research area center for molecular biosciences (cmbi) · bringing together these research units...
TRANSCRIPT
scientific report |2016/2017
Scientific Coordinators
Bert Hobmayer, Ronald Micura, Jörg Striessnig
Research Area Center for Molecular Biosciences (CMBI)
2 3
Content: Bert Hobmayer, Professor of Zoology
Ronald Micura, Professor of Organic Chemistry
Jörg Striessnig, Professor of Pharmacology
Layout: Stephanie Brejla, Gabi Reiter
Contact: Research Area Center for
Molecular Biosciences (CMBI)
University of Innsbruck
Innrain 80-82a
A-6020 Innsbruck
Tel: +43 512 507-57501
Fax: +43 512 507-57599
www.uibk.ac.at/cmbi
© 2018 by CMBI
imprint |
Cover figure:
Induced neural stem cells (iNSCs) being reprogrammed from human skin fibroblasts by the team of
CMBI group leader Frank Edenhofer. Colonies of proliferating iNSCs start to differentiate into neurons
in the periphery. Differentiating neurons exhibit characteristic outgrowth of TUJ1-positive neurites
(green) that reach out to contact other neurons to build a functional network.
In our biannual report, the Center for Molecular Biosciences of Innsbruck University (CMBI) presents
its recent scientific achievements, new developments in ongoing research projects and success
stories of its faculty members, especially of young researchers. Molecular biosciences represent one
of the most exciting fields of modern research among the natural sciences. They bridge the gap
between single molecules and the complex functions in living organisms under normal conditions
and in disease. Minor changes in bioactive molecules such as DNA, RNA and proteins affect and
change the properties of cells, microorganisms, animals and plants. Advances in technologies
including microscopic imaging, new generation sequencing applications and techniques to
analyze molecular structures result in an explosion of information and understanding of biological
systems primarily oriented to improve human health. The CMBI aims at providing a platform for
this extremely rapidly developing research field by taking advantage of the visibility and expertise
of the CMBI’s internationally competitive groups to strengthen interdisciplinary research activities.
The CMBI currently consists of 21 research teams originating from the faculties of Chemistry and
Pharmacy, of Biology, and of Mathematics, Informatics and Physics, and their activities focus on
research and teaching. CMBI members contribute to the FWF special research program SFB-F44
“Cell Signaling in Chronic CNS Disorders”, which is currently in its second funding period, and
to several FWF-funded doctoral programs, all in collaboration with the Medical University of
Innsbruck. Notably, several member labs have now initiated a first CMBI-embedded university PhD
program under the topic “Ageing and Regeneration”. Furthermore, CMBI members were able
to successfully compete in the recent FFG call for university infrastructure and now establish new
facilities for Nuclear Magnetic Resonance (NMR) spectroscopy. These will significantly advance
biomolecular structural analysis in the Western-Austrian area. In order to cross-link with the
Tyrolean Life Science community and to foster career perspectives of young scientist, the CMBI is
a co-organizer of the internationally visible Innsbruck Life Science meetings, and it has started to
coordinate its activities as a core research unit within the newly established initiative “Tyrolean
Health and Life Science Cluster”.
In spite of these achievements, the CMBI faces challenges of general and also local nature. Rapid
technological progress in the Life Sciences requires ongoing investments into essential state-of
the art infrastructure. Ever-increasing demand for big data sets needs development of adequate
computing units and bioinformatics expertise. More than half of the 21 research teams are located
together with Life Science research departments of the Innsbruck Medical University in the recently
built Center for Chemistry and Biomedicine (CCB) building at the university’s central campus. Nine
of those, however, are spatially fragmented at the Technics Campus, the Department of Botany,
and the Research Department for Biomedical Aging Research. Bringing together these research
units within a single research campus would strongly stimulate scientific interactions and facilitate
the efficient use of expensive infrastructure. Long-term strategies towards this goal are needed to
enable competition with a large number of Life Science Research centers rapidly emerging across
Europe. All these issues require coordinated efforts at academic and political levels.
The CMBI coordinators:
Bert Hobmayer Jörg Striessnig Ronald Micura
The Research Area Center for Molecular Biosciences Innsbruck (CMBI) – a life science network in western Austria
Imprint
4 5
con
ten
ts |
Contents
Overview 6
CMBI - news
CMBI - specials 10
Research Summary
Signal transduction in cellular growth control and
carcinogenesis
18
Advanced chromatographic and spectroscopic analytical
tools in natural product analysis & molecular biology
20
Characterization of RNA, proteins, and their noncovalent
complexes by mass spectrometry
22
Gastropod metallothioneins in evolution: New rules for an
old protein family
24
Radiation damage in biological compounds induced by low
energy electrons
26
Regenerative potential of reprogrammed neural stem cells 28
Immuno-gerontology 30
Development of selectively acting antitumor drugs 32
Developmental biology and bioadhesion in basal animal
model systems
34
Molecular and cell biology of human aging 36
Plant biochemistry and metabolism 38
Chemistry, chemical and structural biology of the pigments
of life
40
Protein dynamics and biomolecular recognition 42
Developmental biology 44
Synthesis, structure, and function of non-coding RNAs 46
Cell physiology and gene regulation 48
Structure-functional activity relationship investigations on
ligands interacting with opioid receptors
50
Targeted proteolysis in human diseases and its impact on
drug development and production
52
Cell signaling in chronic CNS disorders 54
Pharmacognosy – combining traditional knowledge with
innovation
56
Biomolecular NMR spectroscopy 58
Publications 60
CMBI - careers of young researchers 92
Awards & Honors for CMBI scientists 96
CMBI Meetings and Seminar Series 99
The Research Area Center for Molecular Biosciences (CMBI) at the
University of Innsbruck is an integrative and multidisciplinary research
and teaching institution. The mission of the CMBI is to advance studies on
the structure, function, and interaction of biological macromolecules and
low molecular weight compounds relevant for cellular growth, metabolism,
and development. The research activities in the CMBI take advantage of
existing research strength in different fields and have strongly promoted
interdisciplinary research activities in five major fields of biomolecular sciences.
Twenty-one research groups from the faculty of Chemistry and Pharmacy,
the faculty of Biology, and the faculty of Mathematics, Informatics &
Physics are members of the CMBI.
Basic and applied biomolecular research fields at the CMBI
• Structure, dynamics and interactions of biologically important molecules
• Molecular basis of physiological and pathophysiological processes
• Metabolites, natural and synthetic compounds that modulate important
biological processes
• Cell-to-cell communication and cellular function
• Development, regeneration and aging of whole organisms
mem
ber
s |
Overview Overview6 7
CMBI members received scientific awards and prizes over the last two
years thus documenting their successful research activities also to the
scientific community and general public. Among those are the Bruker
research award 2017 and the Research Award of the Stiftung Südtiroler
Sparkasse 2017 to Hermann Stuppner, the Edmund Optics Educational
Award Europe 2017 to Torsten Schwerte, and the Würdigungspreis des
Bundesministeriums für Wissenschaft, Wirtschaft und Forschung 2017
to Anita Siller. Ilse Kranner was elected as President of the Austrian
Society of Plant Biology (ATSPB). Furthermore, several CMBI members
are members of the Austrian Academy of Sciences (Kathrin Breuker,
Ronald Micura, Bernhard Kräutler, Jörg Striessnig) and of the German
Academy of Sciences, Leopoldina (Bernhard Kräutler, Jörg Striessnig).
The activities of the CMBI are currently coordinated by Bert Hobmayer
(head), Jörg Striessnig and Ronald Micura.
In the years 2013 - 2017 the CMBI member labs published 737 papers
in peer reviewed journals. This includes 28 publications in the world
leading journals Nature, Nature Structural Biology, Nature Genetics,
Nature Cell Biology, Nature Chemical Biology, Nature Neuroscience,
Nature Communications, Nature Methods, Proceedings of the
National Academy of Sciences of the United States of America, and
Scientific Reports, 2 papers in Cell and 38 papers in top journals of
chemistry and physics, including Journal of the American Chemical
Society, Chemical Society Reviews, Angewandte Chemie and EMBO
J. The total amount of outside grant support of the last three years
amounts to about 9,4 Mio. €. Modern infrastructure obtained through
special governmental funding for research equipment significantly
strengthens research in structural and cell biology, bioanalytics and
biophysics at the CMBI.
CMBI members Areas of expertise
Chemistry
K. Bister, M. Hartl, E. Stefan biochemistry, molecular genetics
G. Bonn, C. Huck bioanalytics
K. Breuker biomolecular mass spectrometry
B. Kräutler, T. Müller structural biology, natural products chemistry
K. Liedl, D. Schuster theoretical chemistry, computer-aided molecular design
R. Micura chemical biology of nucleic acids
R. Schneider, B. Auer molecular biology, biotechnology
M. Tollinger, C. Kreutz biomolecular NMR spectroscopy
Pharmacy
R. Gust medicinal chemistry, drug design
H. Schmidhammer, M. Spetea pharmaceutical chemistry, drug design
J. Striessnig, A. Koschak, N. Singewald cell biology, neuropharmacology
H. Stuppner, M. Ganzera pharmaceutical biology, phytochemistry
Biology
R. Dallinger cell physiology, ecotoxicology
F. Edenhofer stem cell biology
B. Grubeck-Loebenstein immuno-gerontology
B. Hobmayer, P. Ladurner cell and developmental biology
P. Jansen-Dürr cell biology, molecular biology
I. Kranner plant physiology and biochemistry
D. Meyer, P. Aanstad developmental biology
B. Pelster, A. Sandbichler, T. Schwerte cell biology, cell physiology
Physics
S. Denifl biophysics, radiation physics
>> CMBI facts
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top
ics
| Research topics
• Protein and nucleic acid structure, folding, and dissociation in the gas phase (Breuker)
• Proteomics, metabolomics, phytomics (Bonn, Huck)
• Inelastic interaction of low energy electrons with molecules of biological relevance
(Denifl)
• Development of theoretical and computational methods describing molecular interac-
tions in chemical and biological systems (Liedl, Schuster)
• Biomolecular NMR spectroscopy (Tollinger, Kreutz)
• Synthesis, structure, and function of chemically modified RNA (Micura)
• Regulation of cell function by protein modification (Auer, Schneider)
• Oncogenic transcription factors and their cellular targets (Bister, Hartl, Stefan)
• Natural products chemistry, chemical and structural biology of the pigments of life
(Kräutler, Müller)
• Bioactive natural products from the plant kingdom (Stuppner, Ganzera)
• Development of potential drugs interacting with opioid receptors (Schmidhammer,
Spetea)
• Development of selectively acting antitumor drugs (Gust)
• Ion channels as new drug targets and the neuropathological basis of anxiety disorders
(Striessnig, Koschak, Singewald)
• Cell ion and volume homeostasis and metabolic activity (Pelster, Sandbichler, Schwerte)
• Trace element homeostasis in animal cells (Dallinger)
• Molecular and genetic control of vertebrate development (Meyer, Aanstad)
• Stem cell differentiation, regeneration and bioadhesion of basal Metazoa (Hobmayer,
Ladurner)
• Stem cell biology, cellular reprogramming & regeneration (Edenhofer)
• The aging T cell repertoire and its impact on vaccinations of the elderly (Grubeck-Loe-
benstein)
• Biology of aging, mitochondrial physiology (Jansen-Dürr)
• Stress metabolites and signalling pathways in plants (Kranner)
The specific research topics of the 21 CMBI member labs are listed below.
10 11
With a new infrastructure worth two million Euros, interdisci-
plinary research on RNA at the University of Innsbruck will be
further strengthened. Since November 2017, two new NMR
spectrometers are available to scientists.
Models of high-energy excited states of nucleic acids
The structural dynamics of nucleic acids and their interactions with
proteins or small molecule compounds has already been successfully
researched at the University of Innsbruck in several working groups.
With the acquisition of new nuclear magnetic resonance (NMR)
spectrometers with frequencies of 400 and 700 MHz, this research
focus will be further strengthened. With their application to the 1st
F&E Infrastructure Call (2016) of the Austrian Research Promotion
Agency FFG, the Innsbruck scientists around Ronald Micura, Christoph
Kreutz, Martin Tollinger, Kathrin Breuker, Ronald Gust, and Hermann
Stuppner prevailed in a very tough Austria-wide competition. “The
new devices expand the possibilities in the area of structural chemistry
and they complement the existing spectrometers, which have been
fully utilized for several years”, says a delighted Ronald Micura.
The new infrastructure will further enhance the international visibility
of the various fields at the Center for Molecular Biosciences. Several
research groups are concerned here with the structure and folding
of RNA and their interaction with low molecular weight compounds.
Complex dynamic folding mechanisms are involved, which can be
elucidated by means of NMR spectroscopy. Another focus is on the
study of RNA-modifying enzymes and proteins that can trigger allergies
or are relevant to inflammatory signaling pathways, and in the search
for plant-derived natural products that can exert antibacterial effects
via RNA target molecules.
“The wealth of information that can be made accessible by NMR
spectroscopy is an ideal complement to the ‘static’ crystallographic
images of biomolecular systems, and it is poised to become the
method of choice for studying the dynamic interaction networks of
biomolecules for understanding in cells”, says Ronald Micura. Based
on the new infrastructure, the research groups of Robert Konrat from
the Max F. Perutz Laboratories in Vienna, Fatima Ferreira-Briza at
the University of Salzburg and Michael Oberhuber at the Laimburg
Research Center in South Tyrol, who are involved in comprehensive
scientific cooperation, will also benefit.
CMBI news CMBI news
>> NEW NMR-SPECTROMETERS
picture: Otto Peter
>> SEEING THE INVISIBLE – RNA AND DNA EXCITED STATES
Using nuclear magnetic resonance (NMR) spectroscopy, unexpected
high-energy excited states of nucleic acids could be detected and
characterized. These transiently existing conformations are present
at < 10%, but they represent important functional intermediates
in cellular processes. These states were addressed via novel NMR
spectroscopic methods. It could be shown, that a small, undesired
modification of DNA, a methylation, induces highly localized
transiently populated structural alteration in base pairing. These
high energy states very likely serve as a beacon for repair enzymes
and are therefore very important for the preservation of genetic
information. In contrast, naturally occurring RNA methylations lead
to drastic structural changes and expand the functional properties
of RNA. The different behavior of DNA and RNA could also explain
why nature stores the genetic information in the double helix of DNA
and not in the evolutionarily much older RNA. The work was done
by international cooperation with working groups at Duke University
(USA), Max F. Perutz Laboratories in Vienna and University College
London (UK).
Juen MA et al. Excited States of Nucleic Acids Probed by Proton Relaxation Dispersion NMR
Spectroscopy. Angew. Chem. Int. Ed. 55, 12008 (2016).
Zhou H et al. m1A and m1G disrupt A-RNA structure through the intrinsic instability of Hoogsteen
base pairs. Nature Structural & Molecular Biology 23, 803–810 (2016).
Structural model of ribozyme function
>> ELUCIDATION OF RIBOZYME STRUCTURES AND MECHANISMS
Three years ago, four new classes of ribozymes were discovered.
Like enzymes, these RNA species accelerate chemical reactions in the
cell. A research group led by Ronald Micura and researchers in China
around Aiming Ren have now elucidated the structure of the so-called
Twister-Sister ribozyme. The sequence design and the syntheses for
the investigations were done in Innsbruck, the crystallization and
X-ray structure analysis was undertaken by the scientists at Zhejiang
University in Hangzhou. Moreover, the Micura group also investigated
the Pistol ribozyme and elucidated its chemical mechanism. The
functional analysis was laborious, because the chemists had to
synthesize numerous new variants of this RNA, each of which only a
single atom was exchanged. Only then was it possible to check which
of the modified ribozymes is still functional. From this, it was possible
to deduce the positions responsible for reaction catalysis in the RNA
structure.
Zheng L et al. Structure-based insights into self-cleavage by a four-way junctional twister-sister
ribozyme. Nature Communications 8, 1180 (2017).
Neuner S et al. Atom-Specific Mutagenesis Reveals Structural and Catalytic Roles for an Active-Site
Adenosine and Hydrated Mg2+ in Pistol Ribozymes. Angew. Chem. Int. Ed. 56, 15954–15958 (2017).
CMBI - specials
12 13
CMBI - specials
Klaus Bister from the Department of Biochemistry and Eric Hunter
from the Emory University (Atlanta) have served as editors for a special
volume - Viruses, Genes, and Cancer - of the book series Current Topics
in Microbiology and Immunology. The editors were able to engage
eminent researchers from the cancer field as contributors for this
volume, including the Nobel laureates Mike Bishop (San Francisco),
Harold Varmus (New York), and Harald zur Hausen (Heidelberg). The
chapters focus on virus-host cell interactions, cellular genes acquired
or modulated by viruses, the pathological effects of these interactions,
and therapeutic interventions. Several articles specifically address the
role of viruses and genes – such as oncogenes, proto-oncogenes, or
tumor suppressor genes – in the etiology of human cancer. Oncogenic
signaling by PI3 kinase, mTOR, Akt, or the major cancer drivers MYC
and RAF, and the role of tumor suppressors like p53, are discussed
in detail. The volume also explores the emerging role of noncoding
RNAs such as microRNAs in tumorigenesis and cancer therapeutics.
Hunter E, Bister K (eds). Viruses, Genes, and Cancer - Current Topics in Microbiology and
Immunology, Vol. 407. Springer International Publishing (2017).
Stefan E, Bister K. MYC and RAF: Key effectors in cellular signaling and major drivers in human
cancer. Curr. Top. Microbiol. Immunol. 407, 117-151 (2017).
>> MOLECULAR BASIS OF CANCER AND OTHER CHRONIC DISEASES
>> „INNSBRUCK” MODEL ORGANISM: TRANSGENESIS ESTABLISHED
The free-living flatworm Macrostomum lignano is a suitable model
system for regeneration, reproduction, evolution and bio-adhesion
research. However, a major cornerstone of research methods – the
ability to generate transgenic animals – was missing for Macrostomum
and the whole flatworm community. In cooperation with colleagues
from the European Institute for the Biology of Ageing (Groningen,
NL), the Ladurner group published the generation of stable
transgenic Macrostomum lines expressing fluorescent proteins under
several tissue-specific promoters. The reported method will permit
sophisticated research approaches including gene overexpression,
dissection of gene regulatory elements, real-time imaging and lineage
tracing. It provides a technological platform for harvesting the power
of Macrostomum as an experimental model organism for flatworm
biology and biomedical research.
Wudarski J et al. Efficient transgenesis and annotated genome sequence of the regenerative
flatworm model Macrostomum lignano. Nature Communications 8, 2120 (2017).
CMBI news CMBI news
Various transgenic Macrostomum lines expressing
fluorescent proteins under tissue-specific promoters
An international research team including the group of Frank Edenhofer
investigated the role of gap junctional intercellular communication
(GJIC) by generating Connexin43/Connexin45-double deficient mouse
embryonic stem cells. These Connexin double-knock-out cells show
almost complete breakdown of GJIC and a block of differentiation
in embryoid bodies. However, pluripotency marker expression and
proliferation are unaffected. They fail to form primitive endoderm
in embryoid body cultures, representing the inductive key step of
gastrulation-like events. At a molecular level, GJIC-incompetent
embryonic stem cells exhibit significantly less activated NFATc3 in
cellular nuclei than control cells suggesting that Connexin-mediated
communication is needed for synchronized NFAT activation to induce
orchestrated primitive endoderm formation.
Wörsdörfer P et al. Abrogation of gap junctional communication in ES cells results in a disruption of
primitive endoderm formation in embryoid bodies. Stem Cells 35, 859-871 (2017)
>> GAP JUNCTIONAL INTERCELLULAR COMMUNICATION ESSENTIAL
FOR ENDODERM FORMATION
Development of embryonic stem cells of the inner cell mass
into endodermal and ectodermal tissue layers
Researchers of the German Cancer Research Center and the team of
Frank Edenhofer at the Institute of Molecular Biology have identified
that Myc depletion in mouse embryonic stem cells results in a
reversible biosynthetic dormancy and proliferation arrest. Likewise,
Myc inhibition in mouse blastocysts induces dormancy mimicking
hormonally controlled diapause without affecting the pluripotency
capacity, suggesting the importance of Myc regulation in controlling
entry and exit from stem cell dormancy during development.
Furthermore, Myc-depleted stem cells and diapause embryos do
exhibit similar expression signatures. Thus, dormancy is a transient
stem cell state, molecularly defined by low levels of Myc expression,
where the most primitive cells within the stem cell compartment can
be stored as a transiently quiescent reservoir to preserve genomic
integrity and be protected from microenvironmental hazards and
replicative stress.
Scognamiglio R et al. Myc depletion induces a pluripotent dormant state mimicking diapause. Cell
164, 668–680 (2016).
Working model for Myc-induced dormancy in stem cells
>>NEW ROLE FOR MYC IN STEM CELL DORMANCY AND SELF RENEWAL
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CMBI - specials
CMBI news CMBI news
Using a combination of pharmacophore models for soluble epoxide
hydrolase and 5-lipoxygenase activating protein, Daniela Schuster
and her co-workers discovered and participated in a detailed
characterization of a potent dual inhibitor targeting both proteins
in sub-micromolar concentrations. The substance, which was
named Diflapolin, selectively inhibited leukotriene formation and
epoxyeicosatrienoic acid degradation, and was not active against
other targets from the arachidonic acid cascade. Importantly, it
showed anti-inflammatory activity in vivo in mice. A patent was filed
on this and structurally related compounds, and they are currently
optimized towards more favorable properties in collaboration with
Prof. Matuszczak and Mag. Vieider.
Temml V et al. Discovery of the first dual inhibitor of the 5-lipoxygenase-activating protein and
soluble epoxide hydrolase using pharmacophore-based virtual screening. Scientific Reports 7,
42751 (2017).
Garscha U et al. Pharmacological profile and efficiency in vivo of diflapolin, the first dual inhibitor
of 5-lipoxygenase-activating protein and soluble epoxide hydrolase. Scientific Reports 7, 79398
(2017).
>> DISCOVERY OF DIFLAPOLIN AS AN ANTI-INFLAMMATORY SUBSTANCE
>>MICRO-RNA MIR-144 AND ANXIETY DISORDER
Effective long-term treatment for fear, trauma and anxiety-related
disorders is a continuing challenge. One emerging new treatment
strategy is combining exposure-based cognitive behavioural therapy
with extinction-facilitating drugs. We, in collaboration with national
and international partners identified a specific microRNA, mir-144,
that is critically involved in orchestrating the rescue of impaired
extinction learning. Its expression was shown to be decreased in
extinction-impaired mice and upregulated upon extinction learning
in extinction-competent mice. We identified an important locus of
action, since overexpression of mir-144 in the amygdala was sufficient
to fully rescue the extinction learning impairment. Since specific
drugs have been shown previously to increase mir-144 expression,
this route will be followed to develop drug-based strategies to boost
and normalize aberrant fear-inhibitory learning, which is a common
deficiency observed in human anxiety disorders.
Murphy CP et al. MicroRNA-mediated rescue of fear extinction memory by miR-144-3p in extinction-
impaired mice. Biol. Psychiatry 81, 979-989 (2016).
Nicolas Singewald and his team
Daniela Schuster (left) and Veronika Temml (right)
Recent research of Bernhard Kräutler and his group brought major
further discoveries concerning the biological role of the seasonal
disappearance of chlorophyll, as well as on the metabolic function
and molecular logic of vitamin B12.
The abundant and highly visual green leaf pigment chlorophyll is
broken down in plants by strictly regulated biological processes
furnishing ‘phyllobilins’ in an amount of 1000 million tons each
year on Earth. In contrast to all earlier views, phyllobilins are now
presumed to have physiological functions that are still enigmatic,
but possibly similar to those of related heme catabolites, such as
the yellow bilirubin. Attractive roles of phyllobilins in plants could
concern photo-regulation, as well as pathogen defense. We have
studied yellow phyllobilins recently and discovered their behavior as
medium responsive photo-switches, a property that hints at a possible
role in photo-regulation.
In order to understand better some of the proposed enigmatic
(‘moonlighting’) activities of the B12-cofactors, we have recently
suggested to study effects of ‘antivitamins B12’, structural analogs
of vitamin B12 that cannot function as the vitamin does. Thus, these
types of ‘wolf in a sheep’s clothes’ inhibit the canonical enzymatic
B12-functions, enabling researchers to determine the intact structures
of key enzymes. In this context, a synthetic methodology to the
particularly intriguing group of analogs of vitamins B12 has been
recently opened up, in which the B12’s own cobalt center is replaced
by another transition metal, such as the homologue rhodium. This
extremely difficult chemical task was achieved in collaboration
with biologists in England, providing the long awaited road to
fundamentally new B12-analogues and a new group of excellent
enzyme inhibitors.
Ruetz et al. Antivitamin B12 inhibition of the human B12 -processing enzyme CblC: Crystal structure
of an inactive ternary complex with glutathione as the cosubstrate. Angew. Chem Intl. Ed. 56, 7387
(2017).
Li et al. Chlorophyll-derived yellow phyllobilins of higher plants as medium-responsive chiral
photoswitches. Angew. Chem Intl. Ed. 55, 15760 (2016).
Widner et al. Total synthesis, structure, and biological activity of adenosylrhodibalamin, the non-
natural rhodium homologue of coenzyme B12. Angew. Chem Intl. Ed. 55, 11281 (2016).
>> CHLOROPHYLL AND VITAMIN B12 - TWO ‘PIGMENTS OF LIFE’
Phyllobilin structure and autumn leaves with disappearing
chlorophyll
16 17
CMBI - specials
CMBI news CMBI news
The CavX project has been established as a doctoral program with
a cell- and neurobiological focus on cellular signaling through ion
channels. The research groups of Alexandra Koschak, Petronel Tuluc
and Jörg Striessnig are the CMBI project leaders in the newly FWF-
funded doc.funds project CavX together with colleagues from the
Medical University (Marta Campiglio, Bernhard E. Flucher and Gerald
Obermair, who also serves as a CavX coordinator). This program
provides a special platform for the training of graduate students in
cellular signaling in electrically excitable cells. The FWF doc.funds
initiative was started only recently and has been awarded for the
first time in fall 2017. 45 proposals were submitted and from those
an international multidisciplinary jury selected 16 for a final hearing.
Seven of those were finally recommended for funding. The application
process of the CavX program was strongly supported and guided by
the vice-rectors for research of the two participating universities.
In a transnational approach combining research competences in
structural chemistry, medicine and molecular biology, the molecular
details of apple allergy are studied and potential apple varieties for
therapy of birch pollen allergy are identified. Roughly 20% of the mid-
European population are affected by birch pollen allergy, and more
than 70% of them subsequently develop allergic reactions to apples
due to cross-reactivity of IgE antibodies between homologous proteins
in birch pollen and apples. This immunological cross-reaction may
present an opportunity to use apples in a controlled and established
dosage to cure birch pollen allergy. Using NMR spectroscopy, the
three-dimensional structures of different isoforms of the major apple
allergen, the protein Mal d 1, and the birch pollen allergen Bet v 1 are
compared in order to identify those apple varieties ideal for successful
long-term therapy of birch pollen allergy by apple consumption.
Within the framework of the project “applecare”, complementary
research competences in Tyrol and South Tyrol are pooled, including
the Laimburg Research Centre, Bolzano Hospital, Innsbruck Medical
University and the University of Innsbruck.
>> FWF-FUNDED DOCTORAL DOCFUNDS PROGRAM „CAVX“ STARTS AT THE
INNSBRUCK UNIVERSITIES WITH CMBI PARTICIPATION
>> START OF THE INTERREG V-A ITALIA-ÖSTERREICH PROJECT „APPLECARE“
FUNDED BY THE EUROPEAN REGIONAL DEVELOPMENT FUND
Researchers from the Institute of Molecular Biology cooperated with
Stefan Kubicek, Group Leader at the CeMM (Vienna), to demonstrate
in vivo the beta cell-promoting effects of artemisinins, compounds
which were discovered through screening efforts in cell lines to steer
alpha cells towards a beta cell fate. In work done by the group of
Dirk Meyer, zebrafish with severely reduced beta cells were treated
with artemisinins. This resulted in increased beta cell numbers
and normalized glucose levels. Chemicals which enhance beta cell
production have potential as therapies for diabetes, in which these
critical cells are lost. Follow up studies have been aimed to more
precisely define the effects of artemisinins.
Li J et al. Artemisinins target GABAa receptor signaling and impair α cell identity. Cell 168, 86-100
(2017).
>> ARTEMISININS AS POTENTIAL COMPOUNDS IN DIABETES THERAPY?
>> NEWLY IDENTIFIED STRESS PROTEIN PROTECTS SNAILS
Snails are model organisms for research on metal stress and
detoxification of heavy metals. As other animals, they use
Metallothionein proteins to bind and neutralize heavy metals such
as cadmium. An international research team organized by Reinhard
Dallinger including collaborators in Zurich and Barcelona succeeded in
isolating and characterizing an unexpected form of Metallothionein
protein from a marine snail, which exhibits three instead of two metal-
binding motifs. Thereby, one of these proteins is able to bind nine
Cadmium ions, much more than other Metallothioneins, resulting in
a much higher detoxification efficiency and higher stress resistance of
theses snails. Identification of this new protein structure is a result of
a FWF DACH project on the evolution of the Metallothionein protein
family funded together with the Swiss National Science Foundation
SNSF.
Baumann C et al. Structural adaptation of a protein to increased metal stress: NMR structure of
a marine snail Metallothionein with an additional domain. Angew. Chem. Int. Ed. 56, 4617-4622
(2017).
Commented on by: Fahrenkamp-Uppenbrink L. Heavy metals? No problem for this snail. Science
356, 150-151 (2017).
The “applecare” team at the CMBI: R. Eidelpes, L. Ahammer,
J. Unterhauser and M. Tollinger (left to right)
18 19
>> Goal: Molecular mechanisms of cellular growth control and
carcinogenesis
>> Background: Research in our lab is focused on the analysis of signal
transduction pathways, mediated by plasma membrane receptors,
second messengers, cytoplasmic kinases, and transcriptional regulators.
Both physiological and pathogenic forms of these pathways are
investigated, with specific focus on their role in carcinogenesis.
>> Research Highlights and Outlook: The bHLH-LZ (basic region/
helix-loop-helix/leucine zipper) oncoprotein Myc and the bHLH-LZ
protein Max form a binary transcription factor complex controlling
fundamental cellular processes. Deregulated Myc expression leads to
neoplastic transformation and is a hallmark of most human cancers. Myc
transcription factor activities are controlled by defined protein-protein
interactions (PPI). We have recently obtained evidence for a second
messenger controlled physical interaction between the Ca2+ sensor
calmodulin (CaM) and all Myc variants (v-Myc, c-Myc, N-Myc, and L-Myc).
The predominantly cytoplasmic Myc:CaM interaction is Ca2+-dependent,
and the binding site maps to the conserved bHLH domain of Myc.
Ca2+-loaded CaM binds the monomeric and intrinsically disordered Myc
protein with high affinity, whereas Myc:Max heterodimers show less,
and Max homodimers no affinity for CaM. NMR spectroscopic analyses
corroborate the biochemical results on the Myc:CaM interaction and
confirm the interaction site mapping. Cell-based reporter analyses and
cell transformation assays suggest that increasing CaM levels enhance
Myc transcriptional and oncogenic activities. Our results point to a
possible involvement of Ca2+ sensing CaM in the fine-tuning of Myc
function.
Myc is regulated by several signaling cascades implicated in
development and oncogenesis. The Wnt/β-catenin/Tcf axis drives
cell differentiation and organismal patterning. Disturbances of this
pathway - like mutation of the APC tumor suppressor in colon cancer
- leads to tumorigenic processes including transcriptional deregulation
of the c-myc protooncogene. The early diploblastic cnidarian Hydra has
two myc genes (myc1, myc2), with myc2 being closer related to c-myc.
Wnt/β-catenin signaling has crucial functions in cell differentiation and
development in Hydra. In collaboration with the Hobmayer group,
we found that activation of Wnt/β-catenin signaling in Hydra leads
to downregulation of myc1 but not of myc2. Mapping and analysis
of the myc1 and myc2 promoter regions revealed the presence of
consensus binding sites for the transcription factor Tcf. In vivo binding
of Hydra Tcf to both promoter regions was demonstrated by chromatin
immunoprecipitation. Reporter gene assays showed that the myc1
promoter is repressed by ectopic Hydra β-catenin/Tcf, whereas the myc2
promoter was not affected. The identification of the Wnt/β-catenin/
Tcf axis as a regulatory pathway of Hydra myc genes indicates that
principal links in the Wnt signaling network have emerged very early in
metazoan evolution.
At the plasma membrane an array of more than 800 G protein-coupled
receptors (GPCRs) receive, convert, amplify, and transmit incoming
signals. Activated GPCRs team-up with intracellular scaffolding proteins
to compartmentalize signal transmission. Scaffolds, such as β-arrestin
and A-kinase anchoring proteins (AKAPs), function as a physical nexus
between receptors and molecular switches. Typically, these receptor-
bound AKAPs recruit protein kinase A (PKA) to assemble dedicated
polyvalent signaling complexes that are spatially and temporally
confined. We showed that the orphan GPCR, Gpr161, is a PKA substrate
and also has an AKAP motif embedded in its C-terminal tail. Our results
suggest that Gpr161, by directly recruiting type I PKA holoenzymes
to the receptor, creates a cAMP-sensing signalosome. Furthermore,
we propose that Gpr161 plays a role in recruiting isoform-specific
PKA complexes to primary cilia. Currently we analyze and perturb the
receptor-effector relationship in the primary cilium.
>> Research GrantsFWF: P23652 (2011-2016), P27606 (2015-2018), P30441
(2017-2021), SFB-F44 associated member (2015-2016),
TWF: UNI-0404/1525 (2014-2016); TWF: UNI-0404/1990
(2017), Alfonso M. Escudero fellowship (2015-2016)
>> CoworkersV. Bachmann, P. Raffeiner, O. Torres-Quesada (postdocs);
M. Bucher, F. Enzler, A. Feichtner, J. Mayrhofer, R. Röck,
C. Schneider, B. Texler (master and Ph.D. students); S.
Beiler, K. Puglisi, A. Raffeiner, A. Reintjes (technicians)
Signal transduction in cellular growth control and carcinogenesis
Klaus Bister, Markus Hartl, and Eduard Stefan
>> Department of Biochemistry
Figure 1: Schematic diagram of basic interconnections
between Myc and Ca2+/CaM signaling. The binding reactions
and equilibria involved are indicated by black dashed arrows,
cytoplasmic proteolytic processing or nuclear transport of
Myc is depicted by red or green arrows, respectively. Specific
cleavage to Myc-nick requires the action of Ca2+-dependent
proteases (red dashed arrow). (Raffeiner et al., Oncotarget
2017)
Figure 2: Schematic depiction of the canonical Wnt signalling
pathway. Wnt binds to the Frizzled (FZD) receptor leading
to disruption of the APC/GSK3β complex which normally
degrades β-catenin (β-Cat). Accumulated β-Cat translocates
into the nucleus where it binds to the Tcf transcription factor
leading to transcriptional activation of Wnt signalling targets
via Tcf binding elements (TBE, 5’-CCTTTGA/TA/T-3’). (Gufler et
al., Dev. Biol. 2018, Epub 2017; Hartl et al., unpublished).
Figure 3: PPI network emanating from PKA. Following phos-
phoproteomic analyses using LC-MS/MS, a static PPI network
of the confident set of PKA interacting proteins (endogenous
complexes isolated from osteosarcoma cells) was generated.
(Bachmann*, Mayrhofer* et al., PNAS 2016).
Research summary Research summary
20 21 Research summary
Christian Huck and Günther Bonn
>> Department of Analytical Chemistry and Radiochemistry
>> Goal: Novel chromatographic and vibrational spectroscopic tools with
enhanced efficiency, selectivity and sensitivity, are developed in order to
get detailed analytical information upon the composition, origin and/or
species of samples in the fields of phytomics, metabolomics, proteomics
and foodomics.
>> Background: The development of novel monolithic stationary phases
for the separation of small molecules was highly successfully continued.
Those stationary phases have been designed for either sample
preparation by solid phase extraction (SPE) or analytical separations by
high performance liquid chromatography (HPLC). Thereby, the monolithic
format offers several advantages, including superior efficiency, high
permeability, mechanical robustness, and extended useful life-circle.
New methodologies for solid-phase extraction (SPE) based on polymeric,
highly selective and hydrophilic mixed-mode have been established.
The incorporation of an, e.g., imidazole residue featured auspicious
characteristics including possible analyte interactions via hydrophobic as
well as hydrogen bonding or pH dependent electrostatic interactions.
By the additional post-polymerization derivatization, imidazole was
converted into a strong ion-exchanger which increasingly extended the
application of solid-phase extraction in analytical platforms.
In the field of vibrational spectroscopy the development of non-invasive,
fast techniques based on near-&mid-infrared (NIR&MIR), Raman
spectroscopy plays a crucial role enabling simultaneous analysis of physical
and chemical parameters, respectively. The development of miniaturized
portable spectrometers is highly useful. Imaging and mapping MIR/NIR/
Raman methods are developed for screening of sample composition with
a spatial resolution down to 1 µm, which enables the development of
early diagnosis tools for cancer detection. Quantum chemical calculation
for spectrum simulation can provide substantial support especially in the
interpretation of complex spectra. In case of low concentrated analytes
the combination of selective enrichment techniques with IR and/or
Raman spectroscopy has been shown to be suitable. These techniques
are termed as SEIRS (Surface enhanced infrared spectroscopy); MEIRS
(Material enhanced infrared spectroscopy) and SERS (Surface enhanced
Raman spectroscopy).
>> Research Highlights and Outlook: The realization of polymeric
monolithic sorbents with retention mechanisms based on more than
one type of interaction was realized and this type is referred to as mixed
mode stationary phases. Fast gradient separations allowed the analysis
of alkyl benzenes and parabens within a few minutes. Compared to
silica based particles, the polymeric stationary phase provides pH
stability over the complete pH range and its preparation as monolith
in capillary successfully shows several advantages compared to packed
columns.
Polymeric mixed-mode stationary phases are of high importance
regarding their use as small SPE columns in sample preparation
approaches. For that polymeric mixed-mode sorbents were based on
an imidazole network and feature auspicious characteristics including
a high polarity, an aromatic system and good points of applications for
further derivatizations. It comprised suitable applications for complex
samples containing lipophilic aromatic or aliphatic frameworks as well
as opposing polar, acidic substance classes (Figure 1).
One aim of Huck´s lab is the development of non-invasive NIR portable
measurement technology for the determination of optimum harvest
time for medicinal plants (phytomics). With this approach it is for the
first time possible to detect within one measurement quality related
chemical parameters such as the concentration of distinct ingredients
and also physical parameters, e.g. anti-oxidative and or anti-bacterial
activity, respectively. Thereby, reference analytical methods as described
in the prior paragraph play a crucial role next to quantum chemical
spectrum simulation and 2D-COS (Figure 2).
Since the milk and horsemeat scandal it became clear that early food
fraud detection is essential. Therefore, it is the aim to develop easy
applicable vibrational spectroscopic tools in order to determine the
origin and/or species of food such as apples, milk, cheese, meat and
cereals. Additionally, NIR/MIR and especially Raman Imaging is highly
suitable for the discrimination of cancerous tissue from healthy with
a resolution down to 1 µm. These techniques give promise that in due
time non-invasive light fiber based measurement can be applied.
>> Research GrantsFFG GZ 859502; OEAD GZ ZA 07/2017; EPU 53/2016,
EPU 54/2016; Interreg GZ AB116; Interreg GZ ITAT1005;
BMWFW 402.000/003-II/6b/2012
>> CoworkersPD Dr. Rania Bakry, Assoz.-Prof. Dr. Matthias Rainer,
Prof.Dr. Sevgi Türker (visiting professor); Mag.Dr.
Cornelia Pezzei, Dr. Justina Grabska, Dr. Krzysztof Bec,
(postdoc); Mag. Lukas Bittner, Mag. Raphael Henn,
Mag. Markus Huber, Stefanie Delueg MSc, Mag. Karl
Handle, Mag. Christian Kirchler, Verena Wiedemair
MSc., Anel Beganovic MSc., Sophia Mayr MSc. (Ph.D.
students); Andreas Agerer, Sebastian Lörcher (diploma
students)
Advanced chromatographic and spectroscopic analytical tools in natural product analysis & molecular biology
Figure 2: Strategy for the development of an on-line quality
assurance procedure of medicinal plants
Figure 1: HPLC chromatograms of a mustard seeds extract
before and after SPE using Poly(NVI/EGDMA). Highly acidic,
water soluble glucosinolates are interacting with the
quaternized imidazolium ring by ion-exchange interactions.
Displacement during elution process is enabled by counter-
ions of high relative binding strengths.
Research summary
22 23 Research summary Research summary
activated dissociation (CAD), thus allowing its use for probing tat
binding sites in TAR RNA by top-down MS. At the same time, the MS
data revealed time-dependent 1:2 and 1:1 stoichiometries of TAR-tat
complexes and suggest structural rearrangements of TAR RNA induced
by tat peptide binding.
Many RNA-protein and RNA-drug complexes involve interactions
between guanidine and phosphate moieties. We have investigated
noncovalently bound complexes of an 8 nt RNA and six different
ligands, all of which comprise a guanidinium moiety, by electrospray
ionization (ESI) and CAD MS, and found that the order of complex
stability correlated almost linearly with the number of ligand atoms
that can potentially be involved in hydrogen bond or salt bridge
interactions with the RNA but not with the proton affinity (PA) of
the ligands. However, ligand dissociation in CAD of the complex ions
was generally accompanied by proton transfer (PT) from protonated
ligand to deprotonated RNA, indicating conversion of salt bridge into
hydrogen bond interactions. The relative stabilities and dissociation
pathways of the (RNA+mL-nH)n- complexes of differing stoichiometry
(m = 1-5) and net charge (n = 2-5) revealed both specific and unspecific
ligand binding to the RNA.
Nucleobase methylations are ubiquitous posttranscriptional
modifications (PTMs) that can substantially increase the structural
diversity of RNA in a highly dynamic fashion with implications for
gene expression and human disease. Especially for noncoding RNAs,
research progresses at a high rate but is still critically hindered by
lack of adequate methodology for the characterization of PTMs; high
throughput deep sequencing does not generally provide information
on PTMs. We have investigated how specific nucleobase methylations
affect RNA ionization in ESI, and backbone cleavage in CAD and electron
detachment dissociation (EDD), and developed two new top-down MS
approaches for the characterization of RNA methylations in mixtures
of either RNA isomers or nonisomeric RNA forms. Fragment ions were
analyzed to identify the modification type, to localize the modification
sites, and to reveal the site-specific, relative extent of modification for
each site.
>> Research Grants
FWF Y372, FWF P27347, FWF P30087
>> CoworkersHeidelinde Glasner, Eva-Maria Schneeberger, Jovana
Vusurovic, Matthias Halper, Giovanni Calderisi, Simon
Chwatal
Figure 3: Top-down MS using CAD can identify RNA
modifications, localize modification sites, and reveal the
site-specific, relative extent of modification for each site in
mixtures of RNA isomers or forms (H. Glasner, C. Riml, R.
Micura, K. Breuker Nucleic Acids Res. 45, 8014-8025, 2017)Figure 1: Native top-down MS reveals the sites of tat peptide
binding to TAR RNA in the 1:2 complex (E.M. Schneeberger,
K. Breuker Angew. Chem. Int. Ed. 56, 1254-1258, 2017).
Figure 2: CAD MS of RNA-guanidine derivative complexes
shows that their stability increases with the number of ligand
atoms that can be involved in hydrogen bond or salt bridge
interactions, but not with the proton affinity of the ligands
(J. Vusurovic, E.M. Schneeberger, K. Breuker ChemistryOpen
6, 739-750, 2017).
>> Goal: A major focus of our research is to explore the determinants
of biomolecular structure, stability, binding, and dissociation in the gas
phase. Based on insight from fundamental and mechanistic studies,
we develop new methodology for protein and ribonucleic acid (RNA)
characterization by mass spectrometry (MS), including the identification,
localization, and relative quantitation of posttranslational and
posttranscriptional modifications, and the determination of
stoichiometry and binding sites of noncovalent complexes of RNA.
>> Background: Mass spectrometry is an evolving technique with unique
potential for biomolecular characterization beyond mere sequencing.
Current research in the field aims, for example, at developing “top-
down” and “middle-down” MS approaches for studying different
proteoforms, posttranscriptional modifications of non-coding RNA, and
the higher order structure of functional biomolecular assemblies, for
which a solid understanding of biomolecular gas phase ion structure,
stability, binding, and dissociation is critical.
>> Research Highlights and Outlook: RNA frequently associates with
proteins in many biological processes. The characterization of RNA-
protein complex structures and binding interfaces by NMR spectroscopy,
X-ray crystallography, or strategies based on chemical crosslinking,
however, can be quite challenging. We have explored the use of an
alternative method, native top-down mass spectrometry, for probing of
complex stoichiometry and protein binding sites at the single-residue
level of RNA. Our data showed that the electrostatic interactions
between HIV-1 TAR RNA and a peptide comprising the arginine-rich
binding region of tat protein are sufficiently strong in the gas phase
to survive phosphodiester backbone cleavage of RNA by collisionally
Kathrin Breuker
>> Department of Organic Chemistry
Characterization of RNA, proteins, and their noncovalent complexes by mass spectrometry
24 25 Research summary Research summary
Reinhard Dallinger
>> Department of Zoology
>> Goal: To achieve an extensive perception of the potential and
significance of metallothionein (MT) genes and proteins for metal
metabolism in animals by exploring their evolution and diversification
towards novel structures and functions in different animal lineages.
>> Background: For a long time, MT research has been focused on the role
and significance of this protein family in vertebrates (mainly mammals)
and a few selected model organisms. We believe, however, that the
true potential of a protein family can only be comprehended and
acknowledged by encompassing its structural and functional diversity
across all major organismic phyla. During the last years, a plethora of
primary MT sequences has been provided from a variety of different
bacteria, plants, fungi and animal lineages. Our group has contributed
to a better understanding of structural and functional MT diversity by
in-depth research of MT structures and functions in the mollusk clade
of Gastropoda (limpets, snails and slugs). These animals represent, in
terms of evolutionary radiation, one of the most successful and diverse
animal phyla whose members have successfully adapted, several times
independently, to life in terrestrial and freshwater habitats. One of the
most challenging questions in this concern is, to which extent gastropod
MT structures and functions have been inherited from marine ancestors,
and by how much they may have undergone adaptive modifications
upon transition from sea to land and to freshwater environments.
>> Research Highlights and Outlook: Through evolution of gastropod
MTs, there has been a trend towards diversification into metal-specific
isoforms, with a particular prevalence, in some gastropod lineages (such
as Stylommatophora snails), of Cd- and Cu-selective MTs (Palacios et al.
2011). Evidently, Cd specificity has evolved prior to Cu specificity and must
therefore, be regarded as the ancestral metal-specific feature, occurring
today in species of both, Caenogastropoda and Heterobranchia snails
(Figure 1). In some Cd-selective MTs, the capacity of metal loading has
been boosted by addition of one Cd binding protein domain, as shown
by us for the first NMR structure of a three-domain MT from the marine
snail Littorina littorea in cooperation with the Oliver Zerbe group
(University of Zürich) (Baumann et al. 2017). More recently, we discovered
a further three-domain Cd MT structure in Pomatias elegans, a close
terrestrial relative of Littorian littorea (Schmielau et al., submitted). In
some other species of Caenogastropoda and Heterobranchia snails, the
Cd loading capacity has been boosted by invention of MT isoforms with
as much as 10 (ten!) Cd-binding domains, as recently discovered by us in
Alinda biplicata (Heterobranchia) (unpublished data, Figure 1). In most
cases, Cd specificity at the protein level is accompanied by Cd-specific
upregulation of respective CdMT genes. Interestingly, Cu-selective MT
isoforms have evolved from pre-existing Cd-specific ancestral variants
only in species of the Stylommatophora lineage (terrestrial snails in
the clade of Heterobranchia) through gene duplication, followed by
structural modification towards Cu selectivity. This has been achieved,
among others, by increasing in the primary structure of CuMTs the
K : N (lysine : asparagine) ratio, which indicates that the selectivity
towards distinct metal ions may at least in part be owing to structural
constraints affecting the ionic charge and size of metal binding pockets
in the MT metal clusters (Palacios et al. 2011). A striking difference to
other animal MTs is the evident lack of Zn2+ affinity in gastropod MTs.
Instead, in Gastropoda this metal ion is consistently associated with low-
molecular metal binding ligands such as phytochelatins or carbohydrate
compounds (unpublished data, in preparation). As an intriguing
outlook, it becomes more and more apparent that one additional
and so far neglected functional significance of MTs in gastropods, and
perhaps in other animal clades too, may be their important protective
role in favor of Ca2+ pathways (unpublished data, in preparation).
References
Palacios et al. 2011, BMC Biology BMC 2011, 9:4, 1-20.
Baumann et al. 2017, Angew. Chem. Int. Ed. 56, 4617-4622.
Schmielau et al. 2018, Sci. Tot. Environ., submitted.
>> Research GrantsFWF I1482-N28 (DACH, leading agency: FWF); FWF
I3032-B21 (DACH, leading agency: FWF)
>> CoworkersVeronika Pedrini-Martha (postdoc); Reinhard Lackner
(technical assistance); Michael Niederwanger, Martin
Dvorak, Raimund Schnegg (Ph.D. students); Lara Schmi-
elau (diploma student)
Gastropod metallothioneins in evolution: New rules for an old protein family
Figure 1: Flowchart of MT evolution in Gastropoda, showing
the major gastropod subclasses (Patellogastropoda,
Vetigastropoda, Neritimorpha, Caenogastropoda and
Heterobranchia) on the left-hand site. Two-domain MTs of
low or no metal specificity at all have so far been observed
in Patellogastropoda, Vetigastropoda and Neritimorpha
(above, in blue). In contrast, metal-specific MT isoforms
(CdMTs and CuMTs) have evolved in Caenogastropoda and
Heterobranchia (middle and lower part). Two-domain Cd-
specific isoforms (as found in Pomatias elegans) are ancestral
and have given rise to higher-molecular MT structures by
addition of a third (like in Littorina littorea) or even up to
ten (as in Alinda biplicata) Cd-binding domains (middle part,
in red). Cu-specific MT isoforms have been derived in some
Heterobranchia by gene duplication from two-domain Cd-
specific ancestors (lower part, in green). In some families of
Heterobranchia, metal specificity has finally been lost again
by primary structure modification.
26 27 Research summary Research summary
Stephan Denifl
remains bound to an intact THF molecule due to the high proton affinity
of the molecule. Rather unexpected is the exclusive formation of (THF
– OH)+ from clusters, since in this case intramolecular bond cleavage
is favored over intermolecular bond cleavage although substantial
energy is deposited by the colliding electron. However, additional
experiments with the deuterated molecule allowed an unambiguous
identification of this reaction channel, since we observed the loss of
OD in this case. Studies with the deuterated compound also allowed
the identification of reaction pathways in the case of nanohydration.
In case of nanohydrated THF, fragmentation of the sugar is reduced in
favor of fragmentation by the solvent molecules.
Finally, we recently also intensified our studies with potential
radiosensitizers developed for the improvement of radiation therapy.
For future studies on the molecular level, nitroimidazolic compounds
will be promising since those compounds have been successfully
established for radiation therapy in Nordic countries.
>> Research GrantsFWF-I1015, FWF-P22443
>> CoworkersMichael Neustetter (postdoc), Jusuf Khreis, Anita Ribar,
Rebecca Meißner, Joao Ameixa (Ph.D. students), Katha-
rina Fink, Bea Haslwanter, Julia Reitshammer (master
students)
Radiation damage in biological compounds induced by low energy electrons
Figure 1: Electron ionization mass spectrum of isolated
tetrahydrofuran (orange line) and tetrahydrofuran clusters
(black line), respectively. Both spectra were recorded at the
electron energy of about 70 eV. In case of clusters, a peak is
present at m/z 55, which can be assigned to the loss of OH
from tetrahydrofuran.
>> Goal: Exploring negative and positive ion formation by secondary
electrons formed upon radiation of biological compounds.
>> Background: A large number of secondary particles are generated
when energetic primary radiation (e.g. photons, ions or cosmic
radiation) interacts with biological material like living cells. The most
abundant secondary species formed are electrons which are released
with an average kinetic energy of a few eV. These electrons subsequently
interact with cell components before they become a chemically inactive
species. The electron interaction may however be severe even leading
to single and double strand breaks of DNA. Therefore it is crucial
to investigate the interaction of low energy electrons with simple
biomolecules representing building blocks of biological material
(nucleobases, amino acids, etc.). Mass spectrometry of anions formed
by electron attachment represents our experimental approach.
>> Research Highlights and Outlook: In recent experiments we carried out
mass spectrometric studies with clusters of tetrahydrofuran. Studies in
the field of chemical physics often use tetrahydrofuran (THF) as model
compound for the sugar moiety of DNA. The clusters were created by
the so-called supersonic expansion technique and crossed with a beam
of electrons. Figure 1 shows the resulting mass spectrum below the
monomer, when THF clusters are ionized by electrons with the kinetic
energy of about 70 eV. Most of the ions formed correspond to those
when a single THF molecule is ionized. Only two exceptions can be
found: The protonated THF ion and the (THF – OH)+ ion are not found
in the mass spectrum for the single molecule. The former ion is easily
formed by fragmentation of a larger cluster, where the weak bond
between the THF moieties is broken upon the ionization, and a proton
>> Department of Ion Physics and Applied Physics
28 29
>> Goal: To obtain human neural stem cells for disease modeling and
cell therapy
>> Background: The Edenhofer group is working with mammalian
stem cells and has a long-standing interest in cellular regeneration
and disease modeling particularly of neurological disorders. Cellular
reprogramming enables the derivation of induced pluripotent stem
cells (iPSCs) from somatic cells such as skin or blood cells. iPSCs are
functionally equivalent to embryonic stem cells (ESCs) i.e. they exhibit
an unlimited differentiation and self renewal potential. We aim at i)
understanding the transcriptional program of stemness properties, ii)
exploring novel 2nd generation reprogramming paradigms and iii)
harnessing the potential of patient-specific reprogrammed cells for
biomedical applications such as disease modeling and cell therapy.
>> Research Highlights and Outlook: One aim of our lab is the elucidation
of transcriptional regulation of self-renewal of mammalian stem cells.
Self-renewal belongs with differentiation to the major features of
stem cells that are closely associated with cell cycle progression. The
molecular processes underlying the choice between cell division,
differentiation and dormancy are uniquely regulated in stem cells and
represent a fundamental principle to control cell type specification,
organ homeostasis, and potentially tumorigenesis. We explored the
mechanistic role of transcriptional regulators Nanog and Myc in cell
cycle control of pluripotent stem cells. Nanog is a homeodomain
transcription factor that is necessary for the natural induction of
pluripotency in early mammalian development but dispensable for
its maintenance in vitro. We found that Nanog enhances cell cycle
progression of NIH 3T3, primary fibroblasts and ESCs by downregulation
of the cell cycle inhibitor p27KIP1 (also known as CDKN1B) establishing
a direct link between pluripotency establishment and cell cycle control.
The Myc family of transcription factors has been implicated in both
i) the induction of artificial pluripotency in somatic cells, and ii) the
generation of a variety of human tumors. In a collaborative study
with the group of Andreas Trumpp (German Cancer Research Center,
Heidelberg) we functionally analyzed the role of Myc in pluripotent
stem cells. Deletion of both c-myc and N-myc strongly decreases
transcription, splicing, and protein synthesis, leading to a proliferation
arrest. This study shows that Myc controls the biosynthetic machinery of
stem cells without affecting their potency, thus regulating their entry
and exit from the dormant state.
Cell fate specification of stem cells exiting the pluripotent state and
undergoing cell differentiation represents another key question that
our group addressed. In this respect we employed a 3D organoid model,
embryoid bodies (EBs), to study the role of gap junctional intercellular
communication (GJIC) in early embryonic development.
Connexin (Cx) 43 and Cx45 are co-expressed in ESCs, form gap junctions
and are considered to exhibit adhesive function and/or to contribute
to the establishment of defined communication compartments. We
generated Cx43/45-double deficient mouse ESCs and achieved almost
complete breakdown of GJIC. Cx43/45-dKO results in a block of
differentiation in EBs without affecting pluripotency and proliferation.
We further demonstrated that GJIC-incompetent ESCs fail to form
primitive endoderm in EB cultures, representing the inductive key
step of subsequent differentiation events. This work helps to gain
comprehensive understanding into mechanisms underlying early
lineage specification, which is essential in order to understand
embryonic development and stem cell based organoid cultures.
>> Research GrantsFWF I 3029-B30, FWF W 1206-B18, bmwfw 10.420-WF/
V/3c/2016, DFG AOBJ 635622
>> CoworkersKatharina Günther, Katharina Kruszewski, Jerome
Mertens, Sandra Rizzi, Ahmad Salti (postdoc); Anita
Erharter, Gabriella Fenkart, Larissa Traxler (Ph.D.
students); Veronika Fricke, Regina Gassler, Anna
Hausruckinger, Felix Strasser (master students); Marta
Suarez Cubero, Urban Tscheikner-Gratl (technicians);
Caroline Baldemair, Marion Staudinger (secretary)
Regenerative potential of reprogrammed neural stem cells
Frank Edenhofer
>> Department of Molecular Biology, Department of Genomics, Stem Cell Biology &
Regenerative Medicine
Figure 1: Genetic ablation of Cx43/45 by Cre/loxP-mediated
mutagenesis disrupts primitive endoderm formation in
embryoid bodies (EBs). (A-F): Immunofluorescence analyses of
the primitive endoderm marker Gata6 and the pluripotency
marker Nanog in EBs on day 6 of differentiation. Gata6 is
detectable in a substantial number of nuclei of 4-day-old
Cx43/45 flox EBs (A-C) while it is only rarely found in Cx43/45-
deficient cells (D-F). (G-H): Control EBs on day 6 exhibit a
well-structured surface layer of extraembryonic endoderm
(Gata6) (G) and a-feto protein (AFP). Cells of the outer Gata6-
and AFP-positive layer stained negative for the pluripotency
marker Nanog. A defined outer layer of Gata6-positive cells
was not observed in Cx43/45-deficient EBs (I). Scale: (A-F): 100
mm. Scale: (G-I): 50 mm.
Research summary Research summary
30 31 Research summary Research summary
Beatrix Grubeck-Loebenstein
>> Research Department for Biomedical Aging Research
>> Goal: To gain a better understanding of age-related changes within
the immune system in order to find new ways to prevent the loss of
immune function with age.
>> Background: Age-related changes in T-lymphocytes, immune cells
responsible for eliminating virus-infected cells and cancer cells from the
body, are most detrimental. This is due to early degenerative changes
that take place in the thymus, the organ in which T cells mature. As the
thymus gradually loses its ability to replenish, the naïve T cells decrease
while memory and effector T cells increase in number and dominate
the repertoire. This can lead to the loss of certain T cell specificities and
changes in the composition of the T cell repertoire. One point of interest
in this respect is to explore the role of the bone marrow (BM) for the
maintenance of immunological memory in old age. Of practical relevance
is the question how vaccination can be optimized for the elderly.
>> Research Highlights and Outlook:
The bone marrow (BM) and immunological memory in old age:
The BM is important for the long-term maintenance of immunological
memory, but the influence of aging on the production of survival
factors for effector/memory T cells and plasma cells in the human
BM has not yet been investigated. We could demonstrate that the
expression of molecules involved in the maintenance of immunological
memory in the human BM changes with age. While IL-15 that protects
potentially harmful CD8+CD28− T cells increases, IL-7 decreases. IL-6 is
also overexpressed. In contrast, APRIL, a plasma cell survival factor for B
cells, is reduced. In contrast, IFN-y, TNF, and ROS accumulate in the BM
in old age. IL-15 and IL-6 correlate with ROS levels in BM mononuclear
cells. IL-15 and IL-6 are also overexpressed in the BM of superoxide
dismutase 1 knockout mice compared to their WT counterparts. Our
results demonstrate the role of inflammation and oxidative stress in age-
related changes of immune cell survival factors in the BM. Antioxidants
may therefore be beneficial in counteracting immunosenescence by
improving immunological memory in old age (Pangrazzi et al, Eur J
Immunol 2017;47:481-492).
Vaccination for the elderly:
Vaccines against tetanus and diphtheria are among the most frequently
used vaccines worldwide, but previous studies from our laboratory
have shown that protection against tetanus and particularly against
diphtheria is unsatisfactory in adults and older persons. In the course
of the EU project “MARK-AGE” we analyzed tetanus- and diphtheria-
specific antibody concentrations in 2100 adults of different age from 6
selected European countries (Austria, Belgium, Germany, Greece, Italy,
Poland) in order to investigate differences in the level of protection
against tetanus and diphtheria across Europe. The data demonstrate
that tetanus- and diphtheria-specific antibody concentrations vary
greatly between countries, which is also reflected in the percentage
of persons with antibody concentrations below the protective level
(0.1IU/ml), which ranged from 2 to 31% for tetanus and 28-63%
for diphtheria. In most countries, tetanus- and diphtheria-specific
antibody concentrations decrease with age. Tetanus-specific antibody
concentrations are generally higher in males than in females, whereas
no gender-related differences were found for diphtheria-specific
antibodies. The studies demonstrate that the European population is
not satisfactorily protected against tetanus and diphtheria. Protection
should be improved by a life-long perspective on vaccination and more
education to increase awareness of the necessity of regular vaccination
throughout life all over Europe (Weinberger B et al, Exp Gerontol 2017;
Oct 7. pii: S0531-5565(17)30516-8).
>> Research GrantsEU HEALTH-F4-2011-280873, EU SSH-2012-1-320333,
EU H2020-PHC-2014-2015-633964, EUREGIO-EFH, FWF
ZFW012530, ÖAW-DOC 24089, TWF UNI-0404/2018, D.
Swarovski 2015/BIO-15, D. Swarovski 2016/BIO-22
>> CoworkersCarmen Giefing-Kröll, Stella Lukas Yani, Andreas Me-
ryk, Birgit Weinberger (postdocs); Marco Grasse, Carina
Miggitsch, Erin Naismith, Luca Pangrazzi (Ph.D. stu-
dents); Daniel Breitenberger, Christina Putzer, Rebecca
Ralser (diploma students); Magdalena Hagen, Florian
Hatzmann, Franz Melzer (master students); Brigitte
Jenewein, Michael Keller (technicians)
Immuno-gerontology
32 33 Research summary Research summary
Ronald Gust
>> Department of Pharmacy, Pharmaceutical Chemistry
>> Goal: Development of new antitumor drugs, which address new
targets to overcome intrinsic and acquired resistance of tumor cells.
>> Background: Nowadays cancer chemotherapy is yet accompanied
by limiting unwanted side effects and the development of intrinsic or
acquired resistance. Therefore, the search for new targets and novel
antitumor drugs are topics in the research of medicinal chemists.
Especially, metal-based drugs as alternatives to cisplatin and carboplatin
are of high interest. They should address not the DNA but other targets
in the tumor cells to circumvent cross-resistance. Of further interest
is the design of selective estrogen receptor modulators (SERM) with
a unique binding mode at the estrogen receptor to get alternatives
to tamoxifen with a safer hormonal profile. Therefore, we focussed
our interest on metal complexes, which i) inhibit the cyclooxygenase 2
(COX-2) over-expressed in mammary and colon carcinoma or ii) induce
ferroptosis, an iron-dependent form of non-apoptotic cell death. Our
new SERMs represent bivalent drugs with affinity to the ligand binding
domain (LBD) and the coactivator-binding site to exclude agonistic
growth stimulating effects.
>> Research Highlights and Outlook: In a preliminary structure activity
study we could show that the acetyl salicylic acid derivative [prop-2-
ynyl-2-acetoxybenzoate]dicobalthexacarbonyl (Co-ASS) represents
an unselective COX-1/2 inhibitor with cytotoxicity against breast
cancer cells comparable to cisplatin. Exchange of the cobalt cluster
by [ethylene]trichloroplatinate(II) (Zeise´s salt) strongly increased the
inhibitory effects at COX-1, but drastically reduced the COX-2 inhibition
and the cytotoxicity. With the objective of increasing the selectivity for
COX-2, we introduced a chlorine substituent in position 3, 4, 5, or 6 at
the ASS moiety of Co-ASS. This substituent utilizes on the one hand
the larger binding cave of COX-2 to prevent activity at this isoenzyme
and on the other hand it reduces the binding to COX-1 due to steric
repulsion. Indeed, all complexes retained their activity at COX-2 and
were inactive at COX-1. In this context, we characterized the MDA-MB
231 breast cancer as well as the HT-29 colon carcinoma cells as COX-1/2-
positive and the MCF-7 breast cancer cells as COX-negative. The missing
COX content led to almost inactivity of the complexes against MCF-7
cells indicating that COX-2 is involved in the mode of action of the
Co-ASS derivatives.
Ironsalene complexes were designed to get a carrier-mediated uptake
in tumor cells. Inside the cells, they generate an iron-dependent
form of non-apoptotic cell death. This effect called ferroptosis is
morphologically, biochemically, and genetically distinct from apoptosis
and necrosis. It is induced by Fe(II/III) because of building of reactive
oxygen species and can be suppressed by the potent ferroptose-
inhibitor ferrostatin-1. With our compounds, it was demonstrated for
the first time that iron complexes can induce ferroptosis and free iron
ions are not a prerequisite.
Nuclear receptors play a crucial role in the development of hormone-
dependent tumors. Tamoxifen and fulvestrant are promising drugs in
the hormone therapy of the ER-positive mammary carcinoma. They
prevent in different ways the binding of coregulators to the activated
estrogen receptors thereby causing antiestrogenic properties. Our
approach targets both the ligand binding domain (LBD) and the
coactivator-binding site. 4-Hydroxytamoxifen (4-OHT) or derivatives
were linked by an alkyl spacer with small molecules, so called nuclear
receptor alternate-site modulators (NRAMs), which competes with the
coaktivator for its binding site (Figure 1). In this case, the LBD binder
(e.g. 4-OHT) causes selectivity for the ER and the coactivator can
effectively be prevented from ER activation. Dependent on the used
LBD binder, the dimers show high affinity to the ER only slightly lower
than estradiol. High advantages are the fluorescence properties, which
allow first investigations on the mode of action. The bivalent drugs are
vesicular accumulated in MCF-7 cells and were identified especially in
vesicles in the cytoplasm (Figure 2).
>> Research Grants
FFG (West-Austrian BioNMR)
>> CoworkersBenjamin Ma, Daniel Bäcker, Natalie Fahrner, Sina
Götzfried, Alexandra Knox, Robert Mauersberger,
Victoria Obermoser, Anna Schöpf, Alexander Weninger
(PhD students); Monika Cziferszky (postdoc)
Development of selectively acting antitumor drugs
Figure 1: Connection of the 4-hydroxytamoxifen derivative
GW 7604 with an alkylpyrimidine NRAM .
Figure 2: Intracellular localization in the cytoplasm of MCF-7 cells.
34 35 Research summary Research summary
Bert Hobmayer and Peter Ladurner
>> Department of Zoology
>> Goal: We focus on stem cell differentiation during embryonic
development, tissue turnover and regeneration, and analyze bio-
adhesion in basal animal model organisms.
>> Background: By using simple model organisms such as cnidarian
polyps, flatworms, and sea squirts, we study basic molecular and cellular
processes of cell differentiation, pattern formation, and bioadhesion.
Of central interest are evolutionary conserved developmental pathways
and master regulatory genes known to act throughout the animal
kingdom. Thereby, we aim at a better understanding of molecular
mechanisms and transfer our knowledge to higher organisms in order
to point to potential targets for biomedical research. Furthermore,
we have started to characterize bio-adhesive substances used by our
animals to attach to the substrate.
>> Research Highlights and Outlook: We have characterized adhesive
proteins of the flatworm Macrostomum lignano using a transcriptomic
and high throughput in situ screen approach combined with Mass
spectrometry, confocal- and electron microscopy, RNA interference,
specific antibodies and Lectin staining. Flatworms have evolved
adhesives adapted to different environments such as freshwater,
seawater and parasite attachment onto its host. We have started to
identify bio-adhesives also in the cnidarian polyp Hydra and the larvae
of sea squirts. In addition, we now expand our search for bio-adhesives
to 20 different flatworm species. It is the goal to understand the
mode of action of these molecules to enable the development of new
synthetic counterparts.
The cnidarian polyp Hydra and various flatworm species show an
unparalleled capacity for whole body regeneration. In order to understand
cellular aspects of regeneration, the formation of organized tissue layers
was analysed including changes in apical-basal and planar polarities of
epithelial cells at the closing wound. These behaviours are under molecular
control of conserved signalling pathways. We have concentrated on
the role of the Wnt/beta-Catenin signalling pathway. It is activated by
initial wound healing and then orchestrates a regeneration-specific gene
regulatory network involved in position-specific differentiation events.
Regeneration is commonly based on the action of naïve, stem cell-like
cells, and their behaviour is regulated by stemness-factors of the Myc
family. The Hydra genome encodes for four myc gene family members
similar to the genomes of vertebrates and mammals. In a long-going
effort and in strong collaboration with the CMBI group of Bister/Hartl/
Stefan, we study these ancestral forms of Myc factors, their structural
and biochemical properties in comparison to mammalian Myc factors,
and their different roles in decision making in the interstitial stem cell
lineage of Hydra. First data sets suggest actions in stem cell self-renewal,
cell multiplication, but also nerve cell differentiation.
>> Research GrantsFWF 25404; FWF 30347; J4071 Schrödinger-Program;
Marie Curie FP7 626525; 4x ÖAW DOC Fellowships;
EU-COST Action Networks TD0906, CA15216, CA16203
>> CoworkersUte Rothbächer (Associate Professor); Bernhard Egger
(Assistant Professor); Marcelo Rodrigues (postdoc);
Birgit Lengerer, Robert Pjeta, Julia Wunderer, Willi
Kari, Sabine Gufler, Fan Zheng (PhD students); Lena
Zitzelsberger, Belinda Artes, Veronika Prantl, Willi Sal-
venmoser, Thomas Ostermann, Hermine Hohensinner
(technical assistants).
Developmental biology and bioadhesion in basal animal model systems
Figure 1: Transgenic flatworms expressing fluorescent
proteins in different cell lineages.
Figure 2: Live image of polarity changes in the actin
cytoskeleton of Hydra epithelial cells in a bud just evaginating
towards the right.
36 37 Research summary Research summary
Pidder Jansen-Dürr
>> Research Department for Biomedical Aging Research
>> Goal: The group studies molecular mechanisms of cellular senescence
in human dermal fibroblasts and vascular endothelial cells, with a focus
is on the role of reactive oxygen species,. In addition, we are interested
in the role of mitochondrial proteins as regulators of senescence
and in age-associated metabolic dysregulation. We also investigate
the relationship between cellular senescence and age-associated
dysfunctions and diseases, such as skin aging and cardiovascular
diseases. Specific topics include the role of various stress signals on
cellular aging and age-associated pathologies of human tissues. We
also developed a new diagnostic test system for detection of HPV E7
proteins in cervical smears which was shown to be an efficient tool for
triage of HPV-positive women.
>> Background: The group has elucidated the role of oxidative stress
on senescence phenotypes of human endothelial cells and dermal
fibroblasts. To study molecular mechanisms underlying photoaging of
the skin, we have used a model for UVB induced cellular senescence of
human skin fibroblasts in which we identified protein quality control
mechanisms, such as proteasome activity and autophagy as new players
in cellular senescence of human dermal fibroblasts. We also developed
a quasi-physiological model for photoaging of the skin, consisting
of reconstructed human skin equivalents and used it to confirm the
role of protein quality control systems in skin aging. In addition,
the mitochondrial protein FAHD1 was identified as a new player in
regulation of mitochondrial function and cellular senescence; studies
of molecular mechanisms are underway.
>> Research Highlights and Outlook: Human Aging is modulated by a
complex network of interacting genetic pathways, which have been
elucidated through studies on lower eukaryotic model organisms,
such as yeast, flies and worms. However, not all mechanisms of aging
identified in animal models can be faithfully and completely translated
into human aging. Accordingly, there is a need to study aging processes
also in systems more closely mimicking human aging. In this respect,
the concept of cellular senescence has gained a lot of impact in the last
decade primarily by the discoveries that i) cellular senescence occurs in
aged organisms from primitive vertebrates up to humans and ii) the
recent demonstration that the accumulation of senescent cells in mouse
models drives the aging process.
In the Jansen-Dürr group, basic research and translational work is being
conducted on mechanisms of cellular senescence using model systems
reflecting aging of the human skin To this end we study human cells
which are grown in vitro to either achieve replicative senescence through
extended passaging (telomere shortening) or by using exogenous
stressors to drive cells in stress-induced premature senescence (SIPS). We
have extended previous findings aiming at a better understanding of
molecular mechanisms underlying UVB-induced senescence of diploid
human dermal fibroblasts (HDFs), an experimental model to study the
process of photoaging of the skin. Our data suggest that autophagy
is required for the establishment of the senescent phenotype in UVB-
treated HDFs and that inhibition of autophagy is sufficient to change
the cell fate from senescence to cell death by apoptosis (Fig. 1).
Studies in reconstructed skin equivalents revealed that UVB irradiation
triggers hallmarks of autophagy induction in the dermal layer. These
findings have potential implications for fundamental as well as
translational research into skin aging, in particular photoaging. (Fig. 2).
In a second project we have continued to characterize the function
of FAHD1, a newly discovered metabolic enzyme which is the first
eukaryotic member of the family of oxaloacetate decarboxylases. The
position of FAHD1 at the crossroads between carbohydrate metabolism
and fatty acid metabolism suggests that FAHD1 plays an important role
as metabolic key regulator. Phenotypic alterations of FAHD1 KO mice
relative to wild-type mice are currently being investigated. In an attempt
to speed up this analysis we also knocked down FAHD1 in human
umbilical vein endothelial cells (HUVEC). We found that depletion of
FAHD1 from human endothelial cells inhibited mitochondrial energy
metabolism and subsequently induced premature senescence. Whereas
senescence induced by FAHD1 depletion was not associated with
DNA damage, we noted a reduction of mitochondrial ATP-coupled
respiration associated with upregulation of the cdk inhibitor p21 (Fig. 3).
These results provide additional support to the growing evidence that
mitochondrial dysfunction can induce cellular senescence by metabolic
alterations independent of the DNA damage response pathway.
In collaboration with Mikrogen GmbH in Neuried, Germany, and a
clinical partner from Theassaloniki, Greece, we evaluated high-risk(hr)
HPVE7-protein detection as a triage method to colposcopy for hrHPV-
positive women, using a newly developed sandwich-ELISA-assay. This
assay could be a useful partner to HPV testing for cervical cancer
screening.
>> Research GrantsH2020 Marie Curie Actions RISE 691158 MediHealth,
EU FP7 305483 FRAILOMICS, Tiroler Wissenschaftsfond
UNI-0404/1625 ExomiR in OsteoAge, FFG Bridge 1
848474 Alpine Pflanzen in der Kosmetik, Swarowski
grants, industry grant Mikrogen GmbH, Neuried, Ger-
many, industry grant Cura Marketing GmbH, Innsbruck,
Austria, AWS Grant FAHD1 Inhibitors, COST Action
MITOEAGLE, PhD position LFUI Nachwuchsförderung
>> CoworkersHuaije Bu, Solmaz Etemad, Rafal Koziel, Maria Amalia
Cavinato Nascimento, Alexander Weiss (postdocs); Eva
Albertini, Giorgia Baraldo, Michele Petit, Christina
Metzger, Sophia Wedel (Ph.D. students); Max Holz-
knecht, Anne Buchmann (diploma students); Annabella
Pittl, Beata Szalka (technicians)
Molecular and cell biology of human aging
Figure 2: UVB-induced changes in the morphology of recon-
structed skin. Skin equivalents were submitted to UVB and
stained by hematoxylin–eosin for morphological analysis.
Figure 3: Depletion of oxaloacetate decarboxylase FAHD1
inhibits cell proliferation (A), induces cellular senescence in
human endothelial cells (B-C), and inhibits mitochondrial
function (D-E). SA-ß-gal activity was increased in FAHD1 KD
cells (B). Western blots showing the expression of FAHD1,
p53, p21, and γ-H2AX (C). Mitochondrial membrane poten-
tial (MMP) (D) and oxygen consumption rate (OCR) (E) were
reduced in FAHD1 KD cells.
Figure 1: UVB induces autophagy. (A) LC3-GFP expressing
HDFs were submitted to UVB and processed for confocal
microscopy. Wild type HDFs were subjected to the same
treatment and analyzed by (B) Western blot or (C) electron
microscopy. (A) Representative images of three indepen-
dent experiments showing the punctuation of LC3 upon
1, 2, 3, and 4 days of UVB treatment (D1, D2, D3 and D4,
respectively) and 3 days after the last UVB stress (D7). (B)
Representative Western blot showing the lipidation of LC3
upon UVB, where LC3-I corresponds to unlipidated and LC3-
II to lipidated form of the protein. (C) Electron micrograph
of cells submitted for 2 days to UVB irradiation and their
respective controls.
38 39 Research summary Research summary
Ilse Kranner
>> Goal: To deepen our understanding of plant metabolism with the
aim to identify key molecular switchboards that determine plant stress
response.
>> Background: Plants are the basis of life on Earth. All food is directly
or indirectly derived from plants, and plants also produce the oxygen
we breathe. In other words: no plants, no food, no oxygen. The current
climate change is accompanied by stress factors such as drought
and elevated temperature - with potentially deleterious effects on
agriculture and biodiversity, compromising food security for an ever-
increasing human population. Our research group is dedicated to
making significant contributions to unravelling the molecular basis of
plant stress response. In the past two years, much of our work focussed
on research into the impacts of climate change on seed production of
crop plants. In addition, we worked on wild plant species from extreme
environments and of micro-algae, to further increase our understanding
of plant response to environmental stress factors. We use mainly
hyphenated techniques (UHPLC-MS/MS, GC-MS/MS) in combination
with spectrophotometric methods to identify check points in plant
metabolism that trigger cell, tissue and plant fate – to die or to survive.
>> Research Highlights and Outlook: In this reporting period, much
effort was directed towards delivering the € 3 million FP7 project
“Impacts of Environmental Conditions on Seed Quality” (EcoSeed).
Coordinated by the University of Innsbruck, the consortium involved
11 partners from five European countries. The EcoSeed project was
dedicated to unravelling the effects on seed quality of the stresses
predicted to occur more frequently due to climate change: elevated
temperature and drought. Using a full omics approach complemented
by various biochemical and biophysical techniques, four main species
were investigated, the model plant Arabidopsis thaliana, and the
crops Brassica oleracea, Helianthus annuus and Hordeum vulgare. A
complementing study of bread wheat showed that seed germination
is intricately regulated by thiol-disulphide conversions involving the
tripeptide antioxidant glutathione (γ-glutamyl-cysteinyl-glycine) in a
tissue specific manner.
>> Research Grants
EU FP7 grant 311840, EU FP7 Marie Curie grant 328370
>> CoworkersThomas Roach; Wolfgang Stöggl (Assistant Professors);
Erwann Arc, Beatriz Fernández-Marín, Chae Sun Na, Fa-
bio Candotto Carniel (postdocs); Davide Gerna, Gregor
Pichler (PhD students); Julian Wimmer, Theresa Baur
(MSc students); Birgit Stenzel, Bettina Lehr, Siegfried
Aigner (technicians)
Plant biochemistry and metabolism
Figure 1: Schematic representation of the involvement of hydrogen peroxide (H2O2) and low-molecular-
weight (LMW) thiols and disulphides during bread wheat germination and early seedling growth.
From left to right, changes in LMW thiol- disulphides and H2O2 production rates in Triticum aestivum:
in a whole dry seed, seed structures isolated from non-germinated seeds after 15h from the onset of
seed water uptake, and seed structures isolated from germinated seeds after 15 and 48h. Whole dry
seed, endosperm including aleurone (large oval), and embryo or seedling (small oval) are divided by
vertical lines. These lines delimit areas proportional to the concentrations of total glutathione [i.e.
GSH (glutathione) + GSSG (glutathione disulphide)], area left of line) and cyst(e)ine [i.e. Cys (cysteine)
+ CySS, (cysteine) area right of line], in the respective seed structure. The redox states (Ehcs in mV) of
total glutathione and cyst(e)ine are indicated by the blue-to-red (reducing-to-oxidising) shadings of
each area, as shown by the bottom right scale. Yellow background shadings indicate the rates of H2O2
production (nmol g-1 DW s-1), as shown by the bottom left scale. The dashed vertical line separates
seeds from seedlings. Taken from Gerna et al. Free Radical Research 51:6, 568-581.
>> Department of Botany
40 41 Research summary
Chemistry, chemical and structural biology of the pigments of life
Bernhard Kräutler and Thomas Müller
>> Department of Organic Chemistry
Research summary
crystal structure was the first of a metal analogue of a natural B12-
derivative. The ‘mother’ ligand of vitamin B12, hydrogenobyric acid,
gave first insights into the intriguing capacity of the ‘contracted’ corrin
macrocycle for binding and activating transition metals. AdoRhbl and
other ‘antivitamins B12’ are inhibitors of B12-dependent enzymes and
interfere with B12-riboswitches, as predicted.
Our lab has also pioneered studies on the structure and chemistry of
chlorophyll catabolites from higher plants, named ‘phyllobilins’. In the
context of such studies we have become interested in the colored natural
‘phyllochromobilins’, which are strikingly similar, structurally, to bilins
derived from heme catabolism. Finding evidence for (still hypothetical)
physiological effects of phyllobilins in plants, animals and humans is
one of the goals of this research. Furthermore, we have developed
MALDI-TOF and DESI mass spectrometry imaging methodology for the
2D localization and identification of biologically relevant molecules in
biological tissue. The imaging studies on chlorophyll breakdown also
involved students from local partner high schools (’Sparkling Science’
project). Exciting results as well as simple experiments in this context
were presented to a broader public at the “Lange Nacht der Forschung
2016”.
>> Research GrantsFWF P-28522, FWF P-28892, Sparkling Science project
SPA/04-140/INDIAN SUMMER IN TYROL.
>> CoworkersCh. Li, S. Moser, F. Widner (postdocs), S. Murtaza (ÖAD
guest scientist), T. Erhart, C. Kieninger C. Meisenbichler,
M. Scherl, C. Vergeiner, St. Vergeiner (Ph.D. students), C.
Brenig, M. Huber, J. Mayr, P. Moser, S. Schatz, P. Singe-
wald (diploma students), M. Schäfer (master student),
G. Scherzer (chemo-technician).
>> Goal: To gain knowledge on the chemistry, on biological roles and
bio-molecular interactions of the porphyrinoid ‘pigments of life’, and
to apply this in biology and medicine.
>> Background: A large part of our research concerns the ‘pigments of
life’, which have crucial and diverse roles in cells, e.g. as cofactors in
enzymes, in biological processes driven by solar light and as metabolites
regulating expression of genes. They comprise the porphyrinoids
(heme, chlorophyll, and corrinoids) and linear tetrapyrroles, which
result from breakdown of heme and of chlorophyll. Porphyrinoids owe
their important roles in Nature to their unique molecular properties
and some of their basic structures are assumed to have pre-biotic origin.
Frequently they are functional complements to biological macro-
molecules, as coenzymes or as structuring and regulating ligands, e.g.,
in riboswitches. Our approach is geared at providing chemical insights
for the natural biological roles of the ‘porphyrinoid pigments of life’, as
well as at exploring their effects in important cellular processes.
>> Research Highlights and Outlook:Our lab has made key contributions
to the chemistry of vitamin B12-derivatives, in particular as part of
our recent program on ‘antivitamins B12’, metabolically inert B12-
derivatives. This research will help us learn more about mechanisms
of B12-dependent metabolic processes in microorganisms, animals and
humans, and in looking at still enigmatic effects of B12-deficiency by B12-
chemical biological approaches. In this context, we have developed a
synthetic approach towards a group of B12-mimics that contain transition
metals other than the B12’s own cobalt (Figure 1). A combination of
biological and chemical total synthesis was established. A first example
was AdoRhbl, the unnatural rhodium analogue of coenzyme B12. Its
Figure 1: Natural Vitamin B12-derivatives are intimately as-
sociated with their cobalt-center (the element cobalt was
named by German miners as the undesirable contamination
put into various ores by a mine ‘Kobold’).
Figure 3: 2D Localization and identification of a chlorophyll
degradation product in senescent leaves of fern using MAL-
DI-TOF mass spectrometry imaging.
Figure 2: Phyllochromobilins, the colored catabolites of chlo-
rophyll, are components of the fall colors in the leaves of de-
ciduous tree
42 43 Research summary
>> Goal: The focus of our work lies on the characterization of key
features of biomolecular recognition by employing a wide range of
state of the art computational methods and developing new methods
to extract and profile key traits of biomolecules.
>> Background: Molecular recognition is a vital aspect of nearly all
biological processes, however, understanding them on a microscopical
level is not trivial. One of the most important findings of the last few
decades is the fact that biomolecules cannot be described as a static
entity. In other words, looking at a single static crystal structure is not
enough to understand the biological mechanisms of a molecule. The
studying of the dynamics of the protein and describing it as a structural
ensemble is essential for understanding the proteins’ characteristics
and functions.
The use of theoretical methods such as molecular modelling, molecular
dynamics or docking has become more and more important in the past.
It has long passed from being solely supplemental to experiments to an
Klaus R. Liedl and Daniela Schuster
>> Department of General, Inorganic and Theoretical Chemistry
Research summary
independent research field. It not only enables a better understanding
of experimental findings, but also creates insights in macromolecular
properties inaccessible to experiments.
>> Research Highlights and Outlook: Hydrophobicity plays a key role
in biomolecular recognition processes. Although there are various
experimental and theoretical techniques which are widely used, they
provide only little information about water dynamics and entropic
effects. We developed a new metric which derives spatial hydrophobicity
values directly from the dynamics of the water molecules in molecular
dynamics simulations.
Classical molecular dynamics simulations are currently restricted to the
nanosecond to microsecond timescale because of hardware limitations.
Most of the available enhanced sampling techniques use a biased potential
energy function, which makes it difficult to extract dynamical properties
of the unbiased ensemble. Following up on our previously presented
metric of the dihedral entropies we developed a metric which allows
us to obtain reweighted dihedral entropies from accelerated molecular
dynamics simulations. Thus, we can capture dynamics happening on the
millisecond timescale with microsecond long simulations.
In close collaboration with the Tollinger group as well as the lab
of Richard Weiss at the University of Salzburg we focus on the
characterization of the dynamical properties of plant pollen allergens.
Employing our previously presented dihedral entropy metric, we were
able to link molecular flexibilities of the major birch pollen allergen Bet
v 1a, captured with molecular dynamics simulations, to experimental
thermal and proteolytic stabilities. We currently investigate these
dynamics on extended timescales using our aforementioned metric of
calculating reweighted dihedral entropies from accelerated molecular
dynamics simulations.
>> Research GrantsFWF P26997, FWF P30565, FWF P30737, FWF P26782,
FFG Bridge EARLYSNOW, FWF/TWF Lise-Meitner grant
Maren Podewitz, ÖAW DOC/Birgit Waldner, ÖAD
FR9/2017, ÖAD ICM-2017-07338 grant to Navista Sri
Octa Ujiantari, CAPES Science Without Borders, bmwfw
PRIZE prototype grant, Boehringer Ingelheim
>> CoworkersMaren Podewitz, Michael Schauperl, Veronika Temml
(postdocs), Stefania Monteleone, Wang Yin, Birgit
Waldner, Anna S. Kamenik, Johannes R. Löffler, Ursula
Kahler, Monica Fernandez Quintero, Johannes Kraml,
Florian Hofer, Muhammad Akram, Sonja Herdlinger,
Fabian Mayr, Navista Sri Octa Ujiantari (Ph.D. students),
Emanuel Ehmki, Melanie Wachter, Franz Waibl, Radu
Talmazan, Dennis Dinu, Theresa Steinacher, Elisabeth
Vorhofer, Erika Strieder, Ralph Kandel, Sandra Wagner,
Christian Vieider, Alois Dalkner (MSc. Students), Alexan-
der Spinn, Lisa Retter (system administrator)
>> Department of Pharmacy, Pharmaceutical Chemistry
Protein dynamics and biomolecular recognition
44 45 Research summary
Developmental biology
Dirk Meyer and Pia Aanstad
>> Goal: To understand molecular mechanisms underlying regulation
and coordination of fate specification, differentiation, proliferation
and migration in vertebrate embryogenesis and regeneration, with a
focus on gastrulation and pancreas formation.
>> Background: Development of endodermal organs such as the pancreas
requires complex and still poorly understood interactions of signaling
pathways in order to guarantee the temporary and spatially correct
coordination of cell proliferation, migration and differentiation. In our
research we study three specific aspects of endoderm formation by applying
genetics, molecular and in vivo imaging approaches in zebrafish: (1) the
functions of TGF-beta regulated transcription factors in early endodermal
induction, (2) the role and regulation of Hedgehog (Hh) signaling in
endodermal patterning, cell proliferation and cell migration and (3) the
molecular mechanisms underlying pancreatic islet cell formation and
maturation during embryonic development and regeneration.
>> Research Highlights and Outlook: Hh-signaling: In collaboration
with Eduard Stefan (Biochemistry) we showed that the orphan receptor
Gpr161 localises the Hh-signalling inhibitor PKA to the primary cilium,
the main site of Hh signal transduction.
>> Department of Molecular Biology
Research summary
Pancreatic regeneration: We established new tools for efficient
conditional pancreatic cell ablation in zebrafish. Using these tools we
identified a novel precursor population for acinar cell regeneration and
in collaboration with Stefan Kubicek (CeMM,/Vienna) we determined
activities of the malaria drug artemether on improved beta-cell
regeneration.
Islet development: High resolution imaging of emerging endocrine cells
revealed until now unappreciated dynamic motility. By applying novel
quantitative assays, we determined that this motility is regulated by
PI3K and GPCR signaling, and is important for islet formation.
Diabetes genes: Work on zebrafish homologs of the neonatal diabetes
and sacral agenesis gene MNX1 revealed irx1 as a direct Mnx target
and a requirement for Mnx/Irx interaction in kidney formation. Further
investigations make use of our recently established pdx1 and mnx1
zebrafish mutants as diabetes model to uncover mechanisms behind
long-term deleterious effects of hyperglycemia. In international
collaborative studies, we are defining the progression and mechanisms
of diabetes-induced effects on tissue damage and on regeneration
capacities.
>> Research GrantsFWF P25659, FWF P27338, FWF P30038, TWF 236277,
DOC 24701
>> CoworkersRobin Kimmel (Assistant Professor); Patrick Fischer,
Armin Wilfinger (postdoc); Julia Freudenblum, Réka
Lorincz, Dominik Regele, Nicole Schmitner, Philipp
Tschaikner, Onur Temocin (Ph.D. Students), Greta
Ebnicher, Gerald Lerchbaumer, Fabian Martin (master
students); Eve Holtorf, Dzenana Tufegdzic, Sonja Töch-
terle (technician)
46 47 Research summary
Ronald Micura
>> Goal: To obtain an integrated understanding of RNA modifi cation
and RNA mediated regula tion and catalysis.
>> Background: For many years it was believed that there were only
a small number of non-protein-coding RNAs (ncRNAs) and that
they (tRNAs, rRNAs, spliceosomal RNAs) were involved primarily in
assembling the predominant protein macromolecules. Even large RNA
classes, such as snoRNAs and microRNAs, remained undetected. In
recent years, it became apparent that ncRNAs are numerous and that
their cellular functions – on their own or in complex with proteins – are
diverse and important. Our lab aims at a comprehensive molecular
understanding of cellular processes involving ncRNAs, in particular of
gene regulation by riboswitches but also of traditional ncRNAs such
as encountered during ribosomal translation. Our lab has a major
focus on the chemical synthesis of RNA allowing the introduction of
site-specific modifications, naturally occurring and artificial ones. This
enables us to evaluate their structure and function by a great diversity
of chemical and biophysical methods, with a focus on chemical and
biochemical probing techniques, fluorescence spectroscopy (including
single molecule imaging), NMR spectroscopy, and X-ray crystallography.
>> Research Highlights and Outlook: The discovery of four novel self-
cleaving ribozyme classes in the years 2014 and 2015 has opened a unique
opportunity to undertake structure-function studies to comparatively
assess the architectural diversity, catalytic cores and mechanism of
action. To this end, we have provided insights into the topological
>> Department of Organic Chemistry
Research summary
constraints contributing to catalysis of these ribozymes by chemical,
structural, and biochemical studies. One of the new self-cleaving RNAs
contains the so-called pistol motif revealed by comparative genomic
analysis; its precise biological function is yet unknown. Our recent
crystal structure of a pre-catalytic state of this RNA shows guanosine
G40 and adenosine A32 close to the G53–U54 cleavage site (see
graphics a). While the N1 of G40 is within 3.4 Å of the G53 2’-OH group
that attacks the scissile phosphate (see graphics b), thus suggesting
a direct role in general acid–base catalysis, the function of A32 was
less clear. We found evidence from atom-specific mutagenesis that
neither the N1 nor N3 base positions of A32 are involved in catalysis. By
contrast, the ribose 2’-OH of A32 turned out to be crucial for the proper
positioning of G40 through a H-bond network that involves G42 as a
bridging unit between A32 and G40. We also found that disruption of
the inner-sphere coordination of the active-site Mg2+ cation to N7 of
G33 makes the ribozyme drastically slower. A mechanistic scenario with
A32 playing a major structural role and hydrated Mg2+ playing a major
catalytic role in cleavage, was therefore disclosed.
Another aim of our lab is to understand the functional roles of RNA
in the cell. Consequently, it is essential to elucidate the dynamics of
their production, processing and decay. A recent method for assessing
mRNA dynamics is metabolic labeling with 4-thiouridine (4sU), followed
by thio-selective attachment of affinity tags. Detection of labeled
transcripts by affinity purification and hybridization to microarrays or
by deep sequencing then reveals RNA expression levels. Our own efforts
focused on the development of a novel sequencing method (TUC-seq)
that eliminates affinity purification and allows for direct assessment
of 4sU-labeled RNA. It employs an OsO4-mediated transformation to
convert 4sU into cytosine. We exemplified the utility of the new method
for verification of endogenous 4sU in tRNAs and for the detection of
pulse-labeled mRNA of seven selected genes in mammalian cells to
determine the relative abundance of the new transcripts. The results
prove TUC-seq as a straight-forward and highly versatile method for
studies of cellular RNA dynamics.
Finally, the continuous development of synthetic methods for efficient
access to chemically modified RNA with novel functional properties is in
the center of our research interests.
>> Research GrantsFWF (I1040, P27947), SNF (Early Postdoc.Mobility), FFG
(West-Austrian BioNMR)
>> CoworkersJennifer Gebetsberger, Thomas Amort (postdocs);
Marina Frener, Lukas Jud, Sandro Neuner, Christian
Riml, Nikola Vušurović, Catherina Gasser, Elisabeth
Fuchs, Elisabeth Mairhofer, Christoph Falschlunger, Eva
Neuner, Josef Leiter, Maximilian Himmelstoß (Ph.D.);
Daniel Fellner (technician)
Synthesis, structure, and function of non-coding RNAs
48 49 Research summary
Cell physiology and gene regulation
Bernd Pelster, Adolf Sandbichler, Thorsten Schwerte
>> Goal: Our research aims at the analysis of molecular and structural
mechanisms as well as genetic control pathways of physiological
phenomena.
>> Background: The adaptation of animals to changing environmental
conditions includes adaptations at the cellular and molecular level in
order to maintain homeostasis of energy metabolism, ion regulation
and acid base balance. Changing oxygen partial pressures, variable light
regimes or exposure to toxicants, for example, are readily perceived by
animals of different developmental stage. In our work we focus on the
large scale changes in the overall gene expression patterns induced by
these environmental perturbations, typically resulting in characteristic
modifications in metabolic defense reactions, activity patterns, oxygen
transport capacities and overall metabolic or ion regulatory activity. Of
particular interest are the control mechanisms guiding these expression
changes at the transcriptional and translational level. The sophisticated
interconnection and interaction between the different regulatory
pathways is addressed using appropriate invertebrate and vertebrate
model animals. The data, obtained at the cellular, molecular and organ
level, are discussed with respect to the possible adaptational benefit for
the whole organism.
>> Research Highlights and Outlook: The mutant line POPDC1S201F of
the zebrafish is characterized by muscular dystrophy and arrhythmia
Abb. 2: Cadmium exposure leads to phosphorylation of ATF and an increased expression of wMT-
2. The expression of wMT-2 is, however, suppressed when Cd-exposed earthworms are in addition
injured.
>> Department of Zoology
Research summary
by affecting protein trafficking. Characterization of the phenotype of
this mutant showed that it could be a disease model for the analysis of
the genetic background for muscular dystrophy and heart dysfunction.
In our research focusing on cellular redox balance and it‘s role in
circadian timekeeping and hypoxia stress response we established the
use of new and improved fluorescent protein sensors enabling us to
measure the redox balance in different cellular organelles and their
contribution to whole cell redox equilibrium. The cell physiological
consequences of redox alterations and their effect on cellular oxygen
consumption and glycolytic metabolism are being addressed.
Our studies demonstrated that remote levels of heavy metal stress
already cause epigenetic changes in earthworms, which persist even
after the stressor has long disappeared. Moreover, we were able to
reveal that wound repair suppresses specific detoxification mechanisms,
which might demonstrate a link between stress response and immunity.
During the spawning migration the European eel is exposed to extreme
hydrostatic pressures, and in a process named silvering eels prepare for
this migration. Silvering encompasses significant modifications at the
transcriptional level in swimbladder tissue to adjust gas permeability,
metabolism and ion transport capacities to elevated hydrostatic
pressure. Infection of the swimbladder with the nematode Anguillicola
crassus significantly impairs these silvering induced changes in
swimbladder tissue, which may compromise the spawning migration.
By an improved sequencing the genome assembly for the European eel
could be significantly improved.
>> Research GrantsFWF P26363-B25; FWF I2984-B25; §27 Projekt DB-Nr:
215529; Nachwuchsförderung Projekt Nr.: 226115;
Förderung des Vizerektorats für Forschung Nr.: 235916;
Lise Meitner (M2262-BBL)
>> CoworkersMartina Höckner (Associate Professor); Birgit Fiechtner,
Bettina Peer (technicians); Maja Šrut, Gabriel
Schneebauer, Sigrid Zobl (postdocs); Victoria Drechsel
(PhD student)
Abb. 1: (Top) Anguillicola crassus, ~70 parasites of a single
swimbladder in a 90 mm petri dish; European eel with
position of the swimbladder (red), (Middle) swimbladder;
scale bar represents 10 mm, (Bottom) Enzymes and
metabolites (blue) involved in ROS detoxification in gas
gland cells to avoid various oxidative damages (red);
superoxide dismutase (SOD), glutathione peroxidase (GPx),
glutathione reductase (GR), reduced glutathione (GSH),
oxidized glutathione (GSSG), malondialdehyde (MDA).
50 51 Research summary
Structure-functional activity relationship investigations on ligands interacting with opioid receptors
Helmut Schmidhammer and Mariana Spetea
>> Goal: To perform basic and applied research as theoretical and ex-
perimental work in order to advance the current understanding on
structure-functional activity relationships for ligands interacting with
opioid receptors.
>> Background: The kappa opioid receptor (KOR) and its endogenous
ligand, dynorphin, have received major attention in past years due to
their involvement in a variety of physiological and behavioral responses
(i.e. pain, stress, motivation, emotion, cognition, reward). Dysregulation
of the KOR/dynorphin system is responsible for the development and
maintenance of neuropsychiatric conditions (Figure 1A). Preclinical
and clinical evidence indicates that this system contributes to symptom
clusters that are shared by many neuropsychiatric disorders, and thus
to their comorbidity (Figure 1A). Differential modulation of the KOR
is regarded as a promising strategy for developing therapies for pain,
drug addiction, mood disorders, neurological conditions, and itching
skin diseases by either activating or blocking the receptor (Figure 1B).
Although KOR activation does not produce dependence, euphoria, or
leads to respiratory suppression, it induces dysphoria, sedation and
psychotomimesis. The concept of biased signaling has come forward
with the realization that the KOR activates G protein-dependent and
independent signaling networks. Biased ligands can alter the linkage
>> Department of Pharmacy, Pharmaceutical Chemistry
Research summary
between G protein-dependent (responsible for beneficial effects, e.g.
analgesia) and β-arrestin2-dependent (responsible for adverse effects)
pathways with important therapeutic implications.
>> Research Highlights and Outlook: Our research group has generated
new KOR ligands as small molecules featuring a diphenethylamine
scaffold (Figure 1C). Multidisciplinary, synergistic approaches ranging
from molecular in silico and in vitro levels to in vivo systems were
combined by linking bioinformatics and computational systems
with biochemical, pharmacological and disease animal models. Our
lab established for the new KOR ligands: (i) a KOR target-oriented
pharmacological profile (high affinity, selectivity, full/partial agonism
or antagonism at the KOR, and biased signaling towards G protein
activation), (ii) antinociceptive efficacy in thermal nociceptive and
visceral mouse pain models, (iii) antiseizure efficacy in prodynorphin-
knockout mice, (iv) anticonvulsant efficacy in a mouse model of
temporal lobe epilepsy, and (v) reduced propensity for unwanted
behavioral and side effects (i.e. aversion, sedation, motor dysfunction).
Structural, molecular and functional mechanisms that can form the
basis for such an improvement of the benefit/risk index were analyzed
in detail. The emerged findings underline the strong potential of the
developed KOR ligands as new and improved therapeutics for human
diseases. Furthermore, the emerged G protein biased KOR ligands
may be exploited for use as research tools for understanding the basic
biology of KOR signaling, and most important to have a tremendous
prospective for innovative drug discovery strategies.
>> Research GrantsFWF I2463, FWF P30430, TWF UNI-0404/1596 (TWF),
Aktion D. Swarovski KG 2014 P7400-029-011, ÖAD-WTZ
FR12/2016.
>> CoworkersAquilino Lantero, Stefan Noha (postdocs); Filippo
Erli, Maria Dumitrascuta (Ph.D. students); Michael
Mairegger, Andreas Ritsch, Lea Schläfer, Birgit
Steinkellner, Dominik Bucher, Katja Walker, Lisa-Marie
Watzke (diploma students)
Figure 1: The KOR is a key target for developing pharmacotherapies for neuropsychiatric disorders.
(A) Dysfunction of the KOR/dynorphin system is responsible for the development of neuropsychiatric
disorders and their comorbidity. (B) Differential modulation (activation or inhibition) of the
KOR is regarded as a promising strategy for developing therapies for pain, addiction, mood and
neurological disorders. (C) Generation of a new class of KOR ligands as small molecules featuring
a diphenethylamine scaffold, which evolved as G protein KOR biased agonists, partial agonists and
antagonists.
52 53 Research summary Research summary
Rainer Schneider and Bernhard Auer
>> Department of Biochemistry
>> Goal: We are studying targeted proteolysis in a wide range of aspects
from the human ubiquitin system to specific directed evolution of
proteases for the development and production of drugs to treat human
diseases.
>> Background: One of our main research fields covers the structure
and functions of the MID1 protein complex, an important player in the
regulation of phosphorylation and translational control. The ubiquitin
ligase MID1 targets the catalytic subunit of Protein Phosphatase 2A
(PP2A) for proteolytic degradation. Lack of human MID1 causes Opitz
syndrome (midline defect with cognitive impairment). Furthermore
MID1 has an impact on mTOR signaling, alterations of which are
involved in several intellectual disability and epilepsy syndromes. As
we are also involved in a study on a novel, potentially mTOR-related
epilepsy syndrome caused by a protease-mutation found in a family
in Tyrol, we are interested to study the impact mTOR exerts on the
local protein homeostasis in hippocampal synaptosomes of mice models
reflecting such mTOR-related syndromes and how this process might be
regulated by specific protease activities.
Additionally, we are engaged in the development of biotechnological
tools namely novel proteases to improve the biotechnological
production of biogenic drugs.
>> Research Highlights and Outlook: With our central research on the
structure and function of the MID1 complex and the study of movement
disorder diseases as well as with our biotechnological/bioinformatic
approaches we achieved several major goals:
a) After we had identified MID1 as an important player in the
development of prostate cancer together with groups from the Medical
University of Innsbruck, Berlin, Bonn and Dundee, we were able to
identify small substance modulators of MID1 which are potential new
drugs that could interfere with cancer and neurodegeneration.
We found a potential anti prostate cancer drug that ablates the
translation enhancing effect of MID1 on AR-mRNA, namely Metformin,
which is a safe drug that is used extensively since 60 years to treat
type 2 diabetes mellitus. Our finding provides an explanation for the
recently found inverse correlation between Metformin-treatment and
cancer incidence.
In further searches for small substances targeting the MID1 complex,
we recently identified resveratrol, the famous polyphenol found in
red wine, as an inhibitor of the MID1-pathway that can trigger the
dephosphorylation of hyperphosphorylated tau as found in Alzheimer´s
disease. This finding was achieved in cooperations with the groups of
Sybille Krauss at the DZNE in Bonn and Susann Schweiger in Mainz (1).
Together with an EU-consortium (ERANET NEURON) including groups
from Milan, Berlin and Mainz we are studying several syndromes that
are associated with altered MID1/mTOR signaling and present with
epilepsy and/or intellectual disabilities. Together with the proteomics
platform from the Medical University of Innsbruck (Lindner group)
we try to elucidate altered expression profiles of hippocampal
synaptosomes from different MID1- , TSC2- and Rett-syndrome mouse
models to decipher the impact of mTOR in these diseases.
Furthermore, in cooperation with the department of Neurology at the
Medical University of Innsbruck we are engaged in several research
projects concerning movement disorder diseases. In a Tyrolian case
of myoclonus epilepsy we were now able to identify the respective
mutated gene, a protease which seems to influence mTOR signaling,
thus connecting another epilepsy syndrome with this pathway.
b) Under the framework of the Austrian Center of Industrial
Biotechnology (ACIB) we are working successfully on several projects
(strategic projects and company projects) in which we are developing
novel biotechnological tools for up- and downstream processing (2,
patents pending).
c) Additionally, we are using bioinformatic approaches to understand
the structure/function/evolution relationships between proteins. In this
respect we are analyzing highly variable viral proteins (Coronaviruses)
and peptides that modulate the immune system like Thymulin (3).
>> Research GrantsFWF-TRP002330, FFG-ACIB(K2) P25.081 (Company
Project), FFG-ACIB P25.111 (Strategic Project), EFACTS-
EU242193, FWF- I 1570-B13 (ERANET NEURON), MFF253
>> CoworkersRainer Schneider (Project leader), Sandra Pfurtscheller,
Kamil Rolski, Petra Engele, Christina Kröß, Alexander
Mödlhammer, Kevin Vince (PhD students), Simon Hofer,
Stefan Felderer, Bernhard Sprenger (diploma students)
Figure 1: MID1 is a modulator of PP2Ac influencing several
major players and pathways
Targeted proteolysis in human diseases and its impact on drug development and production
54 55 Research summary
Cell signaling in chronic CNS disorders
Nicolas Singewald, Alexandra Koschak and Jörg Striessnig
The major research areas of the CMBI project leaders in the Department of
Pharmacology and Toxicology the pathophysiology of neuropsychiatric
disorders (in particular fear, anxiety, autism spectrum disorders and
Parkinson’s Disease), retinal disorders and endocrine disease (such as
primary hyperaldosteronism and diabetes mellitus). Most of this work
is embedded in the FWF-funded Spezialforschungsbereich SFB F44 “Cell
signaling in chronic CNS disorders” (2011-2019), the doctoral programs
Molecular Cell Biology and Oncology (MCBO, 2005-2018), Signal
Processing in Neurons (SPIN), the recently approved doc.funds network
“CavX” and a European Training Network.
Neuropharmacology group (N. Singewald)
>> Goal: Our main aim is to identify novel drug targets that facilitate
anxiety- and fear inhibitory mechanisms, including fear extinction, to
guide improved treatment strategies for different forms of anxiety
disorders, which are the most prevalent of all mental disorders.
>> Background: Effective long-term treatment for fear and anxiety-
related disorders is a continuing challenge. One emerging treatment
strategy is combining exposure-based cognitive behavioral therapy with
extinction-facilitating drugs. Current research identified facilitation of
dopaminergic signaling and/or modulation of epigenetic mechanism,
in particular histone deacetylases and microRNAs, as means to boost
and normalize aberrant fear-inhibitory learning, which is common in
human anxiety disorders.
>> Research Highlights and Outlook: On the basis of these results we
are now gaining detailed insight into which dopamine receptors and
brain region(s) mediate the normalization of impaired fear extinction
learning by using pharmacological, optogenetic and chemogenetic
approaches. One of our prominent findings was that the microRNA
mir-144 is involved in orchestrating the rescue of impaired extinction
learning. We are currently establishing whether this and other
microRNAs can be used as bio-markers/novel therapeutic targets for
the treatment of anxiety disorders. In addition, we aim to improve the
tolerability of exposure based therapy by novel non-sedative anxiolytic
drugs which do not impair extinction learning. Neuropeptide S (NPS)
is one such promising candidate. We currently pursue identification
of NPS-receptor agonists by virtual screening and in-vitro studies in
collaboration with CMBI groups of H. Stuppner, D. Schuster and R. Gust.
>> Department of Pharmacy, Pharmacology and Toxicology
Research summary
>> Research GrantsFWF SFB-F4401, FWF SFB-F4402, FWF SFB-F4410,
FWF P24785, FWF P25014, FWF P25375, FWF
W1101, FWF W1206, FWF P26881, FWF P27809,
FWF I2433, ITN Horizon 2020 “switchboard”, Tiroler
Wissenschaftsförderung (TWF) ZAP740036, Univ. of
Innsbruck (FLD #242170, #194449, #217264, #214976),
County of Tyrol (FLD #225100, #152787), H. Lundbeck
A/S, FWF P27852, FWF P28146, FWF I02215
>> Scientific coworkers (2016/2017)Petronel Tuluc, Thomas Fenzl, Alexandra Pinggera,
Nadja Hofer, Nadine J Ortner, Kathrin Kähler, Hartwig
Seitter, Karl Ebner, Maria Kharitonova, Simone Sartori,
Anupam Sah, Conor Murphy, Verena Maurer, Thomas
Keil, Veronica Fontebasso, Sinead Rooney, Michael
Oberhauser, Lucia Zanetti, Irem Kilicarslan, Anita Siller,
Eva Maria Fritz, Joseph Moreno Rius
Molecular Pharmacology group (J. Striessnig)
>> Goal: This group tries to better understand the physiological and
pathophysiological role of voltage gated Ca2+ channels (VGCCs) in
human disease. Recently, a major focus was on autism spectrum
disorders (ASD) and Parkinson’s Disease (PD).
>> Background: Excessive Ca2+ signalling can be harmful for cell function
and survival. We have recently found that excessive cellular Ca2+ entry
into neurons through voltage-gated Ca2+ channels may also cause CNS
diseases, such as migraine or autism.
>> Research Highlights and Outlook: We have characterized sporadic
mutations in the CACNA1D gene in patients with autism with our
without neurological disorders, such as epilepsy. From six such mutations
in seven patients we now learned that all cause characteristic gating
changes of the channel that allow enhanced Ca2+ entry in neurons.
Although only few patients with these mutations are described, Ca2+
channel blockers may be useful to prevent excessive signalling. We
therefore tested if clinically used Ca2+ channel blockers inhibit these
(so-called Cav1.3 L-type) calcium channels during simulated neuronal
activity (Figure). Our experiments suggest that the required therapeutic
dose would be slightly higher than for blood pressure lowering. This
hypothesis is now tested in a new animal model containing one of
these mutations.
Molecular sensory physiology (A. Koschak)
>> Goal: Mapping the role of L-type calcium channels in retinal diseases.
>> Background: In photoreceptors Cav1.4 L-type calcium channels
(LTCCs) serve as the predominant source for Ca2+ entry to allow sustained
release of glutamate at their synaptic sites. Mutations in the encoding
CACNA1F gene have been associated with a number of human retinal
diseases, such as congenital stationary night blindness type 2 (CSNB2).
>> Research Highlights and Outlook: We investigate mice carrying a
CSNB2 mutation which reproduces the functional phenotype described
in a family with the corresponding mutation. We showed that similar
to human CSNB2 both rod and cone signaling pathways are affected.
We demonstrated a defect in neuronal wiring in diseased mice evident
as formation of aberrant synaptic contacts and show remodeling of
second order neurons. We currently investigate if Cav1.4 might also
be functionally relevant also in bipolar cells by generating cell-type
specific Cav1.4 knock out mice.
Figure: The Figure shows Ca2+ inward current through
Cav1.3 L-type Ca2+ channels (stably expressed in HEK-293
cells) during electrical activity simulating the continuous
activity of a dopamine neuron in the substantia nigra of
the midbrain. We tested if isradipine, a Ca2+ channel blocker
currently clinically used as antihypertensive, can inhibit
these channels at nanomolar concentrations (20 nM, 3 µM).
Inhibition of Cav1.3 channels occurred with IC50 values in the
low nanomolar range that should allow the in vivo inhibition
of these channels by very high therapeutic doses of this drug
in patients.
56 57 Research summary
Pharmacognosy – combining traditional knowledge with innovation
Markus Ganzera and Hermann Stuppner
>> Goal: Based on the traditional use of medicinal plants from around
the globe, modern approaches concerning the identification and bioac-
tivity of therein found natural products, their analysis in crude drugs,
products or biological samples by innovative techniques, and the use of
in-silico activity prediction tools are the main targets of research.
>> Background: It is more likely that natural products show bioactivity,
because their biosynthesis proceeds with sequential binding of the
biosynthetic intermediates to different proteins. Thus, they are
promising leads for drug discovery, and not surprisingly the vast majority
of commercial drugs actually derive from them. Pharmacognosy, which
focuses on the study of medicinal drugs derived from plants, has
evolved from its classical, microscopy based origin to a modern and
interdisciplinary area of research within the last decades. Today the
covered topics range from the isolation and structural characterization
of natural products, to the development of analytical tools for
their qualitative and quantitative assessment, studies investigating
metabolism or pharmacological properties by conventional or
computer based approaches, or ecologically relevant questions. At
the Department of Pharmacy / Pharmacognosy all of these aspects
are covered and numerous publications as well as many successfully
conducted research projects indicate an outstanding position in natural
products research. Experienced staff scientists, motivated PhD students
and a broad range of available equipment (LC-MS, GC-MS, CE-MS, LC-
NMR, SFC-MS, 3D-databases, etc.) are the reason for this situation.
>> Research Highlights and Outlook: One main target of research is the
evaluation of alternative, innovative techniques for natural products
analysis. Supercritical Fluid Chromatography (SFC) showed to be an
interesting option, as for example the first successful separation
of coumarins in Angelica dahurica and Ammi visnaga, or that of six
lactones in Piper methysticum (fig. 1) could be achieved. All methods
impress with extremely fast separations in the range of a few minutes
only. In an FWF funded project, novel stationary phases for Capillary
Electrochromatography (CEC) are evaluated. In cooperation with the
Department for Analytical Chemistry and Radiochemistry, an innovative
zwitterionic monolithic phase was developed and applied for the
>> Department of Pharmacy, Pharmacognosy
Research summary
>> Research GrantsFWF P296710, FWF P293050, FWF P26917, FWF P24168,
FWF T942, FFG Alpine Kosmezeutika P7400-012-048, FFG
VASCage P7400-012-047, BMWF P7400-012-052, EU-FP7
IAPP – NATPROTEC P7400-012-037, EU H2020-MSCA-RISE
- MediHealth P7400-012-049, EUREGIO ZFIPN000550,
EUREGIO ZFIPN000310
>> CoworkersStefan Schwaiger, Sonja Sturm, Birgit Waltenberger
(research associates); Anja Hartmann, Bianka Siewert,
Veronika Temml (postdocs); Nora Engels, Gibitz-Eisath
Nora, Gratl Verena, Stefanie Hofer, Stefan Loos, Fabian
Mayr, Simon Moosmang, Adele Murauer, Benjamin
Mutschlechner, Maria Orfanoudaki, Luca Pompermaier,
Silvia Revoltella (Ph.D. students)
quantitative determination of several phenolic acids in coffee beans.
Two aspects render this study noteworthy: first, the unique chemical
composition / structure of the monolith and second, the fact that CEC
has barely been used for the analysis of small molecules.
Another focus is the discovery of bioactive natural products by
activity guided isolation. Recent examples are investigations on the
proanthocyanidin fraction of Ephedra sinica, which is able to significantly
inhibit XIAP (X-linked inhibitor of apoptosis protein), or the identification
of anti-inflammatory compounds (i.e. benzofuranes, fig. 2) in the roots of
Doronicum austriacum. In particular, 6,12-dihydroxy-(−)-2S-tremetone (1)
showed the highest activity in the performed experiments and reduced
ROS (reactive oxygen species) production in macrophages at 10 µM by
approximately 50%. Comparable results were observed for nitric oxide-
release and iNOS (inducible nitric oxide synthase) expression.
In order to permit a comprehensive insight in our metabolome and
to monitor small differences caused by diseases, lifestyle or nutrition,
highly sophisticated, selective, and sensitive analytical techniques like
(U)HPLC-QToF-MS or NMR spectroscopy in combination with powerful
multivariate statistical tools such as PCA or OPLS-DA are applied. Within
an ongoing FFG funded K-project “VASCage – Gut, Diet, Microbiota
and Vascular Ageing” we work on the establishment and validation
of improved sample preparation protocols for the body fluids
urine, serum and feces (fig. 3). They are evaluated using the above
mentioned analytical and statistical techniques, and permit a conclusive
identification of diverse biomarkers.
Since 2016, we are also coordinating the project “MediHealth – Novel
natural products for healthy ageing from Mediterranean diet and food
plants of other global sources”, which is funded by the Commission
of the European Community (Research and Innovation Staff Exchange
(RISE), Marie Curie Actions). The project is based on a well-balanced
exchange of researchers between 5 universities and 4 companies
from European countries as well as 4 universities from non-European
countries. The main goal of the MediHealth project (http://medihealth.
eu/) is to introduce a novel approach for the discovery of active
agents of food plants from the Mediterranean diet and other global
sources to promote healthy ageing. To achieve this goal, plants from
the Mediterranean diet and edible plants from Africa, Asia and South
America have been carefully selected and subjected to in silico, in vitro,
in vivo and metabolism analysis. Bioactive plant constituents will be
isolated and identified. Pharmacological profiling of bioactive natural
products as well as identification and synthesis of their metabolites will
be carried out. Finally, process optimization studies will be performed
to develop innovative nutraceuticals, dietary supplements or herbal
medicinal products.
Figure 1: Separation of six lactones in Piper methysticum
roots by SFC. Murauer, A., Ganzera, M. Planta Med. 2017, 83,
1053-1057, doi: 10.1055/s-0043-100632.
Figure 2: DC separation and structures of bioactive
compounds isolated from the roots of Doronicum
austriacum. Marzocco, S., Adesso, S., Alilou, M., Stupppner,
H., Schwaiger, S. Molecules 2017, 22/6, Nr. 1003, doi: 10.3390/
molecules22061003.
Figure 3: Results of NMR studies indicating that directly
prepared human feces extracts (orange) provide more
reproducible results than those obtained with multi step
procedures (blue). Moosmang, S., Pitscheider, M., Sturm, S.,
Seger, C., Tilg, H., Halabalaki, M., Stuppner H. Clin. Chim.
Acta. In press, doi: 10.1016/j.cca.2017.10.029.
58 59 Research summary
Biomolecular NMR spectroscopy
Martin Tollinger and Christoph Kreutz
>> Goal: The experimental characterization of structure, dynamics and
function of proteins and (ribo)nucleic acids.
>> Background: It has become increasingly clear in the last decade that
the three-dimensional structures of proteins and (ribo)nucleic acids
are generally flexible. Typically, these biomolecules adapt a defined
distribution of structures around the „ground state“ that is obtained
by standard structure determination protocols. Structural flexibility
is required for the biological function of a biomolecule per se. For
example, recognition and binding of bioactive ligands, catalysis of
enzymatic reactions, regulation of enzymatic turnover and processing
of allosteric information all rely on structural flexibility. In our group we
aim at measuring and understanding structural flexibility of proteins
and (ribo)nucleic acids at atomic resolution using NMR spectroscopy.
We determine solution structures by standard NMR techniques and
complement these data by NMR relaxation measurements to provide a
genuine description of how these molecules function. We specifically
focus on the mechanisms of ligand recognition and binding, protein
and RNA folding and stability, and enzymatic catalysis.
>> Research Highlights and Outlook: One focus at our laboratory is
the characterization of functional dynamics of (ribo)nucleic acids.
In this context, we are advancing the current protocols for isotope
(13C, 15N, 2H) labeling of DNA and RNA. This is especially important
for the application of dynamic NMR experiments, such as saturation
transfer and relaxation dispersion experiments, where simple spin
topologies are a mandatory prerequisite. For this task, we combine
chemical synthesis and NMR in a unique way. Recently, a method to
introduce isotope labeling patterns into larger RNAs comprising up
to 80 nucleotides was established in our group. We currently focus
on probing the functional dynamics of catalytically active non-coding
RNAs, such as a group II intron construct or the pistol ribozyme.
This will give unprecedented insights into the structural flexibility
underlying biological function.
>> Department of Organic Chemistry
Research summary
>> Research GrantsFWF-P26550, FWF-P26849, FWF-P28725, FWF-P30370,
FWF-P31054, FFG-858017, ERDF-ITAT1013, OEAW DOC
fellowship, Alpine Research Center Obergurgl
>> CoworkersL. Ahammer, V. Dietrich, R. Eidelpes, S. Führer, S.
Grutsch, M. Juen, J. Kremser, J. Ludescher, F. Nußbaumer,
R. Plangger, E. Strebitzer (Ph.D. students), K. Erharter, J.
Unterhauser (master students)
Another focus at our laboratory are allergenic proteins such as Bet
v 1, which represents the main cause for allergic responses to birch
pollen. A substantial proportion of individuals who suffer from birch
pollen allergy develop intolerance to different kinds of fruits, nuts and
vegetables due to immunologic cross-reactivity of Bet v 1-specific IgE
antibodies with homologous proteins in these kinds of food. The most
frequent cross-allergies are directed towards apples and hazelnuts. We
have recently determined the three-dimensional structure of the major
apple allergen Mal d 1 and are currently working on allergenic proteins
from hazelnut and peach. In future experiments, we are planning
to establish how naturally occurring isoforms of these proteins with
>95% sequence identity and identical three-dimensional ground state
structures can elicit different immunologic responses.
Figure 1: General work flow. Chemical synthesis is used
to introduce atom-specific stable isotope labels (e.g. 13C,
highlighted in orange) into RNA precursors. After sequence
assembly, solution NMR experiments are carried out to probe
structure and function of the target RNA.
Figure 2: Left: Three-dimensional solution NMR structure of the major apple allergen Mal d 1. This 17.5 kDa protein is responsible for allergic reactions to apples in
>70% of all birch pollen sensitized patients. Center: Fully assigned, 2-dimensional 1H15N NMR spectrum of Mal d 1. Right: Mal d 1 was first identified and isolated from
Golden Delicious and Granny Smith apples.
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Publications Publications
K. Bister, M. Hartl, E. Stefan
Stefan E, Troppmair J, Bister K. Targeting the architecture of deregu-
lated protein complexes in cancer. Adv. Protein. Chem. Struct. Biol. in
press (2018). (Published online 18 August 2017).
Gufler S, Artes B, Bielen H, Krainer I, Eder MK, Falschlunger J, Bollmann
A, Ostermann T, Valovka T, Hartl M, Bister K, Technau U, Hobmayer B.
β-Catenin acts in a position-independent regeneration response in the
simple eumetazoan Hydra. Dev. Biol. 433, 310-323 (2018). (Published
online 3 November 2017).
Hunter E, Bister K (eds). Viruses, Genes, and Cancer - Current Topics
in Microbiology and Immunology, Vol. 407. Springer International
Publishing (2017).
Stefan E, Bister K. MYC and RAF: Key effectors in cellular signaling and
major drivers in human cancer. Curr. Top. Microbiol. Immunol. 407, 117-
151 (2017).
Raffeiner P, Schraffl A, Schwarz T, Röck R, Ledolter K, Hartl M, Konrat
R, Stefan E, Bister K. Calcium-dependent binding of Myc to calmodulin.
Oncotarget 8, 3327-3343 (2017).
Torres-Quesada O, Mayrhofer JE, Stefan E. The many faces of compart-
mentalized PKA signalosomes. Cell Signal. 37, 1-11 (2017).
Torres-Quesada O, Röck R, Stefan E. Systematic quantification of cAMP-
controlled PKA interactions. Horm. Metab. Res. 49, 240-249 (2017).
Bruystens JG, Wu J, Fortezzo A, Del Rio J, Nielsen C, Blumenthal DK,
Röck R, Stefan E, Taylor SS. Structure of a PKA RIα Recurrent Acrodys-
ostosis Mutant Explains Defective cAMP-Dependent Activation. J. Mol.
Biol. 428, 4890-4904 (2016).
Bachmann VA, Mayrhofer JE, Ilouz R, Tschaikner PM, Raffeiner P, Röck
R, Courcelles M, Apelt F, Lu T, Baillie GS, Thibault P, Aanstad P, Stelzl U,
Taylor SS, Stefan E. Gpr161 anchoring of PKA consolidates GPCR and
cAMP signaling. Proc. Natl. Acad. Sci. USA 113, 7786-7791 (2016).
Rinaldi L, Delle Donne R, Sepe M, Porpora M, Garbi C, Chiuso F, Gallo
A, Parisi S, Russo L, Bachmann V, Huber RG, Stefan E, Russo T, Feliciello
A. praja2 regulates KSR1 stability and mitogenic signaling. Cell Death
Dis. 7: e2230 (2016).
Ijaz M, Bonengel S, Zupančič O, Yaqoob M, Hartl M, Hussain S, Huck CW,
Bernkop-Schnürch A. Development of oral self nano-emulsifying delivery
system(s) of lanreotide with improved stability against presystemic thiol-
disulfide exchange reactions. Expert Opin. Drug Deliv. 13, 923-929 (2016).
Hartl M. The quest for targets executing MYC-dependent cell transfor-
mation. Front. Oncol. 6, 132 (2016).
Patents
Stefan E, Röck R, Raffeiner P, Bachmann V. Quantification of an interac-
tion between a Ras protein and a Raf protein. European Patent Office,
EP16191530.1 (2016).
Stefan E, Mayrhofer J. Full-length kinase conformation reporter. Euro-
pean Patent Office, EP16165865.3 (2016).
G. Bonn, C. Huck
Bec K, Grabska J, Ozaki Y, Huck CW. Influence of non-fundamental
modes on mid-infrared spectra anharmonic DFT study of aliphatic
ethers. J. Phys. Chem. A 121, 1412-1424 (2017).
Henn R, Kirchler CG, Grossgut ME, Huck CW. Comparison of sensitivity
to artificial spectral errors and multivariate LOD in NIR spectroscopy –
Determining the performance of miniaturizations on melamine in milk
powder. Talanta 166, 109-118 (2017).
Huck, CW. Selected latest applications of molecular spectroscopy in
natural product analysis. Phytochemistry Letters 20, 491-498 (2017).
Kirchler CG, Pezzei CK, Bec KB, Henn R, Ishigaki M, Ozaki Y, Huck CW.
Critical Evaluation of NIR and ATR-IR Spectroscopic Quantifications of
Rosmarinic Acid in Rosmarini folium Supported by Quantum Chemical
Calculations. Planta Med. 83/12/13, 1076-1084 (2017).
Murauer A, Bakry R, Schottenberger H, Huck CW, Ganzera, M. An in-
novative monolithic zwitterionic stationary phase for the separation of
phenolic acids in coffee bean extracts by capillary electrochromatogra-
phy. Anal. Chim. Acta 963, 136-142 (2017).
Jabeen F, Najam-ul-Haq M, Rainer M, Huck CW, Bonn GK. In-Tip
Lanthanum Oxide Monolith for the Enrichment of Phosphorylated
Biomolecules. Anal. Chem. 89/19, 10232-10238 (2017).
Pezzei CK, Schönbichler SA, Kirchler CG, Schmelzer J, Hussain S, Huck-
Pezzei VA, Popp M, Krolitzek J, Bonn GK, Huck CW. Application of
benchtop and portable near-infrared spectrometers for predicting the
optimum harvest time of Verbena officinalis. Talanta 169, 70-76 (2017).
Teshome DA, Rainer M, Noel JC, Schüßler G, Fuchs D, Bliem HR, Bonn
GK. Chemical compositions of traditional alcoholic beverages and con-
sumers’ characteristics, Ethiopia. African Journal of Food Science 11/7,
234-245 (2017).
K. Breuker
Vušurović J, Schneeberger EM, Breuker K. Interactions of protonated
guanidine and guanidine derivatives with multiply deprotonated RNA
probed by electrospray ionization and collisionally activated dissocia-
tion. ChemistryOpen 6, 739-750 (2017).
Kremser J, Strebitzer E, Plangger R, Juen MA, Nußbaumer F, Glasner H,
Breuker K, Kreutz C. Chemical synthesis and NMR spectroscopy of long
stable isotope labelled RNA. Chem. Commun. (Camb) 53, 12938-12941
(2017).
Skinner OS, McAnally MO, Van Duyne RP, Schatz GC, Breuker K, Comp-
ton PD, Kelleher NL. Native electron capture dissociation maps to Iron-
binding channels in horse spleen Ferritin. Anal. Chem. 89, 10711-10716
(2017).
Glasner H, Riml C, Micura R, Breuker K. Label-free, direct localization
and relative quantitation of the RNA nucleobase methylations m6A,
m5C, m3U, and m5U by top-down mass spectrometry. Nucleic Acids Res.
45, 8014-8025 (2017).
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Publications Publications
Schneeberger EM, Breuker K. Native top-down mass spectrometry of
TAR RNA in complex with a wild-Type tat peptide for binding site map-
ping. Angew. Chem. 129, 1274-1278 (2017); Angew. Chem. Int. Ed. Engl.
56, 1254-1258 (2017).
Schennach M, Schneeberger EM, Breuker K. Unfolding and folding of
the three-helix bundle protein KIX in the absence of solvent. J. Am. Soc.
Mass Spectrom. 27, 1079-1088 (2016).
Cabedo Martinez AI, Weinhäupl K, Lee WK, Wolff NA, Storch B, Żerko
S, Konrat R, Koźmiński W, Breuker K, Thévenod F, Coudevylle N. Bio-
chemical and structural characterization of the interaction between
the Siderocalin NGAL/LCN2 and the N-terminal domain of its endocytic
receptor SLC22A17. J. Biol. Chem. 291, 2917-2930 (2016).
Hoernes TP, Clementi N, Faserl K, Glasner H, Breuker K, Lindner H,
Hüttenhofer A, Erlacher M. Nucleotide modifications within bacterial
messenger RNAs regulate their translation and are able to rewire the
genetic code. Nucleic Acids Res. 44, 852-862 (2016).
Flamm AG, Le Roux AL, Mateos B, Díaz-Lobo M, Storch B, Breuker K,
Konrat R, Pons M, Coudevylle N. N-lauroylation during the expression
of recombinant N-myristoylated proteins. Implications and solutions.
Chembiochem. 17, 82-89 (2016).
R. Dallinger
Pedrini-Martha V, Schnegg R, Baurand PE, de Vaufleury A, Dallinger R.
The physiological role and toxicological significance of the non-metal-
selective Cadmium/Copper-Metallothionein isoform differ between
embryonic and adult helicid snails. Comp.Biochem.Physiol. C: Toxicol-
ogy & Pharmacology 199, 38-47 (2017).
Baumann C, Beil A, Jurt S, Niederwanger M, Palacios Ò, Capdevila M,
Atrian S, Dallinger R, Zerbe O. Structural Adaptation of a Protein to
Increased Metal Stress: NMR Structure of a Marine Snail Metallothio-
nein with an Additional Domain. Angew. Chem. Int. Ed. 56, 4617-4622
(2017).
Benito D, Niederwanger M, Izagirre U, Dallinger R, Soto M. Successive
onset of molecular, cellular and tissue-specific responses in midgut gland
of Littorina littorea exposed to sub-lethal cadmium concentrations. Int.
J. Mol. Sci. 18, 1815; doi: 10.3390/ijms18081815, pp. 1-26 (2017).
Niederwanger M, Dvorak M, Schnegg R, Pedrini-Martha V, Bacher K,
Bidoli M, Dallinger R. Challenging the metallothionein (MT) gene of
Biomphalaria glabrata: unexpected response patterns due to cadmium
exposure and temperature stress. Int. J. Mol. Sci. 18, 1747; doi: 10.3390/
ijms18081747, pp. 1-15 (2017).
Niederwanger M, Calatayud S, Zerbe O, Atrian S, Albalat R, Capdevila
M, Palacios Ò, Dallinger R. Biomphalaria glabrata metallothionein:
lacking metal specificity of the protein and missing gene upregulation
suggest metal sequestration by exchangeiInstead of through selective
binding. Int. J. Mol. Sci. 2017, 18, 1457; doi: 10.3390/ijms18071457, pp.
1-15 (2017).
Palacios Ò, Jiménez-Marti E, Niederwanger M, Gil-Moreno S, Zerbe O,
Atrian S, Dallinger R, Capdevila M. Analysis of metal-binding features
of the wild type and two domain-truncated mutant variants of Litto-
rina littorea Metallothionein reveals its Cd-specific character. Int. J. Mol.
Sci. 2017, 18, 1452; doi:10.3390/ijms18071452, pp. 1-16 (2017).
Schmielau L, Dvorak M, Niederwanger M, Dobieszewski N, Pedrini-
Martha V, Ladurner P, Rodríguez-Guerra Pedregal J, Maréchal JD, Dal-
linger R. Differential response to Cadmium exposure by expression of
a two and a three-domain metallothionein isoform in the land winkle
Pomatias elegans: valuating the marine heritage of a land snail. Sci.
Tot. Envion., submitted.
S. Denifl
Huber SE, Smialek MA, Tanzer K, Denifl S. Dissociative electron attach-
ment to the radiosensitizing chemotherapeutic agent hydroxyurea. J.
Chem. Phys. 144, 224309 (2016).
Itälä E, Tanzer K, Granroth S, Kooser K, Denifl S, Kukk E. Fragmentation
patterns of 4(5)-nitroimidazole and 1-methyl-5-nitroimidazole - The
effect of the methylation. J. Mass Spectrom. 52, 770–776 (2017).
Neustetter M, Mahmoodi-Darian M, Denifl S. Study of electron ioniza-
tion and fragmentation of non-hydrated and hydrated tetrahydrofuran
clusters. J. Am. Soc. Mass Spectrom. 28, 866–872 (2017).
Ribar A, Fink K, Li Z, Ptasinska S, Carmichael I, Feketeová L, Denifl S.
Stripping off hydrogens in imidazole triggered by the attachment of a
single electron. Phys. Chem. Chem. Phys. 19, 6406-6415 (2017).
Ribar A, Fink K, Probst M, Huber SE, Feketeová L, Denifl S. Isomer Selec-
tivity in Low-Energy Electron Attachment to Nitroimidazoles. Chemistry
23, 12892-12899 (2017).
Schürmann R, Tanzer K, Dabkowska I, Denifl S, Bald I. Stability of the
Parent Anion of the Potential Radiosensitizer 8-Bromoadenine Formed
by Low-Energy (<3 eV) Electron Attachment. J Phys Chem B: Condensed
Matter, Materials, Surfaces, Interfaces & Biophysical 121, 5730–5734
(2017).
F. Edenhofer
Edenhofer F, Dobeš J, Vobořil M, Brabec T, Dobešová M, Čepková A,
Klein L, Rajewsky K, Filipp D. A novel conditional Aire allele enables
cell-specific ablation of the immune tolerance regulator Aire. Eur. J.
Immunol., Epub ahead of print (2017).
Forero A, Rivero O, Wäldchen S, Ku HP, Kiser DP, Gärtner Y, Penning-
ton LS, Waider J, Gaspar P, Jansch C, Edenhofer F, Resink TJ, Blum R,
Sauer M, Lesch KP. Cadherin-13 Deficiency Increases Dorsal Raphe 5-HT
Neuron Density and Prefrontal Cortex Innervation in the Mouse Brain.
Front. Cell. Neurosci. 11, 307 (2017).
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Publications Publications
Kwok CK, Ueda Y, Kadari A, Günther K, Heron A, Schnitzler AC, Rook
M, Edenhofer F. Scalable stirred suspension culture for the generation
of billions of human induced pluripotent stem cells using single-use
bioreactors. J. Tiss. Eng. Regen. Med., in press (2017).
Appelt-Menzel A, Cubukova A, Günther K, Edenhofer F, Piontek J,
Krause G, Stüber T, Walles H, Neuhaus W, Metzger M. Establishment
of a Human Blood-Brain Barrier Co-culture Model Mimicking the
Neurovascular Unit Using Induced Pluri- and Multipotent Stem Cells.
Stem Cell Reports 8(4), 894-906 (2017).
Wörsdörfer P, Bosen F, Gebhardt M, Russ N, Zimmermann K, Komla
Kessie D, Sekaran T, Egert A, Ergün S, Schorle H, Pfeifer A, Edenhofer
F, Willecke K. Abrogation of Gap Junctional Communication in ES Cells
Results in a Disruption of Primitive Endoderm Formation in Embryoid
Bodies. Stem Cells 35(4), 859-871 (2017).
Wörsdörfer P, Mekala SR, Bauer J, Edenhofer F, Kuerten S, Ergün S.
The vascular adventitia: An endogenous, omnipresent source of stem
cells in the body. Pharmacol. Ther. 171, 13-29 (2016).
Günther K, Menzel AA, Kwok CK, Walles H, Metzger M, Edenhofer F. Rapid
Monolayer Neural Induction of induced Pluripotent Stem Cells Yields Stably
Proliferating Neural Stem Cells. J. Stem Cell Res. Ther. 6, 341(2016).
Safina D, Schlitt F, Romeo R, Pflanzner T, Pietrzik CU, Narayanaswami
V, Edenhofer F, Faissner A. Low-density lipoprotein receptor-related
protein 1 is a novel modulator of radial glia stem cell proliferation,
survival, and differentiation. Glia. 64(8), 1363-80 (2016).
Schulze M, Hoja S, Winner B, Winkler J, Edenhofer F, Riemenschneider
MJ. Model testing of PluriTest® with next-generation sequencing data.
Stem Cells Dev. 25(7), 569-71 (2016).
Münst B, Thier M, Winnemöller D, Helfen M, Thummer RP, Edenhofer
F. Nanog induces suppression of senescence via down-regulation of
p27KIP1 expression. J. Cell. Sci. 129(5), 912-20 (2016).
Scognamiglio R, Cabezas-Wallscheid N, Thier MC, Altamura S, Reyes
A, Prendergast ÁM, Baumgärtner D, Carnevalli LS, Atzberger A, Haas
S, von Paleske L, Boroviak T, Wörsdörfer P, Essers MA, Kloz U, Eisen-
man RN, Edenhofer F, Bertone P, Huber W, van der Hoeven F, Smith
A, Trumpp A. Myc Depletion Induces a Pluripotent Dormant State
Mimicking Diapause. Cell 164(4), 668–680 (2016).
B. Grubeck-Loebenstein
Weinberger B. Vaccines for the elderly: Current use and future chal-
lenges. Immun. Ageing, in press (accepted Dec 1, 2017).
Giacconi R, Costarelli L, Piacenza F, Basso A, Bürkle A, Moreno-Villanueva
M, Grune T, Weber D, Stuetz W, Gonos ES, Schön C, Grubeck-Loebenstein
B, Sikora E, Toussaint O, Debacq-Chainiaux F, Franceschi C, Hervonen
A, Slagboom E, Ciccarone F, Zampieri M, Caiafa P, Jansen E, Dollé MET,
Breusing N, Mocchegiani E, Malavolta M. Zinc-induced metallothionein
in centenarian offspring from a large European population: The MARK-
AGE project. J. Gerontol. A Biol. Sci. Med. Sci., Epub ahead of print (2017).
Weinberger B, Keller M, Putzer C, Breitenberger D, Koller B, Fiegl S,
Moreno-Villanueva M, Bernhardt J, Franceschi C, Voutetakis K, Gonos
ES, Hurme M, Sikora E, Toussaint O, Debacq-Chainiaux F, Grune T,
Breusing N, Bürkle A, Grubeck-Loebenstein B. Protection against Teta-
nus and Diphtheria in Europe: The impact of age, gender and country
of origin based on data from the MARK-AGE Study. Exp. Gerontol.,
pii: S0531-5565(17)30516-8 (2017).
Weinberger B, Keller M, Grubeck-Loebenstein B. Long-term mainte-
nance of diphtheria-specific antibodies after booster vaccination is
hampered by latent infection with Cytomegalovirus. Immun. Ageing
14, 16 (2017).
Pangrazzi L, Naismith E, Meryk A, Keller M, Jenewein B, Trieb K,
Grubeck-Loebenstein B. Increased IL-15 production and accumulation
of highly differentiated CD8+ effector/memory T cells in the bone mar-
row of persons with Cytomegalovirus. Front. Immunol. 8, 715 (2017).
Pangrazzi L, Meryk A, Naismith E, Koziel R, Lair J, Krismer M, Trieb K,
Grubeck-Loebenstein B. “Inflamm-aging” influences immune cell sur-
vival factors in human bone marrow. Eur. J. Immunol. 47, 481-492 (2017).
Weinberger B. Immunosenescence: The importance of considering age
in health and disease. Clin. Exp. Immunol. 187, 1-3 (2017).
Weinberger B. Adult vaccination against tetanus and diphtheria: The
European perspective. Clin. Exp. Immunol. 187, 93-99 (2017).
Stuetz W, Weber D, Dollé MET, Jansen E, Grubeck-Loebenstein B, Fiegl
S, Toussaint O, Bernhardt J, Gonos ES, Franceschi C, Sikora E, Moreno-
Villanueva M, Breusing N, Grune T, Bürkle A. Plasma carotenoids,
tocopherols, and retinol in the age-stratified (35-74 years) general
population: Cross-sectional study in six European countries. Nutrients
8, 614 (2016).
Zlamy M, Almanzar G, Parson W, Schmidt C, Leierer J, Weinberger B,
Jeller V, Unsinn K, Eyrich M, Würzner R, Prelog M. Efforts of the hu-
man immune system to maintain the peripheral CD8+ T cell compart-
ment after childhood thymectomy. Immunity & Ageing 13, 3 (2016).
Pinti M, Appay V, Campisi J, Frasca D, Fülöp T, Sauce D, Larbi A,
Weinberger B, Cossarizza A. Aging of the immune system: Focus on
inflammation and vaccination. Eur. J. Immunol. 46, 2286-2301 (2016).
Grasse M, Meryk A, Schirmer M, Grubeck-Loebenstein B, Weinberger
B. Booster vaccination against tetanus and diphtheria: Insufficient
protection against diphtheria in young and elderly adults. Immun.
Ageing 13, 26 (2016).
Ciccarone F, Malavolta M, Calabrese R, Guastafierro T, Bacalini MG,
Reale A, Franceschi C, Capri M, Hervonen A, Hurme M, Grubeck-
Loebenstein B, Koller B, Bernhardt J, Schön C, Slagboom PE, Toussaint
O, Sikora E, Gonos ES, Breusing N, Grune T, Jansen E, Dollé M,
Moreno-Villanueva M, Sindlinger T, Bürkle A, Zampieri M, Caiafa P.
Age-dependent expression of DNMT1 and DNMT3B in PBMCs from a
large European population enrolled in the MARK-AGE study. Aging
Cell 15, 755-765 (2016).
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Weinberger B, Joos C, Reed SG, Coler R, Grubeck-Loebenstein B. The
stimulatory effect of the TLR4-mediated adjuvant glucopyranosyl lipid
A is well preserved in old age. Biogerontology 17, 177-187 (2016).
Grubeck-Loebenstein B, Pangrazzi L. Role of the bone marrow for
adaptive immunity in old age. In: Handbook of Immunosenescence, 2nd
edition, Fulop T, Franceschi C, Hirokawa K, Pawelec G (eds), Springer,
in press
Weinberger B. Effects of ageing on the vaccination response. In: The
Ageing Immune System and Health. Bueno V, Lord J, Jackson T (eds),
Springer International Publishing Switzerland 2017, pp 69-86. ISBN 978-
3-319-43365-3
R. Gust
Kaserer T, Obermoser V, Weninger A, Gust R, Schuster D. Evaluation
of selected 3D virtual screening tools for the prospective identification
of peroxisome proliferator-activated receptor (PPAR)γ partial agonists.
European Journal of Medicinal Chemistry 124, 49-62 (2016).
Obermoser V, Urban ME, Murgueitio MS, Wolber G, Gust R. New
telmisartan-derived PPAR γ agonists: impact of the 3D-binding mode
on the pharmacological profile. European Journal of Medicinal
Chemistry 124, 138-152 (2016).
Kinthada P, Gust R. Synthesis and characterization, nuclease activity
studies and anticancer activity of Au(III)isostatinthiosemicarbazone
complexes as potential anticancer drugs. World Journal of Pharmacy
and Pharmaceutical Science 8, 727-739 (2016).
Liu W, Gust R. Update on metal N-heterocyclic carbene complexes as
potential anti-tumor metallodrugs. Coordination Chemical Reviews
329, 191-213 (2016).
Obermoser V, Mauersberger R, Schuster D, Czifersky M, Lipova M,
Siegl M, Kintscher U, Gust R. Importance of 5/6-aryl substitution on
the pharmacological profile of 4´-((2-propyl-1H-benzo[d]imidazol-1-yl)
methyl)-[1,1´-biphenyl]-2-carboxylic acid derived PPARγ agonists.
European Journal of Medicinal Chemistry 126, 590-603 (2017).
Maia P I da S, Carneiro Z A, Lopes C D, Oliveira C G, Silva J S, de Albu-
querque S, Hagenbach A, Gust R, Deflon V M, Abram U. Organometal-
lic gold(III) complexes with hybrid SNS-donating thiosemicarbazone
ligands: cytotoxicity and anti-trypanosoma cruzi activity. Dalton
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B. Hobmayer, P. Ladurner
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structural similarity and allergenic divergence within the Ole e 1–like
protein family. J. Allergy Cli. Immunol. 140(1), 277-80 (2017).
Schmitt MK, Podewitz M, Liedl KR, Huppertz H. High-Pressure Synthesis
and Characterization of the Ammonium Yttrium Borate (NH4) YB8O14.
Inorg. Chem. 56(22), 14291-9 (2017).
Schauperl M, Podewitz M, Ortner TS, Waibl F, Thoeny A, Loerting T, Liedl
KR. Balance between hydration enthalpy and entropy is important for
ice binding surfaces in Antifreeze Proteins. Sci. Rep. 7(1), 11901 (2017).
Schauperl M, Czodrowski P, Fuchs JE, Huber RG, Waldner BJ, Podewitz
M, Kramer C, Liedl KR. Binding Pose Flip Explained via Enthalpic and
Entropic Contributions. J. Cheml. Inf. Model. 57(2), 345-54 (2017).
Rossi D, Rui M, Di Giacomo M, Schepmann D, Wuensch B, Monteleone
S, Liedl KR, Collina S. Gaining in pan-affinity towards sigma 1 and sigma
2 receptors. SAR studies on arylalkylamines. Bioorg. Med. Chem. 25(1),
11-9 (2017).
Peduto A, Scuotto M, Krauth V, Roviezzo F, Rossi A, Temml V, Esposito V,
Stuppner H, Schuster D, D’Agostino B. Optimization of benzoquinone
and hydroquinone derivatives as potent inhibitors of human 5-lipoxy-
genase. Eur. J. Med. Chem. 127, 715-26 (2017).
Obermoser V, Mauersberger R, Schuster D, Czifersky M, Lipova M,
Siegl M, Kintscher U, Gust R. Importance of 5/6-aryl substitution on the
pharmacological profile of 4ʹ-((2-propyl-1H-benzo [d] imidazol-1-yl)
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Med. Chem. 126, 590-603 (2017).
Monteleone S, Lieb A, Pinggera A, Negro G, Fuchs JE, Hofer F, Striessnig
J, Tuluc P, Liedl KR. Mechanisms Responsible for ω-Pore Currents in Ca v
Calcium Channel Voltage-Sensing Domains. Biophys. J. 113(7), 1485-95
(2017).
Monteleone S, Fuchs JE, Liedl KR. Molecular Connectivity Predefines
Polypharmacology: Aliphatic Rings, Chirality, and sp3 Centers Enhance
Target Selectivity. Front. Pharmacol. 8, 552 (2017).
Hoffmann A, Richter M, von Grafenstein S, Walther E, Xu Z, Schumann
L, Grienke U, Mair CE, Kramer C, Rollinger JM. Discovery and Character-
ization of Diazenylaryl Sulfonic Acids as Inhibitors of Viral and Bacterial
Neuraminidases. Front. Microbiol. 8, 205 (2017).
Hochleitner J, Akram M, Ueberall M, Davis RA, Waltenberger B,
Stuppner H, Sturm S, Ueberall F, Gostner JM, Schuster D. A combinato-
rial approach for the discovery of cytochrome P450 2D6 inhibitors from
nature. Sci. Rep. 7(1), 8071 (2017).
Hitzenberger M, Schuster D, Hofer TS. The Binding Mode of the Sonic
Hedgehog Inhibitor Robotnikinin, a combined Docking and QM/MM
MD Study. Front. Chem. 5, 76 (2017).
Haq FU, Abro A, Raza S, Liedl KR, Azam SS. Molecular dynamics simula-
tion studies of novel β-lactamase inhibitor. J. Mol. Graph. Model. 74,
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| Hanáková Z, Hošek J, Kutil Zf, Temml V, Landa Pe, Vanek Ts, Schuster
D, Dall’Acqua S, Cvacka J, Polansky Oe. Anti-inflammatory Activity of
Natural Geranylated Flavonoids: Cyclooxygenase and Lipoxygenase
Inhibitory Properties and Proteomic Analysis. J. Nat. Prod. 80(4), 999-
1006 (2017).
Grutsch S, Fuchs JE, Ahammer L, Kamenik AS, Liedl KR, Tollinger M.
Conformational Flexibility Differentiates Naturally Occurring Bet v 1
Isoforms. Int. J. Mol. Sci. 18(6), 1192 (2017).
Garscha U, Romp E, Pace S, Rossi A, Temml V, Schuster D, König S, Gerst-
meier J, Liening S, Werner M. Pharmacological profile and efficiency in
vivo of diflapolin, the first dual inhibitor of 5-lipoxygenase-activating
protein and soluble epoxide hydrolase. Sci. Rep. 7(1), 9398 (2017).
Engeli RT, Rohrer SR, Vuorinen A, Herdlinger S, Kaserer T, Leugger S,
Schuster D, Odermatt A. Interference of Paraben Compounds with
Estrogen Metabolism by Inhibition of 17β-Hydroxysteroid Dehydroge-
nases. Int. J. Mol. Sci. 18(9), 2007 (2017).
E Fuchs J, Schilling O, R Liedl K. Determinants of Macromolecular Speci-
ficity from Proteomics-De rived Peptide Substrate Data. Curr. Protein.
Pept. Sci. 18(9), 905-13 (2017).
Dreier D, Latkolik S, Rycek L, Schnürch M, Dymáková A, Atanasov AG,
Ladurner A, Heiss EH, Stuppner H, Schuster D. Linked magnolol dimer
as a selective PPARγ agonist–Structure-based rational design, synthesis,
and bioactivity evaluation. Sci. Rep. 7(1), 13002 (2017).
Bruns J, Podewitz M, Schauperl M, Joachim B, Liedl KR, Huppertz H.
CaB2S4O16: A Borosulfate Exhibiting a New Structure Type with Phyl-
losilicate Analogue Topology. Chemistry 23(66), 16773-81 (2017).
Bernard J, Köck E-M, Huber RG, Liedl KR, Call L, Schlögl R, Grothe H,
Loerting T. Carbonic acid monoethyl ester as a pure solid and its confor-
mational isomerism in the gas-phase. Rsc Adv. 7(36), 22222-33 (2017).
Beck KR, Kaserer T, Schuster D, Odermatt A. Virtual screening appli-
cations in short-chain dehydrogenase/reductase research. J. Steroid
Biochem. Mol. Biol. 171, 157-177 (2017).
Beck KR, Bächler M, Vuorinen A, Wagner S, Akram M, Griesser
U, Temml V, Klusonova P, Yamaguchi H, Schuster D. Inhibition of
11β-hydroxysteroid dehydrogenase 2 by the fungicides itraconazole
and posaconazole. Biochem. Pharmacol. 130, 93-103 (2017).
Akram M, Waratchareeyakul W, Haupenthal J, Hartmann RW, Schuster
D. Pharmacophore modeling and in silico/in vitro screening for human
cytochrome P450 11B1 & cytochrome P450 11B2 inhibitors. Front.
Chem. 5, 104 (2017).
Ahammer L, Grutsch S, Kamenik AS, Liedl KR, Tollinger M. Structure of
the Major Apple Allergen Mal d 1. J. Agric. Food Chem. 65(8), 1606-12
(2017).
Zatelli GA, Temml V, Kutil Z, Landa P, Vanek T, Schuster D, Falkenberg
M. Miconidin Acetate and Primin as Potent 5-Lipoxygenase Inhibitors
from Brazilian Eugenia hiemalis (Myrtaceae). Planta Medica Letters
3(01), e17-e9 (2016).
Xu Z, Von Grafenstein S, Walther E, Fuchs JE, Liedl KR, Sauerbrei A,
Schmidtke M. Sequence diversity of NanA manifests in distinct enzyme
kinetics and inhibitor susceptibility. Sci. Rep. 6, 25169 (2016).
Wang Y, Gkeka P, Fuchs JE, Liedl KR, Cournia Z. DPPC-cholesterol
phase diagram using coarse-grained Molecular Dynamics simulations.
Biochim. Biophys. Acta (BBA)-Biomembranes 1858(11), 2846-57 (2016).
Waltenberger B, Garscha U, Temml V, Liers J, Werz O, Schuster D,
Stuppner H. Discovery of potent soluble epoxide hydrolase (sEH) inhibi-
tors by pharmacophore-based virtual screening. J. Chem. Inf. Model.
56(4), 747-62 (2016).
Waltenberger B, Atanasov AG, Heiss EH, Bernhard D, Rollinger JM,
Breuss JM, Schuster D, Bauer R, Kopp B, Franz C. Drugs from nature
targeting inflammation (DNTI): a successful Austrian interdisciplinary
network project. Monatsh. Chem. 147(3), 479-91 (2016).
Waldner BJ, Fuchs JE, Schauperl M, Kramer C, Liedl KR. Protease Inhibi-
tors in View of Peptide Substrate Databases. J. Chem. Inf. Model. 56(6),
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Waldner BJ, Fuchs JE, Huber RG, von Grafenstein S, Schauperl M,
Kramer C, Liedl KR. Quantitative Correlation of Conformational Bind-
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Scherl M, Müller T, Kreutz CR, Huber RG, Zass E, Liedl KR, Kräutler B.
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Schauperl M, Podewitz M, Waldner BJ, Liedl KR. Enthalpic and Entropic
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Scharinger B, Messner B, Türkcan A, Schuster D, Vuorinen A, Pitterl F,
Heinz K, Arnhard K, Laufer G, Grimm M. Leoligin, the major lignan
from Edelweiss, inhibits 3-hydroxy-3-methyl-glutaryl-CoA reductase
and reduces cholesterol levels in ApoE−/− mice. J. Mol. Cell. Cardiol. 99,
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Schaible AM, Filosa R, Krauth V, Temml V, Pace S, Garscha U, Liening
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tor RF-22c potently suppresses leukotriene biosynthesis in cellulo and
blocks bronchoconstriction and inflammation in vivo. Biochem. Phar-
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Reintjes A, Fuchs JE, Kremser L, Lindner HH, Liedl KR, Huber LA, Valovka
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Machado Y, Freier R, Scheiblhofer S, Thalhamer T, Mayr M, Briza P,
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endolysosomal acidification is a key factor for allergenicity and immu-
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137(5), 1525-34 (2016).
Loeffler JR, Ehmki ES, Fuchs JE, Liedl KR. Kinetic barriers in the isom-
erization of substituted ureas: implications for computer-aided drug
design. J. Comput. Aided Mol. Des. 30(5), 391-400 (2016).
Li C, Wurst K, Jockusch S, Gruber K, Podewitz M, Liedl KR, Kräutler B.
Chlorophyll-Derived Yellow Phyllobilins of Higher Plants as Medium-
Responsive Chiral Photoswitches. Angew. Chem. Int. Ed. Engl. 55(51),
15760-5 (2016).
Kratz JM, Mair CE, Oettl SK, Saxena P, Scheel O, Schuster D, Hering S,
Rollinger JM. hERG Channel Blocking Ipecac Alkaloids Identified by
Combined In Silico–In Vitro Screening. Planta Med. 82(11/12), 1009-15
(2016).
Kramer C, Mochalski P, Unterkofler K, Agapiou A, Ruzsanyi V, Liedl KR.
Prediction of blood: air and fat: air partition coefficients of volatile or-
ganic compounds for the interpretation of data in breath gas analysis.
J. Breath Res. 10(1), 017103 (2016).
Kaserer T, Rigo R, Schuster P, Alcaro S, Sissi C, Schuster D. Optimized virtual
screening workflow for the identification of novel G-quadruplex ligands.
Journal of chemical information and modeling 56(3), 484-500 (2016).
Kaserer T, Obermoser V, Weninger A, Gust R, Schuster D. Evaluation
of selected 3D virtual screening tools for the prospective identification
of peroxisome proliferator-activated receptor (PPAR) γ partial agonists.
Europ. J. Med. Chem. 124, 49-62 (2016).
Kaserer T, Lantero A, Schmidhammer H, Spetea M, Schuster D. µ Opi-
oid receptor: novel antagonists and structural modeling. Sci. Rep. 6,
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Kamenik AS, Kahler U, Fuchs JE, Liedl KR. Localization of Millisecond
Dynamics: Dihedral Entropy from Accelerated MD. J. Chem. Theory
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Glätzle M, Schauperl M, Hejny C, Tribus M, Liedl KR, Huppertz H. Or-
thorhombic HP-REOF (RE= Pr, Nd, Sm–Gd)–High-Pressure Syntheses and
Single-Crystal Structures (RE= Nd, Sm, Eu). Zeitschrift für anorganische
und allgemeine Chemie 2016(20), 1134-42 (2016).
Beck KR, Sommer TJ, Schuster D, Odermatt A. Evaluation of tetrabro-
mobisphenol A effects on human glucocorticoid and androgen recep-
tors: A comparison of results from human-with yeast-based in vitro
assays. Toxicology 370, 70-7 (2016).
Alsabil K, Suor-Cherer S, Koeberle A, Viault G, Lavaud A, Temml V,
Waltenberger B, Schuster D, Litaudon M, Lorkowski S. Semisynthetic
and Natural Garcinoic Acid Isoforms as New mPGES-1 Inhibitors. Planta
Med. 82(11/12), 1110-6 (2016).
Abbasi S, Raza S, Azam SS, Liedl KR, Fuchs JE. Interaction mechanisms
of a melatonergic inhibitor in the melatonin synthesis pathway. J. Mol.
Liq. 221, 507-17 (2016).
D. Meyer, P. Aanstad
Facchinello N, Tarifeno-Saldivia E, Grisan E, Schiavone M, Peron M,
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F. Tcf7l2 plays pleiotropic roles in the control of glucose homeostasis,
pancreas morphology, vascularization and regeneration. Sci. Rep. 7,
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Li J, Casteels T, Frogne T, Ingvorsen C, Honore C, Courtney M, Huber
KV, Schmitner N, Kimmel RA, Romanov RA, Sturtzel C, Lardeau CH,
Klughammer J, Farlik M, Sdelci S, Vieira A, Avolio F, Briand F, Baburin I,
Majek P, Pauler FM, Penz T, Stukalov A, Gridling M, Parapatics K, Bar-
bieux C, Berishvili E, Spittler A, Colinge J, Bennett KL, Hering S, Sulpice
T, Bock C, Distel M, Harkany T, Meyer D, Superti-Furga G, Collombat P,
Hecksher-Sorensen J, Kubicek S. Artemisinins. Target GABAA Receptor
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Schmitner N, Kohno K, Meyer D. ptf1a+ , ela3l- cells are developmen-
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Bachmann VA, Mayrhofer JE, Ilouz R, Tschaikner P, Raffeiner P, Röck R,
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Neuner S, Falschlunger C, Fuchs E, Himmelstoss M, Ren A, Patel DJ,
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Roles for an Active-Site Adenosine and Hydrated Mg2+ in Pistol Ribo-
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Zheng L, Mairhofer E, Teplova M, Zhang Y, Ma J, Patel DJ, Micura R, Ren
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Riml C, Amort T, Rieder D, Gasser C, Lusser A, Micura R. Osmium-Medi-
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Vušurović N, Altman RB, Terry DS, Micura R, Blanchard SC. Pseudoknot
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Danhart EM, Bakhtina M, Cantara WA, Kuzmishin AB, Ma X, Sanford
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Ren A, Micura R, Patel DJ. Structure-based mechanistic insights into
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Riml C, Lusser A, Ennifar E, Micura R. Synthesis, Thermodynamic
Properties, and Crystal Structure of RNA Oligonucleotides Containing
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Glasner H, Riml C, Micura R, Breuker K. Label-free, direct localization
and relative quantitation of the RNA nucleobase methylations m6A,
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Riml C, Micura R. Automated Chemical Solid-Phase Synthesis and De-
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Mairhofer E, Fuchs E, Micura R. Facile synthesis of a 3-deazaadenosine
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Neuner S, Kreutz C, Micura R. The synthesis of 15N(7)-Hoogsteen face-
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Amort T, Rieder D, Wille A, Khokhlova-Cubberley D, Riml C, Trixl L, Jia
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Gebetsberger J, Micura R. Unwinding the twister ribozyme: from struc-
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Jud L, Micura R. An Unconventional Acid-Labile Nucleobase Protection
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Melnikov S, Mailliot J, Rigger L, Neuner S, Shin BS, Yusupova G, Dever
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Sothiselvam S, Neuner S, Rigger L, Klepacki D, Micura R, Vázquez-Laslop
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Riml C, Micura R. Synthesis of 5-Hydroxymethylcytidine- and 5-Hydroxy-
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Melnikov S, Mailliot J, Shin BS, Rigger L, Yusupova G, Micura R, Dever
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Pelster B, Giacomin M, Wood CM, Val AL. Improved ROS defence in
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Schneebauer G, Hanel R, Pelster B. Anguillicola crassus impairs the
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Kwong R, Kumai Y, Tzaneva V, Azzi E, Hochhold N, Robertson C, Pelster
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Sandbichler AM, Höckner M. Cadmium Protection Strategies-A Hidden
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Drechsel V, Schauer K, Šrut M, Höckner M. Regulatory Plasticity of
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Šrut M, Drechsel V, Höckner M. Low levels of Cd induce persisting
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Kaserer T, Lantero A, Schmidhammer H, Spetea M, Schuster D. µ Opioid
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Martin C, Oyen E, Mangelschots J, Bibian M, Ben Haddou T, Andrade
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Guerrieri E, Bermudez M, Wolber G, Berzetei-Gurske IP, Schmidhammer
H, Spetea M. Structural determinants of diphenethylamines for interac-
tion with the κ opioid receptor: Synthesis, pharmacology and molecular
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Lagard C, Chevillard L, Guillemyn K, Risède P, Laplanche J-L, Spetea
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Martin C, Oyen E, Van Wanseele Y, Ben Haddou T, Schmidhammer H,
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Noha SM, Schmidhammer H, Spetea M. Molecular docking, molecular
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Erli F, Guerrieri E, Ben Haddou T, Lantero A, Mairegger M, Schmidham-
mer H, Spetea M. Highly potent and selective new diphenethylamines
interacting with the κ-opioid receptor: Synthesis, pharmacology, and
structure-activity relationships. J. Med. Chem. 60, 579-7590 (2017).
Dumitrascuta M, Ben Haddou T, Guerrieri E, Noha SM, Schläfer L,
Schmidhammer H, Spetea M. Synthesis, pharmacology and molecular
modeling studies on 6-desoxo-N-methylmorphinans as potent µ-opioid
receptor agonists. J. Med. Chem. 60, 9407-9412 (2017).
Schmidhammer H, Spetea M, Guerrieri E. Diphenethylamine derivatives
which are inter alia useful as analgesics and method for their produc-
tion. United States Patent Application, US15/561,614 (2017).
Schmidhammer H, Spetea M, Guerrieri E. Diphenethylamine derivatives
which are inter alia useful as analgesics and method for their produc-
tion. European Patent Application, EP16712338.9 (2017).
R. Schneider, B. Auer
Schweiger S, Matthes F, Posey K, Kickstein E, Weber S, Hettich MM,
Pfurtscheller S, Ehninger D, Schneider R, Krauß S. Resveratrol induces
dephosphorylation of Tau by interfering with the MID1-PP2A complex.
Sci. Rep. 7, 13753 (2017).
Schindler S, Missbichler B, Walther C, Sponring M, Cserjan-Puschmann
M, Auer B, Schneider R, Dürauer A. Npro fusion technology: On-column
complementation to improve efficiency in biopharmaceutical produc-
tion. Protein Expr. Purif. 120, 42-50 (2016).
Lemmermeyer T, Lamp B, Schneider R, Ziebuhr J, Tekes G, Thiel H-J.
Characterization of monoclonal antibodies against feline coronavirus
accessory protein 7b. Vet. Microbiol. 184, 11-19 (2016).
J. Striessnig, N. Singewald, A. Koschak
Adori C, Barde S, Vas S, Ebner K, Su J, Svensson C, Mathé AA, Singewald
N, Reinscheid RR, Uhlén M, Kultima K, Bagdy G, Hökfelt T. Exploring
the role of neuropeptide S in the regulation of arousal: a functional
anatomical study. Brain Struct. Funct. 221, 3521-3546 (2016).
Mesirca P, Bidaud I, Briec F, Evain S, Torrente AG, Le Quang K, Mangoni
ME. G protein-gated IKACh channels as therapeutic targets for treat-
ment of sick sinus syndrome and heart block. Proc. Natl. Acad. Sci. USA
113, 932-941 (2016).
84 85
Puschban Z, Sah A, Grutsch I, Singewald N, Dechant G. Reduced Anx-
iety-Like Behavior and Altered Hippocampal Morphology in Female
p75NTR(exon IV-/-) Mice. Front. Behav. Neurosci. 10, 103 (2016).
Sartori SB, Maurer V, Murphy C, Schmuckermair C, Muigg P, Neu-
mann ID, Whittle N, Singewald N. Combined neuropeptide S and
D-cycloserine augmentation prevents the return of fear in extinction
impaired rodents: advantage of dual vs. single drug approaches. Int. J.
Neuropsychopharmacol. 19, 1-11 (2016).
Schaufler J, Ronovsky M, Savalli G, Cabatic M, Sartori SB, Singewald N,
Pollak DD. Fluoxetine normalizes disrupted light-induced entrainment
fragmented ultradian rhythms and altered hippocampal clock gene
expression in an animal model of high trait anxiety- and depression-
related behavior. Ann. Med. 48, 17-27 (2016).
Stanika R, Campiglio M, Pinggera A, Lee A, Striessnig J, Flucher BE,
Obermair GJ. Splice variants of the Cav1.3 L-type calcium channel regu-
late dendritic spine morphology. Sci. Rep. 6, 34528 (2016).
Sultana N, Dienes B, Benedetti A, Tuluc P, Szentesi P, Sztretye M, Rainer
J, Hess MW, Schwarzer C, Obermair GJ, Csernoch L, Flucher BE. Restrict-
ing calcium currents is required for correct fiber type specification in
skeletal muscle. Development 143, 1547-1559 (2016).
Torrente AG, Mesirca P, Neco P, Rizzetto R, Dubel S, Barrere C, Sinneg-
ger-Brauns M, Striessnig J, Richard S, Nargeot J, Gomez AM, Mangoni
ME. L-type Cav1.3 Channels Regulate Ryanodine receptor-dependent
calcium release during sino-atrial node pacemaker activity. Cardiovasc.
Res. 109, 451-61 (2016).
Tuluc P, Benedetti B, Coste de Bagneaux P, Grabner M, Flucher BE. Two
distinct voltage-sensing domains control voltage sensitivity and kinetics
of current activation in CaV1.1 calcium channels. J. Gen. Physiol. 147,
437 (2016).
Tuluc P, Yarov-Yarovoy V, Benedetti B, Flucher BE. Molecular Interac-
tions in the Voltage Sensor Controlling Gating Properties of CaV
Calcium Channels. Structure 24, 261-271 (2016).
Whittle N, Maurer V, Murphy C, Rainer J, Bindreither D, Hauschild M,
Scharinger A, Oberhauser M, Keil T, Brehm C, Valovka T, Striessnig J,
Singewald N. Enhancing dopaminergic signaling and histone acetyla-
tion promotes long-term rescue of deficient fear extinction. Transl.
Psychiatry 6, e974 (2016).
Wille A, Amort T, Singewald N, Sartori SB, Lusser A. Dysregulation of se-
lect ATP-dependent chromatin remodeling factors in high trait anxiety.
Behav. Brain Res. 311, 141-146 (2016).
Härtner L, Keil TWM, Kreuzer M, Fritz EM, Wenning GK, Stefanova N,
Fenzl T. Distinct Parameters in the EEG of the PLP α-SYN Mouse Model
for Multiple System Atrophy Reinforce FaceValidity. Front. Behav. Neu-
rosci. 10, 252 (2017).
Martínez-Rivera A, Hao J, Tropea TF, Giordano TP, Kosovsky M, Rice RC,
Lee A, Huganir RL, Striessnig J, Addy NA, Han S, Rajadhyaksha AM. En-
hancing VTA Cav13 L-type Ca2+ channel activity promotes cocaine and
mood-related behaviors via overlapping AMPA receptor mechanisms in
the nucleus accumbens. Mol. Psychiatry 22, 1735-1745 (2017).
Mastrolia V, Flucher SM, Obermair GJ, Drach M, Hofer H, Renström E,
Schwartz A, Striessnig J, Flucher BE, Tuluc P. Loss of α2δ-1 Calcium Chan-
nel Subunit Function Increases the Susceptibility for Diabetes. Diabetes
66, 867-907 (2017).
Monteleone Stefania, Lieb Andreas, Pinggera Alexandra, Negro Giulia,
Fuchs Julian E, Hofer Florian, Striessnig Jörg, Tuluc Petronel, Liedl Klaus
R. Mechanisms Responsible for ω-Pore Currents in Cav Calcium Channel
Voltage-Sensing Domains. Biophys. J. 113, 1485-1495 (2017).
Ortner NJ, Bock G, Dougalis A, Kharitonova M, Duda J, Hess S, Tuluc T,
Pomberger T, Stefanova N, Pitterl F, Ciossek T, Oberacher H, Draheim
HJ, Kloppenburg P, Liss B, Striessnig J. Lower Affinity of Isradipine for
L-Type Ca2+ Channels during Substantia Nigra Dopamine Neuron-like
Activity: Implications for Neuroprotection in Parkinson’s Disease. J.
Neurosci. 37, 6761-6777 (2017).
Pinggera A, Mackenroth L, Rump A, Schallner J, Beleggia F, Wollnik B,
Striessnig J. New Gain-of-Function Mutation Shows CACNA1D as Recur-
rently Mutated Gene in Autism Spectrum Disorders and Epilepsy. Hum.
Mol. Genet. 26, 2923-2932 (2017).
Tan GC, Negro G, Pinggera A, Tizen Laim NMS, Rose I, Ceral J, Ryska
A, Chin LK, Kamaruddin NA, Mohd Mokhtar N, A Jamal AR, Sukor N,
Solar M, Striessnig J, Brown MJ, Azizan EA. Aldosterone-Producing
Adenomas: Histopathology-Genotype Correlation and Identification of
a Novel CACNA1D Mutation. Hypertension 70, 129-136 (2017).
Toyoda F, Mesirca P, Dubel S, Ding W-G, Striessnig J, Mangoni ME,
Matsuura H. CaV13 L-type Ca2+ channel contributes to the heartbeat
by generating a dihydropyridine-sensitive persistent Na+ current. Sci.
Rep. 7, 7869 (2017).
Alexander SP, Striessnig J, Kelly E, Marrion NV, Peters JA, Faccenda
E, Harding SD, Pawson AJ, Sharman JL, Southan C, Davies JA; CGTP
Collaborators. THE CONCISE GUIDE TO PHARMACOLOGY 2017/18:
Voltage-gated ion channels. Br. J. Pharmacol. 174 (Suppl 1) S160-S194
(2017).
Alexander SP, Kelly E, Marrion NV, Peters JA, Faccenda E, Harding SD,
Pawson AJ, Sharman JL, Southan C, Buneman OP, Cidlowski JA, Christo-
poulos A, Davenport AP, Fabbro D, Spedding M, Striessnig J, Davies JA;
CGTP Collaborators.THE CONCISE GUIDE TO PHARMACOLOGY 2017/18:
Overview. Br. J. Pharmacol. 174 (Suppl 1) S1-S16 (2017).
Ortner NJ, Striessnig J. L-type calcium channels as drug targets in CNS
disorders. Channels (Austin) 10, 7-13 (2016).
Pinggera A, Striessnig J. Cav 1.3 (CACNA1D) L-type Ca2+ channel dys-
function in CNS disorders. J. Physiol. 594, 5839-5849 (2016).
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Striessnig J. Voltage-gated calcium channels - from basic mechanisms to
disease. J. Physiol. 594, 5817-5821 (2016).
Sartori BS, Singewald N. Neue pharmakologische Strategien zur Aug-
mentation von Extinktionslernen in der Angsttherapie. Neuroforum
23, 197-211 (2017).
Sartori BS, Singewald N. New pharmacological strategies for augment-
ing extinction learning in anxiety disorders. Neuroforum 23, A145-A156
(2017).
Seitter H, Koschak A. Relevance of tissue specific subunit expression in
channelopathies. Neuropharmacology 17, 30302-7 (2017).
Ebner K, Singewald N. Individual differences in stress susceptibility and
stress inhibitory mechanisms. Current Opinion in Behavioral Sciences
14, 54-64 (2017).
Murphy CP, Singewald N. Potential of microRNAs as novel targets in
the alleviation of pathological fear. Genes Brain Behav, doi: 10.1111/
gbb.12427. [Epub ahead of print]
Striessnig, Jörg: Editorial Board - Channels, 01.01.2007 lfd.
Singewald, Nicolas: Editor - Amino Acids, 01.01.1999 lfd.
H. Stuppner, M. Ganzera
Dreier D, Latkolik S, Rycek L, Schnürch M, Dymáková A, Atanasov AG,
Ladurner A, Heiss EH, Stuppner H, Schuster D, Mihovilovic MD, Dirsch
VM. Linked magnolol dimer as a selective PPARγ agonist – Structure-
based rational design, synthesis, and bioactivity evaluation. Sci. Rep. 7,
13002 (2017).
Gvazava L, Gorgaslidze N, Ganzera M, Skhirtladze A. A new lupane
triterpene glycoside from Euphorbia boissierana Prokh. Trends in Phy-
tochemical Research 1, 149-152 (2017).
Haller J, Schwaiger S, Stuppner H, Gafner F, Ganzera M. Isolation of
Three Triterpene Saponins, Including Two New Oleanane Derivatives,
from Soldanella alpina and Hydrophilic Interaction Liquid Chromatog-
raphy-Evaporative Light Scattering Detection of these Three Saponins
in Four Soldenella Species. Phytochemical Anal. 28, 567-574 (2017).
Hartmann A, Murauer A, Ganzera M. Quantitative analysis of mycospo-
rine-like amino acids in marine algae by capillary electrophoresis with
diode-array detection. J. Pharm. Biomed. Anal. 138, 153-157 (2017).
Hochleitner J, Akram M, Ueberall M, Davis RA, Waltenberger B,
Stuppner H, Sturm S, Ueberall F, Gostner JM, Schuster D. A combinato-
rial approach for the discovery of cytochrome P450 2D6 inhibitors from
nature. Sci. Rep. 7, 8071 (2017).
Kemertelidze E, Skhirthladze M, Ganzera M. Furostanol and triterpene
saponins from the roots of Digitalis ciliata. Chemistry of Natural Com-
pounds 53, 492-496 (2017).
Khan SY, Awad EM, Oszwald A, Mayr M, Yin X, Waltenberger B,
Stuppner H, Lipovac M, Pavel U, Breuss JM. Premature senescence of
endothelial cells upon chronic exposure to TNFα can be prevented by
N-acetyl cysteine and plumericin. Sci. Rep. 7, 39501 (2017).
Mailainer C, Schachner D, Sangiovanni E, Atanasov AG, Schwaiger S,
Stuppner H, Heiss EH, Dirsch VM. Eurycomalactone Inhibits Expression
of Endothelial Adhesion Molecules at a Post-Transcriptional Level. J.
Nat. Prod. 80, 3186-3193 (2017).
Marzocco S, Adesso S, Alilou M, Stuppner H, Schwaiger S. Anti-Inflam-
matory and Anti-Oxidant Potential of the Root Extract and Constituents
of Doronicum austriacum. Molecules 22, 1003 (2017).
Murauer A, Bakry R, Schottenberger H, Huck CW, Ganzera M. An in-
novative monolithic zwitterionic stationary phase for the separation of
phenolic acids in coffee bean extracts by capillary electrochromatogra-
phy. Anal. Chim. Acta 963, 136-142 (2017).
Murauer A, Ganzera M. Quantitative Determination of Lactones in
Piper methysticum (Kava-Kava) by Supercritical Fluid Chromatography.
Planta Med. 83, 1053-1057 (2017).
Nebieridze VG, Skhirtladze AV, Kemertelidze EP, Ganzera M. Nucleo-
sides from Tribulus terrestris. Chemistry of Natural Compounds 53,
1010-1011 (2017).
Nicolaus C, Junghanns S, Hartmann A, Murillo R, Ganzera M, Merfort I.
In vitro studies to evaluate the wound healing properties of Calendula
officinalis extracts. J. Etnopharmacol. 196, 94-103 (2017).
Pataczek L, Cheilari A, Zikeli S, Sturm S, Stuppner H, Gruber S. Cen-
taurium erythraea Cultivation Method for Optimal Yield and Product
Quality. Journal of Herbs, Spices & Medicinal Plants 23, 193-215 (2017).
Peduto A, Scuotto M, Krauth V, Roviezzo F, Rossi A, Temml V, Esposito V,
Stuppner H, Schuster D, D´Agostino B., Schiraldi C, De Rosa M, Werz O,
Filosa R. Optimization of benzoquinone and hydroquinone derivatives
as potent inhibitors of human 5-lipoxygenase. Eur. J. Med. Chem. 127,
715-726 (2017).
Schäfer S, Schwaiger S, Stuppner H. Aristolic Acid Derivates from the
Bark of Antidesma ghaesembilla. Planta Med. 83, 1097-1102 (2017).
Siewert B, Langerman M, Hontani Y, Kennis JTM, Van Rixel VHS, Lim-
burg B, Siegler MA, Saez Talens V, Kieltyka RE, Bonnet S. Turning on
the red phosphorescence of a [Ru(tpy)(bpy)(Cl)]Cl complex by amide
substitution: self-aggregation, toxicity, and cellular localization of an
emissive ruthenium-based amphiphile. Chemical Commun. 53, 11126-
11129 (2017).
Skhirtladze A, Nebieridze V, Benidze M, Kemertelidze E, Ganzera M.
Furostanol glycosides from the roots of Tribulus terrestris L. Bulletin of
the Georgian National Academy of Sciences 11, 122-126 (2017).
Skhirtladze AV, Kopaliani TA, Nebieridze VG; Kemertelidze EP, Ganzera
M. New steroidal glycosides from pericarp of Digitalis ferruginea.
Chemistry of Natural Compounds 53, 1083-1087 (2017).
Taibon J, Sturm S, Strasser H, Stuppner H. Combination of a QuEChERS-
based extraction protocol with a fast and selective UHPLC-QTOF-MS
assay for the detection and quantification of Metarhizium brunneum
metabolites from honey samples. SOJ Pharmacy & Pharmaceutical Sci-
ences 4, 1-5 (2017).
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Temml V, Garscha U, Romp E, Schubert G, Gerstmeier J, Kutil Z, Ma-
tuszczak B, Waltenberger B, Stuppner H, Werz O, Schuster D. Discovery
of the first dual inhibitor of the 5-lipoxygenase-activating protein and
soluble epoxide hydrolase using pharmacophore-based virtual screen-
ing. Sci. Rep. 7, 42751 (2017).
Vrabl P, Schinagl CW, Artmann DJ, Krüger A, Ganzera M, Pötsch A,
Burgstaller W. The Dynamics of Plasma Membrane, Metabolism and
Respiration (PM-M-R) in Penicillium ochrochloron CBS 123824 in
Response to Different Nutrient Limitations—A Multi-level Approach
to Study Organic Acid Excretion in Filamentous Fungi. Frontiers in
Microbiol. 8, 2475 (2017).
Vuorinen A, Engeli RT, Leugger S, Bachmann F, Akram M, Atanasov AG,
Waltenberger B, Temml V, Stuppner H, Krenn L, Ateba SB, Njamen D,
Davis RA, Odermatt A, Schuster D. Potential Antiosteoporotic Natural
Product Lead Compounds That Inhibit 17β-Hydroxysteroid Dehydroge-
nase Type 2. J. Nat. Prod. 80, 965-974 (2017).
Alsabil K, Suor-Cherer S, Koeberle A, Viault G, Lavaud A, Temml V,
Waltenberger B, Schuster D, Litaudon M, Lorkowski S, de Vaumas R,
Helesbeux JJ, Guilet D, Stuppner H, Werz O, Seraphin D, Richomme P.
Semisynthetic and Natural Garcinoic Acid Isoforms as New mPGES-1
Inhibitors. Planta Med. 82, 1110-1116 (2016).
Antal DS, Pinzaru I, Borcan F, Marti TD, Ledeti I, Coricovac D, Schwaiger
S, Stuppner H, Dehelean CA, Ollivier E, Soica C. Inclusion Complexes of
the Aurone Sulfuretin and the Chalcone Butein from Cotinus coggygria
Wood in Two Cyclodextrin Types: First data on physico-chemical proper-
ties. Revista De Chimie 67, 1104-1109 (2016).
Becker K, Hartmann A, Ganzera M, Fuchs D, Gostner JM. Immuno-
modulatory Effects of the Mycosporine-Like Amino Acids Shinorine and
Porphyra-334. Mar. Drugs 14, 119 (2016).
Cheilari A, Sturm S, Intelmann D, Seger C, Stuppner H. Head-to-Head
Comparison of Ultra-High-Performance Liquid Chromatography with
Diode Array Detection versus Quantitative Nuclear Magnetic Resonance
for the Quantitative Analysis of the Silymarin Complex in Silybum mari-
anum Fruit Extracts. J. Agric. Food Chem. 64, 1618-1626 (2016).
Hartmann A, Holzinger A, Ganzera M, Karsten U. Prasiolin, a new
UV-sunscreen compound in the terrestrial green macroalga Prasiola
calophylla (Carmichael ex Greville) Kützing (Trebouxiophyceae, Chlo-
rophyta). Planta 243, 161-169 (2016).
Heiss EH, Liu R, Waltenberger B, Khan S, Schachner D, Kollmann P, Zim-
mermann K, Cabaravdic M, Uhrin P, Stuppner H, Breuss JM, Atanasov
AG, Dirsch VM. Plumericin inhibits proliferation of vascular smooth
muscle cells by blocking STAT3 signaling via S-glutathionylation. Sci.
Rep. 6, 20771 (2016).
Papadakis ES, Robson N, Yeomans A, Bailey S, Laversin S, Beer S, Sayan
A, Ashton-Key M, Schwaiger S, Stuppner H, Troppmair J, Packham
G, Cutress R. A combination of trastuzumab and BAG-1 inhibition
synergistically targets HER2 positive breast cancer cells. Oncotarget 7,
18851-18864 (2016).
Papadakis ES, Barker CR, Syed H, Reeves T, Schwaiger S, Stuppner H,
Troppmair J, Blaydes JP, Cutress RI. The Bag-1 inhibitor, Thio-2, reverses
an atypical 3D morphology driven by Bag-1L overexpression in a MCF-
10A model of ductal carcinoma in situ. Oncogenesis 5, e215 (2016).
Pfeifer I, Murauer A, Ganzera M. Determination of coumarins in the
roots of Angelica dahurica by supercritical fluid chromatography. J.
Pharm. Biomed. Anal. 129, 246-251 (2016).
Schäfer S, Salcher S, Seiter M, Ranninger C, Moest M, Obexer P, Huber
CG, Ausserlechner MJ, Schwaiger S, Stuppner H. Characterization of
the XIAP-Inhibiting Proanthocyanidin Fraction of the Aerial Parts of
Ephedra sinica. Planta Med. 82, 973-985 (2016).
Schaible AM, Filosa R, Krauth V, Temml V, Pace S, Garscha U, Liening S,
Weinigel C, Rummler S, Schieferdecker S, Nett M, Peduto A, Collarile
S, Scuotto M, Roviezzo F, Spaziano G, De Rosa M, Stuppner H, Schuster
D, D´Agostino B, Werz O. The 5-lipoxygenase inhibitor RF-22c potently
suppresses leukotriene biosynthesis in cellulo and blocks bronchocon-
striction and inflammation in vivo. Biochem. Pharmacol. 112, 60-71
(2016).
Scharinger B, Messner B, Türkcan A, Schuster D, Vuorinen A, Pitterl F,
Heinz K, Arnhard K, Laufer G, Grimm M, Stuppner H, Oberacher H,
Eller P, Ritsch A, Bernhard D. Leoligin, the major lignan from edelweiss,
inhibits 3-hydroxy-3-methyl-glutaryl-CoA reductase and reduces choles-
terol levels in ApoE −/− mice. J. Mol. Cell. Cardiol. 99, 35-46 (2016).
Skhirtladze A, Kemertelidze E, Nebieridze V, Ganzera M. Phenyletha-
noid Glycosides from the Roots of Digitalis ciliata Trautv. Helvetica
Chimica Acta 99, 241-245 (2016).
Waltenberger B, Garscha U, Temml V, Liers J, Werz O, Schuster D,
Stuppner H. Discovery of Potent Soluble Epoxide Hydrolase (sEH) Inhibi-
tors by Pharmacophore-Based Virtual Screening. Journal of Chemical
Information and Modeling 56, 747-762 (2016).
Wang L, Ladurner A, Latkolik S, Schwaiger S, Linder T, Hosek J, Palme V,
Schilcher N, Polansky O, Heiss EH, Stangl H, Mihovilovic MD, Stuppner
H, Dirsch VM, Atanasov AG. Leoligin, the Major Lignan from Edelweiss
(Leontopodium nivale subsp. alpinum), Promotes Cholesterol Efflux
from THP-1 Macrophages. J. Nat. Prod. 79, 1651-1657 (2016).
Winderl B, Schwaiger S, Ganzera M. Fast and improved separation of
major coumarins in Ammi visnaga (L.) Lam. by Supercritical Fluid Chro-
matography. J. Sep. Sci. 39, 4042-4048 (2016).
Zatelli GA, Temml V, Kutil Z, Landa P, Vanke T, Schuster D, Falkenberg
M. Miconidin Acetate and Primin as Potent 5-Lipoxygenase Inhibitors
from Brazilian Eugenia hiemalis (Myrtaceae). Planta Medica Letters 3,
e17-e19 (2016).
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M. Tollinger, C. Kreutz
Juen MA, Wunderlich CH, Nussbaumer F, Tollinger M, Kontaxis G, Kon-
rat R, Hansen DF, Kreutz CK. Excited states of nucleic acids probed by
proton relaxation dispersion NMR Spectroscopy. Angew. Chem. Int. Ed.
Engl. 55, 12008-12012 (2016).
Moschen T, Grutsch S, Juen, MA, Wunderlich CH, Kreutz C, Tollinger M.
Measurement of ligand-target residence times by 1H relaxation disper-
sion NMR spectroscopy. J. Med. Chem. 59, 10788-10793 (2016).
Zhou H, Kimsey IJ, Nikolova EN, Sathyamoorthy B, Grazioli G, McSally
J, Bai T, Wunderlich CH, Kreutz C, Andricioaei I, Al-Hashimi HM. M(1)A
and m(1)G disrupt A-RNA structure through the intrinsic instability of
Hoogsteen base pairs. Nat. Struct. Mol. Biol. 23, 803-810 (2016).
Grutsch S, Brüschweiler S, Tollinger M. NMR methods to study dynamic
allostery. PLoS Comput. Biol. 12, e1004620 (2016).
Machado Y, Freier R, Scheiblhofer S, Thalhamer T, Mayr M, Briza P,
Grutsch S, Ahammer L, Fuchs J, Wallnöfer H, Isakovic A, Kohlbauer V,
Hinterholzer A, Steiner M, Danzer M, Horejs-Hoeck J, Ferreira F, Liedl
KR, Tollinger M, Lackner P, Johnson CM, Brandstetter H, Thalhamer
J, Weiss R. Fold-stability during endolysosomal acidification is a key
factor for allergenicity and immunogenicity of the major birch pollen
allergen. J. Allergy Clin. Immunol. 137, 1525-1534 (2016).
Duchardt-Ferner E, Juen M, Kreutz C, Wöhnert J. NMR resonance as-
signments for the tetramethylrhodamine binding RNA aptamer 3 in
complex with the ligand 5-carboxy-tetramethylrhodamine. Biomol.
NMR Assign. 11, 29-34 (2016).
Ahammer L, Grutsch S, Tollinger M. NMR resonance assignments of the
major apple allergen Mal d 1. Biomol. NMR Assign. 10, 287-290 (2016).
Ren A, Vusurovic N, Gebetsberger J, Gao P, Juen M, Kreutz C, Micura
R, Patel DJ. Pistol ribozyme adopts a pseudoknot fold facilitating site-
specific in-line cleavage. Nat. Chem. Biol. 12, 702-708 (2016).
Scherl M, Müller T, Kreutz C, Huber RG, Zass E, Liedl KR, Kräutler B.
Chlorophyll catabolites in fall leaves of the wych elm tree present a
novel glycosylation motif. Chemistry 22, 9498-9503 (2016).
Longhini AP, LeBlanc RM, Becette O, Salguero C, Wunderlich CH, John-
son BA, D’Souza VM, Kreutz C, Dayie TK. Chemo-enzymatic synthesis of
site-specific isotopically labeled nucleotides for use in NMR resonance
assignment, dynamics and structural characterizations. Nucleic Acids
Res. 44, e52 (2016).
Ahammer L, Grutsch S, Kamenik AS, Liedl KR, Tollinger M. Structure of
the major apple allergen Mal d 1. J. Agric. Food Chem. 65, 1606-1612
(2017).
Nussbaumer F, Juen M, Gasser C, Kremser J, Mueller T, Tollinger M,
Kreutz CK. Synthesis and incorporation of 13C-labeled DNA building
blocks to probe structural dynamics of DNA by NMR. Nucleic Acids Res.
45, 9178-9192 (2017).
Kremser J, Strebitzer E, Plangger R, Juen MA, Nußbaumer F, Glasner H,
Breuker K, Kreutz C. Chemical synthesis and NMR spectroscopy of long
stable isotope labelled RNA. Chem. Commun. 53, 12938-12941 (2017).
Rennella E, Sara T, Juen M, Wunderlich C, Imbert L, Solyom Z, Favier A,
Ayala I, Weinhaeupl K, Schanda P, Konrat R, Kreutz C, Brutscher B. RNA
binding and chaperone activity of E. coli cold-shock protein CspA. Nucl.
Acids Res. 45, 4255-4268 (2017).
Grutsch S, Fuchs JE, Ahammer L, Kamenik AS, Liedl KR, Tollinger M.
Conformational flexibility differentiates naturally occurring Bet v 1
isoforms. Int. J. Mol. Sci. 18, 1192 (2017).
Ahammer L, Grutsch S, Wallner M, Ferreira F, Tollinger M. NMR reso-
nance assignments of a hypoallergenic isoform of the major birch pol-
len allergen Bet v 1. Biomol. NMR Assign. 11, 231-234 (2017).
Neuner S, Kreutz C, Micura R. The synthesis of 15N7-Hoogsteen face-
labeled adenosine amidite for solid phase RNA synthesis. Monatsh.
Chem. 148, 149-155 (2017).
Wolter AC, Weickhmann AK, Nasiri AH, Hantke K, Ohlenschläger O,
Wunderlich CH, Kreutz C, Duchardt-Ferner E, Wöhnert J. A Stably Pro-
tonated Adenine Nucleotide with a Highly Shifted pKa Value Stabilizes
the Tertiary Structure of a GTP-Binding RNA Aptamer. Angew. Chem.
Int. Ed. Engl. 56, 401-404 (2017).
Tants JN, Fesser S, Kern T, Stehle R, Geerlof A, Wunderlich CH, Juen MA,
Hartlmüller C, Böttcher R, Kunzelmann S, Lange O, Kreutz C, Förste-
mann K, Sattler M. Molecular basis for asymmetry sensing of siRNAs by
the Drosophila Loqs-PD/Dcr-2 complex in RNA interference. Nucl. Acids
Res. 45, 12536-12550 (2017).
Vuorinen A, Engeli RT, Leugger S, Kreutz C, Schuster D, Odermatt
A, Matuszczak B. Phenylbenzenesulfonates and -sulfonamides as
17β-hydroxysteroid dehydrogenase type 2 inhibitors: Synthesis and
SAR-analysis. Bioorg. Med. Chem. Lett. 27, 2982-2985 (2017).
Führer S, Ahammer L, Ausserbichler A, Scheffzek K, Dunzendorfer-Matt
T, Tollinger M. NMR resonance assignments of the EVH1 domain of
Neurofibromin’s recruitment factor Spred1. Biomol. NMR Assign. 11,
305-308 (2017).
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92 93 CMBI news
CMBI - careers of young researchers
CMBI news
facu
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app
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t | Daniela Schuster was awarded one of the first two Ingeborg Hochmair
Professorships by the University of Innsbruck. This temporary professor-
ship is awarded to highly successful, young female scientists to increase
the number of female professors in faculties, where female scientists
are underrepresented. This position should also help the awardees to be
appointed full professors at other institutions. In 2018, Daniela Schuster
follows a call as Professor for Pharmaceutical and Medicinal Chemistry at
the Paracelsus Medical Private University of Salzburg. Together with her
team, she will build up teaching courses and infrastructure for the newly
established pharmacy study and continue her research on in silico acti-
vity profiling, especially in the field of environmental chemical toxicity.
Jerome Mertens joined the Institute of Molecular
Biology in 2017 starting his tenure track, and is
currently building his research group at the De-
partment for Genomics, Stem Cell Biology and
Regenerative Medicine. Dr. Mertens is also con-
ducting his research as a staff scientist at the Salk
Institute for Biological Studies in La Jolla, CA, USA.
His work combines human neural cell reprogram-
ming technologies such as the direct neuronal conversion (iN) with next-
generation sequencing strategies, bioinformatics, neuronal cell biology
and functional neuroscience. With a focus on age-related neurodege-
nerative diseases and neuropsychiatric disorders, his goal is to unravel
the impact of epigenetic cellular states on neuronal pathology, and to
direct the interphase between aging and disease. In 2017, he has been
awarded the prestigious K99 Pathway to Independence award from the
National Institute for Aging.
94 95 CMBI news
CMBI - careers of young researchers
CMBI news
CM
BI s
cho
lars
hip
s | David Granig (Simone B. Sartori and Nicolas
Singewald Group, Institute of Pharmacy,
Department of Pharmacology and Toxicology):
Discovery and characterization of non-
peptidergic neuropeptide S receptor agonists as
potential novel anxiolytics
In collaboration with the Dept. of Pharmacognosy
(Prof. Stuppner, Dr. Schwaiger) four derivatives of our previously
identified potential neuropeptide S receptor (NPSR) agonist were
synthesized in house, virtually screened (Prof. Daniela Schuster,
Dept. Pharmaceutical Chemistry) and characterized in-vitro using
a refined cell-based Ca2+-mobilization assay. The parent compound
and its two dimethyl- and diethyl-derivatives demonstrate specific
agonistic properties at the NPSR with moderate efficacy. Since these
two derivatives are suggested to display BBB penetrance, they
represent leads for the development of small NPSR agonists which are
expected to display similar unique characteristics as the parent NPS,
namely to induce anxiolytic effects without any signs of sedation. The
collaborations are ongoing in terms of refining the pharmacophore
model, the synthesis of derivatives and in vivo testing for potential
therapeutic effects.
Anna Hausruckinger (Frank Edenhofer Group,
Department of Molecular Biology): CaV expression
in neurons derived from human iPS cells
Voltage-gated calcium channels (CaVs) are
involved in the regulation of various neuronal
functions in the central nervous system, such as
neurotransmitter secretion, postsynaptic signal
integration and neuronal plasticity. Current research mainly depends
on the analyses of heterologous expression systems (such as HEK cells)
or primary animal neurons that are far from being ideal to correlate
with the physiology of human neurons. Induced pluripotent stem (iPS)
cells represent a promising alternative source of human neurons. The
overall aim of the project is to elaborate on an expression analysis
of CaVs subunits in neurons derived from human iPS cells. Moreover,
we investigate to which extent the modulation of CaV functionality
by subunit overexpression will impact on the maturation and
synaptogenesis of in vitro differentiated neurons.
In 2013, the CMBI initiated an annual call for a young investigator
scholarship. Aim of this scholarship is to support a young career
(Master/PhD level) and to strengthen collaboration within the CMBI
by selecting a candidate, who is engaged in a high-profile research
project connecting two or more CMBI member groups. The scholar and
his project are supported by allocating prize money for expendable
materials and consumables.
Previous CMBI Scholars:
2013: R. Spitzer
(Christoph Kreutz Group, Department of Organic Chemistry)
2014: Johanna E. Mayrhofer
(Eduard Stefan Group, Department of Biochemistry)
2015: Julian Wimmer (Ilse Kranner, Department of Botany)
2016: Florian Enzler (Eduard Stefan, Department of Biochemistry)
The current CMBI Scholars for 2017:
96 97 Awards and honors for CMBI scientists Awards and honors for CMBI scientists
Awards and honors for CMBI scientists
Linda Ahammer, Department of Organic Chemistry:
"Young Investigator Award" at the 27th ICMRBS in Kyoto, Japan,
August 2016.
Erwann Arc, Department of Botany:
Best lecture of an early career scientist, 21th meeting of the ATSPB,
Berchtesgaden, 2016
Giorgia Baraldo, Research Department for Biomedical Aging
Research:
Grant D. Swarovski AG, “Plant-derived compounds for inhibition of
NOX4 to counteract vascular aging”
Giovanni Calderisi, Department of Organic Chemistry:
Student Travel Award of the American Society for Mass
Spectrometry for presentation of a poster at the 65th ASMS
conference, Indianapolis, IN, USA (2017)
Andreas Friedl, Department of Pharmacognosy:
Meda Preis für Phytopharmaka-Forschung 2016
Sebastian Führer, Department of Organic Chemistry:
GÖCH-Förderungspreis für die besten Diplomarbeiten (Gesellschaft
Österreichischer Chemiker), Austria, 2017 Innsbruck 2017.
Marco Grasse, Research Department for Biomedical Aging Research:
Grant D. Swarovski AG 2017, “Effects of GM-CSF application
during tetanus/diphtheria vaccination on the antigen-specific T cell
response in vivo”
Katharina Günther, Department of Molecular Biology:
Poster Prize, 9th ÖGMBT Annual Meeting & 8th Life Science Meeting,
"Molecular and cellular mechanisms of human diseases". Innsbruck, 2017
Nadja Hofer, Department of Pharmacology and Toxicology:
Würdigungspreis Bundesministerium für Wissenschaft, Forschung
und Wirtschaft (2016)
Ilse Kranner, Department of Botany
President of the ATSPB (Austrian Society of Plant Biology) and
national delegate on the FESPB (Federation of European Societies
of Plant Biology) Council
Johannes Kremser, Department of Organic Chemistry:
"Suraj Manrao Poster Award" at the 20th ISMAR in Quebec City,
Canada, July 2017.
Birgit Lengerer, Department of Zoology
Best Poster Award (3rd Place), Life Science PhD Meeting Innsbruck 2017
Carina Miggitsch, Research Department for Biomedical
Aging Research:
Best Short Talk Award, Life Science PhD Meeting Innsbruck 2017
Simon Moosmang, Department of Pharmacognosy:
Young Talent Poster Award, First Place - Best Poster, VASCage
Meeting, 2017
Sandro Neuner, Department of Organic Chemistry
Best Paper Award 2017, Monatshefte für Chemie/Chemical Monthly,
Springer
Michael Neustetter, Department of Ion Physics and Applied Physics:
Award of Excellence of the Austrian Federal Ministry of Science and
Research (2017).
Nadine Ortner, Department of Pharmacology and Toxicology:
Principality of Liechtenstein Prize (2017)
Nadine Ortner, Department of Pharmacology and Toxicology:
Jubiläumsfonds der Universität Innsbruck und der Medizinischen
Universität Innsbruck zur Förderung wissenschaftlicher
Kooperationsprojekte (2017)
Nadine Ortner, Department of Pharmacology and Toxicology:
ALUMNI-I-MED Talk Prize, Life Science PhD Meeting (2017)
Luca Pangrazzi, Research Department for Biomedical
Aging Research:
Grant D. Swarovski AG 2016, “Characterization of niche providing
cells in the bone marrow”
awar
ds
|
Erwann Arc
Marco Grasse Luca Pangrazzi
Ilse Kranner
Sebastian Führer, 17. Österreichische Chemietage,
Univ. Salzburg (2017), Foto: Göch
The successful scientific activities of the CMBI are reflected in numerous
awards and honors received from several members during the reporting
period.
Katharina Günther
98 99
Isabella Pfeifer, Department of Pharmacognosy:
Meda Preis für Phytopharmaka-Forschung 2017
Michael Schauperl, Department of General, Inorganic and
Theoretical Chemistry:
Dr. Otto Seibert Science Award, 11/2017
Michael Schauperl, Department of General, Inorganic and
Theoretical Chemistry:
Science Award 2017 of the Tyrolean Economic Chamber, 11/2017
Daniela Schuster, Department of Pharmaceutical Chemistry:
Ingeborg Hochmair Professorship 2016
Daniela Schuster, Department of Pharmaceutical Chemistry:
Poster award (2nd rank) at Pharma 2030
Torsten Schwerte, Department of Zoology:
Edmund Optics Educational Award Winner in Europe (2017)
Anita Siller, Department of Pharmacology and Toxicology:
Studienförderpreis des Deutschen Freundeskreises der
Universitäten in Innsbruck e. V. (2016)
Anita Siller, Department of Pharmacology and Toxicology:
Best Poster Award, 9th ÖGMBT Annual Meeting (2017)
Anita Siller, Department of Pharmacology and Toxicology:
Best Poster Award, 8th Life Science Meeting (2a017)
Anita Siller, Department of Pharmacology and Toxicology:
Würdigungspreis des Bundesministeriums für Wissenschaft,
Wirtschaft und Forschung (2017)
Hermann Stuppner, Department of Pharmacognosy:
Wissenschaftspreis für außergewöhnliche Forschungsleistung der
Stiftung Südtiroler Sparkasse, 2017
Hermann Stuppner, Department of Pharmacognosy:
Bruker Award, 2017
Birgit Waldner, Department of General, Inorganic and
Theoretical Chemistry:
Poster award of the Molecular Modeling Workshop Erlangen
Alexander Weiss, Research Department for Biomedical Aging
Research:
Grant D. Swarovski AG, “Struktur- und Aktivitätsbestimmung des
menschlichen Stoffwechselenzyms FAHD2a”
Julia Wunderer, Department of Zoology
Best Poster Award (1st Place), Life Science PhD Meeting Innsbruck 2017
Julia Wunderer, Department of Zoology
Best Short Talk Award (1st Place), 6th Annual CMBI Meeting 2016
Awards and honors for CMBI scientists
CMBI - meetings
CMBI - meetings and seminar series
LIFE SCIENCE PHD MEETING
This meeting was held in the Center for Chemistry and Biomedicine in
Innsbruck on April 18-19, 2017. It brings together the annual meetings
of the different FWF-funded excellence doctoral programs and, most
importantly is organized by PhD students. The participating programs
were MCBO, SPIN, and HOROS but all PhD students of both universities
were invited. The student organizers also brought in excellent plenary
speakers: Catherina Becker (University of Edinburgh, UK), Jörg Köhl
(University of Lübeck, DE) and Arnoud Sonnenberg (The Netherlands
Cancer Institute, Amsterdam, NL). Of course, CMBI many CMBI PhD
students and postdocs alo participated and ppresented their recent re-
search findings. Some of them won prizes, such as Nadine Ornter (Phar-
macology, Pharmacy) for an excellent oral presentation (together with
jury member Prof. Raimund Margreiter).
23RD SCIENTIFIC SYMPOSIUM
OF THE AUSTRIAN PHARMACOLOGICAL SOCIETY APHAR
CMBI members are also part of the Austrian Pharmacological Society
APHAR and were in charge of organizing the annual APHAR meeting in
Innsbruck on September 28–29, 2017. In addition to regulatory aspects
of the European Medicines Agency (plenary lecture by Thomas Salmon-
sen, London & Medicinal Products Agency, Uppsala, SWE) John A. Ci-
dlowski (Natl Inst. of Environmental Health Services, USA) and Michel
Bouvier (Univ. de Montréal, CAN) also presented recent work not only
interesting for pharmacologists but also for the CMBI community.
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Hermann Stuppner
Hermann Stuppner
Michael Schauperl
100 101
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CMBI - meetings and seminar seriesCMBI - meetings and seminar series
6TH ANNUAL CMBI MEETING INNSBRUCK 2016
On March 3rd and 4th, the CMBI held its 6th annual joint meeting in
Gnadenwald focusing on drugs and biotechnology, proteomics and me-
tabolomics, protein structure, signaling, disease and stress mechanisms.
About 120 – mostly young – researchers from CMBI member labs gath-
ered in order to share their newest Life Science findings in more than 70
oral and poster presentations and to initiate discussion and interaction.
Three impressive, high-profile plenary speakers, Christian Griesinger
(MPI Göttingen), Remco Sprangers (MPI Tübingen), Almut Schulze (Uni
Würzburg), and an inspiring Introduction Lecture held by the newly ap-
pointed faculty member Frank Edenhofer complemented the program.
As in previous years, three prizes were selected with the help of the
plenary speakers for the best young scientists’ conference presenta-
tions. Two poster prizes were awarded to Marina Frener (Department
for Organic Chemistry) and Armin Wilfinger (Department of Molecular
Biology). The award for the best short talk was given to Julia Wunderer
(Department of Zoology).
9TH ÖGMBT ANNUAL MEETING 2017 &
8TH LIFE SCIENCE MEETING INNSBRUCK
This largest regular life science meeting in western Austria took place
in Innsbruck from September 25–27, 2017. It also serves as a key annual
meeting of the biomedical and biological research community of the
two Innsbruck universities. The CMBI groups also actively participated
with interesting oral and poster presentations thereby increasing the
critical mass of the event. All enjoyed the interdisciplainary conversa-
tions with scientists from all over Austria. Excellent invited speakers also
particpated with the lively discusisons at the posters. Invited speakers
were Andrea Ballabio, TIGEM, IT; Thomas Carell, LMU, DE; Christine Falk,
MHH, DE; Micheala Frye, University of Cambridge, UK; Florian Greten,
FCI, DE; Silvio Gutkind, UCSD, US; Karl Lohner, KFU Graz, AT; Alexander
Mankin, UIC, US; Richard Marais, University of Manchester, UK; Alexan-
der Meissner, Harvard University, US; Maria M. Mota, iMM Lisboa, PT;
Matthias Peter, ETH Zürich, CH; Steven Taylor, University of Manchester,
UK; Andreas Trumpp, DKFZ, DE; Georg Winter, CeMM, AT; Nieng Yan,
Tsinghua University, CN. Students and young scientists from several FWF-
funded excellence consortia participated at this meeting, including the
doctoral programs SPPIN, HOROS and MCBO as well as the neuroscience
research consortium SFB-F44. CMBI investigators actively participate in
all these programs.
102 103 CMBI - meetings and seminar series
External speakers at previous CMBI meetings
In addition to the many exciting short talks and poster presentations from
members of the CMBI and the Biocenter, guest lectures from invited top
scientists contributed to the lively discussions. Like in previous meetings,
the speakers also served as advisory experts for our research activities and
as referees for the poster awards for young scientists.
6th CMBI Meeting Innsbruck, Innsbruck, Tyrol, March 3th - 4th, 2016
>> Christian Griesinger
Max Planck Institute for Biophysical Chemistry Göttingen, Germany
>> Frank Edenhofer, University of Innsbruck, Austria
>> Remco Sprangers, Max Planck Campus Tübingen, Germany
>> Almut Schulze, University of Wuerzburg, Germany
7th Life Science Meeting Innsbruck, Innsbruck, Tyrol, Feb. 27th, 2015
>> Peter Hinterdorfer, University of Linz, Austria
>> Eduard Stefan, University of Innsbruck, Austria
>> Peter Ladurner, University of Innsbruck, Austria
>> Gunter Meister, University of Regensburg, Germany
>> Gerald Obermair, Medical University of Innsbruck, Austria
>> Natascha Kleiter, Medical University of Innsbruck, Austria
>> Pascal Meier, ICR London, UK
>> Marlies Meisl, University of Chicago, USA
>> Martin Puhr, Medical University of Innsbruck, Austria
>> Bill Earnshaw, University of Edinburgh, UK
6th Life Science Meeting Innsbruck, Innsbruck, Tyrol, Sept. 24th - 25th, 2014
>> Robert T. Batey, University of Colorado Boulder, USA
>> Veronika Sexl, University of Veterinary Medicine, Vienna, Austria
>> Florian Kronenberg, Medical University of Innsbruck, Austria
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CMBI - meetings
CMBI - meetings and seminar series
5th Life Science Meeting Innsbruck, Innsbruck, Tyrol, Sept. 25th - 27th, 2013
>> Asifa Akhtar
Max Planck Institute of Immunobiology and Epigenetics, Germany
>> Michel Desjardins, Universite de Montreal, Canada
>> Carl-Philipp Heisenberg, IST Austria
>> Karolin Luger, Colorado State University, USA
>> Frauke Melchior, ZMBH Heidelberg University, Germany
>> Nikolaus Pfanner, University of Freiburg, Germany
>> Britta Qualmann, Friedrich-Schiller-University Jena, Germany
>> Elena Rugarli, University of Cologne, Germany
>> Susan S. Taylor, University of California San Diego, USA
4th Life Science Meeting Innsbruck, Igls, Tyrol, Sept. 27th - 28th, 2012
>> Christine Foyer
Centre for Plant Sciences, University of Leeds, United Kingdom
>> Ari Helenius, Institute of Biochemistry, ETH Zürich, Switzerland
>> Anne-Claude Gavin
Structural and Computational Biology, EMBL Heidelberg, Germany
3rd Life Science Meeting Innsbruck, Igls, Tyrol, Sept. 23th - 24th, 2011
>> Ilme Schlichting
Department of Biomolecular Mechanisms, Max Planck Institute for Medical
Research, Heidelberg, Germany
>> Adrian R. Ferré-D’Amaré
Laboratory of RNA Biophysics and Cellular Physiology, Biochemistry and
Biophysics Center, National Heart, Lung and Blood Institute, Bethesda, USA
>> Daniel Minor
Cardiovascular Research Institute, Departments of Biochemistry & Biophysics,
and Cellular & Molecular Pharmacology California Institute for Quantitative
Biomedical Research, University of California, San Francisco, USA
2nd Life Science Meeting Innsbruck, Igls, Tyrol, Sept. 24th - 25th, 2010
>> Maria Sibilia
Institute for Cancer Research, Medical University of Vienna, Austria
>> Adriano Aguzzi
Institute of Neuropathology, University Hospital of Zürich, Switzerland
>> Rik Korswagen
Hubrecht Institute, Utrecht, Netherlands
1st Life Science Meeting Innsbruck, Igls, Tyrol, Sept. 18th - 19th, 2009
>> Dirk Trauner
Department of Chemistry and Biochemistry, LMU Munich, Germany
>> Didier Stainier, University of California, San Francisco, USA
>> Wolfgang Baumeister
Max-Planck-Institute of Biochemistry, Martinsried, Germany
104 105
5th Annual CMBI-Meeting Igls, Tyrol, Sept. 26th - 27th, 2008
>> Peter Hegemann
Institute for Biology, Experimental Biophysics, Humboldt University Berlin,
Germany
>> Stefan Schulte-Merker
Hubrecht Laboratory, Netherlands Institute for Developmental Biology
Utrecht, Netherlands
4th Annual CMBI-Meeting Igls, Tyrol, Sept. 28th - 29th, 2007
>> Ulf R. Rapp
Medical Radiation & Cell Research, Univ. of Würzburg, Germany
>> Gregory J. Kaczorowski
Merck Research Laboratories, Rahway, New Jersey, USA
>> Thomas W. Holstein
Institute of Zoology, University of Heidelberg, Germany
3rd Annual CMBI-Meeting Vill, Tyrol, Sept. 29th - 30th, 2006
>> Naweed I. Syed, Anatomy and Physiology, University of Calgary, Canada
>> Erwin F. Wagner
Research Institute of Molecular Pathology, Vienna, Austria
>> Walter Schaffner
Institute of Molecular Biology, University of Zurich, Switzerland
2nd Annual CMBI-Meeting Vill, Tyrol, Sept. 30th - Oct. 1st, 2005
>> Wolfram Saenger
Inst. of Chemistry & Crystallography, Free University Berlin, D
>> Peter Herrlich, Institute of Molecular Biotechnology, Jena, Germany
>> Elisabeth Knust, Institute of Genetics, University of Düsseldorf, Germany
1st Annual CMBI-Meeting Vill, Tyrol, Oct. 1st - 2nd, 2004
>> Robert Huber
Nobel Laureate in Chemistry, MPI of Biochemistry, Martinsried, D
>> Reinhard Fässler
Max-Planck-Institute of Biochemistry, Martinsried, Germany
>> Daniela Pietrobon
Dept. of Biomedical Sciences, University of Padova, Italy
CMBI - seminar seriesCMBI - meetingsCMBI - Meetings and Seminar Series
sem
inar
s | The CMBI seminars are a very important integrative and multidisciplinary ac-
tivity of the CMBI and are also part of the PhD programs established within
the CMBI. So far, it hosted 111 lectures from renowned scientists from the US,
Canada, Australia, Sweden, Denmark, France, Italy, UK, Ireland, Netherlands,
Germany, Belgium, Switzerland, and Austria. It also provides a forum for ex-
cellent scientists from the Innsbruck Universities. Seminar speakers of the last
three years are listed here:
2017Rasmus Linser, Ph.D.
Department for Chemistry, Ludwig-Maximilians-University of Munich,
Germany
Michel Bouvier, Ph.D.
F.C.A.H.S., FRSC Université de Montréal, Institute of Research in
Immunology and Cancer, Montréal, Canada
Oliver Rocks, Ph.D.
Max Delbrück Center for Molecular Medicine, Berlin, Germany
David Gillespie, Ph.D.
Institute of Biomedical Technologies, Centre for Biomedical Research
of the Canary Islands
Nathan Lüdtke, Ph.D.
University of Zurich, Department of Chemistry, Zurich, Switzerland
David Henshall, Ph.D.
Professor of Molecular Physiology and Neuroscience, Royal College of
Surgeons in Ireland, Dublin, Ireland
Helmut Schwarz, Ph.D.
Institute of Chemistry, Technical University of Berlin, Germany
Hans Schöler, Ph.D.
Max-Planck Institute for Molecular Biomedicine, Münster, Germany
Andrea Pauli, Ph.D.
IMP - Research Institute of Molecular Pathology, Vienna, Austria
Monika Hassel, Ph.D.
Morphology and Evolution of Invertebrates, Philipps-University of
Marburg, Germany
2016Stephan A. Sieber, Ph.D.
Department of Chemistry, Technical University of Munich, Germany
Dirk Trauner, Ph.D.
Department for Chemistry and Biochemistry, Ludwig-Maximilians-
University of Munich, Germany
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106
CMBI - seminar series
CMBI - meetings and seminar series
Jeffrey Liu, Ph.D.
Max Planck Institute of Biochemistry, Martinsried, Germany
Alois Fürstner , Ph.D.
Organometallic Chemistry, Max-Planck-Institute, Mühlheim, Germany
Dominique Massotte, Ph.D.
Institut des Neurosciences Cellulaires et Intégratives, Strasbourg,
France
Michael Heise, Ph.D.
South Westphalia University of Applied Sciences, Iserlohn, Germany
Norbert Bischofberger, Ph.D.
Gilead Sciences, California, USA
Gerald Schwank, Ph.D.
Institute for Molecular Health Sciences, ETH Zurich, Switzerland
Rudi Vennekens, Ph.D.
Laboratory of Ion Channel Research Biology, KU Leuven, NL
Frank Edenhofer, Ph.D.
Institute of Molecular Biology, University of Innsbruck, A
Jutta Schüller, Ph.D.
Taconic Biosciences, Cologne, G
Roland Sigel, Ph.D.
Department of Chemistry, University of Zurich, CH
2015Stefan Hörtensteiner, Ph.D.
Institute of Plant Biology, University of Zurich, CH
Georg S. Baillie, Ph.D.
Molecular Pharmacology, Institute of Cardiovascular and Medical
Sciences, University of Glasgow, UK
Daniel Gerlich, Ph.D.
IMP, Vienna, AT
Elena Conti, Ph.D.
Director, MPI, Munich, Germany
Alexander Stark, Ph.D.
IMP, Vienna, AT
Markus Ralser, Ph.D.
CSBC, University of Cambridge, UK
Matthias Hentze, MD
EMBL, Heidelberg, Germany
Roger Schibli, Ph.D.
Institute for Pharmaceutical Sciences, ETH Zurich, Switzerland
sem
inar
s |
Centrum für
Molekulare Biowissenschaften Innsbruck
Universität Innsbruck
Office: Innrain 80-82a
A-6020 Innsbruck
Tel: +43 512 507-57501
Fax: +43 512 507-57599
www.uibk.ac.at/cmbi
contact |