Flavonoids affect host-microbiota crosstalk through TLR modulation

Interaction between host cells and microbes is known as crosstalk. Among other mechanisms, this takes place when certain molecules of the micro-organisms are recognized by the toll-like receptors (TLRs) in the body cells, mainly in the intestinal epithelial cells and in the immune cells. TLRs belong to the pattern-recognition receptors and represent the first line of defense against pathogens, playing a pivotal role in both innate and adaptive immunity. Dysregulation in the activity of such receptors can lead to the development of chronic and severe inflammation as well as immunological disorders. Among components present in the diet, flavonoids have been suggested as antioxidant dietary factors able to modulate TLR-mediated signaling pathways. This review focuses on the molecular targets involved in the modulatory action of flavonoids on TLR-mediated signaling pathways, providing an overview of the mechanisms involved in such action. Particular flavonoids have been able to modify the composition of the microbiota, to modulate TLR gene and protein expression, and to regulate the downstream signaling molecules involved in the TLR pathway. These synergistic mechanisms suggest the role of some flavonoids in the preventive effect on certain chronic diseases.

Flavonoids affect host-microbiota crosstalk through TLR modulation

Interaction between host cells and microbes is known as crosstalk. Among other mechanisms, this takes place when certain molecules of the micro-organisms are recognized by the toll-like receptors (TLRs) in the body cells, mainly in the intestinal epithelial cells and in the immune cells. TLRs belong to the pattern-recognition receptors and represent the first line of defense against pathogens, playing a pivotal role in both innate and adaptive immunity. Dysregulation in the activity of such receptors can lead to the development of chronic and severe inflammation as well as immunological disorders. Among components present in the diet, flavonoids have been suggested as antioxidant dietary factors able to modulate TLR-mediated signaling pathways. This review focuses on the molecular targets involved in the modulatory action of flavonoids on TLR-mediated signaling pathways, providing an overview of the mechanisms involved in such action. Particular flavonoids have been able to modify the composition of the microbiota, to modulate TLR gene and protein expression, and to regulate the downstream signaling molecules involved in the TLR pathway. These synergistic mechanisms suggest the role of some flavonoids in the preventive effect on certain chronic diseases.

Photometric and Halpha observations of LSI+61·303: detection of a 26 day V and JHK band modulation

We present new optical and infrared photometric observations and high resolution H α spectra of the periodic radio star LSI+61◦303. The optical photometric data set covers the time interval 1985-1993 and amounts to about a hundred nights. A period of ∼26 days is found in the V band. The infrared data also present evidence for a similar periodicity, but with higher amplitude of variation ((0.m 2). The spectroscopic observations include 16 intermediate and high dispersion spectra of LSI+61◦303 collected between January 1989 and February 1993. The H α emission line profile and its variations are analyzed. Several emission line parameters -- among them the H α EW and the width of the H α red hump -- change strongly at or close to radio maximum, and may exhibit periodic variability. We also observe a significant change in the peak separation. The H α profile of LSI+61◦303 does not seem peculiar for a Be star. However, several of the observed variations of the H α profile can probably be associated with the presence of the compact, secondary star.

Pancreatic Cancer Cell Glycosylation Regulates Cell Adhesion and Invasion through the Modulation of a2b1 Integrin and E-Cadherin Function

In our previous studies we have described that ST3Gal III transfected pancreatic adenocarcinoma Capan-1 and MDAPanc-28 cells show increased membrane expression levels of sialyl-Lewis x (SLex) along with a concomitant decrease in α2,6-sialic acid compared to control cells. Here we have addressed the role of this glycosylation pattern in the functional properties of two glycoproteins involved in the processes of cancer cell invasion and migration, α2β1 integrin, the main receptor for type 1 collagen, and E-cadherin, responsible for cell-cell contacts and whose deregulation determines cell invasive capabilities. Our results demonstrate that ST3Gal III transfectants showed reduced cell-cell aggregation and increased invasive capacities. ST3Gal III transfected Capan-1 cells exhibited higher SLex and lower α2,6-sialic acid content on the glycans of their α2β1 integrin molecules. As a consequence, higher phosphorylation of focal adhesion kinase tyrosine 397, which is recognized as one of the first steps of integrin-derived signaling pathways, was observed in these cells upon adhesion to type 1 collagen. This molecular mechanism underlies the increased migration through collagen of these cells. In addition, the pancreatic adenocarcinoma cell lines as well as human pancreatic tumor tissues showed colocalization of SLex and E-cadherin, which was higher in the ST3Gal III transfectants. In conclusion, changes in the sialylation pattern of α2β1 integrin and E-cadherin appear to influence the functional role of these two glycoproteins supporting the role of these glycans as an underlying mechanism regulating pancreatic cancer cell adhesion and invasion

Multilevel converter modulation: implementation and analysis

Multilevel converters provide an attractive solution to bring the benefits of speed-controlled rotational movement to high-power applications. Therefore, multilevel inverters have attracted wide interest in both the academic community and in the industry for the past two decades. In this doctoral thesis, modulation methods suitable especially for series connected H-bridge multilevel inverters are discussed. A concept of duty cycle modulation is presented and its modification is proposed. These methods are compared with other well-known modulation schemes, such as space-vector pulse width modulation and carrier-based modulation schemes. The advantage of the modified duty-cycle modulation is its algorithmic simplicity. A similar mathematical formulation for the original duty cycle modulation is proposed. The modified duty cycle modulation is shown to produce well-formed phase-to-neutral voltages that have lower total harmonic distortion than the space-vector pulse width modulation and the duty cycle modulation. The space-vector-based solution and the duty cycle modulation, on the other hand, result in a better-quality line-to-line voltage and current waveform. The voltage of the DC links in the modules of the series-connected H-bridge inverter are shown to fluctuate while they are under load. The fluctuation causes inaccuracies in the voltage production, which may result in a failure of the flux estimator in the controller. An extension for upper-level modulation schemes, which changes the switching instants of the inverter so that the output voltage meets the reference voltage accurately regardless of the DC link voltages, is proposed. The method is shown to reduce the error to a very low level when a sufficient switching frequency is used. An appropriate way to organize the switching instants of the multilevel inverter is to make only one-level steps at a time. This causes restrictions on the dynamical features of the modulation schemes. The produced voltage vector cannot be rotated several tens of degrees in a single switching period without violating the above-mentioned one-level-step rule. The dynamical capabilities of multilevel inverters are analyzed in this doctoral thesis, and it is shown that the multilevel inverters are capable of operating even in dynamically demanding metal industry applications. In addition to the discussion on modulation schemes, an overvoltage in multilevel converter drives caused by cable reflection is addressed. The voltage reflection phenomenon in drives with long feeder cables causes premature insulation deterioration and also affects the commonmode voltage, which is one of the main reasons for bearing currents. Bearing currents, on the other hand, cause fluting in the bearings, which results in premature bearing failure. The reflection phenomenon is traditionally prevented by filtering, but in this thesis, a modulationbased filterless method to mitigate the overvoltage in multilevel drives is proposed. Moreover, the mitigation method can be implemented as an extension for upper-level modulation schemes. The method exploits the oscillations caused by two consecutive voltage edges so that the sum of the oscillations results in a mitigated peak of the overvoltage. The applicability of the method is verified by simulations together with experiments with a full-scale prototype.

Viral and cellular modulation of virus-induced apoptosis in experimental infection models

The aim of this study was to investigate herpes simplex virus type 1 (HSV-1)- and measles virus (MV)-induced cell death. HSV-1 with deletion in genes encoding infected cell protein (ICP)4 and protein kinase Us3 (d120) induced apoptosis and cathepsin activation in epithelial (HEp-2) and monocytic (U937) cells. Inhibition of cathepsin activity decreased the amount of d120-induced apoptosis indicating that d120-induced apoptosis could be cathepsin-mediated. Also, HSV-1 infection increased caspase activation suggesting that d120-induced apoptosis is probably caspase-mediated. Cystatin treatment decreased the activity of cathepsins and the replication of HSV-1 indicating that cathepsins contribute to HSV-1 infection. Interestingly, d120 induced also necroptosis in monocytic cells. This is the first report on necroptosis in HSV-1- infected cells. MV induced apoptosis in uninfected bystander T lymphocytes, probably via interaction of MV-infected monocytes with uninfected lymphocytes. The expression of death receptor Fas was clearly increased on the surface of lymphocytes. The number of apoptotic cells and the activation of cathepsins and caspases were increased in MVinfected U937 cells suggesting that MV-induced apoptosis could be cathepsin- and caspase-mediated. Cystatin treatment inhibited cathepsin activities but not MV-induced apoptosis. Besides HSV-1-induced apoptosis, innate immune responses were studied in HSV-1-infection. HSV-1 viruses with either ICP4 and Us3, or Us3 deletion only, increased the expression of Toll-like receptor (TLR)3 and stimulated its downstream pathways leading to increased expression of type I interferon gene and to functional interferons. These findings suggest that besides controlling apoptosis, HSV-1 ICP4 and Us3 genes are involved in the control of TLR3 response in infected cell.

Loss Modelling of Three-Level Inverters controlled with Space Vector Modulation Technique

The objective of this master’s thesis is to investigate the loss behavior of three-level ANPC inverter and compare it with conventional NPC inverter. The both inverters are controlled with mature space vector modulation strategy. In order to provide the comparison both accurate and detailed enough NPC and ANPC simulation models should be obtained. The similar control model of SVM is utilized for both NPC and ANPC inverter models. The principles of control algorithms, the structure and description of models are clarified. The power loss calculation model is based on practical calculation approaches with certain assumptions. The comparison between NPC and ANPC topologies is presented based on results obtained for each semiconductor device, their switching and conduction losses and efficiency of the inverters. Alternative switching states of ANPC topology allow distributing losses among the switches more evenly, than in NPC inverter. Obviously, the losses of a switching device depend on its position in the topology. Losses distribution among the components in ANPC topology allows reducing the stress on certain switches, thus losses are equally distributed among the semiconductors, however the efficiency of the inverters is the same. As a new contribution to earlier studies, the obtained models of SVM control, NPC and ANPC inverters have been built. Thus, this thesis can be used in further more complicated modelling of full-power converters for modern multi-megawatt wind energy conversion systems.

Positron measurements in Mg-doped GaN and development of digital Doppler broadening spectroscopy

In this work parameters of Mg-doped GaN samples were studied using positron annihilation spectroscopy and analyzed. It is shown that gallium vacancies exist in an unintentionally doped sample. Next, the sample with higher concentration of Mg and low growth temperature contains vacancy clusters. In case of low concentration of Mg the growth temperature does not affect the formation of defects. Analog electronics can be replaced by a modern digital device. While promising a high quantity of benefits, the performance of these digitizers requires thorough adjustment. A 14-bit two channel digitizer has been tested in order to achieve better performance than the one of a traditional analog setup, and the adjustment process is described. It has been shown that the digital device is unable to achieve better energy resolution, but it is quite close to the corresponding attribute of the available analog system, which had been used for measurements in Mg-doped GaN.

Correlação entre o doppler da veia hepática direita com a biópsia transcutânea guiada pela ultrassonografia em hepatopatias

OBJETIVOS: Correlacionar os achados da biópsia transcutânea hepática guiada por ultrassonografia com os dados ultrassonográficos modo B e Doppler da veia hepática direita; comparar os padrões de onda entre os grupos de estudo (hepatopatas) e controle (sadios); e avaliar se o Doppler da veia hepática direita serve como marcador de hepatopatia crônica. MÉTODOS: Foram estudados 38 pacientes portadores de hepatopatia crônica comprovada por sorologia e biópsia (grupo de estudo) e dez pacientes sem hepatopatia sorológica (grupo controle), avaliados pela ultrassonografia modo B e Doppler. Os critérios histológicos foram a classificação da Sociedade Brasileira de Patologia de Hepatite Crônica. RESULTADOS: A ultrassonografia modo B e o Doppler diferenciaram os indivíduos portadores de hepatopatia crônica dos normais (p=0,047). Houve diferença significativa entre o grupo de estudo e o controle na comparação entre os achados histopatológicos, ultrassonográficos modo B e o Doppler nos padrões de onda da veia hepática direita (p=0,001). CONCLUSÃO: Foi possível correlacionar a biópsia hepática com a ultrassonografia modo B e o Doppler da veia hepática direita; os hepatopatas apresentaram alteração no fluxo da veia hepática direita e os normais não, sendo que o padrão de onda nos controles saudáveis foi trifásico e nos hepatopatas bifásico ou monofásico; e o Doppler da veia hepática direita serviu como marcador de hepatopatia crônica.

Avaliação da ocorrência do refluxo venoso da safena magna pela ultrassonografia com doppler colorido após tratamento cirúrgico da insuficiência da junção safeno-femoral

OBJETIVO: avaliar a ocorrência do refluxo da safena magna através da ultrassonografia com Doppler colorido em sujeitos submetidos ao tratamento da insuficiência da junção safeno-femoral por ligadura simples ou por ligadura com secção da crossa. MÉTODOS: foram realizadas 60 operações (45 sujeitos) de varizes com insuficiência da junção safeno-femoral (JSF), pertencentes à classificação clínica do CEAP 2 a 5, que foram distribuídos aleatoriamente em dois grupos. Um grupo denominado C, com ligadura e secção da crossa, e um grupo denominado L, com ligadura simples sem secção da crossa da veia safena magna. Foi então pesquisada a ocorrência do refluxo da safena magna nos grupos C e L através da ultrassonografia doppler colorida após o tratamento cirúrgico com intervalos de seis meses a um ano. RESULTADOS: dos 60 membros submetidos à abordagem da crossa da safena magna, 57 foram avaliados pela ultrassonografia doppler pós-operatório, pois dois sujeitos (três membros) não retornaram e foram excluídos do estudo. A média de idade foi 54 anos, 93% do sexo feminino e predominância da classificação (CEAP) C2 de 60,5%. Das 57 operações para o tratamento do refluxo da crossa da safena, 43,9% apresentaram refluxo no pós-operatório, sendo 14,1% do grupo C e 29,8% no grupo L (p<0,05). O risco relativo de apresentar refluxo da crossa da safena no grupo L foi 2,03 vezes maior em comparação com o grupo C. CONCLUSÃO: a secção da crossa da safena magna apresenta menos refluxo pós-operatório do que a ligadura simples no tratamento da insuficiência da crossa da veia safena magna.

Ultra-sonografia transvaginal com doppler colorido para seleção das pacientes para tratamento conservador da gravidez ectópica íntegra

Objetivo: avaliar a eficiência da ultra-sonografia (US) transvaginal com Doppler colorido para a previsão dos resultados do tratamento sistêmico da gravidez ectópica íntegra com dose única de metotrexato. Pacientes e método: vinte pacientes com diagnóstico de gravidez ectópica foram incluídas no estudo. Os critérios de inclusão foram: estabilidade hemodinâmica, massa anexial com diâmetro < 5,0 cm e queda dos títulos de beta-hCG inferior a 15% num intervalo de 24 horas. Foram excluídas as pacientes que apresentaram doença hepática ou renal ou discrasias sangüíneas. O acompanhamento foi realizado com dosagens seriadas de beta-hCG nos dias 4 e 7 após instituído o tratamento, e semanalmente até que os títulos de beta-hCG se tornassem negativos. As pacientes foram classificadas em três conjuntos, conforme a US com doppler colorido: elevado risco (fluxo trofoblástico acometendo mais de 2/3 da massa anexial), médio risco (quando o fluxo trofoblástico comprometia de 1/3 a 2/3 do anel tubário) e de baixo risco (fluxos que acometiam menos de 1/3 da massa anexial). Resultados: o sucesso do tratamento com dose única de MTX foi de 75% (15 pacientes); quando empregamos uma segunda dose, a percentagem de bons resultados foi de 85%. Confrontamos os resultados obtidos pela US transvaginal e Doppler colorido com o sucesso e o insucesso da terapêutica. Observamos que, das 20 pacientes, 4 apresentaram Doppler de elevado risco e todas evoluíram com fracasso, ao passo que em 16 casos o Doppler foi classificado como de médio ou baixo risco, sendo que destes 15 evoluíram com sucesso. Conclusão: a ultra-sonografia transvaginal com Doppler colorido classificado como de elevado risco indica situação desfavorável para o tratamento medicamentoso da gravidez ectópica com dose única de metotrexato, ao passo que o Doppler de médio e baixo risco indica situação favorável para o tratamento clínico, porém estes resultados devem sempre ser analisados em conjunto com a curva de evolução dos títulos de beta-hCG.

Avaliação da Freqüência Cardíaca Embriofetal no Primeiro Trimestre da Gestação por meio da Ultra-sonografia Transvaginal com Doppler Colorido e Pulsátil

Objetivos: avaliar a evolução da freqüência cardíaca embrio-fetal no primeiro trimestre da gestação e determinar sua curva de normalidade. Pacientes e Métodos: em estudo prospectivo foram avaliadas 206 pacientes com diagnóstico clínico e/ou ultra-sonográfico de gestação no primeiro trimestre, por meio de exame ultra-sonográfico transvaginal com Doppler colorido, utilizando-se equipamento da marca Aloka, modelo SSD-2000, com sonda transvaginal convexa na freqüência de 5,0 MHz, todos realizados por um mesmo examinador. Foi determinada a freqüência cardíaca embriofetal. As pacientes foram divididas em grupos de acordo com a idade gestacional, em intervalos de 0,5 semana a partir da 6ª semana de gestação. Foi avaliada a evolução da gestação mediante realização de exame ultra-sonográfico de rotina no final do 2º e 3º trimestre. Foram calculados as médias e desvios-padrão para cada idade gestacional avaliada. Resultados: foi possível determinar a curva de normalidade para a freqüência cardíaca embriofetal. A média da freqüência cardíaca embriofetal apresentou modificações com a evolução da idade gestacional, variando de 110 ± 14 bpm com 6,0 semanas a 150 ± 12 bpm com 14,0 semanas, compatíveis com as fases do desenvolvimento e maturação funcional cardíaca. Conclusões: a ultra-sonografia transvaginal com Doppler colorido tornou possível a avaliação cardiovascular da gestação inicial, sendo um método não-invasivo e inócuo para o embrião. Os valores determinados poderão ser utilizados em estudos futuros neste período gestacional.