---
_id: '6894'
abstract:
- lang: eng
text: "Hybrid automata combine finite automata and dynamical systems, and model
the interaction of digital with physical systems. Formal analysis that can guarantee
the safety of all behaviors or rigorously witness failures, while unsolvable in
general, has been tackled algorithmically using, e.g., abstraction, bounded model-checking,
assisted theorem proving.\r\nNevertheless, very few methods have addressed the
time-unbounded reachability analysis of hybrid automata and, for current sound
and automatic tools, scalability remains critical. We develop methods for the
polyhedral abstraction of hybrid automata, which construct coarse overapproximations
and tightens them incrementally, in a CEGAR fashion. We use template polyhedra,
i.e., polyhedra whose facets are normal to a given set of directions.\r\nWhile,
previously, directions were given by the user, we introduce (1) the first method\r\nfor
computing template directions from spurious counterexamples, so as to generalize
and\r\neliminate them. The method applies naturally to convex hybrid automata,
i.e., hybrid\r\nautomata with (possibly non-linear) convex constraints on derivatives
only, while for linear\r\nODE requires further abstraction. Specifically, we introduce
(2) the conic abstractions,\r\nwhich, partitioning the state space into appropriate
(possibly non-uniform) cones, divide\r\ncurvy trajectories into relatively straight
sections, suitable for polyhedral abstractions.\r\nFinally, we introduce (3) space-time
interpolation, which, combining interval arithmetic\r\nand template refinement,
computes appropriate (possibly non-uniform) time partitioning\r\nand template
directions along spurious trajectories, so as to eliminate them.\r\nWe obtain
sound and automatic methods for the reachability analysis over dense\r\nand unbounded
time of convex hybrid automata and hybrid automata with linear ODE.\r\nWe build
prototype tools and compare—favorably—our methods against the respective\r\nstate-of-the-art
tools, on several benchmarks."
alternative_title:
- ISTA Thesis
article_processing_charge: No
author:
- first_name: Mirco
full_name: Giacobbe, Mirco
id: 3444EA5E-F248-11E8-B48F-1D18A9856A87
last_name: Giacobbe
orcid: 0000-0001-8180-0904
citation:
ama: Giacobbe M. Automatic time-unbounded reachability analysis of hybrid systems.
2019. doi:10.15479/AT:ISTA:6894
apa: Giacobbe, M. (2019). Automatic time-unbounded reachability analysis of hybrid
systems. Institute of Science and Technology Austria. https://doi.org/10.15479/AT:ISTA:6894
chicago: Giacobbe, Mirco. “Automatic Time-Unbounded Reachability Analysis of Hybrid
Systems.” Institute of Science and Technology Austria, 2019. https://doi.org/10.15479/AT:ISTA:6894.
ieee: M. Giacobbe, “Automatic time-unbounded reachability analysis of hybrid systems,”
Institute of Science and Technology Austria, 2019.
ista: Giacobbe M. 2019. Automatic time-unbounded reachability analysis of hybrid
systems. Institute of Science and Technology Austria.
mla: Giacobbe, Mirco. Automatic Time-Unbounded Reachability Analysis of Hybrid
Systems. Institute of Science and Technology Austria, 2019, doi:10.15479/AT:ISTA:6894.
short: M. Giacobbe, Automatic Time-Unbounded Reachability Analysis of Hybrid Systems,
Institute of Science and Technology Austria, 2019.
date_created: 2019-09-22T14:08:44Z
date_published: 2019-09-30T00:00:00Z
date_updated: 2023-09-19T09:30:43Z
day: '30'
ddc:
- '000'
degree_awarded: PhD
department:
- _id: ToHe
doi: 10.15479/AT:ISTA:6894
file:
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creator: mgiacobbe
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date_updated: 2020-07-14T12:47:43Z
file_id: '6916'
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file_size: 4100685
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date_created: 2019-09-27T14:22:04Z
date_updated: 2020-07-14T12:47:43Z
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has_accepted_license: '1'
language:
- iso: eng
license: https://creativecommons.org/licenses/by/4.0/
month: '09'
oa: 1
oa_version: Published Version
page: '132'
publication_identifier:
eissn:
- 2663-337X
publication_status: published
publisher: Institute of Science and Technology Austria
related_material:
record:
- id: '631'
relation: part_of_dissertation
status: public
- id: '647'
relation: part_of_dissertation
status: public
- id: '140'
relation: part_of_dissertation
status: public
status: public
supervisor:
- first_name: Thomas A
full_name: Henzinger, Thomas A
id: 40876CD8-F248-11E8-B48F-1D18A9856A87
last_name: Henzinger
orcid: 0000−0002−2985−7724
title: Automatic time-unbounded reachability analysis of hybrid systems
tmp:
image: /images/cc_by.png
legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
short: CC BY (4.0)
type: dissertation
user_id: c635000d-4b10-11ee-a964-aac5a93f6ac1
year: '2019'
...
---
_id: '7172'
abstract:
- lang: eng
text: "The development and growth of Arabidopsis thaliana is regulated by a combination
of genetic programing and also by the environmental influences. An important role
in these processes play the phytohormones and among them, auxin is crucial as
it controls many important functions. It is transported through the whole plant
body by creating local and temporal concentration maxima and minima, which have
an impact on the cell status, tissue and organ identity. Auxin has the property
to undergo a directional and finely regulated cell-to-cell transport, which is
enabled by the transport proteins, localized on the plasma membrane. An important
role in this process have the PIN auxin efflux proteins, which have an asymmetric/polar
subcellular localization and determine the directionality of the auxin transport.
During the last years, there were significant advances in understanding how the
trafficking molecular machineries function, including studies on molecular interactions,
function, subcellular localization and intracellular distribution. However, there
is still a lack of detailed characterization on the steps of endocytosis, exocytosis,
endocytic recycling and degradation. Due to this fact, I focused on the identification
of novel trafficking factors and better characterization of the intracellular
trafficking pathways. My PhD thesis consists of an introductory chapter, three
experimental chapters, a chapter containing general discussion, conclusions and
perspectives and also an appendix chapter with published collaborative papers.\r\nThe
first chapter is separated in two different parts: I start by a general introduction
to auxin biology and then I introduce the trafficking pathways in the model plant
Arabidopsis thaliana. Then, I explain also the phosphorylation-signals for polar
targeting and also the roles of the phytohormone strigolactone.\r\nThe second
chapter includes the characterization of bar1/sacsin mutant, which was identified
in a forward genetic screen for novel trafficking components in Arabidopsis thaliana,
where by the implementation of an EMS-treated pPIN1::PIN1-GFP marker line and
by using the established inhibitor of ARF-GEFs, Brefeldin A (BFA) as a tool to
study trafficking processes, we identified a novel factor, which is mediating
the adaptation of the plant cell to ARF-GEF inhibition. The mutation is in a previously
uncharacterized gene, encoding a very big protein that we, based on its homologies,
called SACSIN with domains suggesting roles as a molecular chaperon or as a component
of the ubiquitin-proteasome system. Our physiology and imaging studies revealed
that SACSIN is a crucial plant cell component of the adaptation to the ARF-GEF
inhibition.\r\nThe third chapter includes six subchapters, where I focus on the
role of the phytohormone strigolactone, which interferes with auxin feedback on
PIN internalization. Strigolactone moderates the polar auxin transport by increasing
the internalization of the PIN auxin efflux carriers, which reduces the canalization
related growth responses. In addition, I also studied the role of phosphorylation
in the strigolactone regulation of auxin feedback on PIN internalization. In this
chapter I also present my results on the MAX2-dependence of strigolactone-mediated
root growth inhibition and I also share my results on the auxin metabolomics profiling
after application of GR24.\r\nIn the fourth chapter I studied the effect of two
small molecules ES-9 and ES9-17, which were identified from a collection of small
molecules with the property to impair the clathrin-mediated endocytosis.\r\nIn
the fifth chapter, I discuss all my observations and experimental findings and
suggest alternative hypothesis to interpret my results.\r\nIn the appendix there
are three collaborative published projects. In the first, I participated in the
characterization of the role of ES9 as a small molecule, which is inhibitor of
clathrin- mediated endocytosis in different model organisms. In the second paper,
I contributed to the characterization of another small molecule ES9-17, which
is a non-protonophoric analog of ES9 and also impairs the clathrin-mediated endocytosis
not only in plant cells, but also in mammalian HeLa cells. Last but not least,
I also attach another paper, where I tried to establish the grafting method as
a technique in our lab to study canalization related processes."
acknowledged_ssus:
- _id: LifeSc
- _id: Bio
alternative_title:
- ISTA Thesis
article_processing_charge: No
author:
- first_name: Mina K
full_name: Vasileva, Mina K
id: 3407EB18-F248-11E8-B48F-1D18A9856A87
last_name: Vasileva
citation:
ama: Vasileva MK. Molecular mechanisms of endomembrane trafficking in Arabidopsis
thaliana. 2019. doi:10.15479/AT:ISTA:7172
apa: Vasileva, M. K. (2019). Molecular mechanisms of endomembrane trafficking
in Arabidopsis thaliana. Institute of Science and Technology Austria. https://doi.org/10.15479/AT:ISTA:7172
chicago: Vasileva, Mina K. “Molecular Mechanisms of Endomembrane Trafficking in
Arabidopsis Thaliana.” Institute of Science and Technology Austria, 2019. https://doi.org/10.15479/AT:ISTA:7172.
ieee: M. K. Vasileva, “Molecular mechanisms of endomembrane trafficking in Arabidopsis
thaliana,” Institute of Science and Technology Austria, 2019.
ista: Vasileva MK. 2019. Molecular mechanisms of endomembrane trafficking in Arabidopsis
thaliana. Institute of Science and Technology Austria.
mla: Vasileva, Mina K. Molecular Mechanisms of Endomembrane Trafficking in Arabidopsis
Thaliana. Institute of Science and Technology Austria, 2019, doi:10.15479/AT:ISTA:7172.
short: M.K. Vasileva, Molecular Mechanisms of Endomembrane Trafficking in Arabidopsis
Thaliana, Institute of Science and Technology Austria, 2019.
date_created: 2019-12-11T21:24:39Z
date_published: 2019-12-12T00:00:00Z
date_updated: 2023-09-19T10:39:33Z
day: '12'
ddc:
- '570'
degree_awarded: PhD
department:
- _id: JiFr
doi: 10.15479/AT:ISTA:7172
file:
- access_level: closed
checksum: ef981c1a3b1d9da0edcbedcff4970d37
content_type: application/vnd.openxmlformats-officedocument.wordprocessingml.document
creator: mvasilev
date_created: 2019-12-12T09:32:36Z
date_updated: 2020-07-14T12:47:51Z
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file_name: Thesis_Mina_final_upload_7.docx
file_size: 20454014
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content_type: application/pdf
creator: mvasilev
date_created: 2019-12-12T09:33:10Z
date_updated: 2020-07-14T12:47:51Z
file_id: '7176'
file_name: Thesis_Mina_final_upload_7.pdf
file_size: 11565025
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file_date_updated: 2020-07-14T12:47:51Z
has_accepted_license: '1'
language:
- iso: eng
month: '12'
oa: 1
oa_version: Published Version
page: '192'
publication_identifier:
eissn:
- 2663-337X
publication_status: published
publisher: Institute of Science and Technology Austria
related_material:
record:
- id: '1346'
relation: part_of_dissertation
status: public
- id: '6377'
relation: part_of_dissertation
status: public
- id: '449'
relation: part_of_dissertation
status: public
status: public
supervisor:
- first_name: Jiří
full_name: Friml, Jiří
id: 4159519E-F248-11E8-B48F-1D18A9856A87
last_name: Friml
orcid: 0000-0002-8302-7596
title: Molecular mechanisms of endomembrane trafficking in Arabidopsis thaliana
type: dissertation
user_id: c635000d-4b10-11ee-a964-aac5a93f6ac1
year: '2019'
...
---
_id: '6473'
abstract:
- lang: eng
text: "Single cells are constantly interacting with their environment and each other,
more importantly, the accurate perception of environmental cues is crucial for
growth, survival, and reproduction. This communication between cells and their
environment can be formalized in mathematical terms and be quantified as the information
flow between them, as prescribed by information theory. \r\nThe recent availability
of real–time dynamical patterns of signaling molecules in single cells has allowed
us to identify encoding about the identity of the environment in the time–series.
However, efficient estimation of the information transmitted by these signals
has been a data–analysis challenge due to the high dimensionality of the trajectories
and the limited number of samples. In the first part of this thesis, we develop
and evaluate decoding–based estimation methods to lower bound the mutual information
and derive model–based precise information estimates for biological reaction networks
governed by the chemical master equation. This is followed by applying the decoding-based
methods to study the intracellular representation of extracellular changes in
budding yeast, by observing the transient dynamics of nuclear translocation of
10 transcription factors in response to 3 stress conditions. Additionally, we
apply these estimators to previously published data on ERK and Ca2+ signaling
and yeast stress response. We argue that this single cell decoding-based measure
of information provides an unbiased, quantitative and interpretable measure for
the fidelity of biological signaling processes. \r\nFinally, in the last section,
we deal with gene regulation which is primarily controlled by transcription factors
(TFs) that bind to the DNA to activate gene expression. The possibility that non-cognate
TFs activate transcription diminishes the accuracy of regulation with potentially
disastrous effects for the cell. This ’crosstalk’ acts as a previously unexplored
source of noise in biochemical networks and puts a strong constraint on their
performance. To mitigate erroneous initiation we propose an out of equilibrium
scheme that implements kinetic proofreading. We show that such architectures are
favored over their equilibrium counterparts for complex organisms despite introducing
noise in gene expression. "
alternative_title:
- ISTA Thesis
article_processing_charge: No
author:
- first_name: Sarah A
full_name: Cepeda Humerez, Sarah A
id: 3DEE19A4-F248-11E8-B48F-1D18A9856A87
last_name: Cepeda Humerez
citation:
ama: Cepeda Humerez SA. Estimating information flow in single cells. 2019. doi:10.15479/AT:ISTA:6473
apa: Cepeda Humerez, S. A. (2019). Estimating information flow in single cells.
Institute of Science and Technology Austria. https://doi.org/10.15479/AT:ISTA:6473
chicago: Cepeda Humerez, Sarah A. “Estimating Information Flow in Single Cells.”
Institute of Science and Technology Austria, 2019. https://doi.org/10.15479/AT:ISTA:6473.
ieee: S. A. Cepeda Humerez, “Estimating information flow in single cells,” Institute
of Science and Technology Austria, 2019.
ista: Cepeda Humerez SA. 2019. Estimating information flow in single cells. Institute
of Science and Technology Austria.
mla: Cepeda Humerez, Sarah A. Estimating Information Flow in Single Cells.
Institute of Science and Technology Austria, 2019, doi:10.15479/AT:ISTA:6473.
short: S.A. Cepeda Humerez, Estimating Information Flow in Single Cells, Institute
of Science and Technology Austria, 2019.
date_created: 2019-05-21T00:11:23Z
date_published: 2019-05-23T00:00:00Z
date_updated: 2023-09-19T15:13:26Z
day: '23'
ddc:
- '004'
degree_awarded: PhD
department:
- _id: GaTk
doi: 10.15479/AT:ISTA:6473
file:
- access_level: closed
checksum: 75f9184c1346e10a5de5f9cc7338309a
content_type: application/zip
creator: scepeda
date_created: 2019-05-23T11:18:16Z
date_updated: 2020-07-14T12:47:31Z
file_id: '6480'
file_name: Thesis_Cepeda.zip
file_size: 23937464
relation: source_file
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checksum: afdc0633ddbd71d5b13550d7fb4f4454
content_type: application/pdf
creator: scepeda
date_created: 2019-05-23T11:18:13Z
date_updated: 2020-07-14T12:47:31Z
file_id: '6481'
file_name: CepedaThesis.pdf
file_size: 16646985
relation: main_file
file_date_updated: 2020-07-14T12:47:31Z
has_accepted_license: '1'
keyword:
- Information estimation
- Time-series
- data analysis
language:
- iso: eng
month: '05'
oa: 1
oa_version: Published Version
page: '135'
publication_identifier:
issn:
- 2663-337X
publication_status: published
publisher: Institute of Science and Technology Austria
related_material:
record:
- id: '1576'
relation: dissertation_contains
status: public
- id: '6900'
relation: dissertation_contains
status: public
- id: '281'
relation: dissertation_contains
status: public
- id: '2016'
relation: dissertation_contains
status: public
status: public
supervisor:
- first_name: Gašper
full_name: Tkačik, Gašper
id: 3D494DCA-F248-11E8-B48F-1D18A9856A87
last_name: Tkačik
orcid: 0000-0002-6699-1455
title: Estimating information flow in single cells
tmp:
image: /images/cc_by.png
legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
short: CC BY (4.0)
type: dissertation
user_id: c635000d-4b10-11ee-a964-aac5a93f6ac1
year: '2019'
...
---
_id: '6071'
abstract:
- lang: eng
text: 'Transcription factors, by binding to specific sequences on the DNA, control
the precise spatio-temporal expression of genes inside a cell. However, this specificity
is limited, leading to frequent incorrect binding of transcription factors that
might have deleterious consequences on the cell. By constructing a biophysical
model of TF-DNA binding in the context of gene regulation, I will first explore
how regulatory constraints can strongly shape the distribution of a population
in sequence space. Then, by directly linking this to a picture of multiple types
of transcription factors performing their functions simultaneously inside the
cell, I will explore the extent of regulatory crosstalk -- incorrect binding interactions
between transcription factors and binding sites that lead to erroneous regulatory
states -- and understand the constraints this places on the design of regulatory
systems. I will then develop a generic theoretical framework to investigate the
coevolution of multiple transcription factors and multiple binding sites, in the
context of a gene regulatory network that performs a certain function. As a particular
tractable version of this problem, I will consider the evolution of two transcription
factors when they transmit upstream signals to downstream target genes. Specifically,
I will describe the evolutionary steady states and the evolutionary pathways involved,
along with their timescales, of a system that initially undergoes a transcription
factor duplication event. To connect this important theoretical model to the prominent
biological event of transcription factor duplication giving rise to paralogous
families, I will then describe a bioinformatics analysis of C2H2 Zn-finger transcription
factors, a major family in humans, and focus on the patterns of evolution that
paralogs have undergone in their various protein domains in the recent past. '
alternative_title:
- ISTA Thesis
article_processing_charge: No
author:
- first_name: Roshan
full_name: Prizak, Roshan
id: 4456104E-F248-11E8-B48F-1D18A9856A87
last_name: Prizak
citation:
ama: Prizak R. Coevolution of transcription factors and their binding sites in sequence
space. 2019. doi:10.15479/at:ista:th6071
apa: Prizak, R. (2019). Coevolution of transcription factors and their binding
sites in sequence space. Institute of Science and Technology Austria. https://doi.org/10.15479/at:ista:th6071
chicago: Prizak, Roshan. “Coevolution of Transcription Factors and Their Binding
Sites in Sequence Space.” Institute of Science and Technology Austria, 2019. https://doi.org/10.15479/at:ista:th6071.
ieee: R. Prizak, “Coevolution of transcription factors and their binding sites in
sequence space,” Institute of Science and Technology Austria, 2019.
ista: Prizak R. 2019. Coevolution of transcription factors and their binding sites
in sequence space. Institute of Science and Technology Austria.
mla: Prizak, Roshan. Coevolution of Transcription Factors and Their Binding Sites
in Sequence Space. Institute of Science and Technology Austria, 2019, doi:10.15479/at:ista:th6071.
short: R. Prizak, Coevolution of Transcription Factors and Their Binding Sites in
Sequence Space, Institute of Science and Technology Austria, 2019.
date_created: 2019-03-06T16:16:10Z
date_published: 2019-03-11T00:00:00Z
date_updated: 2023-09-22T10:00:48Z
day: '11'
ddc:
- '576'
degree_awarded: PhD
department:
- _id: GaTk
- _id: NiBa
doi: 10.15479/at:ista:th6071
file:
- access_level: open_access
checksum: e60a72de35d270b31f1a23d50f224ec0
content_type: application/pdf
creator: rprizak
date_created: 2019-03-06T16:05:07Z
date_updated: 2020-07-14T12:47:18Z
file_id: '6072'
file_name: Thesis_final_PDFA_RoshanPrizak.pdf
file_size: 20995465
relation: main_file
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checksum: 67c2630333d05ebafef5f018863a8465
content_type: application/zip
creator: rprizak
date_created: 2019-03-06T16:09:39Z
date_updated: 2020-07-14T12:47:18Z
file_id: '6073'
file_name: thesis_v2_merge.zip
file_size: 85705272
relation: source_file
title: Latex files
file_date_updated: 2020-07-14T12:47:18Z
has_accepted_license: '1'
language:
- iso: eng
month: '03'
oa: 1
oa_version: Published Version
page: '189'
project:
- _id: 254E9036-B435-11E9-9278-68D0E5697425
call_identifier: FWF
grant_number: P28844-B27
name: Biophysics of information processing in gene regulation
publication_identifier:
issn:
- 2663-337X
publication_status: published
publisher: Institute of Science and Technology Austria
related_material:
record:
- id: '1358'
relation: part_of_dissertation
status: public
- id: '955'
relation: part_of_dissertation
status: public
status: public
supervisor:
- first_name: Gašper
full_name: Tkačik, Gašper
id: 3D494DCA-F248-11E8-B48F-1D18A9856A87
last_name: Tkačik
orcid: 0000-0002-6699-1455
title: Coevolution of transcription factors and their binding sites in sequence space
type: dissertation
user_id: c635000d-4b10-11ee-a964-aac5a93f6ac1
year: '2019'
...
---
_id: '6179'
abstract:
- lang: eng
text: "In the first part of this thesis we consider large random matrices with arbitrary
expectation and a general slowly decaying correlation among its entries. We prove
universality of the local eigenvalue statistics and optimal local laws for the
resolvent in the bulk and edge regime. The main novel tool is a systematic diagrammatic
control of a multivariate cumulant expansion.\r\nIn the second part we consider
Wigner-type matrices and show that at any cusp singularity of the limiting eigenvalue
distribution the local eigenvalue statistics are uni- versal and form a Pearcey
process. Since the density of states typically exhibits only square root or cubic
root cusp singularities, our work complements previous results on the bulk and
edge universality and it thus completes the resolution of the Wigner- Dyson-Mehta
universality conjecture for the last remaining universality type. Our analysis
holds not only for exact cusps, but approximate cusps as well, where an ex- tended
Pearcey process emerges. As a main technical ingredient we prove an optimal local
law at the cusp, and extend the fast relaxation to equilibrium of the Dyson Brow-
nian motion to the cusp regime.\r\nIn the third and final part we explore the
entrywise linear statistics of Wigner ma- trices and identify the fluctuations
for a large class of test functions with little regularity. This enables us to
study the rectangular Young diagram obtained from the interlacing eigenvalues
of the random matrix and its minor, and we find that, despite having the same
limit, the fluctuations differ from those of the algebraic Young tableaux equipped
with the Plancharel measure."
alternative_title:
- ISTA Thesis
article_processing_charge: No
author:
- first_name: Dominik J
full_name: Schröder, Dominik J
id: 408ED176-F248-11E8-B48F-1D18A9856A87
last_name: Schröder
orcid: 0000-0002-2904-1856
citation:
ama: 'Schröder DJ. From Dyson to Pearcey: Universal statistics in random matrix
theory. 2019. doi:10.15479/AT:ISTA:th6179'
apa: 'Schröder, D. J. (2019). From Dyson to Pearcey: Universal statistics in
random matrix theory. Institute of Science and Technology Austria. https://doi.org/10.15479/AT:ISTA:th6179'
chicago: 'Schröder, Dominik J. “From Dyson to Pearcey: Universal Statistics in Random
Matrix Theory.” Institute of Science and Technology Austria, 2019. https://doi.org/10.15479/AT:ISTA:th6179.'
ieee: 'D. J. Schröder, “From Dyson to Pearcey: Universal statistics in random matrix
theory,” Institute of Science and Technology Austria, 2019.'
ista: 'Schröder DJ. 2019. From Dyson to Pearcey: Universal statistics in random
matrix theory. Institute of Science and Technology Austria.'
mla: 'Schröder, Dominik J. From Dyson to Pearcey: Universal Statistics in Random
Matrix Theory. Institute of Science and Technology Austria, 2019, doi:10.15479/AT:ISTA:th6179.'
short: 'D.J. Schröder, From Dyson to Pearcey: Universal Statistics in Random Matrix
Theory, Institute of Science and Technology Austria, 2019.'
date_created: 2019-03-28T08:58:59Z
date_published: 2019-03-18T00:00:00Z
date_updated: 2024-02-22T14:34:33Z
day: '18'
ddc:
- '515'
- '519'
degree_awarded: PhD
department:
- _id: LaEr
doi: 10.15479/AT:ISTA:th6179
ec_funded: 1
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call_identifier: FP7
grant_number: '338804'
name: Random matrices, universality and disordered quantum systems
publication_identifier:
issn:
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publisher: Institute of Science and Technology Austria
related_material:
record:
- id: '1144'
relation: part_of_dissertation
status: public
- id: '6186'
relation: part_of_dissertation
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relation: part_of_dissertation
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relation: part_of_dissertation
status: public
status: public
supervisor:
- first_name: László
full_name: Erdös, László
id: 4DBD5372-F248-11E8-B48F-1D18A9856A87
last_name: Erdös
orcid: 0000-0001-5366-9603
title: 'From Dyson to Pearcey: Universal statistics in random matrix theory'
type: dissertation
user_id: c635000d-4b10-11ee-a964-aac5a93f6ac1
year: '2019'
...
---
_id: '6392'
abstract:
- lang: eng
text: "The regulation of gene expression is one of the most fundamental processes
in living systems. In recent years, thanks to advances in sequencing technology
and automation, it has become possible to study gene expression quantitatively,
genome-wide and in high-throughput. This leads to the possibility of exploring
changes in gene expression in the context of many external perturbations and their
combinations, and thus of characterising the basic principles governing gene regulation.
In this thesis, I present quantitative experimental approaches to studying transcriptional
and protein level changes in response to combinatorial drug treatment, as well
as a theoretical data-driven approach to analysing thermodynamic principles guiding
transcription of protein coding genes. \r\nIn the first part of this work, I
present a novel methodological framework for quantifying gene expression changes
in drug combinations, termed isogrowth profiling. External perturbations through
small molecule drugs influence the growth rate of the cell, leading to wide-ranging
changes in cellular physiology and gene expression. This confounds the gene expression
changes specifically elicited by the particular drug. Combinatorial perturbations,
owing to the increased stress they exert, influence the growth rate even more
strongly and hence suffer the convolution problem to a greater extent when measuring
gene expression changes. Isogrowth profiling is a way to experimentally abstract
non-specific, growth rate related changes, by performing the measurement using
varying ratios of two drugs at such concentrations that the overall inhibition
rate is constant. Using a robotic setup for automated high-throughput re-dilution
culture of Saccharomyces cerevisiae, the budding yeast, I investigate all pairwise
interactions of four small molecule drugs through sequencing RNA along a growth
isobole. Through principal component analysis, I demonstrate here that isogrowth
profiling can uncover drug-specific as well as drug-interaction-specific gene
expression changes. I show that drug-interaction-specific gene expression changes
can be used for prediction of higher-order drug interactions. I propose a simplified
generalised framework of isogrowth profiling, with few measurements needed for
each drug pair, enabling the broad application of isogrowth profiling to high-throughput
screening of inhibitors of cellular growth and beyond. Such high-throughput screenings
of gene expression changes specific to pairwise drug interactions will be instrumental
for predicting the higher-order interactions of the drugs.\r\n\r\nIn the second
part of this work, I extend isogrowth profiling to single-cell measurements of
gene expression, characterising population heterogeneity in the budding yeast
in response to combinatorial drug perturbation while controlling for non-specific
growth rate effects. Through flow cytometry of strains with protein products fused
to green fluorescent protein, I discover multiple proteins with bi-modally distributed
expression levels in the population in response to drug treatment. I characterize
more closely the effect of an ionic stressor, lithium chloride, and find that
it inhibits the splicing of mRNA, most strongly affecting ribosomal protein transcripts
and leading to a bi-stable behaviour of a small ribosomal subunit protein Rps22B.
Time-lapse microscopy of a microfluidic culture system revealed that the induced
Rps22B heterogeneity leads to preferential survival of Rps22B-low cells after
long starvation, but to preferential proliferation of Rps22B-high cells after
short starvation. Overall, this suggests that yeast cells might use splicing of
ribosomal genes for bet-hedging in fluctuating environments. I give specific examples
of how further exploration of cellular heterogeneity in yeast in response to external
perturbation has the potential to reveal yet-undiscovered gene regulation circuitry.\r\n\r\nIn
the last part of this thesis, a re-analysis of a published sequencing dataset
of nascent elongating transcripts is used to characterise the thermodynamic constraints
for RNA polymerase II (RNAP) elongation. Population-level data on RNAP position
throughout the transcribed genome with single nucleotide resolution are used to
infer the sequence specific thermodynamic determinants of RNAP pausing and backtracking.
This analysis reveals that the basepairing strength of the eight nucleotide-long
RNA:DNA duplex relative to the basepairing strength of the same sequence when
in DNA:DNA duplex, and the change in this quantity during RNA polymerase movement,
is the key determinant of RNAP pausing. This is true for RNAP pausing while elongating,
but also of RNAP pausing while backtracking and of the backtracking length. The
quantitative dependence of RNAP pausing on basepairing energetics is used to infer
the increase in pausing due to transcriptional mismatches, leading to a hypothesis
that pervasive RNA polymerase II pausing is due to basepairing energetics, as
an evolutionary cost for increased RNA polymerase II fidelity.\r\n\r\nThis work
advances our understanding of the general principles governing gene expression,
with the goal of making computational predictions of single-cell gene expression
responses to combinatorial perturbations based on the individual perturbations
possible. This ability would substantially facilitate the design of drug combination
treatments and, in the long term, lead to our increased ability to more generally
design targeted manipulations to any biological system. "
acknowledged_ssus:
- _id: LifeSc
- _id: M-Shop
- _id: Bio
alternative_title:
- IST Austria Thesis
author:
- first_name: Martin
full_name: Lukacisin, Martin
id: 298FFE8C-F248-11E8-B48F-1D18A9856A87
last_name: Lukacisin
orcid: 0000-0001-6549-4177
citation:
ama: Lukacisin M. Quantitative investigation of gene expression principles through
combinatorial drug perturbation and theory. 2019. doi:10.15479/AT:ISTA:6392
apa: Lukacisin, M. (2019). Quantitative investigation of gene expression principles
through combinatorial drug perturbation and theory. IST Austria. https://doi.org/10.15479/AT:ISTA:6392
chicago: Lukacisin, Martin. “Quantitative Investigation of Gene Expression Principles
through Combinatorial Drug Perturbation and Theory.” IST Austria, 2019. https://doi.org/10.15479/AT:ISTA:6392.
ieee: M. Lukacisin, “Quantitative investigation of gene expression principles through
combinatorial drug perturbation and theory,” IST Austria, 2019.
ista: Lukacisin M. 2019. Quantitative investigation of gene expression principles
through combinatorial drug perturbation and theory. IST Austria.
mla: Lukacisin, Martin. Quantitative Investigation of Gene Expression Principles
through Combinatorial Drug Perturbation and Theory. IST Austria, 2019, doi:10.15479/AT:ISTA:6392.
short: M. Lukacisin, Quantitative Investigation of Gene Expression Principles through
Combinatorial Drug Perturbation and Theory, IST Austria, 2019.
date_created: 2019-05-09T19:53:00Z
date_published: 2019-05-09T00:00:00Z
date_updated: 2023-09-22T09:19:41Z
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status: public
supervisor:
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full_name: Bollenbach, Mark Tobias
id: 3E6DB97A-F248-11E8-B48F-1D18A9856A87
last_name: Bollenbach
orcid: 0000-0003-4398-476X
title: Quantitative investigation of gene expression principles through combinatorial
drug perturbation and theory
type: dissertation
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
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...
---
_id: '6435'
abstract:
- lang: eng
text: "Social insect colonies tend to have numerous members which function together
like a single organism in such harmony that the term ``super-organism'' is often
used. In this analogy the reproductive caste is analogous to the primordial germ\r\ncells
of a metazoan, while the sterile worker caste corresponds to somatic cells. The
worker castes, like tissues, are\r\nin charge of all functions of a living being,
besides reproduction. The establishment of new super-organismal units\r\n(i.e.
new colonies) is accomplished by the co-dependent castes. The term oftentimes
goes beyond a metaphor. We invoke it when we speak about the metabolic rate, thermoregulation,
nutrient regulation and gas exchange of a social insect colony. Furthermore, we
assert that the super-organism has an immune system, and benefits from ``social
immunity''.\r\n\r\nSocial immunity was first summoned by evolutionary biologists
to resolve the apparent discrepancy between the expected high frequency of disease
outbreak amongst numerous, closely related tightly-interacting hosts, living in
stable and microbially-rich environments, against the exceptionally scarce epidemic
accounts in natural populations. Social\r\nimmunity comprises a multi-layer assembly
of behaviours which have evolved to effectively keep the pathogenic enemies of
a colony at bay. The field of social immunity has drawn interest, as it becomes
increasingly urgent to stop\r\nthe collapse of pollinator species and curb the
growth of invasive pests. In the past decade, several mechanisms of\r\nsocial
immune responses have been dissected, but many more questions remain open.\r\n\r\nI
present my work in two experimental chapters. In the first, I use invasive garden
ants (*Lasius neglectus*) to study how pathogen load and its distribution among
nestmates affect the grooming response of the group. Any given group of ants will
carry out the same total grooming work, but will direct their grooming effort
towards individuals\r\ncarrying a relatively higher spore load. Contrary to expectation,
the highest risk of transmission does not stem from grooming highly contaminated
ants, but instead, we suggest that the grooming response likely minimizes spore
loss to the environment, reducing contamination from inadvertent pickup from the
substrate.\r\n\r\nThe second is a comparative developmental approach. I follow
black garden ant queens (*Lasius niger*) and their colonies from mating flight,
through hibernation for a year. Colonies which grow fast from the start, have
a lower chance of survival through hibernation, and those which survive grow at
a lower pace later. This is true for colonies of naive\r\nand challenged queens.
Early pathogen exposure of the queens changes colony dynamics in an unexpected
way: colonies from exposed queens are more likely to grow slowly and recover in
numbers only after they survive hibernation.\r\n\r\nIn addition to the two experimental
chapters, this thesis includes a co-authored published review on organisational\r\nimmunity,
where we enlist the experimental evidence and theoretical framework on which this
hypothesis is built,\r\nidentify the caveats and underline how the field is ripe
to overcome them. In a final chapter, I describe my part in\r\ntwo collaborative
efforts, one to develop an image-based tracker, and the second to develop a classifier
for ant\r\nbehaviour."
acknowledged_ssus:
- _id: Bio
- _id: ScienComp
- _id: M-Shop
- _id: LifeSc
alternative_title:
- ISTA Thesis
article_processing_charge: No
author:
- first_name: Barbara E
full_name: Casillas Perez, Barbara E
id: 351ED2AA-F248-11E8-B48F-1D18A9856A87
last_name: Casillas Perez
citation:
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2019. doi:10.15479/AT:ISTA:6435
apa: Casillas Perez, B. E. (2019). Collective defenses of garden ants against
a fungal pathogen. Institute of Science and Technology Austria. https://doi.org/10.15479/AT:ISTA:6435
chicago: Casillas Perez, Barbara E. “Collective Defenses of Garden Ants against
a Fungal Pathogen.” Institute of Science and Technology Austria, 2019. https://doi.org/10.15479/AT:ISTA:6435.
ieee: B. E. Casillas Perez, “Collective defenses of garden ants against a fungal
pathogen,” Institute of Science and Technology Austria, 2019.
ista: Casillas Perez BE. 2019. Collective defenses of garden ants against a fungal
pathogen. Institute of Science and Technology Austria.
mla: Casillas Perez, Barbara E. Collective Defenses of Garden Ants against a
Fungal Pathogen. Institute of Science and Technology Austria, 2019, doi:10.15479/AT:ISTA:6435.
short: B.E. Casillas Perez, Collective Defenses of Garden Ants against a Fungal
Pathogen, Institute of Science and Technology Austria, 2019.
date_created: 2019-05-13T08:58:35Z
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date_updated: 2023-09-07T12:57:04Z
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keyword:
- Social Immunity
- Sanitary care
- Social Insects
- Organisational Immunity
- Colony development
- Multi-target tracking
language:
- iso: eng
month: '05'
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publication_identifier:
issn:
- 2663-337X
publication_status: published
publisher: Institute of Science and Technology Austria
related_material:
record:
- id: '1999'
relation: part_of_dissertation
status: public
status: public
supervisor:
- first_name: Sylvia M
full_name: Cremer, Sylvia M
id: 2F64EC8C-F248-11E8-B48F-1D18A9856A87
last_name: Cremer
orcid: 0000-0002-2193-3868
title: Collective defenses of garden ants against a fungal pathogen
type: dissertation
user_id: c635000d-4b10-11ee-a964-aac5a93f6ac1
year: '2019'
...
---
_id: '6269'
abstract:
- lang: eng
text: 'Clathrin-Mediated Endocytosis (CME) is an aspect of cellular trafficking
that is constantly regulated for mediating developmental and physiological responses.
The main aim of my thesis is to decipher the basic mechanisms of CME and post-endocytic
trafficking in the whole multicellular organ systems of Arabidopsis. The first
chapter of my thesis describes the search for new components involved in CME.
Tandem affinity purification was conducted using CLC and its interacting partners
were identified. Amongst the identified proteins were the Auxilin-likes1 and 2
(Axl1/2), putative uncoating factors, for which we made a full functional analysis.
Over-expression of Axl1/2 causes extreme modifications in the dynamics of the
machinery proteins and inhibition of endocytosis altogether. However the loss
of function of the axl1/2 did not present any cellular or physiological phenotype,
meaning Auxilin-likes do not form the major uncoating machinery. The second chapter
of my thesis describes the establishment/utilisation of techniques to capture
the dynamicity and the complexity of CME and post-endocytic trafficking. We have
studied the development of endocytic pits at the PM – specifically, the mode of
membrane remodeling during pit development and the role of actin in it, given
plant cells possess high turgor pressure. Utilizing the improved z-resolution
of TIRF and VAEM techniques, we captured the time-lapse of the endocytic events
at the plasma membrane; and using particle detection software, we quantitatively
analysed all the endocytic trajectories in an unbiased way to obtain the endocytic
rate of the system. This together with the direct analysis of cargo internalisation
from the PM provided an estimate on the endocytic potential of the cell. We also
developed a methodology for ultrastructural analysis of different populations
of Clathrin-Coated Structures (CCSs) in both PM and endomembranes in unroofed
protoplasts. Structural analysis, together with the intensity profile of CCSs
at the PM show that the mode of CCP development at the PM follows ‘Constant curvature
model’; meaning that clathrin polymerisation energy is a major contributing factor
of membrane remodeling. In addition, other analyses clearly show that actin is
not required for membrane remodeling during invagination or any other step of
CCP development, despite the prevalent high turgor pressure. However, actin is
essential in orchestrating the post-endocytic trafficking of CCVs facilitating
the EE formation. We also observed that the uncoating process post-endocytosis
is not immediate; an alternative mechanism of uncoating – Sequential multi-step
process – functions in the cell. Finally we also looked at one of the important
physiological stimuli modulating the process – hormone, auxin. auxin has been
known to influence CME before. We have made a detailed study on the concentration-time
based effect of auxin on the machinery proteins, CCP development, and the specificity
of cargoes endocytosed. To this end, we saw no general effect of auxin on CME
at earlier time points. However, very low concentration of IAA, such as 50nM,
accelerates endocytosis of specifically PIN2 through CME. Such a tight regulatory
control with high specificity to PIN2 could be essential in modulating its polarity. '
acknowledged_ssus:
- _id: Bio
- _id: EM-Fac
alternative_title:
- ISTA Thesis
article_processing_charge: No
author:
- first_name: Madhumitha
full_name: Narasimhan, Madhumitha
id: 44BF24D0-F248-11E8-B48F-1D18A9856A87
last_name: Narasimhan
orcid: 0000-0002-8600-0671
citation:
ama: Narasimhan M. Clathrin-Mediated endocytosis, post-endocytic trafficking and
their regulatory controls in plants . 2019. doi:10.15479/at:ista:th1075
apa: Narasimhan, M. (2019). Clathrin-Mediated endocytosis, post-endocytic trafficking
and their regulatory controls in plants . Institute of Science and Technology
Austria. https://doi.org/10.15479/at:ista:th1075
chicago: Narasimhan, Madhumitha. “Clathrin-Mediated Endocytosis, Post-Endocytic
Trafficking and Their Regulatory Controls in Plants .” Institute of Science and
Technology Austria, 2019. https://doi.org/10.15479/at:ista:th1075.
ieee: M. Narasimhan, “Clathrin-Mediated endocytosis, post-endocytic trafficking
and their regulatory controls in plants ,” Institute of Science and Technology
Austria, 2019.
ista: Narasimhan M. 2019. Clathrin-Mediated endocytosis, post-endocytic trafficking
and their regulatory controls in plants . Institute of Science and Technology
Austria.
mla: Narasimhan, Madhumitha. Clathrin-Mediated Endocytosis, Post-Endocytic Trafficking
and Their Regulatory Controls in Plants . Institute of Science and Technology
Austria, 2019, doi:10.15479/at:ista:th1075.
short: M. Narasimhan, Clathrin-Mediated Endocytosis, Post-Endocytic Trafficking
and Their Regulatory Controls in Plants , Institute of Science and Technology
Austria, 2019.
date_created: 2019-04-09T14:37:06Z
date_published: 2019-02-04T00:00:00Z
date_updated: 2023-09-08T11:43:03Z
day: '04'
ddc:
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degree_awarded: PhD
department:
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doi: 10.15479/at:ista:th1075
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publication_identifier:
issn:
- 2663-337X
publication_status: published
publisher: Institute of Science and Technology Austria
related_material:
record:
- id: '412'
relation: part_of_dissertation
status: public
status: public
supervisor:
- first_name: Jiří
full_name: Friml, Jiří
id: 4159519E-F248-11E8-B48F-1D18A9856A87
last_name: Friml
orcid: 0000-0002-8302-7596
title: 'Clathrin-Mediated endocytosis, post-endocytic trafficking and their regulatory
controls in plants '
tmp:
image: /images/cc_by.png
legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
short: CC BY (4.0)
type: dissertation
user_id: c635000d-4b10-11ee-a964-aac5a93f6ac1
year: '2019'
...
---
_id: '6947'
abstract:
- lang: eng
text: Lymph nodes are es s ential organs of the immune s ys tem where adaptive
immune responses originate, and consist of various leukocyte populations and a
stromal backbone. Fibroblastic reticular cells (FRCs) are the main stromal cells
and form a sponge-like extracellular matrix network, called conduits , which they thems
elves enwrap and contract. Lymph, containing s oluble antigens , arrive
in lymph nodes via afferent lymphatic vessels that connect to the s ubcaps
ular s inus and conduit network. According to the current paradigm, the conduit network dis
tributes afferent lymph through lymph nodes and thus provides acces
s for immune cells to lymph-borne antigens. An elas tic caps ule s urrounds the organ and confines the
immune cells and FRC network. Lymph nodes are completely packed with lymphocytes and lymphocyte numbers directly dictates the
size of the organ. Although lymphocytes cons tantly enter and leave the lymph node, its s
ize remains remarkedly s table under homeostatic conditions. It is only
partly known how the cellularity and s ize of the lymph node is regulated and how the lymph node is
able to swell in inflammation. The role of the FRC network in lymph node s
welling and trans fer of fluids are inves tigated in this thes is. Furthermore, we s
tudied what trafficking routes are us ed by cancer cells in lymph nodes to form distal
metastases.We examined the role of a mechanical feedback in regulation of lymph node
swelling. Using parallel plate compression and UV-las er cutting experiments we dis
s ected the mechanical force dynamics of the whole lymph node, and individually
for FRCs and the caps ule. Physical forces generated by packed lymphocytes directly affect the tens
ion on the FRC network and capsule, which increases its resistance to swelling. This implies a feedback mechanism between tis
s ue pres s ure and ability of lymphocytes to enter the organ. Following inflammation, the lymph node swells
∼10 fold in two weeks . Yet, what is the role for tens ion on the FRC network and caps
ule, and how are lymphocytes able to enter in conditions that resist
swelling remain open ques tions . We s how that tens ion on the FRC network is important
to limit the swelling rate of the organ so that the FRC network can grow in a coordinated fashion.
This is illustrated by interfering with FRC contractility, which leads to faster
swelling rates and a dis organized FRC network in the inflamed lymph node.
Growth of the FRC network in turn is expected to releas e tens ion on thes
e s tructures and lowers the res is tance to swelling, thereby allowing
more lymphocytes to enter the organ and drive more swelling. Halt of swelling
coincides with a thickening of the caps ule, which forms a thick res
is tant band around the organ and lowers tens ion on the FRC network to form
a new force equilibrium.The FRC and conduit network are further believed to be a privileged s
ite of s oluble information within the lymph node, although many details remain uns
olved. We s how by 3D ultra-recons truction that FRCs and antigen pres
enting cells cover the s urface of conduit s ys tem for more than 99%
and we dis cus s the implications for s oluble information exchangeat the conduit
level.Finally, there is an ongoing debate in the cancer field whether and how
cancer cells in lymph nodes s eed dis tal metas tas es . We s how that cancer cells infus
ed into the lymph node can utilize trafficking routes of immune cells and rapidly migrate to blood vessels.
Once in the blood circulation, these cells are able to form metastases in
distal tissues.
acknowledged_ssus:
- _id: Bio
- _id: PreCl
- _id: EM-Fac
alternative_title:
- ISTA Thesis
article_processing_charge: No
author:
- first_name: Frank P
full_name: Assen, Frank P
id: 3A8E7F24-F248-11E8-B48F-1D18A9856A87
last_name: Assen
orcid: 0000-0003-3470-6119
citation:
ama: 'Assen FP. Lymph node mechanics: Deciphering the interplay between stroma contractility,
morphology and lymphocyte trafficking. 2019. doi:10.15479/AT:ISTA:6947'
apa: 'Assen, F. P. (2019). Lymph node mechanics: Deciphering the interplay between
stroma contractility, morphology and lymphocyte trafficking. Institute of
Science and Technology Austria. https://doi.org/10.15479/AT:ISTA:6947'
chicago: 'Assen, Frank P. “Lymph Node Mechanics: Deciphering the Interplay between
Stroma Contractility, Morphology and Lymphocyte Trafficking.” Institute of Science
and Technology Austria, 2019. https://doi.org/10.15479/AT:ISTA:6947.'
ieee: 'F. P. Assen, “Lymph node mechanics: Deciphering the interplay between stroma
contractility, morphology and lymphocyte trafficking,” Institute of Science and
Technology Austria, 2019.'
ista: 'Assen FP. 2019. Lymph node mechanics: Deciphering the interplay between stroma
contractility, morphology and lymphocyte trafficking. Institute of Science and
Technology Austria.'
mla: 'Assen, Frank P. Lymph Node Mechanics: Deciphering the Interplay between
Stroma Contractility, Morphology and Lymphocyte Trafficking. Institute of
Science and Technology Austria, 2019, doi:10.15479/AT:ISTA:6947.'
short: 'F.P. Assen, Lymph Node Mechanics: Deciphering the Interplay between Stroma
Contractility, Morphology and Lymphocyte Trafficking, Institute of Science and
Technology Austria, 2019.'
date_created: 2019-10-14T16:54:52Z
date_published: 2019-10-09T00:00:00Z
date_updated: 2023-09-13T08:50:57Z
day: '9'
ddc:
- '570'
degree_awarded: PhD
department:
- _id: MiSi
doi: 10.15479/AT:ISTA:6947
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has_accepted_license: '1'
language:
- iso: eng
month: '10'
oa: 1
oa_version: Published Version
page: '142'
publication_identifier:
issn:
- 2663-337X
publication_status: published
publisher: Institute of Science and Technology Austria
related_material:
record:
- id: '664'
relation: part_of_dissertation
status: public
- id: '402'
relation: part_of_dissertation
status: public
status: public
supervisor:
- first_name: Michael K
full_name: Sixt, Michael K
id: 41E9FBEA-F248-11E8-B48F-1D18A9856A87
last_name: Sixt
orcid: 0000-0002-6620-9179
title: 'Lymph node mechanics: Deciphering the interplay between stroma contractility,
morphology and lymphocyte trafficking'
type: dissertation
user_id: c635000d-4b10-11ee-a964-aac5a93f6ac1
year: '2019'
...
---
_id: '6849'
abstract:
- lang: eng
text: 'Brain function is mediated by complex dynamical interactions between excitatory
and inhibitory cell types. The Cholecystokinin-expressing inhibitory cells (CCK-interneurons)
are one of the least studied types, despite being suspected to play important
roles in cognitive processes. We studied the network effects of optogenetic silencing
of CCK-interneurons in the CA1 hippocampal area during exploration and sleep states.
The cell firing pattern in response to light pulses allowed us to classify the
recorded neurons in 5 classes, including disinhibited and non-responsive pyramidal
cell and interneurons, and the inhibited interneurons corresponding to the CCK
group. The light application, which inhibited the activity of CCK interneurons
triggered wider changes in the firing dynamics of cells. We observed rate changes
(i.e. remapping) of pyramidal cells during the exploration session in which the
light was applied relative to the previous control session that was not restricted
neither in time nor space to the light delivery. Also, the disinhibited pyramidal
cells had higher increase in bursting than in single spike firing rate as a result
of CCK silencing. In addition, the firing activity patterns during exploratory
periods were more weakly reactivated in sleep for those periods in which CCK-interneuron
were silenced than in the unaffected periods. Furthermore, light pulses during
sleep disrupted the reactivation of recent waking patterns. Hence, silencing CCK
neurons during exploration suppressed the reactivation of waking firing patterns
in sleep and CCK interneuron activity was also required during sleep for the normal
reactivation of waking patterns. These findings demonstrate the involvement of
CCK cells in reactivation-related memory consolidation. An important part of our
analysis was to test the relationship of the identified CCKinterneurons to brain
oscillations. Our findings showed that these cells exhibited different oscillatory
behaviour during anaesthesia and natural waking and sleep conditions. We showed
that: 1) Contrary to the past studies performed under anaesthesia, the identified
CCKinterneurons fired on the descending portion of the theta phase in waking exploration.
2) CCKinterneuron preferred phases around the trough of gamma oscillations. 3)
Contrary to anaesthesia conditions, the average firing rate of the CCK-interneurons
increased around the peak activity of the sharp-wave ripple (SWR) events in natural
sleep, which is congruent with new reports about their functional connectivity.
We also found that light driven CCK-interneuron silencing altered the dynamics
on the CA1 network oscillatory activity: 1) Pyramidal cells negatively shifted
their preferred theta phases when the light was applied, while interneurons responses
were less consistent. 2) As a population, pyramidal cells negatively shifted their
preferred activity during gamma oscillations, albeit we did not find gamma modulation
differences related to the light application when pyramidal cells were subdivided
into the disinhibited and unaffected groups. 3) During the peak of SWR events,
all but the CCK-interneurons had a reduction in their relative firing rate change
during the light application as compared to the change observed at SWR initiation.
Finally, regarding to the place field activity of the recorded pyramidal neurons,
we showed that the disinhibited pyramidal cells had reduced place field similarity,
coherence and spatial information, but only during the light application. The
mechanisms behind such observed behaviours might involve eCB signalling and plastic
changes in CCK-interneuron synapses. In conclusion, the observed changes related
to the light-mediated silencing of CCKinterneurons have unravelled characteristics
of this interneuron subpopulation that might change the understanding not only
of their particular network interactions, but also of the current theories about
the emergence of certain cognitive processes such as place coding needed for navigation
or hippocampus-dependent memory consolidation. '
acknowledged_ssus:
- _id: Bio
- _id: PreCl
- _id: M-Shop
alternative_title:
- ISTA Thesis
article_processing_charge: No
author:
- first_name: Dámaris K
full_name: Rangel Guerrero, Dámaris K
id: 4871BCE6-F248-11E8-B48F-1D18A9856A87
last_name: Rangel Guerrero
orcid: 0000-0002-8602-4374
citation:
ama: Rangel Guerrero DK. The role of CCK-interneurons in regulating hippocampal
network dynamics. 2019. doi:10.15479/AT:ISTA:6849
apa: Rangel Guerrero, D. K. (2019). The role of CCK-interneurons in regulating
hippocampal network dynamics. Institute of Science and Technology Austria.
https://doi.org/10.15479/AT:ISTA:6849
chicago: Rangel Guerrero, Dámaris K. “The Role of CCK-Interneurons in Regulating
Hippocampal Network Dynamics.” Institute of Science and Technology Austria, 2019.
https://doi.org/10.15479/AT:ISTA:6849.
ieee: D. K. Rangel Guerrero, “The role of CCK-interneurons in regulating hippocampal
network dynamics,” Institute of Science and Technology Austria, 2019.
ista: Rangel Guerrero DK. 2019. The role of CCK-interneurons in regulating hippocampal
network dynamics. Institute of Science and Technology Austria.
mla: Rangel Guerrero, Dámaris K. The Role of CCK-Interneurons in Regulating Hippocampal
Network Dynamics. Institute of Science and Technology Austria, 2019, doi:10.15479/AT:ISTA:6849.
short: D.K. Rangel Guerrero, The Role of CCK-Interneurons in Regulating Hippocampal
Network Dynamics, Institute of Science and Technology Austria, 2019.
date_created: 2019-09-06T06:54:16Z
date_published: 2019-09-09T00:00:00Z
date_updated: 2023-09-19T10:01:12Z
day: '09'
ddc:
- '570'
degree_awarded: PhD
department:
- _id: JoCs
doi: 10.15479/AT:ISTA:6849
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publication_identifier:
isbn:
- '9783990780039'
issn:
- 2663-337X
publication_status: published
publisher: Institute of Science and Technology Austria
related_material:
record:
- id: '5914'
relation: part_of_dissertation
status: public
status: public
supervisor:
- first_name: Jozsef L
full_name: Csicsvari, Jozsef L
id: 3FA14672-F248-11E8-B48F-1D18A9856A87
last_name: Csicsvari
orcid: 0000-0002-5193-4036
title: The role of CCK-interneurons in regulating hippocampal network dynamics
type: dissertation
user_id: c635000d-4b10-11ee-a964-aac5a93f6ac1
year: '2019'
...