Publications by authors named "Renate Schmidt"

40 Publications

Maternal and neonatal complications in women with congenital heart disease: a nationwide analysis.

Eur Heart J 2021 Oct 12. Epub 2021 Oct 12.

Department of Cardiology III, Adult Congenital and Valvular Heart Disease, University Hospital Muenster, Albert-Schweitzer-Campus 1, 48149 Münster, Germany.

Aims: The aim of this study was to provide population-based data on maternal and neonatal complications and outcome in the pregnancies of women with congenital heart disease (CHD).

Methods And Results: Based on administrative data from one of the largest German Health Insurance Companies (BARMER GEK, ∼9 million members representative for Germany), all pregnancies in women with CHD between 2005 and 2018 were analysed. In addition, an age-matched non-CHD control group was included for comparison and the association between adult CHD (ACHD) and maternal or neonatal outcomes investigated. Overall, 7512 pregnancies occurred in 4015 women with CHD. The matched non-CHD control group included 6502 women with 11 225 pregnancies. Caesarean deliveries were more common in CHD patients (40.5% vs. 31.5% in the control group; P < 0.001). There was no excess mortality. Although the maternal complication rate was low in absolute terms, women with CHD had a significantly higher rate of stroke, heart failure and cardiac arrhythmias during pregnancy (P < 0.001 for all). Neonatal mortality was low but also significantly higher in the ACHD group (0.83% vs. 0.22%; P = 0.001) and neonates to CHD mothers had low/extremely low birth weight or extreme immaturity (<0.001) or required resuscitation and mechanical ventilation more often compared to non-CHD offspring (P < 0.001 for both). On multivariate logistic regression maternal defect complexity, arterial hypertension, heart failure, prior fertility treatment, and anticoagulation with vitamin K antagonists emerged as significant predictors of adverse neonatal outcome (P < 0.05 for all). Recurrence of CHD was 6.1 times higher in infants to ACHD mothers compared to controls (P < 0.0001).

Conclusions: This population-based study illustrates a reassuringly low maternal mortality rate in a highly developed healthcare system. Nevertheless, maternal morbidity and neonatal morbidity/mortality were significantly increased in women with ACHD and their offspring compared to non-ACHD controls highlighting the need of specialized care and pre-pregnancy counselling.
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http://dx.doi.org/10.1093/eurheartj/ehab571DOI Listing
October 2021

Lack of specialist care is associated with increased morbidity and mortality in adult congenital heart disease: a population-based study.

Eur Heart J 2021 Jul 16. Epub 2021 Jul 16.

Department of Cardiology III-Adult Congenital and Valvular Heart Disease, University Hospital Muenster, Albert-Schweitzer Campus 1, Building A1, Münster 48149, Germany.

Aims: The aim of this study was to provide population-based data on the healthcare provision for adults with congenital heart disease (ACHD) and the impact of cardiology care on morbidity and mortality in this vulnerable population.

Methods And Results: Based on administrative data from one of the largest German Health Insurance Companies, all insured ACHD patients (<70 years of age) were included. Patients were stratified into those followed exclusively by primary care physicians (PCPs) and those with additional cardiology follow-up between 2014 and 2016. Associations between level of care and outcome were assessed by multivariable/propensity score Cox analyses. Overall, 24 139 patients (median age 43 years, 54.8% female) were included. Of these, only 49.7% had cardiology follow-up during the 3-year period, with 49.2% of patients only being cared for by PCPs and 1.1% having no contact with either. After comprehensive multivariable and propensity score adjustment, ACHD patients under cardiology follow-up had a significantly lower risk of death [hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.67-0.98; P = 0.03) or major events (HR 0.85, 95% CI 0.78-0.92; P < 0.001) compared to those only followed by PCPs. At 3-year follow-up, the absolute risk difference for mortality was 0.9% higher in ACHD patients with moderate/severe complexity lesions cared by PCPs compared to those under cardiology follow-up.

Conclusion: Cardiology care compared with primary care is associated with superior survival and lower rates of major complications in ACHD. It is alarming that even in a high resource setting with well-established specialist ACHD care approximately 50% of contemporary ACHD patients are still not linked to regular cardiac care. Almost all patients had at least one contact with a PCP during the study period, suggesting that opportunities to refer patients to cardiac specialists were missed at PCP level. More efforts are required to alert PCPs and patients to appropriate ACHD care.
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http://dx.doi.org/10.1093/eurheartj/ehab422DOI Listing
July 2021

Unlocking big data doubled the accuracy in predicting the grain yield in hybrid wheat.

Sci Adv 2021 Jun 11;7(24). Epub 2021 Jun 11.

Leibniz Institute of Plant Genetics and Crop Plant Research (IPK), 06466 Stadt Seeland, Germany.

The potential of big data to support businesses has been demonstrated in financial services, manufacturing, and telecommunications. Here, we report on efforts to enter a new data era in plant breeding by collecting genomic and phenotypic information from 12,858 wheat genotypes representing 6575 single-cross hybrids and 6283 inbred lines that were evaluated in six experimental series for yield in field trials encompassing ~125,000 plots. Integrating data resulted in twofold higher prediction ability compared with cases in which hybrid performance was predicted across individual experimental series. Our results suggest that combining data across breeding programs is a particularly appropriate strategy to exploit the potential of big data for predictive plant breeding. This paradigm shift can contribute to increasing yield and resilience, which is needed to feed the growing world population.
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http://dx.doi.org/10.1126/sciadv.abf9106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195483PMC
June 2021

Mortality and morbidity in patients with congenital heart disease hospitalised for viral pneumonia.

Heart 2020 Oct 27. Epub 2020 Oct 27.

Adult Congenital and Valvular Heart Disease Center, Department of Cardiology and Angiology, University Hospital Muenster, Muenster, Germany.

Objectives: Data on the clinical outcome of patients with congenital heart disease (CHD) affected by severe viral pneumonia are limited. We analysed morbidity and mortality of viral pneumonia and evaluated the association between medical conditions, medication, vaccination and outcome specifically in patients with CHD requiring hospitalisation for viral pneumonia.

Methods: Based on data from one of Germany's largest health insurers, all cases of viral pneumonia requiring hospital admission (2005-2018) were studied. Mortality, and composites of death, transplantation, mechanical circulatory support, ventilation or extracorporeal lung support served as endpoints.

Results: Overall, 26 262 viral pneumonia cases occurred in 24 980 patients. Of these, 1180 cases occurred in patients with CHD. Compared with patients without CHD, mortality rate was elevated in patients with CHD. As a group, patients with CHD aged 20-59 years even exceeded mortality rates in patients without CHD aged >60 years. No mortality was observed in patients with CHD with simple defects <60 years of age without associated cardiovascular risk factors. On multivariable logistic regression analysis, age, CHD complexity, chromosomal anomalies, cardiac medication, use of immunosuppressants and absence of vaccination for influenza emerged as risk factors of adverse outcome.

Conclusions: We present timely data on morbidity and mortality of severe viral pneumonia requiring hospital admission in patients with CHD. Need for mechanical ventilation and risk of death in CHD increase early in life, reaching a level equivalent to non-CHD individuals >60 years of age. Our data suggest that except for patients with isolated simple defects, patients with CHD should be considered higher-risk individuals when faced with severe viral pneumonia.
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http://dx.doi.org/10.1136/heartjnl-2020-317706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223651PMC
October 2020

Selecting Closely-Linked SNPs Based on Local Epistatic Effects for Haplotype Construction Improves Power of Association Mapping.

G3 (Bethesda) 2019 12 3;9(12):4115-4126. Epub 2019 Dec 3.

Department of Breeding Research, Leibniz Institute of Plant Genetics and Crop Plant Research (IPK) Gatersleben, 06466 Stadt Seeland, Germany

Genome-wide association studies (GWAS) have gained central importance for the identification of candidate loci underlying complex traits. Single nucleotide polymorphism (SNP) markers are mostly used as genetic variants for the analysis of genotype-phenotype associations in populations, but closely linked SNPs that are grouped into haplotypes are also exploited. The benefit of haplotype-based GWAS approaches SNP-based approaches is still under debate because SNPs in high linkage disequilibrium provide redundant information. To overcome some constraints of the commonly-used haplotype-based GWAS in which only consecutive SNPs are considered for haplotype construction, we propose a new method called functional haplotype-based GWAS (FH GWAS). FH GWAS is featured by combining SNPs into haplotypes based on the additive and epistatic effects among SNPs. Such haplotypes were termed functional haplotypes (FH). As shown by simulation studies, the FH GWAS approach clearly outperformed the SNP-based approach unless the minor allele frequency of the SNPs making up the haplotypes is low and the linkage disequilibrium between them is high. Applying FH GWAS for the trait flowering time in a large population with whole-genome sequencing data revealed its potential empirically. FH GWAS identified all candidate regions which were detected in SNP-based and two other haplotype-based GWAS approaches. In addition, a novel region on chromosome 4 was solely detected by FH GWAS. Thus both the results of our simulation and empirical studies demonstrate that FH GWAS is a promising method and superior to the SNP-based approach even if almost complete genotype information is available.
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http://dx.doi.org/10.1534/g3.119.400451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893203PMC
December 2019

Reinterpreting Dependency Schemes: Soundness Meets Incompleteness in DQBF.

J Autom Reason 2019 24;63(3):597-623. Epub 2018 Sep 24.

3Institute of Information Systems, Vienna University of Technology, Vienna, Austria.

Dependency quantified Boolean formulas (DQBF) and QBF dependency schemes have been treated separately in the literature, even though both treatments extend QBF by replacing the linear order of the quantifier prefix with a partial order. We propose to merge the two, by reinterpreting a dependency scheme as a mapping from QBF into DQBF. Our approach offers a fresh insight on the nature of soundness in proof systems for QBF with dependency schemes, in which a natural property called 'full exhibition' is central. We apply our approach to QBF proof systems from two distinct paradigms, termed 'universal reduction' and 'universal expansion'. We show that full exhibition is sufficient (but not necessary) for soundness in universal reduction systems for QBF with dependency schemes, whereas for expansion systems the same property characterises soundness exactly. We prove our results by investigating DQBF proof systems, and then employing our reinterpretation of dependency schemes. Finally, we show that the reflexive resolution path dependency scheme is fully exhibited, thereby proving a conjecture of Slivovsky.
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http://dx.doi.org/10.1007/s10817-018-9482-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6710225PMC
September 2018

Haplotype-Based Genome-Wide Prediction Models Exploit Local Epistatic Interactions Among Markers.

G3 (Bethesda) 2018 05 4;8(5):1687-1699. Epub 2018 May 4.

Department of Breeding Research, Leibniz Institute of Plant Genetics and Crop Plant Research (IPK) Gatersleben, 06466 Stadt Seeland, Germany

Genome-wide prediction approaches represent versatile tools for the analysis and prediction of complex traits. Mostly they rely on marker-based information, but scenarios have been reported in which models capitalizing on closely-linked markers that were combined into haplotypes outperformed marker-based models. Detailed comparisons were undertaken to reveal under which circumstances haplotype-based genome-wide prediction models are superior to marker-based models. Specifically, it was of interest to analyze whether and how haplotype-based models may take local epistatic effects between markers into account. Assuming that populations consisted of fully homozygous individuals, a marker-based model in which local epistatic effects inside haplotype blocks were exploited (LEGBLUP) was linearly transformable into a haplotype-based model (HGBLUP). This theoretical derivation formally revealed that haplotype-based genome-wide prediction models capitalize on local epistatic effects among markers. Simulation studies corroborated this finding. Due to its computational efficiency the HGBLUP model promises to be an interesting tool for studies in which ultra-high-density SNP data sets are studied. Applying the HGBLUP model to empirical data sets revealed higher prediction accuracies than for marker-based models for both traits studied using a mouse panel. In contrast, only a small subset of the traits analyzed in crop populations showed such a benefit. Cases in which higher prediction accuracies are observed for HGBLUP than for marker-based models are expected to be of immediate relevance for breeders, due to the tight linkage a beneficial haplotype will be preserved for many generations. In this respect the inheritance of local epistatic effects very much resembles the one of additive effects.
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http://dx.doi.org/10.1534/g3.117.300548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5940160PMC
May 2018

A quantitative genetic framework highlights the role of epistatic effects for grain-yield heterosis in bread wheat.

Nat Genet 2017 Dec 16;49(12):1741-1746. Epub 2017 Oct 16.

Department of Breeding Research, Leibniz Institute of Plant Genetics and Crop Plant Research (IPK), Gatersleben, Germany.

Increasing wheat yield is a key global challenge to producing sufficient food for a growing human population. Wheat grain yield can be boosted by exploiting heterosis, the superior performance of hybrids compared with midparents. Here we present a tailored quantitative genetic framework to study the genetic basis of midparent heterosis in hybrid populations derived from crosses among diverse parents. We applied this framework to an extensive data set assembled for winter wheat. Grain yield was assessed for 1,604 hybrids and their 135 parental elite breeding lines in 11 environments. The hybrids outperformed the midparents by 10% on average, representing approximately 15 years of breeding progress in wheat, thus further substantiating the remarkable potential of hybrid-wheat breeding. Genome-wide prediction and association mapping implemented through the developed quantitative genetic framework showed that dominance effects played a less prominent role than epistatic effects in grain-yield heterosis in wheat.
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http://dx.doi.org/10.1038/ng.3974DOI Listing
December 2017

Extracting genotype information of Arabidopsis thaliana recombinant inbred lines from transcript profiles established with high-density oligonucleotide arrays.

Plant Cell Rep 2017 Dec 30;36(12):1871-1881. Epub 2017 Aug 30.

Department of Breeding Research, Leibniz Institute of Plant Genetics and Crop Plant Research (IPK), OT Gatersleben, Corrensstrasse 3, 06466, Seeland, Germany.

Key Message: Polymorphic probes identified via a sequence-based approach are suitable to infer the genotypes of recombinant inbred lines from hybridisation intensities of GeneChip transcript profiling experiments. The sequences of the probes of the ATH1 GeneChip exactly match transcript sequences of the Arabidopsis thaliana reference genome Col-0, whereas nucleotide differences and/or insertions/deletions may be observed for transcripts of other A. thaliana accessions. Individual probes of the GeneChip that show sequence polymorphisms between different A. thaliana accessions may serve as single-feature polymorphism (SFP) markers, provided that the sequence changes cause differences in hybridisation intensity for the accessions of interest. A sequence-based approach identified features on the high-density oligonucleotide array that showed sequence polymorphisms between A. thaliana accessions Col-0 and C24. Hybridisation intensities of polymorphic probes were extracted from genome-wide transcript profiles of Col-0/C24 and C24/Col-0 recombinant inbred lines and assessed after standardisation via sliding window analyses to identify SFP markers. The genotypes of the recombinant inbred lines were determined with the SFP markers and the resulting data were integrated with information, which had been established previously with single nucleotide polymorphism and insertion/deletion markers, to enrich the linkage map of the Col-0/C24 and C24/Col-0 recombinant inbred populations. Congruence between the molecular marker map and the sequence maps of the A. thaliana Col-0 chromosomes proved the reliability of the genotype information which was deduced from the transcript profiles of the Col-0/C24 and C24/Col-0 recombinant inbred lines.
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http://dx.doi.org/10.1007/s00299-017-2200-6DOI Listing
December 2017

Tailoring high-density oligonucleotide arrays for transcript profiling of different Arabidopsis thaliana accessions using a sequence-based approach.

Plant Cell Rep 2017 Aug 22;36(8):1323-1332. Epub 2017 May 22.

Leibniz Institute of Plant Genetics and Crop Plant Research (IPK), OT Gatersleben, 06466, Stadt Seeland, Germany.

Key Message: Excluding polymorphic probes from GeneChip transcript profiling experiments via a sequence-based approach results in improved detection of differentially expressed genes in developing seeds of Arabidopsis thaliana accessions Col-0 and C24. GeneChip arrays represent a powerful tool for transcript profiling experiments. The ATH1 GeneChip has been designed based on the sequence of the Arabidopsis thaliana reference genome Col-0, hence the features on the array exactly match the sequences of Col-0 transcripts. In contrast, transcripts of other A. thaliana accessions or related species may show nucleotide differences and/or insertions/deletions when compared to the corresponding Col-0 transcripts, therefore, comparisons of transcript abundance involving different A. thaliana accessions or related species may be compromised for a certain number of transcripts. To tackle this limitation, a sequence-based strategy was developed. Only features on the array that were identical in sequence for the specimen to be compared were considered for transcript profiling. The impact of the proposed strategy was evaluated for transcript profiles that were established for developing seeds of A. thaliana accessions Col-0 and C24.
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http://dx.doi.org/10.1007/s00299-017-2157-5DOI Listing
August 2017

Genetic dissection of metabolite variation in Arabidopsis seeds: evidence for mQTL hotspots and a master regulatory locus of seed metabolism.

J Exp Bot 2017 03;68(7):1655-1667

Department of Molecular Genetics/Heterosis, Leibniz Institute of Plant Genetics and Crop Plant Research (IPK) Gatersleben, D-06466 Seeland/OT Gatersleben, Germany.

To gain insight into genetic factors controlling seed metabolic composition and its relationship to major seed properties, an Arabidopsis recombinant inbred line (RIL) population, derived from accessions Col-0 and C24, was studied using an MS-based metabolic profiling approach. Relative intensities of 311 polar primary metabolites were used to identify associated genomic loci and to elucidate their interactions by quantitative trait locus (QTL) mapping. A total of 786 metabolic QTLs (mQTLs) were unequally distributed across the genome, forming several hotspots. For the branched-chain amino acid leucine, mQTLs and candidate genes were elucidated in detail. Correlation studies displayed links between metabolite levels, seed protein content, and seed weight. Principal component analysis revealed a clustering of samples, with PC1 mapping to a region on the short arm of chromosome IV. The overlap of this region with mQTL hotspots indicates the presence of a potential master regulatory locus of seed metabolism. As a result of database queries, a series of candidate regulatory genes, including bZIP10, were identified within this region. Depending on the search conditions, metabolic pathway-derived candidate genes for 40-61% of tested mQTLs could be determined, providing an extensive basis for further identification and characterization of hitherto unknown genes causal for natural variation of Arabidopsis seed metabolism.
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http://dx.doi.org/10.1093/jxb/erx049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5444479PMC
March 2017

Risk of Pregnancy in Moderate and Severe Aortic Stenosis: From the Multinational ROPAC Registry.

J Am Coll Cardiol 2016 10;68(16):1727-1737

Division of Adult Congenital and Valvular Heart Disease, Department of Cardiovascular Medicine, University Hospital Muenster, Muenster, Germany. Electronic address:

Background: Controversial results on maternal risk and fetal outcome have been reported in women with aortic stenosis (AS).

Objectives: The authors sought to investigate maternal and fetal outcomes in patients with AS in a large cohort.

Methods: The Registry on Pregnancy and Cardiac Disease (ROPAC) is a global, prospective observational registry of women with structural heart disease, providing a uniquely large study population. Data of women with moderate (peak gradient 36 to 63 mm Hg) and severe AS (peak gradient ≥64 mm Hg) were analyzed.

Results: Of 2,966 pregnancies in ROPAC, the authors identified 96 women who had at least moderate AS (34 with severe AS). No deaths were observed during pregnancy and in the first week after delivery. However, 20.8% of women were hospitalized for cardiac reasons during pregnancy. This was significantly more common in severe AS compared with moderate AS (35.3% vs. 12.9%; p = 0.02), and reached the highest rate (42.1%) in severe, symptomatic AS. Pregnancy was complicated by heart failure in 6.7% of asymptomatic and 26.3% of symptomatic patients, but could be managed medically, except for 1 patient who was symptomatic before pregnancy and underwent balloon valvotomy. Children of patients with severe AS had a significantly higher percentage of low birth weight (35.0% vs. 6.0%; p = 0.006).

Conclusions: Mortality in pregnant women with AS, including those with severe AS, appears to be close to zero in the current era. Symptomatic and severe AS does, however, carry a substantial risk of heart failure and is associated with high rates of hospitalization for cardiac reasons, although heart failure can nearly always be managed medically. The results highlight the importance of appropriate pre-conceptional patient evaluation and counseling.
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http://dx.doi.org/10.1016/j.jacc.2016.07.750DOI Listing
October 2016

Chromosome identification for the carnivorous plant Genlisea margaretae.

Chromosoma 2017 06 7;126(3):389-397. Epub 2016 May 7.

Leibniz Institute of Plant Genetics and Crop Plant Research (IPK), 06466, Gatersleben, Stadt Seeland, Germany.

Genlisea margaretae, subgenus Genlisea, section Recurvatae (184 Mbp/1C), belongs to a plant genus with a 25-fold genome size difference and an extreme genome plasticity. Its 19 chromosome pairs could be distinguished individually by an approach combining optimized probe pooling and consecutive rounds of multicolor fluorescence in situ hybridization (mcFISH) with bacterial artificial chromosomes (BACs) selected for repeat-free inserts. Fifty-one BACs were assigned to 18 chromosome pairs. They provide a tool for future assignment of genomic sequence contigs to distinct chromosomes as well as for identification of homeologous chromosome regions in other species of the carnivorous Lentibulariaceae family, and potentially of chromosome rearrangements, in cases where more than one BAC per chromosome pair was identified.
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http://dx.doi.org/10.1007/s00412-016-0599-0DOI Listing
June 2017

Selective Irreversible Inhibition of Neuronal and Inducible Nitric-oxide Synthase in the Combined Presence of Hydrogen Sulfide and Nitric Oxide.

J Biol Chem 2015 Oct 20;290(41):24932-44. Epub 2015 Aug 20.

From the Departments of Pharmacology and Toxicology and

Citrulline formation by both human neuronal nitric-oxide synthase (nNOS) and mouse macrophage inducible NOS was inhibited by the hydrogen sulfide (H2S) donor Na2S with IC50 values of ∼2.4·10(-5) and ∼7.9·10(-5) m, respectively, whereas human endothelial NOS was hardly affected at all. Inhibition of nNOS was not affected by the concentrations of l-arginine (Arg), NADPH, FAD, FMN, tetrahydrobiopterin (BH4), and calmodulin, indicating that H2S does not interfere with substrate or cofactor binding. The IC50 decreased to ∼1.5·10(-5) m at pH 6.0 and increased to ∼8.3·10(-5) m at pH 8.0. Preincubation of concentrated nNOS with H2S under turnover conditions decreased activity after dilution by ∼70%, suggesting irreversible inhibition. However, when calmodulin was omitted during preincubation, activity was not affected, suggesting that irreversible inhibition requires both H2S and NO. Likewise, NADPH oxidation was inhibited with an IC50 of ∼1.9·10(-5) m in the presence of Arg and BH4 but exhibited much higher IC50 values (∼1.0-6.1·10(-4) m) when Arg and/or BH4 was omitted. Moreover, the relatively weak inhibition of nNOS by Na2S in the absence of Arg and/or BH4 was markedly potentiated by the NO donor 1-(hydroxy-NNO-azoxy)-l-proline, disodium salt (IC50 ∼ 1.3-2.0·10(-5) m). These results suggest that nNOS and inducible NOS but not endothelial NOS are irreversibly inhibited by H2S/NO at modest concentrations of H2S in a reaction that may allow feedback inhibition of NO production under conditions of excessive NO/H2S formation.
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http://dx.doi.org/10.1074/jbc.M115.660316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4599001PMC
October 2015

Aerobic nitric oxide-induced thiol nitrosation in the presence and absence of magnesium cations.

Free Radic Biol Med 2014 Nov 16;76:286-98. Epub 2014 Sep 16.

Department of Pharmacology & Toxicology, Karl-Franzens-Universität Graz, A-8010 Graz, Austria. Electronic address:

Although different routes for the S-nitrosation of cysteinyl residues have been proposed, the main in vivo pathway is unknown. We recently demonstrated that direct (as opposed to autoxidation-mediated) aerobic nitrosation of glutathione is surprisingly efficient, especially in the presence of Mg(2+). In the present study we investigated this reaction in greater detail. From the rates of NO decay and the yields of nitrosoglutathione (GSNO) we estimated values for the apparent rate constants of 8.9 ± 0.4 and 0.55 ± 0.06 M(-1)s(-1) in the presence and absence of Mg(2+). The maximum yield of GSNO was close to 100% in the presence of Mg(2+) but only about half as high in its absence. From this observation we conclude that, in the absence of Mg(2+), nitrosation starts by formation of a complex between NO and O2, which then reacts with the thiol. Omission of superoxide dismutase (SOD) reduced by half the GSNO yield in the absence of Mg(2+), demonstrating O2(-) formation. The reaction in the presence of Mg(2+) seems to involve formation of a Mg(2+)•glutathione (GSH) complex. SOD did not affect Mg(2+)-stimulated nitrosation, suggesting that no O2(-) is formed in that reaction. Replacing GSH with other thiols revealed that reaction rates increased with the pKa of the thiol, suggesting that the nucleophilicity of the thiol is crucial for the reaction, but that the thiol need not be deprotonated. We propose that in cells Mg(2+)-stimulated NO/O2-induced nitrosothiol formation may be a physiologically relevant reaction.
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http://dx.doi.org/10.1016/j.freeradbiomed.2014.08.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4647830PMC
November 2014

Intergenomic single nucleotide polymorphisms as a tool for bacterial artificial chromosome contig building of homoeologous Brassica napus regions.

BMC Genomics 2014 Jul 4;15:560. Epub 2014 Jul 4.

Leibniz Institute of Plant Genetics and Crop Plant Research (IPK), Corrensstraße 3, OT Gatersleben, D-06466 Stadt Seeland, Germany.

Background: Homoeologous sequences pose a particular challenge if bacterial artificial chromosome (BAC) contigs shall be established for specific regions of an allopolyploid genome. Single nucleotide polymorphisms (SNPs) differentiating between homoeologous genomes (intergenomic SNPs) may represent a suitable screening tool for such purposes, since they do not only identify homoeologous sequences but also differentiate between them.

Results: Sequence alignments between Brassica rapa (AA) and Brassica oleracea (CC) sequences mapping to corresponding regions on chromosomes A1 and C1, respectively were used to identify single nucleotide polymorphisms between the A and C genomes. A large fraction of these polymorphisms was also present in Brassica napus (AACC), an allopolyploid species that originated from hybridisation of A and C genome species. Intergenomic SNPs mapping throughout homoeologous chromosome segments spanning approximately one Mbp each were included in Illumina's GoldenGate® Genotyping Assay and used to screen multidimensional pools of a Brassica napus bacterial artificial chromosome library with tenfold genome coverage. Based on the results of 50 SNP assays, a BAC contig for the Brassica napus A subgenome was established that spanned the entire region of interest. The C subgenome region was represented in three BAC contigs.

Conclusions: This proof-of-concept study shows that sequence resources of diploid progenitor genomes can be used to deduce intergenomic SNPs suitable for multiplex polymerase chain reaction (PCR)-based screening of multidimensional BAC pools of a polyploid organism. Owing to their high abundance and ease of identification, intergenomic SNPs represent a versatile tool to establish BAC contigs for homoeologous regions of a polyploid genome.
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http://dx.doi.org/10.1186/1471-2164-15-560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4102721PMC
July 2014

Combining C-arm CT with a new remote operated positioning and guidance system for guidance of minimally invasive spine interventions.

J Neurointerv Surg 2015 Apr 5;7(4):303-8. Epub 2014 Mar 5.

Department of Diagnostic and Interventional Radiology, University Hospital Frankfurt, Goethe-University, Frankfurt am Main, Germany.

Objective: To report our experience using C-arm cone beam CT (C-arm CBCT) combined with the new remote operated positioning and guidance system, iSYS1, for needle guidance during spinal interventions.

Methods: A C-arm CBCT with a flat panel angiography system was acquired (Artis Zeego; Siemens Healthcare Sector, Forchheim, Germany). Reconstruction of CT-like images and planning of the needle path were performed using a common workstation. The needle holder of iSYS1 acted as a guide during insertion of Kirschner (K) wires. 20 percutaneous K wires were placed in the pedicles at T2-T3, T7-T12, and L1-L2 in a cadaver specimen. Postprocedure C-arm CBCT scans were obtained to confirm the accuracy of the K wire placement.

Results: All K wire placements were successfully performed. Mean planning time with Syngo iGuide was 4:16 min, mean positioning time of iSYS1 was 3:35 min, and mean placement time of the K wires was 2:22 min. Mean total intervention time was 10:13 min per pedicle. A mean deviation of 0.35 mm between the planned path and the placed K wire with a mean path length of 6.73 cm was documented.

Conclusions: Our results demonstrate the potential of combining C-arm CBCT with iSYS1 for safe and accurate percutaneous placement of pedicle K wires in spinal interventions.
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http://dx.doi.org/10.1136/neurintsurg-2013-011034DOI Listing
April 2015

Interaction between neuronal nitric-oxide synthase and tetrahydrobiopterin revisited: studies on the nature and mechanism of tight pterin binding.

Biochemistry 2014 Mar 17;53(8):1284-95. Epub 2014 Feb 17.

Department of Pharmacology and Toxicology, Institute of Pharmaceutical Sciences, Karl-Franzens-University Graz , A-8010, Graz, Austria.

Recombinant neuronal nitric-oxide synthase (nNOS) expressed in baculovirus-infected Sf9 cells contains approximately 1 equiv of tightly bound tetrahydrobiopterin (BH4) per dimer and binds a second equivalent with a dissociation constant in the 10(-7)-10(-6) M range. Less is known about the pterin-binding properties of nNOS originating from expression systems such as Escherichia coli that do not produce BH4. We determined the binding properties of E. coli-expressed nNOS for BH4 and several inhibitory pterins by monitoring their effects on enzyme activity. E. coli-expressed nNOS as isolated was activated by BH4 monophasically with EC50 ≈ 2 × 10(-7) M, demonstrating a lack of tight pterin binding. However, overnight incubation with BH4 resulted in tight binding of one BH4 per dimer, yielding an enzyme that resembled Sf9-expressed nNOS. Tight pterin binding was also induced by preincubation with 4-amino-tetrahydrobiopterin, but not by 7,8-dihydrobiopterin or 4-amino-dihydrobiopterin, suggesting that tight-binding site formation requires preincubation with a fully reduced pteridine. Kinetic experiments showed that tight-binding site formation takes approximately 10 min with 1 μM BH4 (2 min with 1 μM 4-amino-BH4) at 4 °C. Anaerobic preincubation experiments demonstrated that O2 is not involved in the process. Gel electrophoretic studies suggest that tight-binding site formation is accompanied by an increase in the strength of the NOS dimer. We propose that incubation of pterin-free nNOS with BH4 creates one tight pterin-binding site per dimer, leaving the other site unaffected, in a reaction that involves redox chemistry.
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http://dx.doi.org/10.1021/bi401307rDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3944803PMC
March 2014

Value of speckle-tracking echocardiography and MRI-based feature tracking analysis in adult patients after Fontan-type palliation.

Congenit Heart Dis 2014 Sep-Oct;9(5):397-406. Epub 2013 Dec 24.

Adult Congenital and Valvular Heart Disease Center, Department of Cardiology and Angiology, University Hospital of Münster, Münster, Germany.

Background: Patients are commonly affected by ventricular dysfunction and heart failure after Fontan palliation. Reliable quantification of ventricular function is of interest but hampered by complex ventricular anatomy and physiology.

Objectives: We aimed to assess myocardial function using a novel cardiac magnetic resonance imaging (CMR)-based feature-tracking (FT) technique and to study its clinical utility in Fontan patients.

Methods: Retrospective study in consecutive patients attending our service.

Results: We included 15 adult Fontan patients (age 27 ± 7 years) who underwent a standardized transthoracic echocardiographic investigation (TTE) with measurement of global strain using speckle tracking. Thirteen patients also underwent CMR, with assessment of myocardial deformation by FT, providing longitudinal and circumferential global strain for the single ventricle. The value of TTE-based strain measurements was limited by the fact that in 63% of patients at least one myocardial segment could not be adequately quantified due to limited acoustic windows. In contrast, CMR allowed for a complete visualization of all wall segments. Not surprisingly, there was poor agreement between the techniques but good or moderate interobserver variability for FT (coefficients of variability 6.6% and 14.3% for circumferential and longitudinal strain). Unlike ejection fraction, FT parameters correlated significantly with age at Fontan completion, New York Heart Association (NYHA) class, and peak oxygen uptake on cardiopulmonary exercise testing.

Conclusions: Assessment of myocardial function using CMR cine-based feature tracking is feasible in Fontan patients. Unlike echocardiographic techniques, FT is independent of inadequate acoustic windows and FT measurements relate to clinical parameters, suggesting that this approach could have clinical relevance in future.
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http://dx.doi.org/10.1111/chd.12156DOI Listing
June 2015

Screening of a Brassica napus bacterial artificial chromosome library using highly parallel single nucleotide polymorphism assays.

BMC Genomics 2013 Sep 6;14:603. Epub 2013 Sep 6.

Leibniz Institute of Plant Genetics and Crop Plant Research (IPK), Corrensstraße 3, OT Gatersleben, D-06466 Stadt Seeland, Germany.

Background: Efficient screening of bacterial artificial chromosome (BAC) libraries with polymerase chain reaction (PCR)-based markers is feasible provided that a multidimensional pooling strategy is implemented. Single nucleotide polymorphisms (SNPs) can be screened in multiplexed format, therefore this marker type lends itself particularly well for medium- to high-throughput applications. Combining the power of multiplex-PCR assays with a multidimensional pooling system may prove to be especially challenging in a polyploid genome. In polyploid genomes two classes of SNPs need to be distinguished, polymorphisms between accessions (intragenomic SNPs) and those differentiating between homoeologous genomes (intergenomic SNPs). We have assessed whether the highly parallel Illumina GoldenGate Genotyping Assay is suitable for the screening of a BAC library of the polyploid Brassica napus genome.

Results: A multidimensional screening platform was developed for a Brassica napus BAC library which is composed of almost 83,000 clones. Intragenomic and intergenomic SNPs were included in Illumina's GoldenGate Genotyping Assay and both SNP classes were used successfully for screening of the multidimensional BAC pools of the Brassica napus library. An optimized scoring method is proposed which is especially valuable for SNP calling of intergenomic SNPs. Validation of the genotyping results by independent methods revealed a success of approximately 80% for the multiplex PCR-based screening regardless of whether intra- or intergenomic SNPs were evaluated.

Conclusions: Illumina's GoldenGate Genotyping Assay can be efficiently used for screening of multidimensional Brassica napus BAC pools. SNP calling was specifically tailored for the evaluation of BAC pool screening data. The developed scoring method can be implemented independently of plant reference samples. It is demonstrated that intergenomic SNPs represent a powerful tool for BAC library screening of a polyploid genome.
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http://dx.doi.org/10.1186/1471-2164-14-603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3846124PMC
September 2013

Longitudinal left ventricular 2D strain is superior to ejection fraction in predicting myocardial recovery and symptomatic improvement after aortic valve implantation.

Int J Cardiol 2013 Sep 4;167(5):2239-43. Epub 2012 Jul 4.

Adult Congenital and Valvular Heart Disease Center, Department of Cardiology and Angiology, University Hospital Muenster, Albert-Schweitzer-Campus 1, 48149 Muenster, Germany.

Background: Predicting improvement of myocardial function after transcatheter aortic valve implantation (TAVI) for aortic stenosis (AS) remains a challenge. As ejection fraction (EF) may be of limited value in detecting early myocardial dysfunction and predicting outcome, we assessed the potential of echocardiographic longitudinal function in this setting.

Materials And Methods: Left ventricular (LV) function was assessed using EF, mitral annular plane systolic excursion (MAPSE), peak longitudinal 2D strain (LS) and strain rate (SR) in101consecutive patients with severe symptomatic AS (age 81 ± 11 years) undergoing TAVI. Echocardiography and assessment of clinical status including NYHA functional class were performed prior and after intervention (median 70 days).

Results: Pre-interventional EF was 57 ± 17% and 32 patients (32%) had an EF<50% while 58 patients (57%) were found to have an impaired LS. After TAVI there was no significant change in EF. In contrast, LS, SR and MAPSE improved significantly (-14.0 ± 4.4 vs. -15.5 ± 4.0%; p=0.007, 0.68 ± 0.24 vs. 0.78 ± 0.23/s, p=0.002; and 9.1 ± 3.2 vs. 10.2 ± 3.3mm, p=0.006, respectively). Receiver Operating Curve characteristic analysis identified a pre-TAVI LS>-13.3% as the optimal cut-off value for predicting lack of LS recovery post TAVI. There was a marked improvement in NYHA FC after intervention (p=0.0002). Among the studied echocardiographic parameters LS change correlated closest with NYHA class improvement (r=0.42, p=0.0008).

Conclusion: Overall, LS appears to be more sensitive for detecting early myocardial damage in patients with AS compared to conventional echocardiographic parameters. More importantly, pre-interventional LS may identify irreversible myocardial dysfunction and LS improvement correlates with symptomatic improvement after intervention.
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http://dx.doi.org/10.1016/j.ijcard.2012.06.012DOI Listing
September 2013

Impact of transcatheter aortic valve implantation or surgical aortic valve replacement on right ventricular function.

Heart 2012 Sep 11;98(17):1299-304. Epub 2012 Jun 11.

Department of Cardiology and Angiology, Adult Congenital and Valvular Heart Disease Center, University Hospital Muenster, Muenster, Germany.

Objective: Transcatheter aortic valve implantation (TAVI) has become an alternative to surgical aortic valve replacement (sAVR) in selected high risk patients. While improvement in left ventricular function after TAVI has been demonstrated, little is known about the impact on right ventricular (RV) function. Since postoperative RV dysfunction is linked to adverse outcomes, the authors sought to investigate the effect of TAVI and aortic valve replacement (AVR) on RV function using speckle tracking echocardiography.

Design: Cross-sectional study in tertiary healthcare setting.

Setting: 101 patients with severe symptomatic aortic stenosis (age 81 ± 11 yrs) who underwent TAVI and 22 patients who underwent sAVR were included. RV function was assessed using 2D longitudinal strain (RV-LS), fractional area change and tricuspid annular plain systolic excursion before and after sAVR and TAVI (median 89 days).

Results: Although the TAVI group had worse baseline characteristics, RV function remained unchanged in this group whereas significant deterioration of RV function was observed in patients undergoing conventional AVR: RV-LS (-25.2 ± 6.1 vs -20.0 ± 7.0%; p=0.009), RV-fractional area change (47.0 ± 7.0 vs 39.8 ± 10.7%, p=0.019) and tricuspid annular plain systolic excursion (24 ± 5 vs 16 ± 4 mm, p=0.0001).

Conclusion: While TAVI did not affect RV function it deteriorated significantly in patients undergoing sAVR. The authors speculate that this may be related to the detrimental effects of pericardiotomy and, to a lesser degree, cardiopulmonary bypass. While further studies are required to assess the clinical significance of this finding, these data suggest that patients with pre-existing RV dysfunction may benefit from TAVI and that RV function should be incorporated into future risk scores.
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http://dx.doi.org/10.1136/heartjnl-2011-301203DOI Listing
September 2012

Heterosis manifestation during early Arabidopsis seedling development is characterized by intermediate gene expression and enhanced metabolic activity in the hybrids.

Plant J 2012 Aug 12;71(4):669-83. Epub 2012 Jun 12.

Leibniz Institute of Plant Genetics and Crop Plant Research (IPK), Corrensstraße 3, 06466 Gatersleben, Germany.

Heterosis-associated cellular and molecular processes were analyzed in seeds and seedlings of Arabidopsis thaliana accessions Col-0 and C24 and their heterotic hybrids. Microscopic examination revealed no advantages in terms of hybrid mature embryo organ sizes or cell numbers. Increased cotyledon sizes were detectable 4 days after sowing. Growth heterosis results from elevated cell sizes and numbers, and is well established at 10 days after sowing. The relative growth rates of hybrid seedlings were most enhanced between 3 and 4 days after sowing. Global metabolite profiling and targeted fatty acid analysis revealed maternal inheritance patterns for a large proportion of metabolites in the very early stages. During developmental progression, the distribution shifts to dominant, intermediate and heterotic patterns, with most changes occurring between 4 and 6 days after sowing. The highest incidence of heterotic patterns coincides with establishment of size differences at 4 days after sowing. In contrast, overall transcript patterns at 4, 6 and 10 days after sowing are characterized by intermediate to dominant patterns, with parental transcript levels showing the largest differences. Overall, the results suggest that, during early developmental stages, intermediate gene expression and higher metabolic activity in the hybrids compared to the parents lead to better resource efficiency, and therefore enhanced performance in the hybrids.
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http://dx.doi.org/10.1111/j.1365-313X.2012.05021.xDOI Listing
August 2012

Local DNA features affect RNA-directed transcriptional gene silencing and DNA methylation.

Plant J 2008 Jan 27;53(1):1-10. Epub 2007 Oct 27.

Leibniz-Institute of Plant Genetics and Crop Plant Research (IPK), Corrensstrasse 3, 06466 Gatersleben, Germany.

Transcription of a nopaline synthase promoter (pNOS) inverted repeat provides an RNA signal that can trigger transcriptional gene silencing and methylation of pNOS promoters in trans. The degree of silencing is influenced by the local DNA features close to the target promoter integration sites. Among 26 transgenic Arabidopsis thaliana lines harbouring single copies of a T-DNA including a pNOS-NPTII reporter gene at different chromosomal loci, NPTII RNA levels showed limited variation. When challenged by the silencer transgene providing the pNOS RNA signal, reduction of the NPTII RNA levels in the F(1) generation varied by more than 100-fold, ranging from no reduction to reduction to <1% of the non-silenced level. Silencing was generally correlated with proportional DNA methylation in the pNOS region, except for one target transgene showing substantial DNA methylation without adequate silencing. Silencing was progressive through generations. Differences in the degree of silencing among the target transgenes were transmitted at least to the F(3) generation, and seemed to be influenced by transgene-flanking sequences. Apparently, close-by repeats promoted, whereas close-by functional genes diminished, the response to the silencing signal.
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http://dx.doi.org/10.1111/j.1365-313X.2007.03311.xDOI Listing
January 2008

The contribution of TRPV4-mediated calcium signaling to calcium homeostasis in endothelial cells.

J Recept Signal Transduct Res 2007 ;27(2-3):113-24

Institute of Pharmaceutical Sciences, Pharmacology and Toxicology, Karl-Franzens-University of Graz, Universitaetsplatz 2, Graz, Austria.

A large variety of cation transport systems are involved in the regulation of calcium homeostasis in endothelial cells. The focus of the present study is to determine the contribution of nonselective cation channels from the TRP (transient receptor potential) family to cellular calcium homeostasis of porcine aortic endothelial cells (PAEC). One member of the TRPV (vanniloid) subfamily, TRPV4, has previously been shown to be involved in cation transport induced by a large variety of stimulations including osmolarity, temperature, mechanical stress, and phosphorylation. Here, we demonstrate the existence of several TRP proteins, including TRPV4, in PAEC using RT-PCR. To test whether this channel is functional, we performed FURA-2 calcium measurements and whole-cell patch-clamp experiments. We observed the induction of large calcium signals following mechanical stress, altered extracellular temperature, and the selective TRPV4 activator 4-alpha -PDD. These effects were diminished in the presence of the TRPV4 inhibitor miconazole, suggesting the involvement of this channel in mediating endothelial calcium signals. The large amounts of transported calcium and the short signaling ways suggest a potentially important role of this channel in many physiological processes.
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http://dx.doi.org/10.1080/10799890701402446DOI Listing
September 2007

Epigenetic mechanisms for breakdown of self-incompatibility in interspecific hybrids.

Genetics 2007 Apr 21;175(4):1965-73. Epub 2007 Jan 21.

Department of Plant Biology, Cornell University, Ithaca, New York 14853, USA.

As a major agent of rapid speciation, interspecific hybridization has played an important role in plant evolution. When hybridization involves species that exhibit self-incompatibility (SI), this prezygotic barrier to self-fertilization must be overcome or lost to allow selfing. How SI, a normally dominant trait, is lost in nascent hybrids is not known, however. Here we demonstrate that hybrid self-fertility can result from epigenetic changes in expression of the S-locus genes that determine specificity in the SI response. We analyzed loss of SI in synthetic hybrids produced by crossing self-fertile and self-incompatible species in each of two crucifer genera. We show that SI is lost in the stigmas of A. thaliana-lyrata hybrids and their neo-allotetraploid derivatives and in the pollen of C. rubella-grandiflora hybrids and their homoploid progenies. Aberrant processing of S-locus receptor kinase gene transcripts as detected in Arabidopsis hybrids and suppression of the S-locus cysteine-rich protein gene as observed in Capsella hybrids are two reversible mechanisms by which SI might break down upon interspecific hybridization to generate self-fertile hybrids in nature.
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http://dx.doi.org/10.1534/genetics.106.069393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1855105PMC
April 2007

Mechanisms of chromosome number reduction in Arabidopsis thaliana and related Brassicaceae species.

Proc Natl Acad Sci U S A 2006 Mar 20;103(13):5224-9. Epub 2006 Mar 20.

Jodrell Laboratory, Royal Botanic Gardens, Kew, Richmond TW9 3AB, United Kingdom.

Evolution of chromosome complements can be resolved by genome sequencing, comparative genetic mapping, and comparative chromosome painting. Previously, comparison of genetic maps and gene-based phylogenies suggested that the karyotypes of Arabidopsis thaliana (n = 5) and of related species with six or seven chromosome pairs were derived from an ancestral karyotype with eight chromosome pairs. To test this hypothesis, we applied multicolor chromosome painting using contiguous bacterial artificial chromosome pools of A. thaliana arranged according to the genetic maps of Arabidopsis lyrata and Capsella rubella (both n = 8) to A. thaliana, A. lyrata, Neslia paniculata, Turritis glabra, and Hornungia alpina. This approach allowed us to map the A. lyrata centromeres as a prerequisite to defining a putative ancestral karyotype (n = 8) and to elucidate the evolutionary mechanisms that shaped the karyotype of A. thaliana and its relatives. We conclude that chromosome "fusions" in A. thaliana resulted from (i) generation of acrocentric chromosomes by pericentric inversions, (ii) reciprocal translocation between two chromosomes (one or both acrocentric), and (iii) elimination of a minichromosome that arose in addition to the "fusion chromosome." Comparative chromosome painting applied to N. paniculata (n = 7), T. glabra (n = 6), and H. alpina (n = 6), for which genetic maps are not available, revealed chromosomal colinearity between all species tested and allowed us to reconstruct the evolution of their chromosomes from a putative ancestral karyotype (n = 8). Although involving different ancestral chromosomes, chromosome number reduction followed similar routes as found within the genus Arabidopsis.
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http://dx.doi.org/10.1073/pnas.0510791103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1458822PMC
March 2006

Plant genome analysis: the state of the art.

Int Rev Cytol 2005 ;247:223-84

Max Planck Institute for Plant Breeding Research, 50829 Cologne, Germany.

Plants are the basis for the survival of all "higher" organisms on Earth. Development of molecular genetics tools has allowed analysis of the structure, evolution, and function of whole plant genomes, rather than individual genes. DNA-based markers were instrumental in constructing detailed genetic maps of model plants and all major crop species. These molecular maps were the basis of physical maps and the first plant whole genome sequences. Comparative analysis based on genetic, cytogenetic, and physical maps and DNA sequence information provided new insights into the evolution of plant nuclear and organellar genomes. Mapping factors controlling Mendelian and quantitative traits made possible the cloning and functional characterization of novel genes, which function in plant development, adaptation to biotic and abiotic stress, or in the formation of other agronomic characters. The parallel analysis of all transcripts, proteins, and metabolites present in plant cells or tissues has generated information that may lead to a better integrated understanding of genome function. Postfunctional analysis of natural variation of gene function and its effects on phenotype is envisaged to provide new diagnostic and therapeutic molecular tools for applications in plant breeding, adaptation, and ecology.
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http://dx.doi.org/10.1016/S0074-7696(05)47005-9DOI Listing
January 2006
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