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1.
Plant Methods. 2018 Mar 26;14:27. doi: 10.1186/s13007-018-0290-y. eCollection 2018.

MowJoe: a method for automated-high throughput dissected leaf phenotyping.

Author information

1
1Max Planck Institute for Plant Breeding Research, Carl-von-Linné-Weg 10, 50829 Cologne, Germany.
2
2Department of Biology, University of Cologne, Zülpicher Str. 47, 50674 Cologne, Germany.
3
3Institute of Medical Statistics and Computational Biology, University of Cologne, Bachemer Strasse 86, 50931 Cologne, Germany.
#
Contributed equally

Abstract

Background:

Accurate and automated phenotyping of leaf images is necessary for high throughput studies of leaf form like genome-wide association analysis and other forms of quantitative trait locus mapping. Dissected leaves (also referred to as compound) that are subdivided into individual units are an attractive system to study diversification of form. However, there are only few software tools for their automated analysis. Thus, high-throughput image processing algorithms are needed that can partition these leaves in their phenotypically relevant units and calculate morphological features based on these units.

Results:

We have developed MowJoe, an image processing algorithm that dissects a dissected leaf into leaflets, petiolule, rachis and petioles. It employs image skeletonization to convert leaves into graphs, and thereafter applies algorithms operating on graph structures. This partitioning of a leaf allows the derivation of morphological features such as leaf size, or eccentricity of leaflets. Furthermore, MowJoe automatically places landmarks onto the terminal leaflet that can be used for further leaf shape analysis. It generates specific output files that can directly be imported into downstream shape analysis tools. We applied the algorithm to two accessions of Cardamine hirsuta and show that our features are able to robustly discriminate between these accessions.

Conclusion:

MowJoe is a tool for the semi-automated, quantitative high throughput shape analysis of dissected leaf images. It provides the statistical power for the detection of the genetic basis of quantitative morphological variations.

2.
Z Gastroenterol. 2018 Feb 9. doi: 10.1055/s-0043-124089. [Epub ahead of print]

G-EYE advanced colonoscopy for improved polyp detection rates - a randomized tandem pilot study with different endoscopists.

Author information

1
Department of Internal Medicine II, Helios Dr. Horst-Schmidt-Kliniken, Wiesbaden.
2
Institute of Medical Statistics and Computational Biology, University of Cologne.
3
Department of Internal Medicine, St. Mary's Hospital, Frankfurt.
#
Contributed equally

Abstract

BACKGROUND AND AIMS:

 The most commonly missed polyps in colonoscopy are those located behind haustral folds. The G-EYE system is a standard colonoscope consisting of re-processable balloon at its distal tip. The G-EYE balloon improves the detection of polyps by straightening the haustral folds. In our back-to-back tandem study, we aimed to determine whether and to what extent the G-EYE system could reduce adenoma miss rates in screening colonoscopy.

METHODS:

 Patients referred to colonoscopy were randomized into 2 groups. Group A underwent a standard colonoscopy (SC) followed by balloon colonoscopy (BC), and Group B underwent BC followed by SC. In this randomized tandem study, the investigator's level of training and the endoscopists themselves were changed after each withdrawal. Each endoscopist was blinded to the results of the first withdrawal.

RESULTS:

 Fifty-eight patients were enrolled and randomized into 2 groups with similar baseline characteristics. Nine patients were excluded from the study. Twenty-five patients underwent SC followed by BC while 24 underwent BC followed by SC. The adenoma miss rate for SC was 41 %, with an additional detection rate of 69 % for BC (ratio 1.69). The overall miss rate for polyps was 60 % for SC, with an additional detection rate of 150 % for BC (ratio 2.5). Experienced investigators who used BC were able to identify an additional 7 polyps while inexperienced investigators.

CONCLUSIONS:

 Although our results could not clearly confirm that BC improves adenoma detection, the investigator's experience appears to be a major determinant of the adenoma detection rate.

Conflict of interest statement

Disclosure The authors report no conflicts of interest in this work.

3.
Z Gastroenterol. 2018 Feb 9. doi: 10.1055/s-0043-124194. [Epub ahead of print]

The Manchester Triage System (MTS): a score for emergency management of patients with acute gastrointestinal bleeding.

Author information

1
First Medical Department, University Medical Center, Mainz, Germany.
2
Department of Internal Medicine II, Helios HSK Hospital, Wiesbaden, Germany.
3
Institute of Medical Biostatistics, Epidemiology and Informatics, University Clinic of Cologne.
4
Asklepios Institute for Emergency Medicine, Hamburg, Germany.
#
Contributed equally

Abstract

BACKGROUND:

 Suspected gastrointestinal (GI) bleeding is a common initial diagnosis in emergency departments. Despite existing endoscopic scores to estimate the risk of GI bleeding, the primary clinical assessment of urgency can remain challenging. The 5-step Manchester Triage System (MTS) is a validated score that is often applied for the initial assessment of patients presenting in emergency departments.

METHODS:

 All computer-based records of patients who were admitted between January 2014 and December 2014 to our emergency department in a tertiary referral hospital were analyzed retrospectively. The aim of our retrospective analysis was to determine if patient triage using the MTS is associated with rates of endoscopy and with presence of active GI bleeding.

RESULTS:

 In summary, 5689 patients with a GI condition were treated at our emergency department. Two hundred eighty-four patients (4.9 %) presented with suspected GI bleeding, and 165 patients (58 %) received endoscopic diagnostic. Endoscopic intervention for hemostasis was needed in 34 patients (21 %). In patients who underwent emergency endoscopy, triage into MTS categories with higher urgency was associated with higher rates of endoscopic confirmation of suspected GI bleeding (79 % of patients with MTS priority levels 1 or 2, 53 % in level 3 patients, and 40 % in levels 4 or 5 patients; p = 0.024).

CONCLUSIONS:

 The MTS is an established tool for triage in emergency departments and could have a potential to guide early clinical decision-making with regards to urgency of endoscopic evaluation in patients with suspected GI bleeding.

Conflict of interest statement

Disclosure The authors report no conflicts of interest in this work.

4.
Hum Hered. 2016;82(1-2):1-15. doi: 10.1159/000475465. Epub 2017 Jul 21.

Efficient Maximum Likelihood Estimation for Pedigree Data with the Sum-Product Algorithm.

Author information

1
Institute for Medical Informatics, Biometry and Epidemiology Ludwig Maximilian University, Munich, Germany.

Abstract

OBJECTIVE:

We analyze data sets consisting of pedigrees with age at onset of colorectal cancer (CRC) as phenotype. The occurrence of familial clusters of CRC suggests the existence of a latent, inheritable risk factor. We aimed to compute the probability of a family possessing this risk factor as well as the hazard rate increase for these risk factor carriers. Due to the inheritability of this risk factor, the estimation necessitates a costly marginalization of the likelihood.

METHODS:

We propose an improved EM algorithm by applying factor graphs and the sum-product algorithm in the E-step. This reduces the computational complexity from exponential to linear in the number of family members.

RESULTS:

Our algorithm is as precise as a direct likelihood maximization in a simulation study and a real family study on CRC risk. For 250 simulated families of size 19 and 21, the runtime of our algorithm is faster by a factor of 4 and 29, respectively. On the largest family (23 members) in the real data, our algorithm is 6 times faster.

CONCLUSION:

We introduce a flexible and runtime-efficient tool for statistical inference in biomedical event data with latent variables that opens the door for advanced analyses of pedigree data.

KEYWORDS:

Cancer risk prediction; Colorectal cancer; EM algorithm; Factor graphs; Pedigrees; Personalized medicine; Sum-product algorithm

PMID:
28728147
DOI:
10.1159/000475465
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5.
Bioinformatics. 2017 Aug 1;33(15):2258-2265. doi: 10.1093/bioinformatics/btx150.

GenoGAM: genome-wide generalized additive models for ChIP-Seq analysis.

Author information

1
Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, 80333 Munich, Germany.
2
Department of Informatics, Technische Universität München, 85748 Garching, Germany.
3
Institut für Medizinische Biometrie, Informatik und Epidemiologie, University Hospital Bonn, 53105 Bonn, Germany.
4
Institute for Genetics, University of Cologne, 50647 Cologne, Germany.

Abstract

Motivation:

Chromatin immunoprecipitation followed by deep sequencing (ChIP-Seq) is a widely used approach to study protein-DNA interactions. Often, the quantities of interest are the differential occupancies relative to controls, between genetic backgrounds, treatments, or combinations thereof. Current methods for differential occupancy of ChIP-Seq data rely however on binning or sliding window techniques, for which the choice of the window and bin sizes are subjective.

Results:

Here, we present GenoGAM (Genome-wide Generalized Additive Model), which brings the well-established and flexible generalized additive models framework to genomic applications using a data parallelism strategy. We model ChIP-Seq read count frequencies as products of smooth functions along chromosomes. Smoothing parameters are objectively estimated from the data by cross-validation, eliminating ad hoc binning and windowing needed by current approaches. GenoGAM provides base-level and region-level significance testing for full factorial designs. Application to a ChIP-Seq dataset in yeast showed increased sensitivity over existing differential occupancy methods while controlling for type I error rate. By analyzing a set of DNA methylation data and illustrating an extension to a peak caller, we further demonstrate the potential of GenoGAM as a generic statistical modeling tool for genome-wide assays.

Availability and Implementation:

Software is available from Bioconductor: https://www.bioconductor.org/packages/release/bioc/html/GenoGAM.html .

Contact:

gagneur@in.tum.de.

Supplementary information:

Supplementary information is available at Bioinformatics online.

PMID:
28369277
DOI:
10.1093/bioinformatics/btx150
[Indexed for MEDLINE]
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6.
PLoS One. 2017 Jan 5;12(1):e0169249. doi: 10.1371/journal.pone.0169249. eCollection 2017.

Accurate Promoter and Enhancer Identification in 127 ENCODE and Roadmap Epigenomics Cell Types and Tissues by GenoSTAN.

Author information

1
Gene Center and Department of Biochemistry, Center for Integrated Protein Science CIPSM, Ludwig-Maximilians-Universität Munich, Germany.
2
Department of Molecular Biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
3
Department of Biology, University of Cologne, Cologne, Germany.
4
Max Planck Institute for Plant Breeding Research, Cologne, Germany.

Abstract

Accurate maps of promoters and enhancers are required for understanding transcriptional regulation. Promoters and enhancers are usually mapped by integration of chromatin assays charting histone modifications, DNA accessibility, and transcription factor binding. However, current algorithms are limited by unrealistic data distribution assumptions. Here we propose GenoSTAN (Genomic STate ANnotation), a hidden Markov model overcoming these limitations. We map promoters and enhancers for 127 cell types and tissues from the ENCODE and Roadmap Epigenomics projects, today's largest compendium of chromatin assays. Extensive benchmarks demonstrate that GenoSTAN generally identifies promoters and enhancers with significantly higher accuracy than previous methods. Moreover, GenoSTAN-derived promoters and enhancers showed significantly higher enrichment of complex trait-associated genetic variants than current annotations. Altogether, GenoSTAN provides an easy-to-use tool to define promoters and enhancers in any system, and our annotation of human transcriptional cis-regulatory elements constitutes a rich resource for future research in biology and medicine.

PMID:
28056037
PMCID:
PMC5215863
DOI:
10.1371/journal.pone.0169249
[Indexed for MEDLINE]
Free PMC Article
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7.
Sci Rep. 2016 Nov 28;6:37462. doi: 10.1038/srep37462.

Continuous single cell imaging reveals sequential steps of plasmacytoid dendritic cell development from common dendritic cell progenitors.

Author information

1
Institute for Immunology, Biomedical Center, Ludwig-Maximilians-University Munich, Großhaderner Str. 9, 82152 Martinsried, Germany.
2
Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, 4058 Basel, Switzerland.
3
Max-Planck-Institute for Plant Breeding Research, Carl-von-Linné-Weg 10, 50829 Cologne, Germany.
4
Department of Biology, University of Cologne, Zülpicher Str. 47, 50829 Cologne, Germany.

Abstract

Functionally distinct plasmacytoid and conventional dendritic cells (pDC and cDC) shape innate and adaptive immunity. They are derived from common dendritic cell progenitors (CDPs) in the murine bone marrow, which give rise to CD11c+ MHCII- precursors with early commitment to DC subpopulations. In this study, we dissect pDC development from CDP into an ordered sequence of differentiation events by monitoring the expression of CD11c, MHC class II, Siglec H and CCR9 in CDP cultures by continuous single cell imaging and tracking. Analysis of CDP genealogies revealed a stepwise differentiation of CDPs into pDCs in a part of the CDP colonies. This developmental pathway involved an early CD11c+ SiglecH- pre-DC stage and a Siglec H+ CCR9low precursor stage, which was followed rapidly by upregulation of CCR9 indicating final pDC differentiation. In the majority of the remaining CDP pedigrees however the Siglec H+ CCR9low precursor state was maintained for several generations. Thus, although a fraction of CDPs transits through precursor stages rapidly to give rise to a first wave of pDCs, the majority of CDP progeny differentiate more slowly and give rise to longer lived precursor cells which are poised to differentiate on demand.

PMID:
27892478
PMCID:
PMC5124969
DOI:
10.1038/srep37462
[Indexed for MEDLINE]
Free PMC Article
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8.
EMBO Mol Med. 2016 Dec 1;8(12):1380-1389. doi: 10.15252/emmm.201606382. Print 2016 Dec.

Non-invasive lung cancer diagnosis by detection of GATA6 and NKX2-1 isoforms in exhaled breath condensate.

Author information

1
LOEWE Research Group Lung Cancer Epigenetic, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
2
Facultad de Ciencias Químicas, Universidad Autonoma "Benito Juarez" de Oaxaca, Oaxaca, Mexico.
3
Department of Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
4
Pulmonary and Critical Care Medicine, Department of Internal Medicine, Justus Liebig University, Giessen, Germany.
5
Section Thoracic Surgery, Justus Liebig University, Giessen, Germany.
6
Chair for Lung Matrix Remodeling, Excellence Cluster Cardio Pulmonary System, Justus Liebig University, Giessen, Germany.
7
Institute of Pathology and Cytology, UEGP, Wetzlar, Germany.
8
Regional Hospital of High Specialties of Oaxaca (HRAEO), Oaxaca, Mexico.
9
Emmy Noether Research Group Origin of Cardiac Cell Lineages, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
10
Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
11
Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, Kazan, Russian Federation.
12
Institute for Genetics, Justus Liebig University, Giessen, Germany.
13
Institute for Pathology, Justus Liebig University, Giessen, Germany.
14
Max Planck Institute for Plant Breeding Research, Cologne, Germany.
15
University of Cologne, Cologne, Germany.
16
Agaplesion Lung Clinic Waldhof Elgershausen, Greifenstein, Germany.
17
LOEWE Research Group Lung Cancer Epigenetic, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany guillermo.barreto@mpi-bn.mpg.de.

Abstract

Lung cancer (LC) is the leading cause of cancer-related deaths worldwide. Early LC diagnosis is crucial to reduce the high case fatality rate of this disease. In this case-control study, we developed an accurate LC diagnosis test using retrospectively collected formalin-fixed paraffin-embedded (FFPE) human lung tissues and prospectively collected exhaled breath condensates (EBCs). Following international guidelines for diagnostic methods with clinical application, reproducible standard operating procedures (SOP) were established for every step comprising our LC diagnosis method. We analyzed the expression of distinct mRNAs expressed from GATA6 and NKX2-1, key regulators of lung development. The Em/Ad expression ratios of GATA6 and NKX2-1 detected in EBCs were combined using linear kernel support vector machines (SVM) into the LC score, which can be used for LC detection. LC score-based diagnosis achieved a high performance in an independent validation cohort. We propose our method as a non-invasive, accurate, and low-price option to complement the success of computed tomography imaging (CT) and chest X-ray (CXR) for LC diagnosis.

KEYWORDS:

EBC ; GATA6 ; NKX2‐1 ; lung cancer; molecular diagnostics

PMID:
27821429
PMCID:
PMC5167131
DOI:
10.15252/emmm.201606382
[Indexed for MEDLINE]
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9.
Science. 2016 Jun 3;352(6290):1225-8. doi: 10.1126/science.aad9841.

TT-seq maps the human transient transcriptome.

Author information

1
Department of Molecular Biology, Max Planck Institute for Biophysical Chemistry, Am Faßberg 11, 37077 Göttingen, Germany.
2
Gene Center Munich, Ludwig-Maximilians-Universität München, Feodor-Lynen-Straße 25, 81377 Munich, Germany.
3
Department of Biosciences and Nutrition, Center for Innovative Medicine, and Science for Life Laboratory, Karolinska Institutet, Novum, Hälsovägen 7, 141 83 Huddinge, Sweden.
4
Department of Biology, University of Cologne, Zülpicher Straße 47, 50647 Cologne, Germany. Max Planck Institute for Plant Breeding Research, Carl-von-Linné Weg 10, 50829 Cologne, Germany.
5
Gene Center Munich, Ludwig-Maximilians-Universität München, Feodor-Lynen-Straße 25, 81377 Munich, Germany. gagneur@in.tum.de patrick.cramer@mpibpc.mpg.de.
6
Department of Molecular Biology, Max Planck Institute for Biophysical Chemistry, Am Faßberg 11, 37077 Göttingen, Germany. Department of Biosciences and Nutrition, Center for Innovative Medicine, and Science for Life Laboratory, Karolinska Institutet, Novum, Hälsovägen 7, 141 83 Huddinge, Sweden. gagneur@in.tum.de patrick.cramer@mpibpc.mpg.de.

Abstract

Pervasive transcription of the genome produces both stable and transient RNAs. We developed transient transcriptome sequencing (TT-seq), a protocol that uniformly maps the entire range of RNA-producing units and estimates rates of RNA synthesis and degradation. Application of TT-seq to human K562 cells recovers stable messenger RNAs and long intergenic noncoding RNAs and additionally maps transient enhancer, antisense, and promoter-associated RNAs. TT-seq analysis shows that enhancer RNAs are short-lived and lack U1 motifs and secondary structure. TT-seq also maps transient RNA downstream of polyadenylation sites and uncovers sites of transcription termination; we found, on average, four transcription termination sites, distributed in a window with a median width of ~3300 base pairs. Termination sites coincide with a DNA motif associated with pausing of RNA polymerase before its release from the genome.

PMID:
27257258
DOI:
10.1126/science.aad9841
[Indexed for MEDLINE]
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10.
Sci Rep. 2016 Feb 23;6:21377. doi: 10.1038/srep21377.

T cell-specific inactivation of mouse CD2 by CRISPR/Cas9.

Author information

1
Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, Germany.
2
Institute of Laboratory Animal Science, University of Zurich, Schlieren, Switzerland.
3
Max-Planck-Institute for Plant Breeding Research, Cologne, Germany.
4
Department of Biology, Albertus-Magnus University, Cologne, Germany.
5
Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.

Abstract

The CRISPR/Cas9 system can be used to mutate target sequences by introduction of double-strand breaks followed by imprecise repair. To test its use for conditional gene editing we generated mice transgenic for CD4 promoter-driven Cas9 combined with guide RNA targeting CD2. We found that within CD4(+) and CD8(+) lymphocytes from lymph nodes and spleen 1% and 0.6% were not expressing CD2, respectively. T cells lacking CD2 carryied mutations, which confirmed that Cas9 driven by cell-type specific promoters can edit genes in the mouse and may thus allow targeted studies of gene function in vivo.

PMID:
26903281
PMCID:
PMC4763270
DOI:
10.1038/srep21377
[Indexed for MEDLINE]
Free PMC Article
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11.
Nucleic Acids Res. 2016 Mar 18;44(5):e44. doi: 10.1093/nar/gkv1184. Epub 2015 Nov 17.

Simultaneous characterization of sense and antisense genomic processes by the double-stranded hidden Markov model.

Author information

1
Gene Center Munich and Department of Biochemistry, Ludwig-Maximilians-Universität München, Feodor-Lynen-Straße 25, 81377 Munich, Germany.
2
Department of Plant Breeding and Genetics, Max Planck Institute for Plant Breeding Research, Carl-von-Linné-Weg 10, 50829 Cologne, Germany Institute for Genetics, University of Cologne, Zülpicher Str. 47b, 50674 Cologne, Germany.
3
Gene Center Munich and Department of Biochemistry, Ludwig-Maximilians-Universität München, Feodor-Lynen-Straße 25, 81377 Munich, Germany Department of Plant Breeding and Genetics, Max Planck Institute for Plant Breeding Research, Carl-von-Linné-Weg 10, 50829 Cologne, Germany.
4
Institute for Genetics, University of Cologne, Zülpicher Str. 47b, 50674 Cologne, Germany.
5
Gene Center Munich and Department of Biochemistry, Ludwig-Maximilians-Universität München, Feodor-Lynen-Straße 25, 81377 Munich, Germany Department of Plant Breeding and Genetics, Max Planck Institute for Plant Breeding Research, Carl-von-Linné-Weg 10, 50829 Cologne, Germany Institute for Genetics, University of Cologne, Zülpicher Str. 47b, 50674 Cologne, Germany tresch@genzentrum.lmu.de.

Abstract

Hidden Markov models (HMMs) have been extensively used to dissect the genome into functionally distinct regions using data such as RNA expression or DNA binding measurements. It is a challenge to disentangle processes occurring on complementary strands of the same genomic region. We present the double-stranded HMM (dsHMM), a model for the strand-specific analysis of genomic processes. We applied dsHMM to yeast using strand specific transcription data, nucleosome data, and protein binding data for a set of 11 factors associated with the regulation of transcription.The resulting annotation recovers the mRNA transcription cycle (initiation, elongation, termination) while correctly predicting strand-specificity and directionality of the transcription process. We find that pre-initiation complex formation is an essentially undirected process, giving rise to a large number of bidirectional promoters and to pervasive antisense transcription. Notably, 12% of all transcriptionally active positions showed simultaneous activity on both strands. Furthermore, dsHMM reveals that antisense transcription is specifically suppressed by Nrd1, a yeast termination factor.

PMID:
26578558
PMCID:
PMC4797261
DOI:
10.1093/nar/gkv1184
[Indexed for MEDLINE]
Free PMC Article
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12.
Proc Natl Acad Sci U S A. 2015 Aug 18;112(33):10539-44. doi: 10.1073/pnas.1419791112. Epub 2015 Aug 4.

Heterochrony underpins natural variation in Cardamine hirsuta leaf form.

Author information

1
Department of Comparative Development and Genetics, Max Planck Institute for Plant Breeding Research, 50829 Cologne, Germany;
2
Department of Plant Sciences, University of Oxford, Oxford OX1 3RB, United Kingdom;
3
Botanical Institute, University of Cologne, 50647 Cologne, Germany; Max Planck Institute for Plant Breeding Research, 50829 Cologne, Germany.
4
Department of Comparative Development and Genetics, Max Planck Institute for Plant Breeding Research, 50829 Cologne, Germany; tsiantis@mpipz.mpg.de.

Abstract

A key problem in biology is whether the same processes underlie morphological variation between and within species. Here, by using plant leaves as an example, we show that the causes of diversity at these two evolutionary scales can be divergent. Some species like the model plant Arabidopsis thaliana have simple leaves, whereas others like the A. thaliana relative Cardamine hirsuta bear complex leaves comprising leaflets. Previous work has shown that these interspecific differences result mostly from variation in local tissue growth and patterning. Now, by cloning and characterizing a quantitative trait locus (QTL) for C. hirsuta leaf shape, we find that a different process, age-dependent progression of leaf form, underlies variation in this trait within species. This QTL effect is caused by cis-regulatory variation in the floral repressor ChFLC, such that genotypes with low-expressing ChFLC alleles show both early flowering and accelerated age-dependent changes in leaf form, including faster leaflet production. We provide evidence that this mechanism coordinates leaf development with reproductive timing and may help to optimize resource allocation to the next generation.

KEYWORDS:

Cardamine hirsuta; Flowering Locus C; compound leaf; heterochrony; natural variation

PMID:
26243877
PMCID:
PMC4547220
DOI:
10.1073/pnas.1419791112
[Indexed for MEDLINE]
Free PMC Article
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13.
World J Gastroenterol. 2015 Jul 14;21(26):8184-94. doi: 10.3748/wjg.v21.i26.8184.

Intraprocedural bowel cleansing with the JetPrep cleansing system improves adenoma detection.

Author information

1
Arthur Hoffman, Johannes Wilhelm Rey, Martin Goetz, Peter Robert Galle, Ralf Kiesslich, First Department of Medicine, Johannes Gutenberg University of Mainz, 65199 Wiesbaden, Germany.

Abstract

AIM:

To investigate the impact of JetPrep cleansing on adenoma detection rates.

METHODS:

In this prospective, randomized, crossover trial, patients were blindly randomized to an intervention arm or a control arm. In accordance with the risk profile for the development of colorectal carcinoma, the study participants were divided into high-risk and low-risk groups. Individuals with just one criterion (age > 70 years, adenoma in medical history, and first-degree relative with colorectal cancer) were regarded as high-risk patients. Bowel preparation was performed in a standardized manner one day before the procedure. Participants in the intervention arm underwent an initial colonoscopy with standard bowel cleansing using a 250-mL syringe followed by a second colonoscopy that included irrigation by the use of the JetPrep cleansing system. The reverse sequence was used in the control arm. The study participants were divided into a high-risk group and a low-risk group according to their respective risk profiles for the development of colorectal carcinoma.

RESULTS:

A total of 64 patients (34 men and 30 women) were included in the study; 22 were included in the high-risk group. After randomization, 30 patients were assigned to the control group (group A) and 34 to the intervention group (group B). The average Boston Bowel Preparation Scale score was 5.15 ± 2.04. The withdrawal time needed for the first step was significantly longer in group A using the JetPrep system (9.41 ± 3.34 min) compared to group B (7.5 ± 1.92 min). A total of 163 polyps were discovered in 64 study participants who underwent both investigation steps. In group A, 49.4% of the polyps were detected during the step of standard bowel cleansing while the miss rate constituted 50.7%. Group B underwent cleansing with the JetPrep system during the first examination step, and as many as 73.9% of polyps were identified during this step. Thus, the miss rate in group B was a mere 26.1% (P < 0.001). When considering only the right side of the colon, the miss rate in group A during the first examination was 60.6%, in contrast to a miss rate of 26.4% in group B (P < 0.001).

CONCLUSION:

JetPrep is recommended for use during colonoscopy because a better prepared bowel enables a better adenoma detection, particularly in the proximal colon.

KEYWORDS:

Adenoma detection rate; Adenoma miss rate; Boston Bowel Preparation Scale; Colon preparation; Flat adenoma; Interval cancer; Right sided colon

PMID:
26185393
PMCID:
PMC4499364
DOI:
10.3748/wjg.v21.i26.8184
[Indexed for MEDLINE]
Free PMC Article
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14.
Bioinformatics. 2015 Jun 1;31(11):1816-23. doi: 10.1093/bioinformatics/btv040. Epub 2015 Jan 31.

Factor graph analysis of live cell-imaging data reveals mechanisms of cell fate decisions.

Author information

1
Gene Center, Department of Chemistry and Biochemistry, Ludwig-Maximilians-University München, Germany, Max-Planck-Institute for Plant Breeding Research, Cologne, Germany Department of Biology, Albertus-Magnus University, Cologne, Germany, Institute for Medical Informatics and Biometry, Faculty of Medicine Carl Gustav Carus, TU Dresden, Germany, Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany and Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland.
2
Gene Center, Department of Chemistry and Biochemistry, Ludwig-Maximilians-University München, Germany, Max-Planck-Institute for Plant Breeding Research, Cologne, Germany Department of Biology, Albertus-Magnus University, Cologne, Germany, Institute for Medical Informatics and Biometry, Faculty of Medicine Carl Gustav Carus, TU Dresden, Germany, Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany and Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland Gene Center, Department of Chemistry and Biochemistry, Ludwig-Maximilians-University München, Germany, Max-Planck-Institute for Plant Breeding Research, Cologne, Germany Department of Biology, Albertus-Magnus University, Cologne, Germany, Institute for Medical Informatics and Biometry, Faculty of Medicine Carl Gustav Carus, TU Dresden, Germany, Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany and Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland.
3
Gene Center, Department of Chemistry and Biochemistry, Ludwig-Maximilians-University München, Germany, Max-Planck-Institute for Plant Breeding Research, Cologne, Germany Department of Biology, Albertus-Magnus University, Cologne, Germany, Institute for Medical Informatics and Biometry, Faculty of Medicine Carl Gustav Carus, TU Dresden, Germany, Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany and Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland Gene Center, Department of Chemistry and Biochemistry, Ludwig-Maximilians-University München, Germany, Max-Planck-Institute for Plant Breeding Research, Cologne, Germany Department of Biology, Albertus-Magnus University, Cologne, Germany, Institute for Medical Informatics and Biometry, Faculty of Medicine Carl Gustav Carus, TU Dresden, Germany, Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany and Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland Gene Center, Department of Chemistry and Biochemistry, Ludwig-Maximilians-University München, Germany, Max-Planck-Institute for Plant Breeding Research, Cologne, Germany Department of Biology, Albertus-Magnus University, Cologne, Germany, Institute for Medical Informatics and Biometry, Faculty of Medicine Carl Gustav Carus, TU Dresden, Germany, Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany and Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland.

Abstract

MOTIVATION:

Cell fate decisions have a strong stochastic component. The identification of the underlying mechanisms therefore requires a rigorous statistical analysis of large ensembles of single cells that were tracked and phenotyped over time.

RESULTS:

We introduce a probabilistic framework for testing elementary hypotheses on dynamic cell behavior using time-lapse cell-imaging data. Factor graphs, probabilistic graphical models, are used to properly account for cell lineage and cell phenotype information. Our model is applied to time-lapse movies of murine granulocyte-macrophage progenitor (GMP) cells. It decides between competing hypotheses on the mechanisms of their differentiation. Our results theoretically substantiate previous experimental observations that lineage instruction, not selection is the cause for the differentiation of GMP cells into mature monocytes or neutrophil granulocytes.

AVAILABILITY AND IMPLEMENTATION:

The Matlab source code is available at http://treschgroup.de/Genealogies.html.

PMID:
25638814
DOI:
10.1093/bioinformatics/btv040
[Indexed for MEDLINE]
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15.
Mol Syst Biol. 2014 Dec 19;10:768. doi: 10.15252/msb.20145654.

Annotation of genomics data using bidirectional hidden Markov models unveils variations in Pol II transcription cycle.

Author information

1
Gene Center and Department of Biochemistry, Center for Integrated Protein Science CIPSM, Ludwig-Maximilians-Universität München, Munich, Germany Institute for Genetics, University of Cologne, Cologne, Germany.
2
Gene Center and Department of Biochemistry, Center for Integrated Protein Science CIPSM, Ludwig-Maximilians-Universität München, Munich, Germany Department of Molecular Biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
3
Gene Center and Department of Biochemistry, Center for Integrated Protein Science CIPSM, Ludwig-Maximilians-Universität München, Munich, Germany tresch@mpipz.mpg.de gagneur@genzentrum.lmu.de.
4
Gene Center and Department of Biochemistry, Center for Integrated Protein Science CIPSM, Ludwig-Maximilians-Universität München, Munich, Germany Institute for Genetics, University of Cologne, Cologne, Germany Max Planck Institute for Plant Breeding Research, Cologne, Germany tresch@mpipz.mpg.de gagneur@genzentrum.lmu.de.

Abstract

DNA replication, transcription and repair involve the recruitment of protein complexes that change their composition as they progress along the genome in a directed or strand-specific manner. Chromatin immunoprecipitation in conjunction with hidden Markov models (HMMs) has been instrumental in understanding these processes, as they segment the genome into discrete states that can be related to DNA-associated protein complexes. However, current HMM-based approaches are not able to assign forward or reverse direction to states or properly integrate strand-specific (e.g., RNA expression) with non-strand-specific (e.g., ChIP) data, which is indispensable to accurately characterize directed processes. To overcome these limitations, we introduce bidirectional HMMs which infer directed genomic states from occupancy profiles de novo. Application to RNA polymerase II-associated factors in yeast and chromatin modifications in human T cells recovers the majority of transcribed loci, reveals gene-specific variations in the yeast transcription cycle and indicates the existence of directed chromatin state patterns at transcribed, but not at repressed, regions in the human genome. In yeast, we identify 32 new transcribed loci, a regulated initiation-elongation transition, the absence of elongation factors Ctk1 and Paf1 from a class of genes, a distinct transcription mechanism for highly expressed genes and novel DNA sequence motifs associated with transcription termination. We anticipate bidirectional HMMs to significantly improve the analyses of genome-associated directed processes.

KEYWORDS:

RNA transcription cycle; bidirectional hidden Markov model; chromatin marks; genome annotation

PMID:
25527639
PMCID:
PMC4300491
[Indexed for MEDLINE]
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16.
PLoS One. 2014 Oct 2;9(9):e107955. doi: 10.1371/journal.pone.0107955. eCollection 2014.

A novel test for independence derived from an exact distribution of ith nearest neighbours.

Author information

1
Institute for Genetics, Universität zu Köln, Cologne, Germany; Max Planck Institute for Plant Breeding Research, Cologne, Germany.
2
IBE, Ludwig-Maximilians-Universität, Munich, Germany.

Abstract

Dependence measures and tests for independence have recently attracted a lot of attention, because they are the cornerstone of algorithms for network inference in probabilistic graphical models. Pearson's product moment correlation coefficient is still by far the most widely used statistic yet it is largely constrained to detecting linear relationships. In this work we provide an exact formula for the [Formula: see text]th nearest neighbor distance distribution of rank-transformed data. Based on that, we propose two novel tests for independence. An implementation of these tests, together with a general benchmark framework for independence testing, are freely available as a CRAN software package (http://cran.r-project.org/web/packages/knnIndep). In this paper we have benchmarked Pearson's correlation, Hoeffding's D, dcor, Kraskov's estimator for mutual information, maximal information criterion and our two tests. We conclude that no particular method is generally superior to all other methods. However, dcor and Hoeffding's D are the most powerful tests for many different types of dependence.

PMID:
25275469
PMCID:
PMC4183502
DOI:
10.1371/journal.pone.0107955
[Indexed for MEDLINE]
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17.
Dig Liver Dis. 2014 Nov;46(11):991-6. doi: 10.1016/j.dld.2014.07.169. Epub 2014 Aug 20.

High definition plus colonoscopy combined with i-scan tone enhancement vs. high definition colonoscopy for colorectal neoplasia: A randomized trial.

Author information

1
St. Mary's Hospital, Department of Medicine, Frankfurt, Germany; 1. Medical Department, Johannes Gutenberg University Mainz, Germany. Electronic address: ahoff66286@aol.com.
2
St. Mary's Hospital, Department of Medicine, Frankfurt, Germany.
3
St. Mary's Hospital, Department of Medicine, Frankfurt, Germany; 1. Medical Department, Johannes Gutenberg University Mainz, Germany.
4
1. Medical Department, Johannes Gutenberg University Mainz, Germany; 1. Medical Department, University of Tübingen, Germany.
5
Institute of Pathology, Johannes Gutenberg University Mainz, Germany; Clinic Lippe, Institute of Pathology, Detmold, Germany.
6
Max Planck Institute, Cologne, Germany.
7
Gene Zentrum Ludwig-Maximilians-Universität München, Germany.
8
1. Medical Department, Johannes Gutenberg University Mainz, Germany.

Abstract

BACKGROUND:

High definition endoscopy is the accepted standard in colonoscopy. However, an important problem is missed polyps.

AIMS:

Our objective was to assess the additional adenoma detection rate between high definition colonoscopy with tone enhancement (digital chromoendoscopy) vs. white light high definition colonoscopy.

METHODS:

In this prospective randomized trial patients were included to undergo a tandem colonoscopy. The first exam was a white light colonoscopy with removal of all visualized polyps. The second examination was randomly assigned in a 1:1 ratio as either again white light colonoscopy (Group A) or colonoscopy with tone enhancement (Group B). Primary endpoint was the adenoma detection rate during the second withdrawal (sample size calculation - 40 per group).

RESULTS:

67 lesions (Group A: n=34 vs. Group B: n=33) in 80 patients (mean age 61 years, male 64%) were identified on the first colonoscopy. The second colonoscopy detected 78 additional lesions: n=60 with tone enhancement vs. n=18 with white light endoscopy (p<0.001). Tone enhancement found more additional adenomas (A n=20 vs. B n=6, p=0.006) and identified significantly more missed adenomas per subject (0.5 vs. 0.15, p=0.006).

CONCLUSIONS:

High definition plus colonoscopy with tone enhancement detected more adenomas missed by white light colonoscopy.

KEYWORDS:

Adenoma detection rate; Adenoma miss rate; I-scan technique; Red flag technology

PMID:
25151550
DOI:
10.1016/j.dld.2014.07.169
[Indexed for MEDLINE]
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18.
World J Gastrointest Endosc. 2014 Apr 16;6(4):137-43. doi: 10.4253/wjge.v6.i4.137.

Efficacy of SpyGlass(TM)-directed biopsy compared to brush cytology in obtaining adequate tissue for diagnosis in patients with biliary strictures.

Author information

1
Johannes Wilhelm Rey, Katja Kramer, Peter Robert Galle, Martin Goetz, Marcus Schuchmann, Ralf Kiesslich, Arthur Hoffman, Department of Internal Medicine I, University Medical Center, 55131 Mainz, Germany.

Abstract

AIM:

To evaluate the diagnostic yield (inflammatory activity) and efficiency (size of the biopsy specimen) of SpyGlass(TM)-guided biopsy vs standard brush cytology in patients with and without primary sclerosing cholangitis (PSC).

METHODS:

At the University Medical Center Mainz, Germany, 35 consecutive patients with unclear biliary lesions (16 patients) or long-standing PSC (19 patients) were screened for the study. All patients underwent a physical examination, lab analyses, and abdominal ultrasound. Thirty-one patients with non-PSC strictures or with PSC were scheduled to undergo endoscopic retrograde cholangiography (ERC) and subsequent peroral cholangioscopy (POC). Standard ERC was initially performed, and any lesions or strictures were localized. POC was performed later during the same session. The Boston Scientific SpyGlass System(TM) (Natick, MA, United States) was used for choledochoscopy. The biliary tree was visualized, and suspected lesions or strictures were biopsied, followed by brush cytology of the same area. The study endpoints (for both techniques) were the degree of inflammation, tissue specimen size, and the patient populations (PSC vs non-PSC). Inflammatory changes were divided into three categories: none, low activity, and high activity. The specimen quantity was rated as low, moderate, or sufficient.

RESULTS:

SpyGlass(TM) imaging and brush cytology with material retrieval were performed in 29 of 31 (93.5%) patients (23 of the 29 patients were male). The median patient age was 45 years (min, 20 years; max, 76 years). Nineteen patients had known PSC, and 10 showed non-PSC strictures. No procedure-related complications were encountered. However, for both methods, tissues could only be retrieved from 29 patients. In cases of inflammation of the biliary tract, the diagnostic yield of the SpyGlass(TM)-directed biopsies was greater than that using brush cytology. More tissue material was obtained for the biopsy method than for the brush cytology method (P = 0.021). The biopsies showed significantly more inflammatory characteristics and greater inflammatory activity compared to the cytological investigation (P = 0.014). The greater quantity of tissue samples proved useful for both PSC and non-PSC patients.

CONCLUSION:

SpyGlass(TM) imaging can be recommended for proper inflammatory diagnosis in PSC patients. However, its value in diagnosing dysplasia was not addressed in this study and requires further investigation.

KEYWORDS:

Biopsy; Brush cytology; Cholangioscopy; Endoscopic retrograde cholangiopancreatography; Primary sclerosing cholangitis

19.
PLoS One. 2014 Mar 21;9(3):e91840. doi: 10.1371/journal.pone.0091840. eCollection 2014.

Selection of higher order regression models in the analysis of multi-factorial transcription data.

Author information

1
Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, Munich, Germany.
2
St. Mary's hospital, Department of Medicine, Frankfurt, Germany; Medical Department, Johannes Gutenberg University, Mainz, Germany.
3
Medical Department, Johannes Gutenberg University, Mainz, Germany.
4
Institute for Medical Informatics, Biometry and Epidemiology (IBE), Ludwig-Maximilians-Universität München, Munich, Germany.
5
Department of Plant Breeding and Genetics, Max Planck Institute for Plant Breeding Research, Cologne, Germany; Institute for Genetics, University of Cologne, Cologne, Germany.

Abstract

INTRODUCTION:

Many studies examine gene expression data that has been obtained under the influence of multiple factors, such as genetic background, environmental conditions, or exposure to diseases. The interplay of multiple factors may lead to effect modification and confounding. Higher order linear regression models can account for these effects. We present a new methodology for linear model selection and apply it to microarray data of bone marrow-derived macrophages. This experiment investigates the influence of three variable factors: the genetic background of the mice from which the macrophages were obtained, Yersinia enterocolitica infection (two strains, and a mock control), and treatment/non-treatment with interferon-γ.

RESULTS:

We set up four different linear regression models in a hierarchical order. We introduce the eruption plot as a new practical tool for model selection complementary to global testing. It visually compares the size and significance of effect estimates between two nested models. Using this methodology we were able to select the most appropriate model by keeping only relevant factors showing additional explanatory power. Application to experimental data allowed us to qualify the interaction of factors as either neutral (no interaction), alleviating (co-occurring effects are weaker than expected from the single effects), or aggravating (stronger than expected). We find a biologically meaningful gene cluster of putative C2TA target genes that appear to be co-regulated with MHC class II genes.

CONCLUSIONS:

We introduced the eruption plot as a tool for visual model comparison to identify relevant higher order interactions in the analysis of expression data obtained under the influence of multiple factors. We conclude that model selection in higher order linear regression models should generally be performed for the analysis of multi-factorial microarray data.

PMID:
24658540
PMCID:
PMC3962375
DOI:
10.1371/journal.pone.0091840
[Indexed for MEDLINE]
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20.
Bioinformatics. 2014 Jul 1;30(13):1933-4. doi: 10.1093/bioinformatics/btu142. Epub 2014 Mar 10.

Genome-wide quantitative analysis of DNA methylation from bisulfite sequencing data.

Author information

1
Tresch Group, Max Planck Institute for Plant Breeding Research, 50829 Cologne, Germany, AG Haaf, Institute of Human Genetics, Julius Maximilians University, 97070 Wuerzburg, Germany and Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.

Abstract

Here we present the open-source R/Bioconductor software package BEAT (BS-Seq Epimutation Analysis Toolkit). It implements all bioinformatics steps required for the quantitative high-resolution analysis of DNA methylation patterns from bisulfite sequencing data, including the detection of regional epimutation events, i.e. loss or gain of DNA methylation at CG positions relative to a reference. Using a binomial mixture model, the BEAT package aggregates methylation counts per genomic position, thereby compensating for low coverage, incomplete conversion and sequencing errors.

AVAILABILITY AND IMPLEMENTATION:

BEAT is freely available as part of Bioconductor at www.bioconductor.org/packages/devel/bioc/html/BEAT.html. The package is distributed under the GNU Lesser General Public License 3.0.

PMID:
24618468
PMCID:
PMC4071208
DOI:
10.1093/bioinformatics/btu142
[Indexed for MEDLINE]
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