2,135 research outputs found

    Differential spectrum modeling and sensitivity for keV sterile neutrino search at KATRIN

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    Starting in 2026, the KATRIN experiment will conduct a high-statistics measurement of the differential tritium β\beta-spectrum to energies deep below the kinematic endpoint. This enables the search for keV sterile neutrinos with masses less than the kinematic endpoint energy m4E0=18.6keVm_\mathrm{4} \leq E_0 = 18.6\,\mathrm{keV}, aiming for a statistical sensitivity of Ue42=sin2θ106|U_\mathrm{e4}|^2=\sin^2\theta\sim 10^{-6} for the mixing amplitude. The differential spectrum is obtained by decreasing the retarding potential of KATRIN\u27s main spectrometer, and by determining the β\beta-electron energies by their energy deposition in the new TRISTAN SDD array. In this mode of operation, the existing integral model of the tritium spectrum is insufficient, and a novel differential model is developed in this work. The new model (TRModel) convolves the differential tritium spectrum using responese matrices to predict the energy spectrum of registered events after data acquisition. Each response matrix encodes the spectral spectral distrortion from individual experimental effects, which depend on adjustable systematic parameters. This approach allows to efficiently assess the sensitivity impact of each systematics individually or in combination with others. The response matrices are obtained from monte carlo simulations, numerical convolution, and analytical computation. In this work, the sensitivity impact of 20 systematic parameters is assessed for the TRISTAN Phase-1 measurement for which nine TRISTAN SDD modules are integrated into the KATRIN beamline. Furthermore, it is demonstrated that the sensitivity impact is significantly mitigated with several beamline field adjustments and minimal hardware modifications

    Structure and Phase Transformations in Thin Films

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    Fundamental Study of Photoluminescence-Shape Relationship of Fluorescent Nanodiamonds using Machine Learning Assisted Correlative Transmission Electron Microscopy and Photoluminescence Microscopy Method

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    Luminescent nanoparticles have shown wide applications ranging from lighting, display, sensors, and biomedical diagnostics and imaging. Among these, fluorescent nanodiamonds (FNDs) containing nitrogen-vacancy (NV) color centers are posed as emerging materials particularly in biomedical and biological imaging applications due to their room-temperature emission, excellent photo- and chemical- stability, high bio-compatibility, and versatile functionalization potentials. The shape variation of nanoparticles has a decisive influence on their fluorescence. However, current relative studies are limited by the lack of reliable statistical analysis of nanoparticle shape and the difficulty of achieving a precise correlation between shape/structure and optical measurements of large numbers of individual nanoparticles. Therefore, new methods are urgently needed to overcome these challenges to assist in nanoparticle synthesis control and fluorescence performance optimization. In this thesis a new correlative TEM and photoluminescence (PL) microscopy (TEMPL) method has been developed that combines the measurements of the optical properties and the materials structure at the exact same particle and sample area, so that accurate correlation can be established to statistically study the FND morphology/structure and PL properties, at the single nanoparticle level. Moreover, machine learning based methods have been developed for categorizing the 2D and 3D shapes of a large number of nanoparticles generated in TEMPL method. This ML-assisted TEMPL method has been applied to understand the PL correlation with the size and shape of FNDs at the single particle level. In this thesis, a strong correlation between particle morphology and NV fluorescence in FND particles has been revealed: thin, flake-like particles produce enhanced fluorescence. The robustness of this trend is proven in FND with different surface oxidation treatments. This finding offers guidance for fluorescence-optimized sensing applications of FND, by controlling the shape of the particles in fabrication. Overall the TEMPL methodology developed in the thesis provides a versatile and general way to study the shape and fluorescence relationship of various nanoparticles and opens up the possibility of correlation methods between other characterisation techniques

    Molecular modeling of drug delivery systems based on carbon nanostructures: structure, function, and potential applications for anticancer complexes of Pt(II)

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    The medication with Pt(II) drugs (cisplatin, carboplatin, and oxaliplatin) has been an effective alternative for treating cancers due to their notable inhibition of cancer cells growth and the prevention of metastasis. Nevertheless, the low selectivity of these metallodrugs for malignant cells produces severe side effects, which limit this chemotherapy. In this context, carbon nanohorns (CNHs) have been considered potential nanovectors for drugs, since they present low toxicity, drug-loading capacity, biodegradation routes, and biocompatibility when oxidized. However, there is still a lack of studies regarding the molecular behavior of these nanocarriers on cell membranes. The present work aims to characterize the interactions between inclusion complexes drug@CNH, which are formed by platinum drugs encapsulated in CNHs, and plasma membranes by using molecular dynamics simulations. The results demonstrated that the van der Waals contribution played a primary role (∼74%) for the complex stability, which explain the confined dynamics of drugs inside the CNHs. The free energy profiles revealed an endergonic character of the drug release processes from CNHs, in which the energy barrier for oxaliplatin release (~24 kcal mol–1 ) was ~30% larger than those for carboplatin and cisplatin (~18 kcal mol-1 ). The simulations also showed four stages of the interaction mechanism CNH--membrane: approach, insertion, permeation, and internalization. Despite the low structural disturbance of the membranes, the free energy barrier of ∼55 kcal mol-1 for the CNHs translocation indicated that this transport is kinetically unfavorable by passive process. The in silico experiments evidenced that the most likely mechanism of cisplatin delivery from CNHs involve the approach and insertion stages, where the nanovector adheres on the surface of cancer cells, as reported in in vitro studies. After this retention, the drug load may be slowly released in the tumor site. Finally, simulations of the cellular uptake of Pt(II) drugs also pointed out significant energy barriers (~30 kcal mol-1 ) for this process, which reflects their low permeability in membranes as discussed in experimental studies. In addition to reinforcing the potential of CNH as nanovector of Pt(II) drugs, the results presented in this thesis may assist and drive new experimental studies with CNHs, focusing on the development of less aggressive formulations for cancer treatments.A medicação com fármacos a base de Pt(II) (cisplatina, carboplatina e oxaliplatina) tem sido uma alternativa efetiva para tratar cânceres devido à sua notável inibição do crescimento de células cancerosas e a prevenção de metástases. No entanto, a baixa seletividade dessas metalodrogas por células cancerosas gera severos efeitos colaterais. Nesse contexto, nanohorns de carbono (CNHs) têm sido considerados potenciais nanovetores de fármacos, devido a baixa toxicidade, capacidade de carreamento de fármacos, rotas de biodegradação, e biocompatibilidade quando oxidados. Porém, existe uma carência de estudos tratando o comportamento desses nanocarreadores em biomembranas. Esse trabalho tem como objetivo caracterizar as interações entre complexos de inclusão fármaco@CNH, formados por fármacos de Pt(II) encapsulados em CNHs, e membranas usando simulações por dinâmica molecular. Os resultados demonstraram que a contribuição de van der Waals teve um papel primário (∼74%) na estabilidade dos complexos, o que explica a dinâmica confinada dos fármacos dentro dos CNHs. Os perfis de energia livre revelaram o caráter endergônico da liberação dos fármacos a partir de CNHs, nos quais a barreira de energia para a liberação da oxaliplatina (~24 kcal mol– 1 ) é ~30% maior do que aquelas para carboplatina e cisplatina. As simulações mostraram quatro estágios do mecanismo de interação CNH-membrana: aproximação, inserção, permeação e internalização. Apesar do baixo distúrbio estrutural das membranas, a barreira de energia livre de ∼55 kcal mol-1 para a translocação de CNHs indicou que esse transporte é desfavorável cineticamente via o processo passivo. Os experimentos in silico evidenciam que o mecanismo mais provável de entrega de cisplatina a partir de CNHs envolve a aproximação e inserção, onde o nanovetor adere na superfície de células cancerosas, como reportado em estudos in vitro. Após essa retenção, a carga de fármaco deve ser ligeiramente liberada no tumor. As simulações de captação celular de fármacos de Pt(II) também apontaram barreiras de energia significativas (∼30 kcal mol-1 ) para esse processo, o que reflete a baixa permeabilidade deles em membranas como discutido em estudos experimentais. Além de reforçar o potencial de CNHs como nanovetores de fármacos de Pt(II), os resultados apresentados nessa tese podem auxiliar e impulsionar novos estudos com CNHs, focando no desenvolvimento de formulações menos agressivas para tratamentos de câncer.FAPEMIG - Fundação de Amparo à Pesquisa do Estado de Minas Gerai

    LIPIcs, Volume 261, ICALP 2023, Complete Volume

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    LIPIcs, Volume 261, ICALP 2023, Complete Volum

    MULTISCALE MOLECULAR MODELING STUDIES OF THE DYNAMICS AND CATALYTIC MECHANISMS OF IRON(II)- AND ZINC(II)-DEPENDENT METALLOENZYMES

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    Enzymes are biological systems that aid in specific biochemical reactions. They lower the reaction barrier, thus speeding up the reaction rate. A detailed knowledge of enzymes will not be achievable without computational modeling as it offers insight into atomistic details and catalytic species, which are crucial to designing enzyme-specific inhibitors and impossible to gain experimentally. This dissertation employs advanced multiscale computational approaches to study the dynamics and reaction mechanisms of non-heme Fe(II) and 2-oxoglutarate (2OG) dependent oxygenases, including AlkB, AlkBH2, TET2, and KDM4E, involved in DNA and histone demethylation. It also focuses on Zn(II) dependent matrix metalloproteinase-1 (MMP-1), which helps collagen degradation. Chapter 2 investigates the substrate selectivity and dynamics on the enzyme-substrate complexes of DNA repair enzymes, AlkB and FTO. Chapter 3 unravels the mechanisms and effects of dynamics on the demethylation of 3-methylcytosine substrate by AlkB and AlkBH2 enzymes. The results imply that the nature of DNA and conformational dynamics influence the electronic structure of the iron center during demethylation. Chapter 4 delineates how second-coordination and long-range residue mutations affect the oxidation of 5-methylcytosine substrate to 5-hydroxymethylcytosine by TET2 enzyme. The results reveal that mutations affect DNA binding/interactions and the energetic contributions of residues stabilizing key catalytic species. Chapter 5 describes the reparation of unnatural alkylated substrates by TET2, their effects on second-coordination interactions and long-range correlated motions in TET2. The study reveals that post-hydroxylation reactions occur in aqueous solution outside the enzyme environment. Chapter 6 establishes how applying external electric fields (EEFs) enhances specificity of KDM4E for C—H over N—H activation during dimethylated arginine substrate demethylation. The results reveal that applying positive EEFs parallel to Fe=O bond enhances C—H activation rate, while inhibiting the N—H one. Chapter 7 addresses the formation of catalytically competent MMP-1·THP complex of MMP-1. The studies reveal the role of MMP-1’s catalytic domain a-helices, the linker, and changes in coordination states of catalytic Zn(II) during the transition. Overall, the presented results contribute to the in-depth understanding of the fundamental mechanisms of the studied enzymes and provide a background for developing enzyme-specific inhibitors against the associated disorders and diseases
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