DNA extracted from isolated cells were subjected to whole genome amplification using an isothermal amplification and strand displacement technology. Oligonucleotide primers bracketing the mutation were synthesized and used to amplify 162 base pairs (bp polymerase chain reaction amplicons originating from each embryo which were subsequently sequenced to detect the presence or absence of the single base polymorphism. RESULTS: Three out of 12 embryos interrogated in this study were found to be normal while 9 were found to harbor the mutation in heterozygous condition. Implantation of one of the normal embryos following by chorionic villus sampling at 11 th week of pregnancy indicated that the baby was free from c.1537G>A; p.G513S mutation within the COL4A1 gene. CONCLUSIONS: Single-cell sequencing is a helpful tool for preimplantation embryo profiling. This is the first report from India describing the birth of a normal child through IVF procedure where a potential pathogenic COL4A1 allele was avoided using this technology.

Characterization of System Level Single Event Upset (SEU) Responses using SEU Data, Classical Reliability Models, and Space Environment Data

Science.gov (United States)

Berg, Melanie; Label, Kenneth; Campola, Michael; Xapsos, Michael

2017-01-01

We propose a method for the application of single event upset (SEU) data towards the analysis of complex systems using transformed reliability models (from the time domain to the particle fluence domain) and space environment data.

Distinct mutational signatures characterize concurrent loss of polymerase proofreading and mismatch repair.

Science.gov (United States)

Haradhvala, N J; Kim, J; Maruvka, Y E; Polak, P; Rosebrock, D; Livitz, D; Hess, J M; Leshchiner, I; Kamburov, A; Mouw, K W; Lawrence, M S; Getz, G

2018-05-01

Fidelity of DNA replication is maintained using polymerase proofreading and the mismatch repair pathway. Tumors with loss of function of either mechanism have elevated mutation rates with characteristic mutational signatures. Here we report that tumors with concurrent loss of both polymerase proofreading and mismatch repair function have mutational patterns that are not a simple sum of the signatures of the individual alterations, but correspond to distinct, previously unexplained signatures: COSMIC database signatures 14 and 20. We then demonstrate that in all five cases in which the chronological order of events could be determined, polymerase epsilon proofreading alterations precede the defect in mismatch repair. Overall, we illustrate that multiple distinct mutational signatures can result from different combinations of a smaller number of mutational processes (of either damage or repair), which can influence the interpretation and discovery of mutational signatures.

KIAA1549-BRAF fusions and IDH mutations can coexist in diffuse gliomas of adults.

Science.gov (United States)

Badiali, Manuela; Gleize, Vincent; Paris, Sophie; Moi, Loredana; Elhouadani, Selma; Arcella, Antonietta; Morace, Roberta; Antonelli, Manila; Buttarelli, Francesca Romana; Figarella-Branger, Dominique; Kim, Young-Ho; Ohgaki, Hiroko; Mokhtari, Karima; Sanson, Marc; Giangaspero, Felice

2012-11-01

KIAA1549-BRAF fusion gene and isocitrate dehydrogenase (IDH) mutations are considered two mutually exclusive genetic events in pilocytic astrocytomas and diffuse gliomas, respectively. We investigated the presence of the KIAA1549-BRAF fusion gene in conjunction with IDH mutations and 1p/19q loss in 185 adult diffuse gliomas. Moreover BRAF(v600E) mutation was also screened. The KIAA1549-BRAF fusion gene was evaluated by reverse-transcription polymerase chain reaction (RT-PCR) and sequencing. We found IDH mutations in 125 out 175 cases (71.4%). There were KIAA1549-BRAF fusion gene in 17 out of 180 (9.4%) cases and BRAF(v600E) in 2 out of 133 (1.5%) cases. In 11 of these 17 cases, both IDH mutations and the KIAA1549-BRAF fusion were present, as independent molecular events. Moreover, 6 of 17 cases showed co-presence of 1p/19q loss, IDH mutations and KIAA1549-BRAF fusion. Among the 17 cases with KIAA1549-BRAF fusion gene 15 (88.2%) were oligodendroglial neoplasms. Similarly, the two cases with BRAF(v600E) mutation were both oligodendroglioma and one had IDH mutations and 1p/19q co-deletion. Our results suggest that in a small fraction of diffuse gliomas, KIAA1549-BRAF fusion gene and BRAF(v600E) mutation may be responsible for deregulation of the Ras-RAF-ERK signaling pathway. Such alterations are more frequent in oligodendroglial neoplasm and may be co-present with IDH mutations and 1p/19q loss. © 2012 The Authors; Brain Pathology © 2012 International Society of Neuropathology.

A Constant Rate of Spontaneous Mutation in DNA-Based Microbes

Science.gov (United States)

Drake, John W.

1991-08-01

In terms of evolution and fitness, the most significant spontaneous mutation rate is likely to be that for the entire genome (or its nonfrivolous fraction). Information is now available to calculate this rate for several DNA-based haploid microbes, including bacteriophages with single- or double-stranded DNA, a bacterium, a yeast, and a filamentous fungus. Their genome sizes vary by ≈6500-fold. Their average mutation rates per base pair vary by ≈16,000-fold, whereas their mutation rates per genome vary by only ≈2.5-fold, apparently randomly, around a mean value of 0.0033 per DNA replication. The average mutation rate per base pair is inversely proportional to genome size. Therefore, a nearly invariant microbial mutation rate appears to have evolved. Because this rate is uniform in such diverse organisms, it is likely to be determined by deep general forces, perhaps by a balance between the usually deleterious effects of mutation and the physiological costs of further reducing mutation rates.

The effect of event repetition on the production of story grammar in children's event narratives.

Science.gov (United States)

Feltis, Brooke B; Powell, Martine B; Roberts, Kim P

2011-03-01

This study examined the effect of event repetition on the amount and nature of story-grammar produced by children when recalling the event. Children aged 4 years (N=50) and 7 years (N=56) participated in either 1 or 6 occurrences of a highly similar event where details varied across the occurrences. Half the children in each age and event group recalled the last/single occurrence 5-6 days later and the other half recalled the last/single occurrence after 5-6 weeks (the final and single occurrence was the same). Children's free recall responses were classified according to the number and proportion of story-grammar elements (Stein & Glenn, 1979-setting, initiating event, internal response, plan, attempt, direct consequence, and resolution) as well as the prevalence of causal links between the individual story-grammar elements. More story-grammar detail and more links between individual story-grammar elements were reported about the final compared to single occurrence. The amount of story-grammar increased with age and decreased over time. Further, an interaction was revealed such that the effect of retention interval on the production of story-grammar was negligible for older children who experienced the repeated event. Event repetition has a beneficial effect on the production of children's story-grammar content in situations where event details varied from occasion to occasion. This study highlights the importance of eliciting free recall when conducting evidential interviews with child witnesses about repeated events. Copyright © 2011 Elsevier Ltd. All rights reserved.

The importance of conventional radiography in the mutational analysis of skeletal dysplasias (the TRPV4 mutational family)

Energy Technology Data Exchange (ETDEWEB)

Nemec, Stefan F.; Cohn, Daniel H.; Krakow, Deborah; Funari, Vincent A.; Rimoin, David L.; Lachman, Ralph S. [Medical Genetics Institute, Cedars Sinai Medical Center, International Skeletal Dysplasia Registry, Los Angeles, CA (United States)

2012-01-15

The spondylo and spondylometaphyseal dysplasias (SMDs) are characterized by vertebral changes and metaphyseal abnormalities of the tubular bones, which produce a phenotypic spectrum of disorders from the mild autosomal-dominant brachyolmia to SMD Kozlowski to autosomal-dominant metatropic dysplasia. Investigations have recently drawn on the similar radiographic features of those conditions to define a new family of skeletal dysplasias caused by mutations in the transient receptor potential cation channel vanilloid 4 (TRPV4). This review demonstrates the significance of radiography in the discovery of a new bone dysplasia family due to mutations in a single gene. (orig.)

Translesion DNA synthesis and mutation induced in a plasmid with a single adduct of the environmental contaminant 3-nitrobenzanthrone in SOS-induced Escherichia coli

International Nuclear Information System (INIS)

Kawanishi, M.; Kanno, T.; Yagi, T.; Enya-Takamura, T.; Fuchs, R.P.

2003-01-01

Full text: 3-Nitrobenzanthrone (NBA) is a powerfully mutagenic nitrated aromatic hydrocarbon found in diesel exhaust and in airborne particulate matters. NBA forms an unusual DNA adduct in vitro that has a C-C bond between the C-8 position of deoxyguanosine and the C-2 position of NBA. We previously found that this adduct is also present in the human cells treated with NBA, and induces mutations in supF shuttle vector system. In this study, we analyzed translesion DNA synthesis (TLS) over a single adduct in lacZ' gene in a plasmid in uvrAmutS Escherichia coli. The result showed that the adduct blocked DNA replication and an observed TLS frequency was 5.4% in non-SOS-induced E. coli. All progenies after the TLS had no mutation. On the other hand, TLS increased to 11.3%, and 4.8% of them had mostly G to T mutations in SOS-induced E. coli. These results suggest that this unusual adduct would be one of causes of lung cancer that is increasing in the urban areas polluted with diesel exhaust. It must be interesting to reveal which DNA polymerase is involved in this TLS

R-process enrichment from a single event in an ancient dwarf galaxy.

Science.gov (United States)

Ji, Alexander P; Frebel, Anna; Chiti, Anirudh; Simon, Joshua D

2016-03-31

Elements heavier than zinc are synthesized through the rapid (r) and slow (s) neutron-capture processes. The main site of production of the r-process elements (such as europium) has been debated for nearly 60 years. Initial studies of trends in chemical abundances in old Milky Way halo stars suggested that these elements are produced continually, in sites such as core-collapse supernovae. But evidence from the local Universe favours the idea that r-process production occurs mainly during rare events, such as neutron star mergers. The appearance of a plateau of europium abundance in some dwarf spheroidal galaxies has been suggested as evidence for rare r-process enrichment in the early Universe, but only under the assumption that no gas accretes into those dwarf galaxies; gas accretion favours continual r-process enrichment in these systems. Furthermore, the universal r-process pattern has not been cleanly identified in dwarf spheroidals. The smaller, chemically simpler, and more ancient ultrafaint dwarf galaxies assembled shortly after the first stars formed, and are ideal systems with which to study nucleosynthesis events such as the r-process. Reticulum II is one such galaxy. The abundances of non-neutron-capture elements in this galaxy (and others like it) are similar to those in other old stars. Here, we report that seven of the nine brightest stars in Reticulum II, observed with high-resolution spectroscopy, show strong enhancements in heavy neutron-capture elements, with abundances that follow the universal r-process pattern beyond barium. The enhancement seen in this 'r-process galaxy' is two to three orders of magnitude higher than that detected in any other ultrafaint dwarf galaxy. This implies that a single, rare event produced the r-process material in Reticulum II. The r-process yield and event rate are incompatible with the source being ordinary core-collapse supernovae, but consistent with other possible sources, such as neutron star mergers.

Development of elvitegravir resistance and linkage of integrase inhibitor mutations with protease and reverse transcriptase resistance mutations.

Directory of Open Access Journals (Sweden)

Mark A Winters

Full Text Available Failure of antiretroviral regimens containing elvitegravir (EVG and raltegravir (RAL can result in the appearance of integrase inhibitor (INI drug-resistance mutations (DRMs. While several INI DRMs have been identified, the evolution of EVG DRMs and the linkage of these DRMs with protease inhibitor (PI and reverse transcriptase inhibitor (RTI DRMs have not been studied at the clonal level. We examined the development of INI DRMs in 10 patients failing EVG-containing regimens over time, and the linkage of INI DRMs with PI and RTI DRMs in these patients plus 6 RAL-treated patients. A one-step RT-nested PCR protocol was used to generate a 2.7 kB amplicon that included the PR, RT, and IN coding region, and standard cloning and sequencing techniques were used to determine DRMs in 1,277 clones (mean 21 clones per time point. Results showed all patients had multiple PI, NRTI, and/or NNRTI DRMs at baseline, but no primary INI DRM. EVG-treated patients developed from 2 to 6 strains with different primary INI DRMs as early as 2 weeks after initiation of treatment, predominantly as single mutations. The prevalence of these strains fluctuated and new strains, and/or strains with new combinations of INI DRMs, developed over time. Final failure samples (weeks 14 to 48 typically showed a dominant strain with multiple mutations or N155H alone. Single N155H or multiple mutations were also observed in RAL-treated patients at virologic failure. All patient strains showed evidence of INI DRM co-located with single or multiple PI and/or RTI DRMs on the same viral strand. Our study shows that EVG treatment can select for a number of distinct INI-resistant strains whose prevalence fluctuates over time. Continued appearance of new INI DRMs after initial INI failure suggests a potent, highly dynamic selection of INI resistant strains that is unaffected by co-location with PI and RTI DRMs.

Epidural Analgesia with Ropivacaine during Labour in a Patient with a SCN5A Gene Mutation

Directory of Open Access Journals (Sweden)

A. L. M. J. van der Knijff-van Dortmont

2016-01-01

Full Text Available SCN5A gene mutations can lead to ion channel defects which can cause cardiac conduction disturbances. In the presence of specific ECG characteristics, this mutation is called Brugada syndrome. Many drugs are associated with adverse events, making anesthesia in patients with SCN5A gene mutations or Brugada syndrome challenging. In this case report, we describe a pregnant patient with this mutation who received epidural analgesia using low dose ropivacaine and sufentanil during labour.

Pitfalls in genetic testing: the story of missed SCN1A mutations

OpenAIRE

Djémié, T.; Weckhuysen, S.; von Spiczak, S.; Carvill, G. L.; Jaehn, J.; Anttonen, A-K; Brilstra, E.; Caglayan, H. S.; de Kovel, C. G.; Depienne, C.; Gaily, E.; Gennaro, E.; Giraldez, B. G.; Gormley, P.; Guerrero-López, R.

2016-01-01

BACKGROUND: Sanger sequencing, still the standard technique for genetic testing in most diagnostic laboratories and until recently widely used in research, is gradually being complemented by next-generation sequencing (NGS). No single mutation detection technique is however perfect in identifying all mutations. Therefore, we wondered to what extent inconsistencies between Sanger sequencing and NGS affect the molecular diagnosis of patients. Since mutations in SCN1A, the major gene implicated ...

Pitfalls in genetic testing : the story of missed SCN1A mutations

OpenAIRE

Djémié, Tania; Weckhuysen, Sarah; von Spiczak, Sarah; Carvill, Gemma L; Jaehn, Johanna; Anttonen, Anna-Kaisa; Brilstra, Eva; Caglayan, Hande S; de Kovel, Carolien G; Depienne, Christel; Gaily, Eija; Gennaro, Elena; Giraldez, Beatriz G; Gormley, Padhraig; Guerrero-López, Rosa

2016-01-01

BACKGROUND: Sanger sequencing, still the standard technique for genetic testing in most diagnostic laboratories and until recently widely used in research, is gradually being complemented by next-generation sequencing (NGS). No single mutation detection technique is however perfect in identifying all mutations. Therefore, we wondered to what extent inconsistencies between Sanger sequencing and NGS affect the molecular diagnosis of patients. Since mutations in SCN1A, the major gene implicated ...

VarWalker: personalized mutation network analysis of putative cancer genes from next-generation sequencing data.

Science.gov (United States)

Jia, Peilin; Zhao, Zhongming

2014-02-01

A major challenge in interpreting the large volume of mutation data identified by next-generation sequencing (NGS) is to distinguish driver mutations from neutral passenger mutations to facilitate the identification of targetable genes and new drugs. Current approaches are primarily based on mutation frequencies of single-genes, which lack the power to detect infrequently mutated driver genes and ignore functional interconnection and regulation among cancer genes. We propose a novel mutation network method, VarWalker, to prioritize driver genes in large scale cancer mutation data. VarWalker fits generalized additive models for each sample based on sample-specific mutation profiles and builds on the joint frequency of both mutation genes and their close interactors. These interactors are selected and optimized using the Random Walk with Restart algorithm in a protein-protein interaction network. We applied the method in >300 tumor genomes in two large-scale NGS benchmark datasets: 183 lung adenocarcinoma samples and 121 melanoma samples. In each cancer, we derived a consensus mutation subnetwork containing significantly enriched consensus cancer genes and cancer-related functional pathways. These cancer-specific mutation networks were then validated using independent datasets for each cancer. Importantly, VarWalker prioritizes well-known, infrequently mutated genes, which are shown to interact with highly recurrently mutated genes yet have been ignored by conventional single-gene-based approaches. Utilizing VarWalker, we demonstrated that network-assisted approaches can be effectively adapted to facilitate the detection of cancer driver genes in NGS data.

Spectrum of small mutations in the dystrophin coding region

Energy Technology Data Exchange (ETDEWEB)

Prior, T.W.; Bartolo, C.; Pearl, D.K. [Ohio State Univ., Columbus, OH (United States)] [and others

1995-07-01

Duchenne and Becker muscular dystrophies (DMD and BMD) are caused by defects in the dystrophin gene. About two-thirds of the affected patients have large deletions or duplications, which occur in the 5` and central portion of the gene. The nondeletion/duplication cases are most likely the result of smaller mutations that cannot be identified by current diagnostic screening strategies. We screened {approximately} 80% of the dystrophin coding sequence for small mutations in 158 patients without deletions or duplications and identified 29 mutations. The study indicates that many of the DMD and the majority of the BMD small mutations lie in noncoding regions of the gene. All of the mutations identified were unique to single patients, and most of the mutations resulted in protein truncation. We did not find a clustering of small mutations similar to the deletion distribution but found > 40% of the small mutations 3` of exon 55. The extent of protein truncation caused by the 3` mutations did not determine the phenotype, since even the exon 76 nonsense mutation resulted in the severe DMD phenotype. Our study confirms that the dystrophin gene is subject to a high rate of mutation in CpG sequences. As a consequence of not finding any hotspots or prevalent small mutations, we conclude that it is presently not possible to perform direct carrier and prenatal diagnostics for many families without deletions or duplications. 71 refs., 2 figs., 2 tabs.

Kin-Driver: a database of driver mutations in protein kinases.

Science.gov (United States)

Simonetti, Franco L; Tornador, Cristian; Nabau-Moretó, Nuria; Molina-Vila, Miguel A; Marino-Buslje, Cristina

2014-01-01

Somatic mutations in protein kinases (PKs) are frequent driver events in many human tumors, while germ-line mutations are associated with hereditary diseases. Here we present Kin-driver, the first database that compiles driver mutations in PKs with experimental evidence demonstrating their functional role. Kin-driver is a manual expert-curated database that pays special attention to activating mutations (AMs) and can serve as a validation set to develop new generation tools focused on the prediction of gain-of-function driver mutations. It also offers an easy and intuitive environment to facilitate the visualization and analysis of mutations in PKs. Because all mutations are mapped onto a multiple sequence alignment, analogue positions between kinases can be identified and tentative new mutations can be proposed for studying by transferring annotation. Finally, our database can also be of use to clinical and translational laboratories, helping them to identify uncommon AMs that can correlate with response to new antitumor drugs. The website was developed using PHP and JavaScript, which are supported by all major browsers; the database was built using MySQL server. Kin-driver is available at: http://kin-driver.leloir.org.ar/ © The Author(s) 2014. Published by Oxford University Press.

Further evidence for elevated human minisatellite mutation rate in Belarus eight years after the Chernobyl accident

International Nuclear Information System (INIS)

Dubrova, Yuri E.; Buard, Jerome; Jeffreys, Alec J.; Nesterov, Valeri N.; Krouchinsky, Nicolay G.; Ostapenko, Vladislav A.; Vergnaud, Gilles; Giraudeau, Fabienne

1997-01-01

Analysis of germline mutation rate at human minisatellites among children born in areas of the Mogilev district of Belarus heavily polluted after the Chernobyl accident has been extended, both by recruiting more families from the affected region and by using five additional minisatellite probes, including multi-locus probe 33.6 and four hypervariable single-locus probes. These additional data confirmed a twofold higher mutation rate in exposed families compared with non-irradiated families from the United Kingdom. An elevated rate was seen at all three independent sets of minisatellites (detected separately by multi-locus probes 33.15, 33.6 and six single-locus probes), indicating a generalised increase in minisatellite germline mutation rate in the Belarus families. Within the Belarus cohort, mutation rate was significantly greater in families with higher parental radiation dose estimated for chronic external and internal exposure to caesium-137, consistent with radiation induction of germline mutation. The spectra of mutation seen in the unexposed and exposed families were indistinguishable, suggesting that increased mutation observed over multiple loci arises indirectly by some mechanism that enhances spontaneous minisatellite mutation

SPATACSIN mutations cause autosomal recessive juvenile amyotrophic lateral sclerosis

OpenAIRE

Orlacchio, Antonio; Babalini, Carla; Borreca, Antonella; Patrono, Clarice; Massa, Roberto; Basaran, Sarenur; Munhoz, Renato P.; Rogaeva, Ekaterina A.; St George-Hyslop, Peter H.; Bernardi, Giorgio; Kawarai, Toshitaka

2010-01-01

The mutation of the spatacsin gene is the single most common cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum. Common clinical, pathological and genetic features between amyotrophic lateral sclerosis and hereditary spastic paraplegia motivated us to investigate 25 families with autosomal recessive juvenile amyotrophic lateral sclerosis and long-term survival for mutations in the spatascin gene. The inclusion criterion was a diagnosis of clinically definite ...

Aftershock Sequences and Seismic-Like Organization of Acoustic Events Produced by a Single Propagating Crack

Science.gov (United States)

Alizee, D.; Bonamy, D.

2017-12-01

In inhomogeneous brittle solids like rocks, concrete or ceramics, one usually distinguish nominally brittle fracture, driven by the propagation of a single crack from quasibrittle one, resulting from the accumulation of many microcracks. The latter goes along with intermittent sharp noise, as e.g. revealed by the acoustic emission observed in lab scale compressive fracture experiments or at geophysical scale in the seismic activity. In both cases, statistical analyses have revealed a complex time-energy organization into aftershock sequences obeying a range of robust empirical scaling laws (the Omori-Utsu, productivity and Bath's law) that help carry out seismic hazard analysis and damage mitigation. These laws are usually conjectured to emerge from the collective dynamics of microcrack nucleation. In the experiments presented at AGU, we will show that such a statistical organization is not specific to the quasi-brittle multicracking situations, but also rules the acoustic events produced by a single crack slowly driven in an artificial rock made of sintered polymer beads. This simpler situation has advantageous properties (statistical stationarity in particular) permitting us to uncover the origins of these seismic laws: Both productivity law and Bath's law result from the scale free statistics for event energy and Omori-Utsu law results from the scale-free statistics of inter-event time. This yields predictions on how the associated parameters are related, which were analytically derived. Surprisingly, the so-obtained relations are also compatible with observations on lab scale compressive fracture experiments, suggesting that, in these complex multicracking situations also, the organization into aftershock sequences and associated seismic laws are also ruled by the propagation of individual microcrack fronts, and not by the collective, stress-mediated, microcrack nucleation. Conversely, the relations are not fulfilled in seismology signals, suggesting that

Application of high energy accelerator to study of single event burn-out (SEB)

Energy Technology Data Exchange (ETDEWEB)

Hada, Takashi; Aoki, Shiro; Nakamura, Masao; Matsuda, Sumio [National Space Development Agency of Japan, Tokyo (Japan); Hirao, Toshio; Nashiyama, Isamu; Hirose, Takayuki; Ohira, Hideharu; Nagai, Yuki

1996-12-01

Hitherto, as nuclear fission fragments of 252-Cf, one of radioactive matters have been used for elucidation of single event mechanism, this method has a limit for analysis of power MOSFET with long charge collection region (generally, empty layer) and is difficult to form the experiment simulating the space environment, because of their wide LET (Linear Energy Transfer) range and of short flying distance of about 15 micrometer. As a result, some irradiation experiments using an accelerator capable of forming charged particle beam with long flying distance and single energy became essential to elucidate the SEB mechanism. In this paper, an experiment result of SEB phenomenon using high energy accelerator was reported. As a result, following items were found: (1) With increase of impressed charge, collected charge shows two peaks, and also increases, (2) commercial power MOSFET shows about 280 V in SEB resistance, and power MOSFET developed for the space use shows about 320 V, which is improved about 40 V for the commercial one, and so forth. (G.K.)

Single event effect hardness for the front-end ASICs in the DAMPE satellite BGO calorimeter

Science.gov (United States)

Gao, Shan-Shan; Jiang, Di; Feng, Chang-Qing; Xi, Kai; Liu, Shu-Bin; An, Qi

2016-01-01

The Dark Matter Particle Explorer (DAMPE) is a Chinese scientific satellite designed for cosmic ray studies with a primary scientific goal of indirect detection of dark matter particles. As a crucial sub-detector, the BGO calorimeter measures the energy spectrum of cosmic rays in the energy range from 5 GeV to 10 TeV. In order to implement high-density front-end electronics (FEE) with the ability to measure 1848 signals from 616 photomultiplier tubes on the strictly constrained satellite platform, two kinds of 32-channel front-end ASICs, VA160 and VATA160, are customized. However, a space mission period of more than 3 years makes single event effects (SEEs) become threats to reliability. In order to evaluate SEE sensitivities of these chips and verify the effectiveness of mitigation methods, a series of laser-induced and heavy ion-induced SEE tests were performed. Benefiting from the single event latch-up (SEL) protection circuit for power supply, the triple module redundancy (TMR) technology for the configuration registers and the optimized sequential design for the data acquisition process, 52 VA160 chips and 32 VATA160 chips have been applied in the flight model of the BGO calorimeter with radiation hardness assurance. Supported by Strategic Priority Research Program on Space Science of the Chinese Academy of Sciences (XDA04040202-4) and Fundamental Research Funds for the Central Universities (WK2030040048)

Systematic Prediction of the Impacts of Mutations in MicroRNA Seed Sequences

Directory of Open Access Journals (Sweden)

Bhattacharya Anindya

2017-05-01

Full Text Available MicroRNAs are a class of small non-coding RNAs that are involved in many important biological processes and the dysfunction of microRNA has been associated with many diseases. The seed region of a microRNA is of crucial importance to its target recognition. Mutations in microRNA seed regions may disrupt the binding of microRNAs to their original target genes and make them bind to new target genes. Here we use a knowledge-based computational method to systematically predict the functional effects of all the possible single nucleotide mutations in human microRNA seed regions. The result provides a comprehensive reference for the functional assessment of the impacts of possible natural and artificial single nucleotide mutations in microRNA seed regions.

Search for Flavour Changing Neutral Currents in single top events

CERN Document Server

CMS Collaboration

2013-01-01

A study of top-quark anomalous couplings is performed through the search for a single top-quark produced in association with a $Z$ boson. The event selection requires the presence of three isolated leptons, electrons or muons, and of at least one jet. The signal extraction is done using kinematic variables and information related to b-tagging, combined using a Boosted Decision Tree. The search is performed in a data sample corresponding to about 5 fb$^{-1}$ of proton-proton collisions at $\\sqrt{s}=7$ TeV recorded with the CMS detector. No evidence of flavor-changing neutral currents is observed and upper limits at 95\\% confidence level are determined. The corresponding upper limits on the coupling strengths of an effective model are found to be $\\kappa_{gut}/\\Lambda < 0.10$ TeV$^{-1}$, $\\kappa_{gct}/\\Lambda < 0.35$ TeV$^{-1}$, $\\kappa_{Zut}/\\Lambda < 0.45$ TeV$^{-1}$ and $\\kappa_{Zct}/\\Lambda < 2.27$ TeV$^{-1}$, where $\\Lambda$ is the expected scale at which new physics could appear. The equivalen...

Estimation of the LET threshold of single event upset of microelectronics in experiments with Cf-252

International Nuclear Information System (INIS)

Kuznetsov, N.V.; Nymmik, R.A.

1996-01-01

A method is proposed for analyzing single event upsets (SEU) in large scale integration circuits of random access memory (RAM) when exposed to Cf-252 fission fragments. The method makes is possible to find the RAM linear energy transfer (LET) threshold to be used for estimations of RAM SEU rates in space. The method is illustrated by analyzing experimental data for the 2 x 8 kbit CMOS/bulk RAM. (author)

It is highly unlikely that the development of an abdominal wall hernia can be attributable to a single strenuous event.

Science.gov (United States)

Pathak, Samir; Poston, Graeme J

2006-03-01

There is a commonly held belief that the development of a hernia can be attributed to a single strenuous or traumatic event. Hence, many litigants are successful in compensation claims, causing mounting financial burdens on employers, the courts, insurance companies and the tax-payer. However, there is very little scientific evidence to support this assertion. The aim of this study was to ascertain whether there was any causal link in this process. A total of 133 new patients with 135 abdominal herniae of all varieties (115 inguinal, 3 femoral, 9 umbilical, 4 incisional, and 4 ventral or epigastric), of which 25 were recurrent received structured questionnaires on arrival in the surgical clinic. These questionnaires covered all possible aetiological factors for hernia development (type of work, COAD, smoking, pregnancy, obesity, chronic bladder outflow obstruction, previous surgery including appendicectomy), in addition to any possible attribution to a single strenuous or traumatic event. We then reviewed the GP records in the surgery of all patients who answered positively to the latter possible cause. In the study group, 119 (89%) reported a gradual onset of symptoms. Of the 15 (12 male, 3 female; 11%) who believed that their hernia might be related to a single strenuous or traumatic event, 5 had no other aetiological factors. However, not one of the 15 was found to have contemporaneous forensic medical evidence to support their possible claim. We conclude that we are unable to find any clinical evidence to support the hypothesis that a hernia might develop as the result of one single strenuous or traumatic event. While we accept that this mechanism might still possibly occur, we believe that, at best, it is extremely uncommon. If a medical expert is preparing a report on such a case in a claim for personal injury, then they have a duty to the court to examine carefully all the contemporaneous medical records. If no clinical evidence exists to support the claim

Addition of molecular methods to mutation studies with Drosophila melanogaster

International Nuclear Information System (INIS)

Lee, W.R.

1989-01-01

For 80 years, Drosophila melanogaster has been used as a major tool in analyzing Mendelian genetics. By using chromosome inversions that suppress crossing over, geneticists have developed a large number of stocks for mutation analysis. These stocks permit numerous tests for specific locus mutations, lethals at multiple loci on any chromosome, chromosome exchanges, insertions, and deletions. The entire genome can be manipulated for a degree of genetic control not found in other germ-line systems. Recombinant DNA techniques now permit analysis of mutations to the nucleotide level. By combining classical genetic analysis with recombinant DNA techniques, it is possible to analyze mutations that range from chromosome aberrations and multilocus deficiencies to single nucleotide transitions

Finding cancer driver mutations in the era of big data research.

Science.gov (United States)

Poulos, Rebecca C; Wong, Jason W H

2018-04-02

In the last decade, the costs of genome sequencing have decreased considerably. The commencement of large-scale cancer sequencing projects has enabled cancer genomics to join the big data revolution. One of the challenges still facing cancer genomics research is determining which are the driver mutations in an individual cancer, as these contribute only a small subset of the overall mutation profile of a tumour. Focusing primarily on somatic single nucleotide mutations in this review, we consider both coding and non-coding driver mutations, and discuss how such mutations might be identified from cancer sequencing datasets. We describe some of the tools and database that are available for the annotation of somatic variants and the identification of cancer driver genes. We also address the use of genome-wide variation in mutation load to establish background mutation rates from which to identify driver mutations under positive selection. Finally, we describe the ways in which mutational signatures can act as clues for the identification of cancer drivers, as these mutations may cause, or arise from, certain mutational processes. By defining the molecular changes responsible for driving cancer development, new cancer treatment strategies may be developed or novel preventative measures proposed.

Mutations in the bacterial ribosomal protein l3 and their association with antibiotic resistance

DEFF Research Database (Denmark)

Klitgaard, Rasmus N; Ntokou, Eleni; Nørgaard, Katrine

2015-01-01

-type genes with mutated L3 genes in a chromosomal L3 deletion strain. In this way, the essential L3 gene is available for the bacteria while allowing replacement of the wild type with mutated L3 genes. This enables investigation of the effect of single mutations in Escherichia coli without a wild-type L3...

Novel USH2A mutations in Japanese Usher syndrome type 2 patients: marked differences in the mutation spectrum between the Japanese and other populations.

Science.gov (United States)

Nakanishi, Hiroshi; Ohtsubo, Masafumi; Iwasaki, Satoshi; Hotta, Yoshihiro; Usami, Shin-Ichi; Mizuta, Kunihiro; Mineta, Hiroyuki; Minoshima, Shinsei

2011-07-01

Usher syndrome (USH) is an autosomal recessive disorder characterized by retinitis pigmentosa and hearing loss. USH type 2 (USH2) is the most common type of USH and is frequently caused by mutations in USH2A. In a recent mutation screening of USH2A in Japanese USH2 patients, we identified 11 novel mutations in 10 patients and found the possible frequent mutation c.8559-2A>G in 4 of 10 patients. To obtain a more precise mutation spectrum, we analyzed further nine Japanese patients in this study. We identified nine mutations, of which eight were novel. This result indicates that the mutation spectrum for USH2A among Japanese patients largely differs from Caucasian, Jewish and Palestinian patients. Meanwhile, we did not find the c.8559-2A>G in this study. Haplotype analysis of the c.8559-2G (mutated) alleles using 23 single nucleotide polymorphisms surrounding the mutation revealed an identical haplotype pattern of at least 635 kb in length, strongly suggesting that the mutation originated from a common ancestor. The fact that all patients carrying c.8559-2A>G came from western Japan suggests that the mutation is mainly distributed in that area; indeed, most of the patients involved in this study came from eastern Japan, which contributed to the absence of c.8559-2A>G.

Genome-wide analysis of mutations in mutant lineages selected following fast-neutron irradiation mutagenesis of Arabidopsis thaliana

KAUST Repository

Belfield, E.J.; Gan, X.; Mithani, A.; Brown, C.; Jiang, C.; Franklin, K.; Alvey, E.; Wibowo, A.; Jung, M.; Bailey, K.; Kalwani, S.; Ragoussis, J.; Mott, R.; Harberd, N.P.

2012-01-01

Ionizing radiation has long been known to induce heritable mutagenic change in DNA sequence. However, the genome-wide effect of radiation is not well understood. Here we report the molecular properties and frequency of mutations in phenotypically selected mutant lines isolated following exposure of the genetic model flowering plant Arabidopsis thaliana to fast neutrons (FNs). Previous studies suggested that FNs predominantly induce deletions longer than a kilobase in A. thaliana. However, we found a higher frequency of single base substitution than deletion mutations. While the overall frequency and molecular spectrum of fast-neutron (FN)-induced single base substitutions differed substantially from those of "background" mutations arising spontaneously in laboratory-grown plants, G:C>A:T transitions were favored in both. We found that FN-induced G:C>A:T transitions were concentrated at pyrimidine dinucleotide sites, suggesting that FNs promote the formation of mutational covalent linkages between adjacent pyrimidine residues. In addition, we found that FNs induced more single base than large deletions, and that these single base deletions were possibly caused by replication slippage. Our observations provide an initial picture of the genome-wide molecular profile of mutations induced in A. thaliana by FN irradiation and are particularly informative of the nature and extent of genome-wide mutation in lines selected on the basis of mutant phenotypes from FN-mutagenized A. thaliana populations.

Genome-wide analysis of mutations in mutant lineages selected following fast-neutron irradiation mutagenesis of Arabidopsis thaliana

KAUST Repository

Belfield, E.J.

2012-04-12

Ionizing radiation has long been known to induce heritable mutagenic change in DNA sequence. However, the genome-wide effect of radiation is not well understood. Here we report the molecular properties and frequency of mutations in phenotypically selected mutant lines isolated following exposure of the genetic model flowering plant Arabidopsis thaliana to fast neutrons (FNs). Previous studies suggested that FNs predominantly induce deletions longer than a kilobase in A. thaliana. However, we found a higher frequency of single base substitution than deletion mutations. While the overall frequency and molecular spectrum of fast-neutron (FN)-induced single base substitutions differed substantially from those of "background" mutations arising spontaneously in laboratory-grown plants, G:C>A:T transitions were favored in both. We found that FN-induced G:C>A:T transitions were concentrated at pyrimidine dinucleotide sites, suggesting that FNs promote the formation of mutational covalent linkages between adjacent pyrimidine residues. In addition, we found that FNs induced more single base than large deletions, and that these single base deletions were possibly caused by replication slippage. Our observations provide an initial picture of the genome-wide molecular profile of mutations induced in A. thaliana by FN irradiation and are particularly informative of the nature and extent of genome-wide mutation in lines selected on the basis of mutant phenotypes from FN-mutagenized A. thaliana populations.

Brief Report: Human Acute Myeloid Leukemia Reprogramming to Pluripotency Is a Rare Event and Selects for Patient Hematopoietic Cells Devoid of Leukemic Mutations.

Science.gov (United States)

Lee, Jong-Hee; Salci, Kyle R; Reid, Jennifer C; Orlando, Luca; Tanasijevic, Borko; Shapovalova, Zoya; Bhatia, Mickie

2017-09-01

Induced pluripotent stem cell reprogramming has provided critical insights into disease processes by modeling the genetics and related clinical pathophysiology. Human cancer represents highly diverse genetics, as well as inter- and intra-patient heterogeneity, where cellular model systems capable of capturing this disease complexity would be invaluable. Acute myeloid leukemia (AML) represents one of most heterogeneous cancers and has been divided into genetic subtypes correlated with unique risk stratification over the decades. Here, we report our efforts to induce pluripotency from the heterogeneous population of human patients that represents this disease in the clinic. Using robust optimized reprogramming methods, we demonstrate that reprogramming of AML cells harboring leukemic genomic aberrations is a rare event with the exception of those with de novo mixed-lineage leukemia (MLL) mutations that can be reprogrammed and model drug responses in vitro. Our findings indicate that unlike hematopoietic cells devoid of genomic aberrations, AML cells harboring driver mutations are refractory to reprogramming. Expression of MLL fusion proteins in AML cells did not contribute to induced reprogramming success, which continued to select for patient derived cells devoid of AML patient-specific aberrations. Our study reveals that unanticipated blockades to achieving pluripotency reside within the majority of transformed AML patient cells. Stem Cells 2017;35:2095-2102. © 2017 AlphaMed Press.

Teaching the fluctuation test in silico by using mutate: a program to distinguish between the adaptive and spontaneous mutation hypotheses.

Science.gov (United States)

Carvajal-Rodríguez, Antonio

2012-07-01

Mutate is a program developed for teaching purposes to impart a virtual laboratory class for undergraduate students of Genetics in Biology. The program emulates the so-called fluctuation test whose aim is to distinguish between spontaneous and adaptive mutation hypotheses in bacteria. The plan is to train students in certain key multidisciplinary aspects of current genetics such as sequence databases, DNA mutations, and hypothesis testing, while introducing the fluctuation test. This seminal experiment was originally performed studying Escherichia coli resistance to the infection by bacteriophage T1. The fluctuation test initiated the modern bacterial genetics that 25 years later ushered in the era of the recombinant DNA. Nowadays we know that some deletions in fhuA, the gene responsible for E. coli membrane receptor of T1, could cause the E. coli resistance to this phage. For the sake of simplicity, we will introduce the assumption that a single mutation generates the resistance to T1. During the practical, the students use the program to download some fhuA gene sequences, manually introduce some stop codon mutations, and design a fluctuation test to obtain data for distinguishing between preadaptative (spontaneous) and induced (adaptive) mutation hypotheses. The program can be launched from a browser or, if preferred, its executable file can be downloaded from http://webs.uvigo.es/acraaj/MutateWeb/Mutate.html. It requires the Java 5.0 (or higher) Runtime Environment (freely available at http://www.java.com). Copyright © 2012 Wiley Periodicals, Inc.

The allele-frequency spectrum in a decoupled Moran model with mutation, drift, and directional selection, assuming small mutation rates.

Science.gov (United States)

Vogl, Claus; Clemente, Florian

2012-05-01

We analyze a decoupled Moran model with haploid population size N, a biallelic locus under mutation and drift with scaled forward and backward mutation rates θ(1)=μ(1)N and θ(0)=μ(0)N, and directional selection with scaled strength γ=sN. With small scaled mutation rates θ(0) and θ(1), which is appropriate for single nucleotide polymorphism data in highly recombining regions, we derive a simple approximate equilibrium distribution for polymorphic alleles with a constant of proportionality. We also put forth an even simpler model, where all mutations originate from monomorphic states. Using this model we derive the sojourn times, conditional on the ancestral and fixed allele, and under equilibrium the distributions of fixed and polymorphic alleles and fixation rates. Furthermore, we also derive the distribution of small samples in the diffusion limit and provide convenient recurrence relations for calculating this distribution. This enables us to give formulas analogous to the Ewens-Watterson estimator of θ for biased mutation rates and selection. We apply this theory to a polymorphism dataset of fourfold degenerate sites in Drosophila melanogaster. Copyright © 2012 Elsevier Inc. All rights reserved.

Influence of edge effects on single event upset susceptibility of SOI SRAMs

International Nuclear Information System (INIS)

Gu, Song; Liu, Jie; Zhao, Fazhan; Zhang, Zhangang; Bi, Jinshun; Geng, Chao; Hou, Mingdong; Liu, Gang; Liu, Tianqi; Xi, Kai

2015-01-01

An experimental investigation of the single event upset (SEU) susceptibility for heavy ions at tilted incidence was performed. The differences of SEU cross-sections between tilted incidence and normal incidence at equivalent effective linear energy transfer were 21% and 57% for the silicon-on-insulator (SOI) static random access memories (SRAMs) of 0.5 μm and 0.18 μm feature size, respectively. The difference of SEU cross-section raised dramatically with increasing tilt angle for SOI SRAM of deep-submicron technology. The result of CRÈME-MC simulation for tilted irradiation of the sensitive volume indicates that the energy deposition spectrum has a substantial tail extending into the low energy region. The experimental results show that the influence of edge effects on SEU susceptibility cannot be ignored in particular with device scaling down

A mutation in the receptor Methoprene-tolerant alters juvenile hormone response in insects and crustaceans.

Science.gov (United States)

Miyakawa, Hitoshi; Toyota, Kenji; Hirakawa, Ikumi; Ogino, Yukiko; Miyagawa, Shinichi; Oda, Shigeto; Tatarazako, Norihisa; Miura, Toru; Colbourne, John K; Iguchi, Taisen

2013-01-01

Juvenile hormone is an essential regulator of major developmental and life history events in arthropods. Most of the insects use juvenile hormone III as the innate juvenile hormone ligand. By contrast, crustaceans use methyl farnesoate. Despite this difference that is tied to their deep evolutionary divergence, the process of this ligand transition is unknown. Here we show that a single amino-acid substitution in the receptor Methoprene-tolerant has an important role during evolution of the arthropod juvenile hormone pathway. Microcrustacea Daphnia pulex and D. magna share a juvenile hormone signal transduction pathway with insects, involving Methoprene-tolerant and steroid receptor coactivator proteins that form a heterodimer in response to various juvenoids. Juvenile hormone-binding pockets of the orthologous genes differ by only two amino acids, yet a single substitution within Daphnia Met enhances the receptor's responsiveness to juvenile hormone III. These results indicate that this mutation within an ancestral insect lineage contributed to the evolution of a juvenile hormone III receptor system.

Mutation breeding research of wheat (T. aestivum) in China

International Nuclear Information System (INIS)

Wang, L.; Zhang, B.; Shi, J.; Tao, S.; Fan, Q.

1990-01-01

Full text: 78 cultivars and various valuable strains have been obtained through induced genic mutation and chromosome translocation. Irradiation of hybrid seeds, gametes, zygotes and in vitro cultured cells, gave increased mutation frequency and expanded spectrum. Various physical agents were examined either singly or in combination with chemical agents. Combined use of γ-irradiation by low dose and in vitro culture proved effective in raising the percentage of seed-set in wide-crosses. (author)

Methylenetetrahydrofolate reductase homozygous mutation in a young boy with cerebellar infarction

Directory of Open Access Journals (Sweden)

Alberto Spalice

2009-11-01

Full Text Available Posterior circulation vascular occlusive disease in children is a rare and uncommonly reported event. Among the numerous risk factors, the methylenetetrahydrofolate reductase (MTHFR mutation is considered to be a common genetic cause of thrombosis in adults and children. Recently, a link between the MTHFR mutation and cerebrovascular disorders was reported in children. Diffusion tensor imaging (DTI is a great improvement on magnetic resonance imaging (MRI, making the in vivo anatomical and pathological study of the brain and its fibers possible. In our patient cerebellar infarction was associated with MTHFR mutation and, in a standard neurological examination, DTI revealed normal white matter tracts.

Single charging events on colloidal particles in a nonpolar liquid with surfactant

Science.gov (United States)

Schreuer, Caspar; Vandewiele, Stijn; Brans, Toon; Strubbe, Filip; Neyts, Kristiaan; Beunis, Filip

2018-01-01

Electrical charging of colloidal particles in nonpolar liquids due to surfactant additives is investigated intensively, motivated by its importance in a variety of applications. Most methods rely on average electrophoretic mobility measurements of many particles, which provide only indirect information on the charging mechanism. In the present work, we present a method that allows us to obtain direct information on the charging mechanism, by measuring the charge fluctuations on individual particles with a precision higher than the elementary charge using optical trapping electrophoresis. We demonstrate the capabilities of the method by studying the influence of added surfactant OLOA 11000 on the charging of single colloidal PMMA particles in dodecane. The particle charge and the frequency of charging events are investigated both below and above the critical micelle concentration (CMC) and with or without applying a DC offset voltage. It is found that at least two separate charging mechanisms are present below the critical micelle concentration. One mechanism is a process where the particle is stripped from negatively charged ionic molecules. An increase in the charging frequency with increased surfactant concentration suggests a second mechanism that involves single surfactant molecules. Above the CMC, neutral inverse micelles can also be involved in the charging process.

Analyzing Test-As-You-Fly Single Event Upset (SEU) Responses using SEU Data, Classical Reliability Models, and Space Environment Data

Science.gov (United States)

Berg, Melanie; Label, Kenneth; Campola, Michael; Xapsos, Michael

2017-01-01

We propose a method for the application of single event upset (SEU) data towards the analysis of complex systems using transformed reliability models (from the time domain to the particle fluence domain) and space environment data.

Whole-genome sequencing of multiple myeloma from diagnosis to plasma cell leukemia reveals genomic initiating events, evolution, and clonal tides.

Science.gov (United States)

Egan, Jan B; Shi, Chang-Xin; Tembe, Waibhav; Christoforides, Alexis; Kurdoglu, Ahmet; Sinari, Shripad; Middha, Sumit; Asmann, Yan; Schmidt, Jessica; Braggio, Esteban; Keats, Jonathan J; Fonseca, Rafael; Bergsagel, P Leif; Craig, David W; Carpten, John D; Stewart, A Keith

2012-08-02

The longitudinal evolution of a myeloma genome from diagnosis to plasma cell leukemia has not previously been reported. We used whole-genome sequencing (WGS) on 4 purified tumor samples and patient germline DNA drawn over a 5-year period in a t(4;14) multiple myeloma patient. Tumor samples were acquired at diagnosis, first relapse, second relapse, and end-stage secondary plasma cell leukemia (sPCL). In addition to the t(4;14), all tumor time points also shared 10 common single-nucleotide variants (SNVs) on WGS comprising shared initiating events. Interestingly, we observed genomic sequence variants that waxed and waned with time in progressive tumors, suggesting the presence of multiple independent, yet related, clones at diagnosis that rose and fell in dominance. Five newly acquired SNVs, including truncating mutations of RB1 and ZKSCAN3, were observed only in the final sPCL sample suggesting leukemic transformation events. This longitudinal WGS characterization of the natural history of a high-risk myeloma patient demonstrated tumor heterogeneity at diagnosis with shifting dominance of tumor clones over time and has also identified potential mutations contributing to myelomagenesis as well as transformation from myeloma to overt extramedullary disease such as sPCL.

Presence of calreticulin mutations in JAK2-negative polycythemia vera.

Science.gov (United States)

Broséus, Julien; Park, Ji-Hye; Carillo, Serge; Hermouet, Sylvie; Girodon, François

2014-12-18

Calreticulin (CALR) mutations have been reported in Janus kinase 2 (JAK2)- and myeloproliferative leukemia (MPL)-negative essential thrombocythemia and primary myelofibrosis. In contrast, no CALR mutations have ever been reported in the context of polycythemia vera (PV). Here, we describe 2 JAK2(V617F)-JAK2(exon12)-negative PV patients who presented with a CALR mutation in peripheral granulocytes at the time of diagnosis. In both cases, the CALR mutation was a 52-bp deletion. Single burst-forming units-erythroid (BFU-E) from 1 patient were grown in vitro and genotyped: the same CALR del 52-bp mutation was noted in 31 of the 37 colonies examined; 30 of 31 BFU-E were heterozygous for CALR del 52 bp, and 1 of 31 BFU-E was homozygous for CALR del 52 bp. In summary, although unknown mutations leading to PV cannot be ruled out, our results suggest that CALR mutations can be associated with JAK2-negative PV. © 2014 by The American Society of Hematology.

Mutations in FUS cause FALS and SALS in French and French Canadian populations.

Science.gov (United States)

Belzil, V V; Valdmanis, P N; Dion, P A; Daoud, H; Kabashi, E; Noreau, A; Gauthier, J; Hince, P; Desjarlais, A; Bouchard, J-P; Lacomblez, L; Salachas, F; Pradat, P-F; Camu, W; Meininger, V; Dupré, N; Rouleau, G A

2009-10-13

The identification of mutations in the TARDBP and more recently the identification of mutations in the FUS gene as the cause of amyotrophic lateral sclerosis (ALS) is providing the field with new insight about the mechanisms involved in this severe neurodegenerative disease. To extend these recent genetic reports, we screened the entire gene in a cohort of 200 patients with ALS. An additional 285 patients with sporadic ALS were screened for variants in exon 15 for which mutations were previously reported. In total, 3 different mutations were identified in 4 different patients, including 1 3-bp deletion in exon 3 of a patient with sporadic ALS and 2 missense mutations in exon 15 of 1 patient with familial ALS and 2 patients with sporadic ALS. Our study identified sporadic patients with mutations in the FUS gene. The accumulation and description of different genes and mutations helps to develop a more comprehensive picture of the genetic events underlying amyotrophic lateral sclerosis.

New insight into the parasitic bipolar amplification effect in single event transient production

International Nuclear Information System (INIS)

Chen Jian-Jun; Chen Shu-Ming; Liang Bin; Deng Ke-Feng

2012-01-01

In this paper, a new method is proposed to study the mechanism of charge collection in single event transient (SET) production in 90 nm bulk complementary metal oxide semiconductor (CMOS) technology. We find that different from the case in the pMOSFET, the parasitic bipolar amplification effect (bipolar effect) in the balanced inverter does not exist in the nMOSFET after the ion striking. The influence of the substrate process on the bipolar effect is also studied in the pMOSFET. We find that the bipolar effect can be effectively mitigated by a buried deep P + -well layer and can be removed by a buried SO 2 layer. (condensed matter: structural, mechanical, and thermal properties)

Effects of drain-wall in mitigating N-hit single event transient via 45 nm CMOS process

International Nuclear Information System (INIS)

Xu, X Y; Tang, M H; Xiao, Y G; Yan, S A; Zhang, W L; Li, Z; Xiong, Y; Zhao, W; Guo, H X

2015-01-01

A three-dimensional (3D) technology computer-aided design (TCAD) simulation in a novel layout technique for N-hit single event transient (SET) mitigation based on drain-wall layout technique is proposed. Numerical simulations of both single-device and mixed-mode show that the proposed layout technique designed with 45 nm CMOS process can efficiently reduce not only charge collection but also SET pulse widths (W SET ). What is more, simulations show that impacts caused by part of ion-incidents can be shielded with this novel layout technique. When compared with conventional layout technique and guard drain layout technique, we find that the proposed novel layout technique can provide the best benefit of SET mitigation with a small sacrifice in effective area. (paper)

Mutational Spectrum in a Worldwide Study of 29,700 Families with BRCA1 or BRCA2 Mutations

DEFF Research Database (Denmark)

Rebbeck, Timothy R; Friebel, Tara M; Friedman, Eitan

2018-01-01

The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on Caucasians in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with...

Mutational Spectrum in a Worldwide Study of 29,700 Families with BRCA1 or BRCA2 Mutations

NARCIS (Netherlands)

Rebbeck, Timothy R.; Friebel, Tara M.; Friedman, Eitan; Hamann, Ute; Huo, Dezheng; Kwong, Ava; Olah, Edith; Olopade, Olufunmilayo I.; Solano, Angela R.; teo, Soo-Hwang; Thomassen, Mads; Weitzel, Jeffrey N.; Chan, T. L.; Couch, Fergus J.; Goldgar, David E.; Kruse, Torben A.; Palmero, Edenir Inêz; Park, Sue Kyung; Torres, Diana; van Rensburg, Elizabeth J.; McGuffog, Lesley; Parsons, Michael T.; Leslie, Goska; Aalfs, Cora M.; Abugattas, Julio; Adlard, Julian; Agata, Simona; Aittomäki, Kristiina; Andrews, Lesley; Andrulis, Irene L.; Arason, Adalgeir; Arnold, Norbert; Arun, Banu K.; Asseryanis, Ella; Auerbach, Leo; Azzollini, Jacopo; Balmaña, Judith; Barile, Monica; Barkardottir, Rosa B.; Barrowdale, Daniel; Benitez, Javier; Berger, Andreas; Berger, Raanan; Blanco, Amie M.; Blazer, Kathleen R.; Blok, Marinus J.; Bonadona, Valérie; Bonanni, Bernardo; Bradbury, Angela R.; Brewer, Carole; Buecher, Bruno; Buys, Saundra S.; Caldes, Trinidad; Caliebe, Almuth; Caligo, Maria A.; Campbell, Ian; Caputo, Sandrine; Chiquette, Jocelyne; Chung, Wendy K.; Claes, Kathleen B. M.; Collée, J. Margriet; Cook, Jackie; Davidson, Rosemarie; de la Hoya, Miguel; de Leeneer, Kim; de Pauw, Antoine; Delnatte, Capucine; Diez, Orland; Ding, Yuan Chun; Ditsch, Nina; Domchek, Susan M.; Dorfling, Cecilia M.; Velazquez, Carolina; Dworniczak, Bernd; Eason, Jacqueline; Easton, Douglas F.; Eeles, Ros; Ehrencrona, Hans; Ejlertsen, Bent; Engel, Christoph; Engert, Stefanie; Evans, D. Gareth; Faivre, Laurence; Feliubadaló, Lidia; Ferrer, Sandra Fert; Foretova, Lenka; Fowler, Jeffrey; Frost, Debra; Galvão, Henrique C. R.; Ganz, Patricia A.; Garber, Judy; Gauthier-Villars, Marion; Gehrig, Andrea; Gerdes, Anne-Marie; Gesta, Paul; Giannini, Giuseppe; Giraud, Sophie; Glendon, Gord; Godwin, Andrew K.; Greene, Mark H.; Gronwald, Jacek; Gutierrez-Barrera, Angelica; Hahnen, Eric; Hauke, Jan; Henderson, Alex; Hentschel, Julia; Hogervorst, Frans B. L.; Honisch, Ellen; Imyanitov, Evgeny N.; Isaacs, Claudine; Izatt, Louise; Izquierdo, Angel; Jakubowska, Anna; James, Paul; Janavicius, Ramunas; Jensen, Uffe Birk; John, Esther M.; Joseph, Vijai; Kaczmarek, Katarzyna; Karlan, Beth Y.; Kast, Karin; Investigators, kConFab; Kim, Sung-Won; Konstantopoulou, Irene; Korach, Jacob; Laitman, Yael; Lasa, Adriana; Lasset, Christine; Lázaro, Conxi; Lee, Annette; Lee, Min Hyuk; Lester, Jenny; Lesueur, Fabienne; Liljegren, Annelie; Lindor, Noralane M.; Longy, Michel; Loud, Jennifer T.; Lu, Karen H.; Lubinski, Jan; Machackova, Eva; Manoukian, Siranoush; Mari, Véronique; Martínez-Bouzas, Cristina; Matrai, Zoltan; Mebirouk, Noura; Meijers-Heijboer, Hanne E. J.; Meindl, Alfons; Mensenkamp, Arjen R.; Mickys, Ugnius; Miller, Austin; Montagna, Marco; Moysich, Kirsten B.; Mulligan, Anna Marie; Musinsky, Jacob; Neuhausen, Susan L.; Nevanlinna, Heli; Ngeow, Joanne; Nguyen, Huu Phuc; Niederacher, Dieter; Nielsen, Henriette Roed; Nielsen, Finn Cilius; Nussbaum, Robert L.; Offit, Kenneth; Öfverholm, Anna; Ong, Kai-Ren; Osorio, Ana; Papi, Laura; Papp, Janos; Pasini, Barbara; Pedersen, Inge Sokilde; MSc, Ana Peixoto; MSc, Nina Peruga; Peterlongo, Paolo; Pohl, Esther; Ba, Nisha Pradhan; Prajzendanc, Karolina; Prieur, Fabienne; Pujol, Pascal; Radice, Paolo; Ramus, Susan J.; Rantala, Johanna; Rashid, Muhammad Usman; Rhiem, Kerstin; Robson, Mark; Rodriguez, Gustavo C.; Rogers, Mark T.; Rudaitis, Vilius; Schmidt, Ane Y.; Schmutzler, Rita Katharina; Senter, Leigha; Shah, Payal D.; Sharma, Priyanka; Side, Lucy E.; Simard, Jacques; Singer, Christian F.; Skytte, Anne-Bine; Slavin, Thomas P.; Snape, Katie; Sobol, Hagay; Southey, Melissa; Steele, Linda; Steinemann, Doris; Sukiennicki, Grzegorz; Sutter, Christian; Szabo, Csilla I.; Tan, Yen Y.; Teixeira, Manuel R.; Terry, Mary Beth; Teulé, Alex; Thomas, Abigail; Thull, Darcy L.; Tischkowitz, Marc; Tognazzo, Silvia; Toland, Amanda Ewart; Topka, Sabine; Trainer, Alison H.; Tung, Nadine; van Asperen, Christi J.; van der Hout, Annemieke H.; van der Kolk, Lizet E.; van der Luijt, Rob B.; van Heetvelde, Mattias; Varesco, Liliana; Varon-Mateeva, Raymonda; Vega, Ana; Villarreal-Garza, Cynthia; von Wachenfeldt, Anna; Walker, Lisa; Wang-Gohrke, Shan; Wappenschmidt, Barbara; Weber, Bernhard H. F.; Yannoukakos, Drakoulis; Yoon, Sook-Yee; Zanzottera, Cristina; Zidan, Jamal; Zorn, Kristin K.; Selkirk, Christina G. Hutten; Hulick, Peter J.; Chenevix-Trench, Georgia; Spurdle, Amanda B.; Antoniou, Antonis C.; Nathanson, Katherine L.

2018-01-01

The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on Caucasians in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with

Rapid identification of HEXA mutations in Tay-Sachs patients.

Science.gov (United States)

Giraud, Carole; Dussau, Jeanne; Azouguene, Emilie; Feillet, François; Puech, Jean-Philippe; Caillaud, Catherine

2010-02-19

Tay-Sachs disease (TSD) is a recessively inherited neurodegenerative disorder due to mutations in the HEXA gene resulting in a beta-hexosaminidase A (Hex A) deficiency. The purpose of this study was to characterize the molecular abnormalities in patients with infantile or later-onset forms of the disease. The complete sequencing of the 14 exons and flanking regions of the HEXA gene was performed with a unique technical condition in 10 unrelated TSD patients. Eleven mutations were identified, including five splice mutations, one insertion, two deletions and three single-base substitutions. Four mutations were novel: two splice mutations (IVS8+5G>A, IVS2+4delAGTA), one missense mutation in exon 6 (c.621T>G (p.D207E)) and one small deletion (c.1211-1212delTG) in exon 11 resulting in a premature stop codon at residue 429. The c.621T>G missense mutation was found in a patient presenting an infantile form. Its putative role in the pathogenesis of TSD is suspected as residue 207 is highly conserved in human, mouse and rat. Moreover, structural modelling predicted changes likely to affect substrate binding and catalytic activity of the enzyme. The time-saving procedure reported here could be useful for the characterization of Tay-Sachs-causing mutations, in particular in non-Ashkenazi patients mainly exhibiting rare mutations. Copyright (c) 2010 Elsevier Inc. All rights reserved.

Experiments on the role of deleterious mutations as stepping stones in adaptive evolution

Science.gov (United States)

Covert, Arthur W.; Lenski, Richard E.; Wilke, Claus O.; Ofria, Charles

2013-01-01

Many evolutionary studies assume that deleterious mutations necessarily impede adaptive evolution. However, a later mutation that is conditionally beneficial may interact with a deleterious predecessor before it is eliminated, thereby providing access to adaptations that might otherwise be inaccessible. It is unknown whether such sign-epistatic recoveries are inconsequential events or an important factor in evolution, owing to the difficulty of monitoring the effects and fates of all mutations during experiments with biological organisms. Here, we used digital organisms to compare the extent of adaptive evolution in populations when deleterious mutations were disallowed with control populations in which such mutations were allowed. Significantly higher fitness levels were achieved over the long term in the control populations because some of the deleterious mutations served as stepping stones across otherwise impassable fitness valleys. As a consequence, initially deleterious mutations facilitated the evolution of complex, beneficial functions. We also examined the effects of disallowing neutral mutations, of varying the mutation rate, and of sexual recombination. Populations evolving without neutral mutations were able to leverage deleterious and compensatory mutation pairs to overcome, at least partially, the absence of neutral mutations. Substantially raising or lowering the mutation rate reduced or eliminated the long-term benefit of deleterious mutations, but introducing recombination did not. Our work demonstrates that deleterious mutations can play an important role in adaptive evolution under at least some conditions. PMID:23918358