28554
2017
eng
7
18
article
1
--
2017-07-05
--
Semi-quantitative mass spectrometry in AML cells identifies new non-genomic targets of the EZH2 methyltransferase
Alterations to the gene encoding the EZH2 (KMT6A) methyltransferase, including both gain-of-function and loss-of-function, have been linked to a variety of haematological malignancies and solid tumours, suggesting a complex, context-dependent role of this methyltransferase. The successful implementation of molecularly targeted therapies against EZH2 requires a greater understanding of the potential mechanisms by which EZH2 contributes to cancer. One aspect of this effort is the mapping of EZH2 partner proteins and cellular targets. To this end we performed affinity-purification mass spectrometry in the FAB-M2 HL-60 acute myeloid leukaemia (AML) cell line before and after all-trans retinoic acid-induced differentiation. These studies identified new EZH2 interaction partners and potential non-histone substrates for EZH2-mediated methylation. Our results suggest that EZH2 is involved in the regulation of translation through interactions with a number of RNA binding proteins and by methylating key components of protein synthesis such as eEF1A1. Given that deregulated mRNA translation is a frequent feature of cancer and that eEF1A1 is highly expressed in many human tumours, these findings present new possibilities for the therapeutic targeting of EZH2 in AML.
International Journal of Molecular Sciences
1422-0067
10.3390/ijms18071440
urn:nbn:de:bvb:20-opus-285541
2022-09-06T10:46:28+00:00
sword
swordwue
attachment; filename=deposit.zip
1365b3ef1bbdc0d02c9d0c3c6878cdb2
International Journal of Molecular Sciences (2017) 18:7, 1440. https://doi.org/10.3390/ijms18071440
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Yordan Sbirkov
Colin Kwok
Amandeep Bhamra
Andrew J. Thompson
Veronica Gil
Arthur Zelent
Kevin Petrie
eng
uncontrolled
acute myeloid leukaemia
eng
uncontrolled
EZH2
eng
uncontrolled
mass spectrometry
eng
uncontrolled
methylation
eng
uncontrolled
eEF1A1
Medizin und Gesundheit
open_access
Theodor-Boveri-Institut für Biowissenschaften
Import
Comprehensive Cancer Center Mainfranken
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/28554/ijms-18-01440.pdf
17211
2017
eng
1
13
article
1
2018-11-19
--
--
Fiji macro 3D ART VeSElecT: 3D automated reconstruction tool for vesicle structures of electron tomograms
Automatic image reconstruction is critical to cope with steadily increasing data from advanced microscopy. We describe here the Fiji macro 3D ART VeSElecT which we developed to study synaptic vesicles in electron tomograms. We apply this tool to quantify vesicle properties (i) in embryonic Danio rerio 4 and 8 days past fertilization (dpf) and (ii) to compare Caenorhabditis elegans N2 neuromuscular junctions (NMJ) wild-type and its septin mutant (unc-59(e261)). We demonstrate development-specific and mutant-specific changes in synaptic vesicle pools in both models. We confirm the functionality of our macro by applying our 3D ART VeSElecT on zebrafish NMJ showing smaller vesicles in 8 dpf embryos then 4 dpf, which was validated by manual reconstruction of the vesicle pool. Furthermore, we analyze the impact of C. elegans septin mutant unc-59(e261) on vesicle pool formation and vesicle size. Automated vesicle registration and characterization was implemented in Fiji as two macros (registration and measurement). This flexible arrangement allows in particular reducing false positives by an optional manual revision step. Preprocessing and contrast enhancement work on image-stacks of 1nm/pixel in x and y direction. Semi-automated cell selection was integrated. 3D ART VeSElecT removes interfering components, detects vesicles by 3D segmentation and calculates vesicle volume and diameter (spherical approximation, inner/outer diameter). Results are collected in color using the RoiManager plugin including the possibility of manual removal of non-matching confounder vesicles. Detailed evaluation considered performance (detected vesicles) and specificity (true vesicles) as well as precision and recall. We furthermore show gain in segmentation and morphological filtering compared to learning based methods and a large time gain compared to manual segmentation. 3D ART VeSElecT shows small error rates and its speed gain can be up to 68 times faster in comparison to manual annotation. Both automatic and semi-automatic modes are explained including a tutorial.
PLoS Computational Biology
10.1371/journal.pcbi.1005317
28056033
urn:nbn:de:bvb:20-opus-172112
PLoS Computational Biology (2017) 13(1):e1005317. https://doi.org/10.1371/journal.pcbi.1005317
true
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Kristin Verena Kaltdorf
Katja Schulze
Frederik Helmprobst
Philip Kollmannsberger
Thomas Dandekar
Christian Stigloher
eng
uncontrolled
Biology
eng
uncontrolled
Vesicles
eng
uncontrolled
Caenorhabditis elegans
eng
uncontrolled
Zebrafish
eng
uncontrolled
Septins
eng
uncontrolled
Synaptic vesicles
eng
uncontrolled
Neuromuscular junctions
eng
uncontrolled
Computer software
eng
uncontrolled
Synapses
Datenverarbeitung; Informatik
Biowissenschaften; Biologie
open_access
Theodor-Boveri-Institut für Biowissenschaften
Center for Computational and Theoretical Biology
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/17211/Kaltdorf_pcbi.1005317.pdf
17378
2017
eng
7
2017
article
1
2018-12-07
--
--
Sexual dimorphism of \(AMBRA1\)-related autistic features in human and mouse
\(Ambra1\) is linked to autophagy and neurodevelopment. Heterozygous \(Ambra1\) deficiency induces autism-like behavior in a sexually dimorphic manner. Extraordinarily, autistic features are seen in female mice only, combined with stronger Ambra1 protein reduction in brain compared to males. However, significance of \(AMBRA1\) for autistic phenotypes in humans and, apart from behavior, for other autism-typical features, namely early brain enlargement or increased seizure propensity, has remained unexplored. Here we show in two independent human samples that a single normal \(AMBRA1\) genotype, the intronic SNP rs3802890-AA, is associated with autistic features in women, who also display lower \(AMBRA1\) mRNA expression in peripheral blood mononuclear cells relative to female GG carriers. Located within a non-coding RNA, likely relevant for mRNA and protein interaction, rs3802890 (A versus G allele) may affect its stability through modification of folding, as predicted by \(in\) \(silico\) analysis. Searching for further autism-relevant characteristics in \(Ambra1^{+/−}\) mice, we observe reduced interest of female but not male mutants regarding pheromone signals of the respective other gender in the social intellicage set-up. Moreover, altered pentylentetrazol-induced seizure propensity, an \(in\) \(vivo\) readout of neuronal excitation–inhibition dysbalance, becomes obvious exclusively in female mutants. Magnetic resonance imaging reveals mild prepubertal brain enlargement in both genders, uncoupling enhanced brain dimensions from the primarily female expression of all other autistic phenotypes investigated here. These data support a role of \(AMBRA1/Ambra1\) partial loss-of-function genotypes for female autistic traits. Moreover, they suggest \(Ambra1\) heterozygous mice as a novel multifaceted and construct-valid genetic mouse model for female autism.
Translational Psychiatry
10.1038/tp.2017.213
28994820
urn:nbn:de:bvb:20-opus-173782
Translational Psychiatry (2017) 7:e1247. https://doi.org/10.1038/tp.2017.213
115300
true
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
M. Mitjans
M. Begemann
A. Ju
E. Dere
L. Wüstefeld
S. Hofer
I. Hassouna
J. Balkenhol
B. Oliveira
S. Van der Auwera
R. Tammer
K. Hammerschmidt
H. Völzke
G. Homuth
F. Cecconi
K. Chowdhury
H. Grabe
J. Frahm
S. Boretius
T. Dandekar
H. Ehrenreich
eng
uncontrolled
biology
eng
uncontrolled
clinical genetics
eng
uncontrolled
molecular neuroscience
Biowissenschaften; Biologie
open_access
Theodor-Boveri-Institut für Biowissenschaften
OpenAIRE
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/17378/Mitjans_tp2017213.pdf
17317
2017
eng
7
article
1
2018-11-28
--
--
ABMA, a small molecule that inhibits intracellular toxins and pathogens by interfering with late endosomal compartments
Intracellular pathogenic microorganisms and toxins exploit host cell mechanisms to enter, exert their deleterious effects as well as hijack host nutrition for their development. A potential approach to treat multiple pathogen infections and that should not induce drug resistance is the use of small molecules that target host components. We identifed the compound 1-adamantyl (5-bromo-2-methoxybenzyl) amine (ABMA) from a cell-based high throughput screening for its capacity to protect human cells and mice against ricin toxin without toxicity. This compound efciently protects cells against various toxins and pathogens including viruses, intracellular bacteria and parasite. ABMA provokes Rab7-positive late endosomal compartment accumulation in mammalian cells without affecting other organelles (early endosomes, lysosomes, the Golgi apparatus, the endoplasmic reticulum or the nucleus). As the mechanism of action of ABMA is restricted to host-endosomal compartments, it reduces cell infection by pathogens that depend on this pathway to invade cells. ABMA may represent a novel class of broad-spectrum compounds with therapeutic potential against diverse severe infectious diseases.
Scientific Reports
10.1038/s41598-017-15466-7
29138439
urn:nbn:de:bvb:20-opus-173170
Scientific Reports (2017) 7:15567. https://doi.org/10.1038/s41598-017-15466-7
true
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Yu Wu
Valérie Pons
Amélie Goudet
Laetitia Panigai
Annette Fischer
Jo-Ana Herweg
Sabrina Kali
Robert A. Davey
Jérôme Laporte
Céline Bouclier
Rahima Yousfi
Céline Aubenque
Goulven Merer
Emilie Gobbo
Roman Lopez
Cynthia Gillet
Sandrine Cojean
Michel R. Popoff
Pascal Clayette
Roger Le Grand
Claire Boulogne
Noël Tordo
Emmanuel Lemichez
Philippe M. Loiseau
Thomas Rudel
Didier Sauvaire
Jean-Christophe Cintrat
Daniel Gillet
Julien Barbier
eng
uncontrolled
biology
eng
uncontrolled
antimicrobials
eng
uncontrolled
high-throughput screening
eng
uncontrolled
infectious diseases
Biowissenschaften; Biologie
open_access
Theodor-Boveri-Institut für Biowissenschaften
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/17317/Wu_s41598-017-15466-7.pdf
17299
2017
eng
8
article
1
2018-11-26
--
--
Quantifying protein densities on cell membranes using super-resolution optical fluctuation imaging
Quantitative approaches for characterizing molecular organization of cell membrane molecules under physiological and pathological conditions profit from recently developed super-resolution imaging techniques. Current tools employ statistical algorithms to determine clusters of molecules based on single-molecule localization microscopy (SMLM) data. These approaches are limited by the ability of SMLM techniques to identify and localize molecules in densely populated areas and experimental conditions of sample preparation and image acquisition. We have developed a robust, model-free, quantitative clustering analysis to determine the distribution of membrane molecules that excels in densely labeled areas and is tolerant to various experimental conditions, i.e. multiple-blinking or high blinking rates. The method is based on a TIRF microscope followed by a super-resolution optical fluctuation imaging (SOFI) analysis. The effectiveness and robustness of the method is validated using simulated and experimental data investigating nanoscale distribution of CD4 glycoprotein mutants in the plasma membrane of T cells.
Nature Communications
10.1038/s41467-017-01857-x
29170394
urn:nbn:de:bvb:20-opus-172993
Nature Communications (2017) 8:1731. https://doi.org/10.1038/s41467-017-01857-x
686271
602812
true
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Tomáš Lukeš
Daniela Glatzová
Zuzana Kvíčalová
Florian Levet
Aleš Benda
Sebastian Letschert
Markus Sauer
Tomáš Brdička
Theo Lasser
Marek Cebecauer
eng
uncontrolled
biology
eng
uncontrolled
fluorescence imaging
eng
uncontrolled
imaging the immune system
eng
uncontrolled
super-resolution microscopy
Biowissenschaften; Biologie
open_access
Theodor-Boveri-Institut für Biowissenschaften
OpenAIRE
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/17299/Tomas_s41467-017-01857-x.pdf
17273
2017
eng
1830-1842
12
7
article
1
2018-11-23
--
--
Structural enzymology comparisons of multifunctional enzyme, type-1 (MFE1): the flexibility of its dehydrogenase part
Multifunctional enzyme, type-1 (MFE1) is a monomeric enzyme with a 2E-enoyl-CoA hydratase and a 3S-hydroxyacyl-CoA dehydrogenase (HAD) active site. Enzyme kinetic data of rat peroxisomal MFE1 show that the catalytic efficiencies for converting the short-chain substrate 2E-butenoyl-CoA into acetoacetyl-CoA are much lower when compared with those of the homologous monofunctional enzymes. The mode of binding of acetoacetyl-CoA (to the hydratase active site) and the very similar mode of binding of NAD\(^+\) and NADH (to the HAD part) are described and compared with those of their monofunctional counterparts. Structural comparisons suggest that the conformational flexibility of the HAD and hydratase parts of MFE1 are correlated. The possible importance of the conformational flexibility of MFE1 for its biocatalytic properties is discussed.
FEBS Open Bio
10.1002/2211-5463.12337
29226071
urn:nbn:de:bvb:20-opus-172732
FEBS Open Bio (2017) 7:12, pp. 1830-1842. https://doi.org/10.1002/2211-5463.12337
true
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Prasad Kasaragod
Getnet B. Midekessa
Shruthi Sridhar
Werner Schmitz
Tiila-Riikka Kiema
Jukka K. Hiltunen
Rik K. Wierenga
eng
uncontrolled
biology
eng
uncontrolled
CoA
eng
uncontrolled
crotonase
eng
uncontrolled
dehydrogenase
eng
uncontrolled
NAD
eng
uncontrolled
substrate channeling
Biowissenschaften; Biologie
open_access
Theodor-Boveri-Institut für Biowissenschaften
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/17273/Kasaragod_2211-5463.12337.pdf
17271
2017
eng
183-190
25
article
1
2018-11-23
--
--
Genetic profiling and surface proteome analysis of human atrial stromal cells and rat ventricular epicardium-derived cells reveals novel insights into their cardiogenic potential
Epicardium-derived cells (EPDC) and atrial stromal cells (ASC) display cardio-regenerative potential, but the molecular details are still unexplored. Signals which induce activation, migration and differentiation of these cells are largely unknown. Here we have isolated rat ventricular EPDC and rat/human ASC and performed genetic and proteomic profiling. EPDC and ASC expressed epicardial/mesenchymal markers (WT-1, Tbx18, CD73,CD90, CD44, CD105), cardiac markers (Gata4, Tbx5, troponin T) and also contained phosphocreatine. We used cell surface biotinylation to isolate plasma membrane proteins of rEPDC and hASC, Nano-liquid chromatography with subsequent mass spectrometry and bioinformatics analysis identified 396 rat and 239 human plasma membrane proteins with 149 overlapping proteins. Functional GO-term analysis revealed several significantly enriched categories related to extracellular matrix (ECM), cell migration/differentiation, immunology or angiogenesis. We identified receptors for ephrin and growth factors (IGF, PDGF, EGF, anthrax toxin) known to be involved in cardiac repair and regeneration. Functional category enrichment identified clusters around integrins, PI3K/Akt-signaling and various cardiomyopathies. Our study indicates that EPDC and ASC have a similar molecular phenotype related to cardiac healing/regeneration. The cell surface proteome repository will help to further unravel the molecular details of their cardio-regenerative potential and their role in cardiac diseases.
Stem Cell Research
10.1016/j.scr.2017.11.006
29156374
urn:nbn:de:bvb:20-opus-172716
Stem Cell Research (2017) 25, pp. 183-190. https://doi.org/10.1016/j.scr.2017.11.006
true
true
CC BY-NC-ND: Creative-Commons-Lizenz: Namensnennung, Nicht kommerziell, Keine Bearbeitungen 4.0 International
Sebastian Temme
Daniela Friebe
Timo Schmidt
Gereon Poschmann
Julia Hesse
Bodo Steckel
Kai Stühler
Meik Kunz
Thomas Dandekar
Zhaoping Ding
Payam Akhyari
Artur Lichtenberg
Jürgen Schrader
eng
uncontrolled
Biology
eng
uncontrolled
Epicardium-derived cells
eng
uncontrolled
Human atrial stromal cells
eng
uncontrolled
Cell surface proteomics
Biowissenschaften; Biologie
open_access
Theodor-Boveri-Institut für Biowissenschaften
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/17271/Temme_1-s2.0-S1873506117302362-main.pdf
17267
2017
eng
12
13
article
1
2018-11-22
--
--
Subspecies in the global human gut microbiome
Population genomics of prokaryotes has been studied in depth in only a small number of primarily pathogenic bacteria, as genome sequences of isolates of diverse origin are lacking for most species. Here, we conducted a large‐scale survey of population structure in prevalent human gut microbial species, sampled from their natural environment, with a culture‐independent metagenomic approach. We examined the variation landscape of 71 species in 2,144 human fecal metagenomes and found that in 44 of these, accounting for 72% of the total assigned microbial abundance, single‐nucleotide variation clearly indicates the existence of sub‐populations (here termed subspecies). A single subspecies (per species) usually dominates within each host, as expected from ecological theory. At the global scale, geographic distributions of subspecies differ between phyla, with Firmicutes subspecies being significantly more geographically restricted. To investigate the functional significance of the delineated subspecies, we identified genes that consistently distinguish them in a manner that is independent of reference genomes. We further associated these subspecies‐specific genes with properties of the microbial community and the host. For example, two of the three Eubacterium rectale subspecies consistently harbor an accessory pro‐inflammatory flagellum operon that is associated with lower gut community diversity, higher host BMI, and higher blood fasting insulin levels. Using an additional 676 human oral samples, we further demonstrate the existence of niche specialized subspecies in the different parts of the oral cavity. Taken together, we provide evidence for subspecies in the majority of abundant gut prokaryotes, leading to a better functional and ecological understanding of the human gut microbiome in conjunction with its host.
Molecular Systems Biology
10.15252/msb.20177589
29242367
urn:nbn:de:bvb:20-opus-172674
Molecular Systems Biology (2017) 13(12):960. https://doi.org/10.15252/msb.20177589
20100317
669830
201052
305312
660375
true
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Paul I. Costea
Louis Pedro Coelho
Shinichi Sunagawa
Robin Munch
Jaime Huerta-Cepas
Kristoffer Forslund
Falk Hildebrand
Almagul Kushugulova
Georg Zeller
Peer Bork
eng
uncontrolled
biology
eng
uncontrolled
genetic variation
eng
uncontrolled
metagenomics
eng
uncontrolled
microbiome
eng
uncontrolled
population structure
eng
uncontrolled
prokaryotic subspecies
Biowissenschaften; Biologie
open_access
Theodor-Boveri-Institut für Biowissenschaften
OpenAIRE
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/17267/Costea_msb.20177589.pdf
18114
2017
eng
12
7
article
1
2019-05-24
--
--
Regulation of sleep plasticity by a thermo-sensitive circuit in Drosophila
Sleep is a highly conserved and essential behaviour in many species, including the fruit fly Drosophila melanogaster. In the wild, sensory signalling encoding environmental information must be integrated with sleep drive to ensure that sleep is not initiated during detrimental conditions. However, the molecular and circuit mechanisms by which sleep timing is modulated by the environment are unclear. Here we introduce a novel behavioural paradigm to study this issue. We show that in male fruit flies, onset of the daytime siesta is delayed by ambient temperatures above 29°C. We term this effect Prolonged Morning Wakefulness (PMW). We show that signalling through the TrpA1 thermo-sensor is required for PMW, and that TrpA1 specifically impacts siesta onset, but not night sleep onset, in response to elevated temperatures. We identify two critical TrpA1-expressing circuits and show that both contact DN1p clock neurons, the output of which is also required for PMW. Finally, we identify the circadian blue-light photoreceptor CRYPTOCHROME as a molecular regulator of PMW, and propose a model in which the Drosophila nervous system integrates information encoding temperature, light, and time to dynamically control when sleep is initiated. Our results provide a platform to investigate how environmental inputs co-ordinately regulate sleep plasticity.
Scientific Reports
10.1038/srep40304
urn:nbn:de:bvb:20-opus-181146
Scientific Reports (2017) 7:40304. https://doi.org/10.1038/srep40304
true
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Angelique Lamaze
Arzu Öztürk-Çolak
Robin Fischer
Nicolai Peschel
Kyunghee Koh
James E. C. Jepson
eng
uncontrolled
Circadian rhythms and sleep
eng
uncontrolled
Genetics
eng
uncontrolled
Drosophila melanogaster
Biowissenschaften; Biologie
open_access
Theodor-Boveri-Institut für Biowissenschaften
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/18114/Lamaze_ScientificReports_2017.pdf
18087
2017
eng
19
2
13
article
1
2019-05-20
--
--
Optimality principles reveal a complex interplay of intermediate toxicity and kinetic efficiency in the regulation of prokaryotic metabolism
A precise and rapid adjustment of fluxes through metabolic pathways is crucial for organisms to prevail in changing environmental conditions. Based on this reasoning, many guiding principles that govern the evolution of metabolic networks and their regulation have been uncovered. To this end, methods from dynamic optimization are ideally suited since they allow to uncover optimality principles behind the regulation of metabolic networks. We used dynamic optimization to investigate the influence of toxic intermediates in connection with the efficiency of enzymes on the regulation of a linear metabolic pathway. Our results predict that transcriptional regulation favors the control of highly efficient enzymes with less toxic upstream intermediates to reduce accumulation of toxic downstream intermediates. We show that the derived optimality principles hold by the analysis of the interplay between intermediate toxicity and pathway regulation in the metabolic pathways of over 5000 sequenced prokaryotes. Moreover, using the lipopolysaccharide biosynthesis in Escherichia coli as an example, we show how knowledge about the relation of regulation, kinetic efficiency and intermediate toxicity can be used to identify drug targets, which control endogenous toxic metabolites and prevent microbial growth. Beyond prokaryotes, we discuss the potential of our findings for the development of antifungal drugs.
PLOS Computational Biology
10.1371/journal.pcbi.1005371
urn:nbn:de:bvb:20-opus-180870
PLOS Computational Biology (2017) 13:2, e1005371. https://doi.org/10.1371/journal.pcbi.1005371
true
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Jan Ewald
Martin Bartl
Thomas Dandekar
Christoph Kaleta
eng
uncontrolled
Enzyme regulation
eng
uncontrolled
Toxicity
eng
uncontrolled
Metabolic pathways
eng
uncontrolled
Enzymes
eng
uncontrolled
Transcriptional control
eng
uncontrolled
Enzyme kinetics
eng
uncontrolled
Enzyme metabolism
eng
uncontrolled
Predictive toxicology
Biowissenschaften; Biologie
open_access
Theodor-Boveri-Institut für Biowissenschaften
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/18087/Ewald_PlosComputationalBiology_2017.pdf