6,630 research outputs found
Nuclear shape instability caused by lamin A deregulation promotes invasiveness in pediatric bone sarcomas: from nucleo-cytoskeleton dynamics to novel therapeutic opportunities
Osteosarcoma (OS) and Ewing sarcoma (EWS) are the two most frequent primary bone tumors, in which metastases remain the most relevant adverse prognostic factor. Lamin A is the main constituent of the nuclear lamina, with a fundamental role in maintaining the connection between nucleus and cytoskeleton (through LINC complex proteins interactions), and its alterations can be implicated in tumor progression.
We investigated how nucleo-cytoskeleton dynamics is influenced by lamin A modulation in OS and EWS, demonstrating that both these cancer models had low levels of lamin A, which are linked to a significantly more marked nuclear misshaping. In our in vitro studies, reduced levels of lamin A promoted migratory abilities in these tumors. Moreover, these findings were corroborated by gene expression analyses on EWS patient samples, showing that LMNA levels were significantly lower in metastatic lesions compared to primary tumors and that patients with low LMNA had a significant worse overall survival. We also found that LMNA expression significantly impaired EWS metastases formation in vivo.
We demonstrated that low lamin A expression was linked to a severe mislocalization of LINC complex proteins, thus disrupting nucleo-cytoskeleton interactions, with a corresponding gain in malignant properties, which resulted in increased invasiveness. Lamin A overexpression or its accumulation by a statin-based pharmacological treatment allowed us to reconstitute a functional nucleo-cytoskeleton interplay, which resulted in significant downmodulation of ROCK2 and YAP, two crucial drivers of EWS aggressiveness.
Our study demonstrated that lamin A is a favorable mediator of nuclear shape stability in bone sarcomas, and its modulation rescues LINC complex protein localization and regulates mechano-signaling pathways, thus promoting a less aggressive cancer phenotype. We also identified statins, already employed in clinical practice, as a tool capable to increase lamin A levels, and to reconstitute functional nucleo-cytoskeletal dynamics, resulting in reduced cellular migration
Studies of excited states in the odd-odd nucleus 178Au
Atomic nuclei close to the Z = 82 shell closure are well known for exhibiting shape coexistence with one of the earliest examples of this being the neutron-deficient gold (Z = 79) nuclei close to the neutron mid shell gap at N=104. Subsequently, such isotopes have been examined with both laser-spectroscopy and decay studies.
The present investigation was motivated by the recent experiments at ISOLDE CERN to study the chain of gold isotopes 176−181 Au. In the odd-odd nucleus, 178 Au (N=99), two α-decaying states were identified, a low spin (I π = 2+ , 3− ) ground state 178 Aug , and a high-spin (I π = 7+ , 8− ) isomer. Laser-spectroscopy measurements have shown both isomers to be deformed with the high-spin state having slightly larger deformation.
In this thesis, excited states of 178 Au (Z=79, N=99) have been established for the first time by means of in-beam γ-ray spectroscopy. The previously established sub-microsecond isomers with half-lives of 294-ns and 373-ns were confirmed and their decay schemes to the α-decaying states of 178 Au were established with new multipolarity assignments.
The existence of sub-microsecond isomers of 178 Au allowed for isomer decay tagging to be utilised to identify excited states. A total of 3 rotational bands were established. Configuration assignments of these bands has been made on the basis of comparison with similar bands in neighbouring odd-odd Ir isotopes, with the πi13/2 ⊗ νi11/2 and πh11/2 ⊗ ν f7/2 bands observed in 178 Au. The establishment of rotational bands is discussed and may also constrain the the spin-parity of both previously established α-decaying states 178 Aug,m
Beam scanning by liquid-crystal biasing in a modified SIW structure
A fixed-frequency beam-scanning 1D antenna based on Liquid Crystals (LCs) is designed for application in 2D scanning with lateral alignment. The 2D array environment imposes full decoupling of adjacent 1D antennas, which often conflicts with the LC requirement of DC biasing: the proposed design accommodates both. The LC medium is placed inside a Substrate Integrated Waveguide (SIW) modified to work as a Groove Gap Waveguide, with radiating slots etched on the upper broad wall, that radiates as a Leaky-Wave Antenna (LWA). This allows effective application of the DC bias voltage needed for tuning the LCs. At the same time, the RF field remains laterally confined, enabling the possibility to lay several antennas in parallel and achieve 2D beam scanning. The design is validated by simulation employing the actual properties of a commercial LC medium
Luminosity for laser-electron colliders
High intensity laser facilities are expanding their scope from laser and
particle-acceleration test beds to user facilities and nuclear physics
experiments. A basic goal is to confirm long-standing predictions of
strong-field quantum electrodynamics, but with the advent of high-repetition
rate laser experiments producing GeV-scale electrons and photons, novel
searches for new high-energy particle physics also become possible. The common
figure of merit for these facilities is the invariant describing the electric field strength in
the electron rest frame relative to the ``critical'' field strength of quantum
electrodynamics where the vacuum decays into electron-positron pairs. However,
simply achieving large is insufficient; discovery or validation requires
statistics to distinguish physics from fluctuations. The number of events
delivered by the facility is therefore equally important. In high-energy
physics, luminosity quantifies the rate at which colliders provide events and
data. We adapt the definition of luminosity to high-intensity laser-electron
collisions to quantify and thus optimize the rate at which laser facilities can
deliver strong-field QED and potentially new physics events. Modeling the
pulsed laser field and electron bunch, we find that luminosity is maximized for
laser focal spot size equal or slightly larger than the diameter of the dense
core of the electron bunch. Several examples show that luminosity can be
maximized for parameters different from those maximizing the peak value of
in the collision. The definition of luminosity for electron-laser
collisions is straightforwardly extended to photon-laser collisions and lepton
beam-beam collisions
Electroweak baryogenesis via top-charm mixing
We investigate a scenario of electroweak baryogenesis in the two Higgs
doublet model with quark flavor mixing. In general, off-diagonal components of
quark Yukawa interactions with additional Higgs bosons are strongly constrained
by the data for flavor changing neutral currents. However, top-charm quark
mixing is not the case, so that a large off-diagonal element can be taken,
which can contribute to generating baryon asymmetry of the universe. It turns
out that CP violating phases of the off-diagonal element in the source term in
the Boltzmann equation are eliminated by the rephasing. This result is somewhat
different from previous works on electroweak baryogenesis by flavor
off-diagonal Yukawa couplings. Instead, we find that the absolute value of the
top-charm off-diagonal element enhances CP violating phases in the Higgs
potential, by which sufficient amount of the baryon number can be generated to
explain the observed baryon asymmetry of the universe. We find that such a
scenario is viable under the current experimental data. The model can be tested
by the current and future measurements of various flavor experiments like Kaon
rare decays, in addition to high energy collider experiments as well as
gravitational wave observations. Characteristic predictions of our model would
be deviations in Kaon rare decays. Branching ratios of and can deviate by the order
of 10% and 1%, respectively, which may be tested at future Kaon experiments
such as NA62 and KOTO step-2.Comment: 26 pages, 4 figures, references and some explanation adde
Estudo da remodelagem reversa miocárdica através da análise proteómica do miocárdio e do lÃquido pericárdico
Valve replacement remains as the standard therapeutic option for aortic
stenosis patients, aiming at abolishing pressure overload and triggering
myocardial reverse remodeling. However, despite the instant hemodynamic
benefit, not all patients show complete regression of myocardial hypertrophy,
being at higher risk for adverse outcomes, such as heart failure. The current
comprehension of the biological mechanisms underlying an incomplete reverse
remodeling is far from complete. Furthermore, definitive prognostic tools and
ancillary therapies to improve the outcome of the patients undergoing valve
replacement are missing. To help abridge these gaps, a combined myocardial
(phospho)proteomics and pericardial fluid proteomics approach was followed,
taking advantage of human biopsies and pericardial fluid collected during
surgery and whose origin anticipated a wealth of molecular information
contained therein.
From over 1800 and 750 proteins identified, respectively, in the myocardium
and in the pericardial fluid of aortic stenosis patients, a total of 90 dysregulated
proteins were detected. Gene annotation and pathway enrichment analyses,
together with discriminant analysis, are compatible with a scenario of increased
pro-hypertrophic gene expression and protein synthesis, defective ubiquitinproteasome system activity, proclivity to cell death (potentially fed by
complement activity and other extrinsic factors, such as death receptor
activators), acute-phase response, immune system activation and fibrosis.
Specific validation of some targets through immunoblot techniques and
correlation with clinical data pointed to complement C3 β chain, Muscle Ring
Finger protein 1 (MuRF1) and the dual-specificity Tyr-phosphorylation
regulated kinase 1A (DYRK1A) as potential markers of an incomplete
response. In addition, kinase prediction from phosphoproteome data suggests
that the modulation of casein kinase 2, the family of IκB kinases, glycogen
synthase kinase 3 and DYRK1A may help improve the outcome of patients
undergoing valve replacement. Particularly, functional studies with DYRK1A+/-
cardiomyocytes show that this kinase may be an important target to treat
cardiac dysfunction, provided that mutant cells presented a different response
to stretch and reduced ability to develop force (active tension).
This study opens many avenues in post-aortic valve replacement reverse
remodeling research. In the future, gain-of-function and/or loss-of-function
studies with isolated cardiomyocytes or with animal models of aortic bandingdebanding will help disclose the efficacy of targeting the surrogate therapeutic
targets. Besides, clinical studies in larger cohorts will bring definitive proof of
complement C3, MuRF1 and DYRK1A prognostic value.A substituição da válvula aórtica continua a ser a opção terapêutica de
referência para doentes com estenose aórtica e visa a eliminação da
sobrecarga de pressão, desencadeando a remodelagem reversa miocárdica.
Contudo, apesar do benefÃcio hemodinâmico imediato, nem todos os pacientes
apresentam regressão completa da hipertrofia do miocárdio, ficando com maior
risco de eventos adversos, como a insuficiência cardÃaca. Atualmente, os
mecanismos biológicos subjacentes a uma remodelagem reversa incompleta
ainda não são claros. Além disso, não dispomos de ferramentas de
prognóstico definitivos nem de terapias auxiliares para melhorar a condição
dos pacientes indicados para substituição da válvula. Para ajudar a resolver
estas lacunas, uma abordagem combinada de (fosfo)proteómica e proteómica
para a caracterização, respetivamente, do miocárdio e do lÃquido pericárdico
foi seguida, tomando partido de biópsias e lÃquidos pericárdicos recolhidos em
ambiente cirúrgico.
Das mais de 1800 e 750 proteÃnas identificadas, respetivamente, no miocárdio
e no lÃquido pericárdico dos pacientes com estenose aórtica, um total de 90
proteÃnas desreguladas foram detetadas. As análises de anotação de genes,
de enriquecimento de vias celulares e discriminativa corroboram um cenário de
aumento da expressão de genes pro-hipertróficos e de sÃntese proteica, um
sistema ubiquitina-proteassoma ineficiente, uma tendência para morte celular
(potencialmente acelerada pela atividade do complemento e por outros fatores
extrÃnsecos que ativam death receptors), com ativação da resposta de fase
aguda e do sistema imune, assim como da fibrose.
A validação de alguns alvos especÃficos através de immunoblot e correlação
com dados clÃnicos apontou para a cadeia β do complemento C3, a Muscle
Ring Finger protein 1 (MuRF1) e a dual-specificity Tyr-phosphoylation
regulated kinase 1A (DYRK1A) como potenciais marcadores de uma resposta
incompleta. Por outro lado, a predição de cinases a partir do fosfoproteoma,
sugere que a modulação da caseÃna cinase 2, a famÃlia de cinases do IκB, a
glicogénio sintase cinase 3 e da DYRK1A pode ajudar a melhorar a condição
dos pacientes indicados para intervenção. Em particular, a avaliação funcional
de cardiomiócitos DYRK1A+/- mostraram que esta cinase pode ser um alvo
importante para tratar a disfunção cardÃaca, uma vez que os miócitos mutantes
responderam de forma diferente ao estiramento e mostraram uma menor
capacidade para desenvolver força (tensão ativa).
Este estudo levanta várias hipóteses na investigação da remodelagem reversa.
No futuro, estudos de ganho e/ou perda de função realizados em
cardiomiócitos isolados ou em modelos animais de banding-debanding da
aorta ajudarão a testar a eficácia de modular os potenciais alvos terapêuticos
encontrados. Além disso, estudos clÃnicos em coortes de maior dimensão
trarão conclusões definitivas quanto ao valor de prognóstico do complemento
C3, MuRF1 e DYRK1A.Programa Doutoral em Biomedicin
Towards a non-equilibrium thermodynamic theory of ecosystem assembly and development
Non-equilibrium thermodynamics has had a significant historic influence on the development
of theoretical ecology, even informing the very concept of an ecosystem. Much of this influence
has manifested as proposed extremal principles. These principles hold that systems will tend
to maximise certain thermodynamic quantities, subject to the other constraints they operate
under. A particularly notable extremal principle is the maximum entropy production principle
(MaxEPP); that systems maximise their rate of entropy production. However, these principles
are not robustly based in physical theory, and suffer from treating complex ecosystems in
an extremely coarse manner. To address this gap, this thesis derives a limited but physically
justified extremal principle, as well as carrying out a detailed investigation of the impact of
non-equilibrium thermodynamic constraints on the assembly of microbial communities. The extremal
principle we obtain pertains to the switching between states in simple bistable systems,
with switching paths that generate more entropy being favoured. Our detailed investigation
into microbial communities involved developing a novel thermodynamic microbial community
model, using which we found the rate of ecosystem development to be set by the availability
of free-energy. Further investigation was carried out using this model, demonstrating the way
that trade-offs emerging from fundamental thermodynamic constraints impact the dynamics of
assembling microbial communities. Taken together our results demonstrate that theory can be
developed from non-equilibrium thermodynamics, that is both ecologically relevant and physically
well grounded. We find that broad extremal principles are unlikely to be obtained, absent
significant advances in the field of stochastic thermodynamics, limiting their applicability to
ecology. However, we find that detailed consideration of the non-equilibrium thermodynamic
mechanisms that impact microbial communities can broaden our understanding of their assembly
and functioning.Open Acces
Nah-Infrarot Cr(III)- und V(III)-Luminophore: Multiphonon Relaxation und Upconversion-Lumineszenz
Diese Arbeit befasst sich mit der Konzeption, Darstellung und photophysikalischen
Charakterisierung von neuen lumineszenten Materialien auf Basis der
3d-Ãœbergangsmetalle Vanadium und Chrom.
Dabei konnte das Konzept von bekannten Chrom(III)-Komplexen mit Spin-Flip-
Emission auf Metallkomplexe des günstigen und reichlich verfügbaren Metalls
Vanadium erweitert werden. Der neu entwickelte [V(ddpd)2](PF6)3-Komplex
(ddpd = N,N’-dimethyl-N,N’-dipyridin-2-ylpyridin-2,6-diamin) ist dabei der erste
3dn-Metallkomplex (n ≠10) überhaupt, welcher NIR-Lumineszenz oberhalb von
1000 nm bei Raumtemperatur und in Lösung zeigt.
Weiter wurden ausführliche Studien zu Multiphonon Relaxation (MR) bei Chrom(III)-
und Vanadium(III)-Spin-Flip-Emittern durchgeführt. MR bezeichnet die strahlungslose
Deaktivierung der angeregten, emittierenden Metallzustände durch Energietransfer
auf Schwingungsobertöne von hochenergetischen Oszillatoren wie beispielsweise
O-H-, N-H- oder C-H-Streckschwingungen der Liganden oder des Lösungsmittels. An
selektiv deuterierten Liganden und der entsprechenden lumineszenten Chrom(III)-
Komplexe konnten erstmals die Obertonsignaturen einzelner aromatischer
C-H-Oszillatoren aus gemessenen Obertondaten ermittelt und so die Beiträge
spezifischer aromatischer C-H-Oszillatoren des Liganden zur MR beurteilt werden.
Zusätzlich wurde der Einfluss von Multiphonon Relaxation auf die Photophysik von
neuen Chrom(III)- und Vanadium(III)-Emittern untersucht.
Darüber hinaus wurden im Rahmen dieser Arbeit neue photoaktive heterometallische
Chrom-Lanthanoid-Architekturen entwickelt, aufgebaut aus einfach zugänglichen Cr3+-
und Ln3+-Komplexionen. Durch Überarbeitung früherer Cr3+/Yb3+-Systeme konnte ein
neuer molekularer Festkörper realisiert werden, welcher NIR→NIR-Upconversion
Lumineszenz in der Gegenwart von Sauerstoff und Wasser zeigt. Des Weiteren
wurden die Lumineszenzeigenschaften weiterer Chrom-Lanthanoid-Salze
charakterisiert und die zugrundeliegenden Energietransferprozesse zwischen den
Metallzentren untersucht
The bone microenvironment as a master regulator of disseminated tumour cells responsible for breast cancer recurrence
Advanced breast cancer is frequently associated with skeletal metastases characterised by dormancy and subsequent incurable metastatic outgrowth accompanied by skeletal related events. Disseminated tumour cells putatively assume residence in metastatic niches within the bone microenvironment, in locations that may be regularly occupied by resident cells and regulated by neighbouring cells in response to local and systemic signals.
My studies explored how modification of the bone microenvironment using a dietary approach (low calcium), a surgical intervention (ovariectomy) and pharmacological inhibition of bone resorption (Zol) impacted breast cancer cell development and progression within the bone in vivo.
The effect of a low calcium diet (0.1%) on the bone microenvironment of mature (12-week old) and dormant disseminated tumour cells was investigated in the absence and presence of bone-colonising tumour cells. In the absence of tumour cells, minor reductions of percent bone volume was detected after 28 days, with a reduction in PINP and increase in TRAP, without significant change to gene expression. Without existing literature on the effect of a low calcium diet on the outgrowth of dormant disseminated breast cancer cells, my research showed a low calcium diet in isolation did not sufficiently alter the bone microenvironment to trigger the outgrowth of dormant tumour cells.
To investigate the effect of repeated doses of Zol on outgrowing tumour cells in bone with rapid turnover, young (6-week old) mice were treated with four once-weekly clinically-relevant doses. Zol significantly increased trabecular percent bone volume, trabecular number and reduced trabecular separation. In agreement with existing literature Zol did not prevent or significantly delay the outgrowth of tumours in the bone with rapid turnover.
Profiling transcriptional changes to the mature (12-week old) bone microenvironment 14 days after ovariectomy, which has been shown to induce the outgrowth of dormant disseminated tumour cells, by RNA-seq revealed POSTN, MMP2, THBS2 and OPN as genes influencing the altered bone microenvironment. Comparison with publicly available RNA-seq data on the bone microenvironment of young (~30 years old), old (~73 years old) and old women treated with oestrogen for 3 weeks (~ 70 years old) found overlap between genes expressed by both young women and old women, suggesting caution in comparison. Comparing genes altered in the bone microenvironment of ovariectomised mice did not show overlap with genes found from in vitro dormant tumour cells. Deconvolution of bulk RNA-seq data to infer cell types did not show any significant differences. Further studies on dormancy gene signatures within the bone microenvironment are required
Full stack development toward a trapped ion logical qubit
Quantum error correction is a key step toward the construction of a large-scale quantum computer, by preventing small infidelities in quantum gates from accumulating over the course of an algorithm. Detecting and correcting errors is achieved by using multiple physical qubits to form a smaller number of robust logical
qubits. The physical implementation of a logical qubit requires multiple qubits, on which high fidelity gates
can be performed.
The project aims to realize a logical qubit based on ions confined on a microfabricated surface trap. Each
physical qubit will be a microwave dressed state qubit based on 171Yb+ ions. Gates are intended to be realized through RF and microwave radiation in combination with magnetic field gradients. The project vertically integrates software down to hardware compilation layers in order to deliver, in the near future, a fully functional small device demonstrator.
This thesis presents novel results on multiple layers of a full stack quantum computer model. On the hardware level a robust quantum gate is studied and ion displacement over the X-junction geometry is demonstrated.
The experimental organization is optimized through automation and compressed waveform data transmission. A new quantum assembly language purely dedicated to trapped ion quantum computers is introduced. The demonstrator is aimed at testing implementation of quantum error correction codes while preparing for larger
scale iterations.Open Acces
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