18666
2016
eng
1752-1767
12
21
article
1
2019-09-02
--
--
Revisiting adult neurogenesis and the role of erythropoietin for neuronal and oligodendroglial differentiation in the hippocampus
Recombinant human erythropoietin (EPO) improves cognitive performance in neuropsychiatric diseases ranging from schizophrenia and multiple sclerosis to major depression and bipolar disease. This consistent EPO effect on cognition is independent of its role in hematopoiesis. The cellular mechanisms of action in brain, however, have remained unclear. Here we studied healthy young mice and observed that 3-week EPO administration was associated with an increased number of pyramidal neurons and oligodendrocytes in the hippocampus of similar to 20%. Under constant cognitive challenge, neuron numbers remained elevated until >6 months of age. Surprisingly, this increase occurred in absence of altered cell proliferation or apoptosis. After feeding a \(^{15}\)N-leucine diet, we used nanoscopic secondary ion mass spectrometry, and found that in EPO-treated mice, an equivalent number of neurons was defined by elevated \(^{15}\)N-leucine incorporation. In EPO-treated NG2-Cre-ERT2 mice, we confirmed enhanced differentiation of preexisting oligodendrocyte precursors in the absence of elevated DNA synthesis. A corresponding analysis of the neuronal lineage awaits the identification of suitable neuronal markers. In cultured neurospheres, EPO reduced Sox9 and stimulated miR124, associated with advanced neuronal differentiation. We are discussing a resulting working model in which EPO drives the differentiation of non-dividing precursors in both (NG2+) oligodendroglial and neuronal lineages. As endogenous EPO expression is induced by brain injury, such a mechanism of adult neurogenesis may be relevant for central nervous system regeneration.
Molecular Psychiatry
10.1038/mp.2015.212
urn:nbn:de:bvb:20-opus-186669
Molecular Psychiatry (2016) 21:12, 1752-1767. https://doi.org/10.1038/mp.2015.212
false
true
CC BY-NC-ND: Creative-Commons-Lizenz: Namensnennung, Nicht kommerziell, Keine Bearbeitungen 4.0 International
I. Hassouna
C. Ott
L. Wüstefeld
N. Offen
R. A. Neher
M. Mitkovski
D. Winkler
S. Sperling
L. Fries
S. Goebbels
I. C. Vreja
N. Hagemeyer
M. Dittrich
M. F. Rossetti
K. Kröhnert
K. Hannke
S. Boretius
A. Zeug
C. Höschen
T. Dandekar
E. Dere
E. Neher
S. O. Rizzoli
K.-A. Nave
A.-L. Sirén
H. Ehrenreich
eng
uncontrolled
neural stem-cells
eng
uncontrolled
recombinat-human-erythropoietin
eng
uncontrolled
cognitive functions
eng
uncontrolled
pyramidal neurons
eng
uncontrolled
nervous-sytem
eng
uncontrolled
brain-injury
eng
uncontrolled
mouse-brain
eng
uncontrolled
progenitors
eng
uncontrolled
mice
eng
uncontrolled
memory
Biowissenschaften; Biologie
Medizin und Gesundheit
open_access
Neurochirurgische Klinik und Poliklinik
Theodor-Boveri-Institut für Biowissenschaften
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/18666/Hassouna_MolecularPsychiatry_2016.pdf
12375
2012
eng
287-302
6
article
1
2015-12-22
--
--
Analyzing Thiol-Dependent Redox Networks in the Presence of Methylene Blue and Other Antimalarial Agents with RT-PCR-Supported in silico Modeling
BACKGROUND: In the face of growing resistance in malaria parasites to drugs, pharmacological combination therapies are important. There is accumulating evidence that methylene blue (MB) is an effective drug against malaria. Here we explore the biological effects of both MB alone and in combination therapy using modeling and experimental data.
RESULTS: We built a model of the central metabolic pathways in P. falciparum. Metabolic flux modes and their changes under MB were calculated by integrating experimental data (RT-PCR data on mRNAs for redox enzymes) as constraints and results from the YANA software package for metabolic pathway calculations. Several different lines of MB attack on Plasmodium redox defense were identified by analysis of the network effects. Next, chloroquine resistance based on pfmdr/and pfcrt transporters, as well as pyrimethamine/sulfadoxine resistance (by mutations in DHF/DHPS), were modeled in silico. Further modeling shows that MB has a favorable synergism on antimalarial network effects with these commonly used antimalarial drugs.
CONCLUSIONS: Theoretical and experimental results support that methylene blue should, because of its resistance-breaking potential, be further tested as a key component in drug combination therapy efforts in holoendemic areas.
Bioinformatics and Biology Insights
10.4137/BBI.S10193
PMC3516044
urn:nbn:de:bvb:20-opus-123751
This is an open access article. Unrestricted non-commercial use is permitted provided the original work is properly cited.
Bioinformatics and Biology Insights 2012:6 287–302. doi: 10.4137/BBI.S10193
J. Zirkel
A. Cecil
F. Schäfer
S. Rahlfs
A. Ouedraogo
K. Xiao
S. Sawadogo
B. Coulibaly
K. Becker
T. Dandekar
eng
uncontrolled
methylene blue
eng
uncontrolled
malaria
eng
uncontrolled
elementary mode analysis
eng
uncontrolled
drug
eng
uncontrolled
resistance
eng
uncontrolled
combination therapy
eng
uncontrolled
pathway
eng
uncontrolled
metabolic flux
Datenverarbeitung; Informatik
Biowissenschaften; Biologie
open_access
Theodor-Boveri-Institut für Biowissenschaften
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/12375/f_3443-BBI-Analyzing-Thiol-Dependent-Redox-Networks-in-the-Presence-of-Methylene-.pdf_4656.pdf
14827
2015
eng
764
6
article
1
2017-05-10
--
--
Integrated inference and evaluation of host-fungi interaction networks
Fungal microorganisms frequently lead to life-threatening infections. Within this group of pathogens, the commensal Candida albicans and the filamentous fungus Aspergillus fumigatus are by far the most important causes of invasive mycoses in Europe. A key capability for host invasion and immune response evasion are specific molecular interactions between the fungal pathogen and its human host. Experimentally validated knowledge about these crucial interactions is rare in literature and even specialized host pathogen databases mainly focus on bacterial and viral interactions whereas information on fungi is still sparse. To establish large-scale host fungi interaction networks on a systems biology scale, we develop an extended inference approach based on protein orthology and data on gene functions. Using human and yeast intraspecies networks as template, we derive a large network of pathogen host interactions (PHI). Rigorous filtering and refinement steps based on cellular localization and pathogenicity information of predicted interactors yield a primary scaffold of fungi human and fungi mouse interaction networks. Specific enrichment of known pathogenicity-relevant genes indicates the biological relevance of the predicted PHI. A detailed inspection of functionally relevant subnetworks reveals novel host fungal interaction candidates such as the Candida virulence factor PLB1 and the anti-fungal host protein APP. Our results demonstrate the applicability of interolog-based prediction methods for host fungi interactions and underline the importance of filtering and refinement steps to attain biologically more relevant interactions. This integrated network framework can serve as a basis for future analyses of high-throughput host fungi transcriptome and proteome data.
Frontiers in Microbiology
10.3389/fmicb.2015.00764
urn:nbn:de:bvb:20-opus-148278
Frontiers in Microbiology 6:764 (2015). DOI: 10.3389/fmicb.2015.00764
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Christian W. Remmele
Christian H. Luther
Johannes Balkenhol
Thomas Dandekar
Tobias Müller
Marcus T. Dittrich
eng
uncontrolled
candida genome database
eng
uncontrolled
computational prediction
eng
uncontrolled
potential role
eng
uncontrolled
network inference
eng
uncontrolled
bioinformatics and computational biology
eng
uncontrolled
protein interaction database
eng
uncontrolled
Aspergillus fumigatus
eng
uncontrolled
cell wall
eng
uncontrolled
functional modules
eng
uncontrolled
alzheimers disease
eng
uncontrolled
molecular cloning
eng
uncontrolled
Candida albicans
eng
uncontrolled
pathogen-host interaction (PHI)
eng
uncontrolled
protein-protein interaction
eng
uncontrolled
pathogenicity
eng
uncontrolled
interolog
Medizin und Gesundheit
open_access
Institut für Humangenetik
Theodor-Boveri-Institut für Biowissenschaften
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/14827/009_Remmele_Frontiers_in_Microbiology.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