Angewandte statistische Optik in der Weißlicht-Interferometrie : Räumliches Phasenschieben und Einfluss optisch rauer Oberflächen

In dieser Dissertation wird eine Methode zur simultanen, optischen Objektvermessung basierend auf Weißlicht-Interferometrie vorgestellt. Das Verfahren beruht auf dem Prinzip des räumlichen Phasenschiebens und profitiert gegenüber herkömmlichen sequentiellen Techniken vom Verzicht beweglicher mechanischer Komponenten. Als statischer optischer Aufbau zeichnet es sich durch seine Robustheit aus und eignet sich somit für Anwendungsgebiete außerhalb des Labors. Auf Grund der simultanen Signalerfassung ist es nicht nur für die berührungslose Qualitätskontrolle interessant, sondern auch für medizinische Applikationen und zur quantitativen Beobachtung dynamischer Oberflächenprozesse. Im ersten Teil der Arbeit wird die Entwicklung des Systems im Kontext physikalischer Voraus-setzungen und technischer Randbedingungen diskutiert. Darauf folgt die Untersuchung einzelner Komponenten und deren Einflusses auf das Gesamtsystem. Ein weiterer Schwerpunkt der Arbeit liegt in den statistischen Eigenschaften der Speckle-Felder, die sich durch Reflexion diffus streuender Medien ausbilden. Bereits existierende Theorien, die den Einfluss von Speckle auf die longitudinale Auflösung der Weißlicht-Interferometrie beschreiben, werden mit dieser Arbeit vervollständigt. Mit Hilfe der entwickelten Methoden zur Simulation und experi-mentellen Überprüfung lassen sich die theoretischen Vorhersagen verdeutlichen und veri-fizieren. Sowohl für simultane als auch sequentielle Verfahren sind diese Ergebnisse insbe-sondere bei der Entwicklung hochaperturiger Systeme entscheidend

Synthesis and Biological Studies of (+)-Liquiditerpenoic Acid A (Abietopinoic Acid) and Representative Analogues: SAR Studies

[EN] The first semisynthesis and biological profiling of the new abietane diterpenoid (+)-liquiditerpenoic acid A (abietopinoic acid) (7) along with several analogues are reported. The compounds were obtained from readily available methyl dehydroabietate (8), which was derived from (-)-abietic acid (1). Biological comparison was conducted according to the different functional groups, leading to some basic structure-activity relationships (SAR). In particular, the ferruginol and sugiol analogues 7 and 10-16 were characterized by the presence of an acetylated phenolic moiety, an oxidized C-7 as a carbonyl, and a different functional group at C-18 (methoxycarbonyl, carboxylic acid, and hydroxymethyl). The biological properties of these compounds were investigated against a panel of six representative human tumor solid cells (A549, HBL-100, HeLa, SWI573, T-47D, and WiDr), five leukemia cellular models (NALM-06, KOPN-8, SUP-B15, UoCB1, and BCR-ABL), and four Leishmania species (L. infantum, L. donovani, L. amazonensis, and L. guyanensis). A molecular docking study pointed out some targets in these Leishmania species. In addition, the ability of the compounds to modulate GABA(A) receptors (alpha(1)beta(2)gamma(2s)) is also reported. The combined findings indicate that these abietane diterpenoids offer a source of novel bioactive molecules with promising pharmacological properties from cheap chiral-pool building blocks.Financial support by the Spanish Government [Consejo Superior de Investigaciones Cientificas (2016801008)] is gratefully acknowledged. M.S. thanks the support by the doctoral program "Molecular Drug Targets" (Austrian Science Fund FWF W 1232). F.R thanks the American Lebanese Syrian Associated Charities (ALSAC). M.A.D.-A. thanks the Santander Bank for the support for her project in consolidable groups of CEU-UCH.Hamulic, D.; Stadler, M.; Hering, S.; Padron, JM.; Bassett, R.; Rivas, F.; Loza-Mejia, M.... (2019). Synthesis and Biological Studies of (+)-Liquiditerpenoic Acid A (Abietopinoic Acid) and Representative Analogues: SAR Studies. Journal of Natural Products. 82(4):823-831. https://doi.org/10.1021/acs.jnatprod.8b00884S82383182

Signature of Electronic Correlations in the Optical Conductivity of the Doped Semiconductor Si:P

Electronic transport in highly doped but still insulating silicon at low temperatures is dominated by hopping between localized states; it serves as a model system of a disordered solid for which the electronic interaction can be investigated. We have studied the frequency-dependent conductivity of phosphorus-doped silicon in the THz frequency range (30 GHz to 3 THz) at low temperatures $T\geq 1.8$ K. The crossover in the optical conductivity from a linear to a quadratic frequency dependence as predicted by Efros and Shklovskii is observed qualitatively; however, the simple model does not lead to a quantitative agreement. Covering a large range of donor concentration, our temperature- and frequency-dependent investigations reveal that electronic correlation effects between the localized states play an important and complex role at low temperatures. In particular we find a super-linear frequency dependence of the conductivity that highlights the influence of the density of states, i.e. the Coulomb gap, on the optical conductivity. When approaching the metal-to-insulator transition by increasing doping concentration, the dielectric constant and the localization length exhibit critical behavior.Comment: 9 pages, 8 figures, 1 tabl

Comparison of positivity frequency of bcl-2 expression in prostate adenocarcinoma with low and high Gleason score

CONTEXT: Multiple genetic and epigenetic factors have been implicated in the oncogenesis and progression of prostate cancer. The major difficulty is in that the clinical management stems from the reality that reliable and accurate prognostic biomarkers are not available and that effective treatment regimens forming hormone-resistant prostate cancers are yet to be developed. Among the most important regulators of apoptosis and programmed cell death is the bcl-2 gene and its related proteins. Elevated levels of bcl-2 protein may contribute to the progression of prostate cancers to a metastatic and hormone-insensitive state characterized by poor responses to chemotherapy. OBJECTIVE: To characterize the expression of bcl-2 proteins as a prognostic factor in humans. DESIGN: A retrospective approach. SETTING: Urology section, Federal University of São Paulo. DIAGNOSTIC TEST USED: Immunohistochemical analysis using bcl-2 protein antibody and normal staining by hematoxylin-eosin. MAIN MEASUREMENTS: Prognostic relations and protein expression were evaluated considering the total sample (28) divided into two groups, high (8 to 10) and low (2 to 4), separated according to the histological differentiation grade (Gleason score) with 10 and 18 samples, respectively. RESULTS: The differentiation of grade into two groups separated according to the Gleason score in low and high types presented different bcl-2 expression (P < 0.001). CONCLUSION: The higher frequency of bcl-2 immunostaining in tumor samples was observed in association with more advanced Gleason scores and suggests that an increase in the ratio of this anti-apoptotic protein often occurs during progression of prostate cancers.CONTEXTO: Diversos fatores genéticos e ambientais têm sido relacionados à oncogênese e progressão do câncer de próstata. A principal dificuldade na conduta clínica frente a esses tumores consiste no fato de não existirem marcadores prognósticos precisos, e que tratamentos eficazes dos tumores hormônio-resistentes não estão ainda disponíveis. Entre os reguladores mais importantes para avaliar a taxa de apoptose, destaca-se a expressão da proteína bcl-2. Os níveis elevados dessa proteína podem contribuir na progressão dos tumores prostáticos para um estado metastático e/ou hormônio independente, que caracteristicamente não apresenta resposta satisfatória ao tratamento quimioterápico. OBJETIVO: Investigar a expressão da proteína bcl-2 como fator prognóstico em portadores de tumores prostáticos. TIPO DE ESTUDO: Estudo retrospectivo. LOCAL: Disciplina de Urologia da Universidade Federal de São Paulo (UNIFESP). TESTE DIAGNÓSTICO: Exame anatomopatológico convencional por hematoxilina-eosina (HE) e imunohistoquímico. VARIÁVEIS ESTUDADAS: Expressão prognóstica da proteína bcl-2, por técnica imunohistoquímica em portadores de adenocarcinoma da próstata submetidos a prostatectomia radical. AMOSTRA: 28 amostras de tumores de próstata fixadas em parafina, provenientes de pacientes submetidos à prostatectomia radical sem ablação androgênica prévia, avaliadas por HE e por imunohistoquímica para a caracterização da expressão da proteína bcl-2. A expressão foi correlacionada ao grau de diferenciação do tumor, dividindo-se os tumores em dois grupos, segundo o escore de Gleason, em baixo (escore 2 a 4), e alto grau (8 a 10), sendo que os grupos foram divididos em 18 e 10 pacientes, respectivamente. RESULTADOS: Observou-se associação estatisticamente significativa (P < 0, 001) entre expressão elevada da proteína e os casos que apresentavam um escore de Gleason mais elevado (83, 3%), enquanto que no grupo de escore de baixo grau não foi detectada expressão da bcl-2 em 90% das amostras. CONCLUSÕES: O aumento na expressão da proteína bcl-2 em tumores de próstata com escore de Gleason elevado pode estar associado à progressão do adenocarcinoma de próstata.Universidade Federal de São Paulo (UNIFESP) Escola Paulista de Medicina Department of SurgeryUNIFESP, EPM, Department of SurgerySciEL

Pig-to-Nonhuman Primates Pancreatic Islet Xenotransplantation: An Overview

The therapy of type 1 diabetes is an open challenging problem. The restoration of normoglycemia and insulin independence in immunosuppressed type 1 diabetic recipients of islet allotransplantation has shown the potential of a cell-based diabetes therapy. Even if successful, this approach poses a problem of scarce tissue supply. Xenotransplantation can be the answer to this limited donor availability and, among possible candidate tissues for xenotransplantation, porcine islets are the closest to a future clinical application. Xenotransplantation, with pigs as donors, offers the possibility of using healthy, living, and genetically modified islets from pathogen-free animals available in unlimited number of islets. Several studies in the pig-to-nonhuman primate model demonstrated the feasibility of successful preclinical islet xenotransplantation and have provided insights into the critical events and possible mechanisms of immune recognition and rejection of xenogeneic islet grafts. Particularly promising results in the achievement of prolonged insulin independence were obtained with newly developed, genetically modified pigs islets able to produce immunoregulatory products, using different implantation sites, and new immunotherapeutic strategies. Nonetheless, further efforts are needed to generate additional safety and efficacy data in nonhuman primate models to safely translate these findings into the clinic

Synaptic Vesicle Docking: Sphingosine Regulates Syntaxin1 Interaction with Munc18

Consensus exists that lipids must play key functions in synaptic activity but precise mechanistic information is limited. Acid sphingomyelinase knockout mice (ASMko) are a suitable model to address the role of sphingolipids in synaptic regulation as they recapitulate a mental retardation syndrome, Niemann Pick disease type A (NPA), and their neurons have altered levels of sphingomyelin (SM) and its derivatives. Electrophysiological recordings showed that ASMko hippocampi have increased paired-pulse facilitation and post-tetanic potentiation. Consistently, electron microscopy revealed reduced number of docked vesicles. Biochemical analysis of ASMko synaptic membranes unveiled higher amounts of SM and sphingosine (Se) and enhanced interaction of the docking molecules Munc18 and syntaxin1. In vitro reconstitution assays demonstrated that Se changes syntaxin1 conformation enhancing its interaction with Munc18. Moreover, Se reduces vesicle docking in primary neurons and increases paired-pulse facilitation when added to wt hippocampal slices. These data provide with a novel mechanism for synaptic vesicle control by sphingolipids and could explain cognitive deficits of NPA patients

Evaluating expert-based habitat suitability information of terrestrial mammals with GPS-tracking data

Aim Macroecological studies that require habitat suitability data for many species often derive this information from expert opinion. However, expert-based information is inherently subjective and thus prone to errors. The increasing availability of GPS tracking data offers opportunities to evaluate and supplement expert-based information with detailed empirical evidence. Here, we compared expert-based habitat suitability information from the International Union for Conservation of Nature (IUCN) with habitat suitability information derived from GPS-tracking data of 1,498 individuals from 49 mammal species. Location Worldwide. Time period 1998-2021. Major taxa studied Forty-nine terrestrial mammal species. Methods Using GPS data, we estimated two measures of habitat suitability for each individual animal: proportional habitat use (proportion of GPS locations within a habitat type), and selection ratio (habitat use relative to its availability). For each individual we then evaluated whether the GPS-based habitat suitability measures were in agreement with the IUCN data. To that end, we calculated the probability that the ranking of empirical habitat suitability measures was in agreement with IUCN's classification into suitable, marginal and unsuitable habitat types. Results IUCN habitat suitability data were in accordance with the GPS data (> 95% probability of agreement) for 33 out of 49 species based on proportional habitat use estimates and for 25 out of 49 species based on selection ratios. In addition, 37 and 34 species had a > 50% probability of agreement based on proportional habitat use and selection ratios, respectively. Main conclusions We show how GPS-tracking data can be used to evaluate IUCN habitat suitability data. Our findings indicate that for the majority of species included in this study, it is appropriate to use IUCN habitat suitability data in macroecological studies. Furthermore, we show that GPS-tracking data can be used to identify and prioritize species and habitat types for re-evaluation of IUCN habitat suitability data

External validation of prognostic models for preeclampsia in a Dutch multicenter prospective cohort

Objective: To perform an external validation of all published prognostic models for first-trimester prediction of the risk of developing preeclampsia (PE). Methods: Women <14 weeks of pregnancy were recruited in the Netherlands. All systematically identified prognostic models for PE that contained predictors commonly available were eligible for external validation. Results: 3,736 women were included; 87 (2.3%) developed PE. Calibration was poor due to overestimation. Discrimination of 9 models for LO-PE ranged from 0.58 to 0.71 and of 9 models for all PE from 0.55 to 0.75. Conclusion: Only a few easily applicable prognostic models for all PE showed discrimination above 0.70, which is considered an acceptable performance