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

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    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

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    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

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    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

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    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 χ≃2γe∣E⃗laser∣/Ec\chi\simeq 2\gamma_e|\vec E_{\rm laser}|/E_c 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 χ\chi 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 χ\chi 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

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    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 K+→π+νν‾K^+ \to \pi^+ \nu \overline{\nu} and KL→π0νν‾K_L \to \pi^0 \nu \overline{\nu} 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 líquido pericárdico

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    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 benefício hemodinâmico imediato, nem todos os pacientes apresentam regressão completa da hipertrofia do miocárdio, ficando com maior risco de eventos adversos, como a insuficiência cardíaca. 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 líquido pericárdico foi seguida, tomando partido de biópsias e líquidos pericárdicos recolhidos em ambiente cirúrgico. Das mais de 1800 e 750 proteínas identificadas, respetivamente, no miocárdio e no líquido pericárdico dos pacientes com estenose aórtica, um total de 90 proteínas 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 síntese proteica, um sistema ubiquitina-proteassoma ineficiente, uma tendência para morte celular (potencialmente acelerada pela atividade do complemento e por outros fatores extrínsecos que ativam death receptors), com ativação da resposta de fase aguda e do sistema imune, assim como da fibrose. A validação de alguns alvos específicos através de immunoblot e correlação com dados clínicos 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 caseína cinase 2, a família 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 cardíaca, 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 clínicos 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

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    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

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    Diese Arbeit befasst sich mit der Konzeption, Darstellung und photophysikalischen Charakterisierung von neuen lumineszenten Materialien auf Basis der 3d-Übergangsmetalle 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

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    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

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    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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