Quantitative proteomic analysis of the tizoxanide effect in vero cells.

Nitazoxanide (NTZ) is effective against helminths and numerous microorganisms, including bacteria and viruses. In vivo, NTZ is metabolized into Tizoxanide (TIZ), which is the active circulating metabolite. With the emergence of SARS-Cov-2 as a Pandemic agent, NTZ became one of the molecules already approved for human use to engage clinical trials, due to results in vitro showing that NTZ was highly effective against the SARS-Cov-2, agent of COVID-19. There are currently several ongoing clinical trials mainly in the USA and Brazil involving NTZ due not only to the in vitro results, but also for its long-known safety. Here, we study the response of Vero cells to TIZ treatment and unveil possible mechanisms for its antimicrobial effect, using a label-free proteomic approach (LC/MS/MS) analysis to compare the proteomic profile between untreated- and TIZ-treated cells. Fifteen differentially expressed proteins were observed related to various biological processes, including translation, intracellular trafficking, RNA processing and modification, and signal transduction. The broad antimicrobial range of TIZ points towards its overall effect in lowering cell metabolism and RNA processing and modification. The decreased levels of FASN, HNRNPH and HNRNPK with the treatment appear to be important for antiviral activity.

Isomeric effects tuning the electron transport in carotenoid derivatives: from ohmic to rectifier behavior.

Single-molecules have been widely investigated in the last decades due to their promises as devices in molecular electronics. One of the advantages in the use of natural compounds in molecular electronics is the economy of material and molecular synthesis, which makes the process both cheaper and self-sustaining. Although many studies have considered electronic transport in single molecules, there are few studies associated with isomeric effects in biologically appealing systems. In the present work, we have studied ballistic electron transport in two isomeric forms of a retinol molecule: 11-cis and all-trans-retinol. The molecules were connected between two Au(111) electrodes and calculations were performed with the NEGF-DFT methodology. Current-voltage, differential conductance, and rectification curves were obtained and compared for two structures. While 11-cis-retinol shows a more symmetrical current-voltage curve, all-trans-retinol acts as molecular diode for low applied voltages. Our results suggest that a simple isomeric effect modulates the molecular device from nanowires to diodes with potential applications as field-effect transistors.

Investigation of electronic transport under mechanical strain in a molecular junction composed of a polyyne bridge connected to SWCNT electrodes.

In the present work we propose a novel treatment to investigate ballistic electron transport under mechanical strain in a 1-D molecular bridge composed of alternating simple and triple bonds (polyyne) connected between two Single-Wall Carbon Nanotube (SWCNT) electrodes. Calculations with the DFT-NEGF methodology were performed in order to analyze this system at low values of mechanical strain (compression and distension) and at equilibrium length in the presence of bias voltages applied along the longitudinal direction. The results show that, while the mechanical strain displaces the energy levels and changes the band gap in the nanotube caps, the applied bias breaks the degeneracy in the nanotube cap states and defines the electrical conductance along the system. The analysis of the PDOS suggests that the main contribution to the electrical current comes from the superposition of the nanotube cap states, which is in agreement with the transmission calculation, and this device can be employed as a transistor observed in the I-V curve.

Non-parametric approach to the study of phenotypic stability.

The aim of this study was to undertake the theoretical derivations of non-parametric methods, which use linear regressions based on rank order, for stability analyses. These methods were extension different parametric methods used for stability analyses and the result was compared with a standard non-parametric method. Intensive computational methods (e.g., bootstrap and permutation) were applied, and data from the plant-breeding program of the Biology Department of UFLA (Minas Gerais, Brazil) were used to illustrate and compare the tests. The non-parametric stability methods were effective for the evaluation of phenotypic stability. In the presence of variance heterogeneity, the non-parametric methods exhibited greater power of discrimination when determining the phenotypic stability of genotypes.

Use of discriminant analysis based on echocardiography for classification of congestive heart failure in dogs with myxomatous mitral valve disease / Utilização da análise discriminante baseada na ecocardiografia para classificação de insuficiência cardíaca congestiva em cães com degeneração mixomatosa da valva mitral

Mixomatous mitral valve disease (MMVD) is one of the most common cardiac abnormalities in dogs and humans that can lead to cardiac heart failure (CHF). Its diagnosis remains based on echocardiography and clinical signs. However, the early diagnose of MMVD can contribute to a better prognosis and avoid CHF. The aim of this study was to evaluate the clinical, radiographic and echocardiographic presence of CHF in dogs with MMVD in combination with a statistical model as a mathematical tool. For this purpose, dogs were divided into three groups (healthy; MMVD without CHF; and MMVD with CHF), according the clinical, radiographic and echocardiographic evaluation findings. Thus, linear discriminant functions were obtained by analyzing the variables weight, body surface area, aortic diameter, the ratio of the left atrium/aortic diameter, the ratio between the mitral regurgitation jet area and the left atrial area, vena contracta diameter and mitral valve proximal isovelocity surface area. Then, mathematical equations were established for each group of dogs. Statistical functions obtained in this study enabled to classify the dogs, regarding the presence of CHF with a probability of correct classification of 90.4%. Thus the statistical model demonstrated that it could be used as an auxiliary method for identifying CHF in dogs with MMVD.

A doença mixomatosa da valva mitral (DMVM) é uma das alterações cardíacas mais comuns em cães e humanos, a qual pode levar à insuficiência cardíaca congestiva (ICC). O diagnóstico dessa alteração ocorre com base principalmente no exame ecocardiográfico e na presença de sinais clínicos. No entanto, o diagnóstico precoce da DMVM pode contribuir para um melhor prognóstico e evitar o desenvolvimento de ICC. Assim, o objetivo do presente estudo foi avaliar a presença de ICC em cães com DMVM, por meio de exames clínico, radiográfico e ecocardiográfico em combinação com um modelo estatístico. Para este propósito, os cães foram divididos em três grupos (sadios; DMVM sem ICC; e DMVM com ICC), de acordo com os achados dos exames realizados. Então, as funções lineares discriminantes foram obtidas por meio da análise das variáveis peso; superfície de área corporal; diâmetro aórtico; relação entre o diâmetro do átrio esquerdo e aórtico; relação entre a área do jato regurgitante mitral e a área do átrio esquerdo; diâmetro da vena contracta e área da isovelocidade proximal mitral (PISA). As equações matemáticas foram estabelecidas para cada grupo de cães e demonstraram ser possível classificar os animais de acordo com a presença de ICC, com uma probabilidade de classificação correta de 90,4%. Diante disso, o modelo estatístico poderia ser uma ferramenta auxiliar para a identificação de ICC em cães com DMVM.

Use of discriminant analysis based on echocardiography for classification of congestive heart failure in dogs with myxomatous mitral valve disease / Utilização da análise discriminante baseada na ecocardiografia para classificação de insuficiência cardíaca congestiva em cães com degeneração mixomatosa da valva mitral

Mixomatous mitral valve disease (MMVD) is one of the most common cardiac abnormalities in dogs and humans that can lead to cardiac heart failure (CHF). Its diagnosis remains based on echocardiography and clinical signs. However, the early diagnose of MMVD can contribute to a better prognosis and avoid CHF. The aim of this study was to evaluate the clinical, radiographic and echocardiographic presence of CHF in dogs with MMVD in combination with a statistical model as a mathematical tool. For this purpose, dogs were divided into three groups (healthy; MMVD without CHF; and MMVD with CHF), according the clinical, radiographic and echocardiographic evaluation findings. Thus, linear discriminant functions were obtained by analyzing the variables weight, body surface area, aortic diameter, the ratio of the left atrium/aortic diameter, the ratio between the mitral regurgitation jet area and the left atrial area, vena contracta diameter and mitral valve proximal isovelocity surface area. Then, mathematical equations were established for each group of dogs. Statistical functions obtained in this study enabled to classify the dogs, regarding the presence of CHF with a probability of correct classification of 90.4%. Thus the statistical model demonstrated that it could be used as an auxiliary method for identifying CHF in dogs with MMVD...

A doença mixomatosa da valva mitral (DMVM) é uma das alterações cardíacas mais comuns em cães e humanos, a qual pode levar à insuficiência cardíaca congestiva (ICC). O diagnóstico dessa alteração ocorre com base principalmente no exame ecocardiográfico e na presença de sinais clínicos. No entanto, o diagnóstico precoce da DMVM pode contribuir para um melhor prognóstico e evitar o desenvolvimento de ICC. Assim, o objetivo do presente estudo foi avaliar a presença de ICC em cães com DMVM, por meio de exames clínico, radiográfico e ecocardiográfico em combinação com um modelo estatístico. Para este propósito, os cães foram divididos em três grupos (sadios; DMVM sem ICC; e DMVM com ICC), de acordo com os achados dos exames realizados. Então, as funções lineares discriminantes foram obtidas por meio da análise das variáveis peso; superfície de área corporal; diâmetro aórtico; relação entre o diâmetro do átrio esquerdo e aórtico; relação entre a área do jato regurgitante mitral e a área do átrio esquerdo; diâmetro da vena contracta e área da isovelocidade proximal mitral (PISA). As equações matemáticas foram estabelecidas para cada grupo de cães e demonstraram ser possível classificar os animais de acordo com a presença de ICC, com uma probabilidade de classificação correta de 90,4%. Diante disso, o modelo estatístico poderia ser uma ferramenta auxiliar para a identificação de ICC em cães com DMVM...

Heart rate variability and arrhythmias evaluated with Holter in dogs with degenerative mitral valve disease / Variabilidade da frequência cardíaca e arritmias detectadas pelo exame Holter em cães com degeneração valvar mitral

Cardiac diseases promote alterations in the autonomic control of the heart, leading to an increase in heart rate and, as a result, a decrease in heart rate variability (HRV).The aim of this study was to evaluate if the development of heart failure secondary to degenerative mitral valve disease (DMVD) concurs with changes in autonomic modulation of heart rhythm which are assessed by long electrocardiography examination (Holter). Dogs were evaluated by clinical examination and echocardiography in order to be categorized into the following groups: Control (healthy; n=6), DMVD (disease without heart failure; n=8), and DMVD heart failure (disease with heart failure; n=13). Arrhythmias and frequency domain HRV were determined by Holter. Diseased animals, when compared to healthy, had significantly lower total power, which indicates overall HRV. DMVD heart failure dogs also showed other disturbances such as high incidence of supraventricular arrhythmias, high heart rate, little amount of pauses (2.0s long between consecutive heartbeats), longer time in tachycardia, shorter time in bradycardia, low high frequency (parasympathetic control), and high low frequency (sympathetic and parasympathetic control) when compared to control (p<0.05). In DMVD dogs, Holter-derived variables changed with the development of heart failure...

As cardiopatias cursam com alterações do controle autonômico do coração, resultando em taquicardia e consequente diminuição na variabilidade da frequência cardíaca (VFC). O objetivo deste estudo foi avaliar se o desenvolvimento de insuficiência cardíaca secundária à degeneração valvar mitral (DVM) leva a alterações no controle autonômico do coração, as quais podem ser determinadas pela eletrocardiografia contínua (Holter). Cães foram distribuídos em grupos experimentais após avaliação clínica e ecocardiográfica da seguinte maneira: controle (saudáveis; n=6), DVM sem insuficiência cardíaca (n=8) e DVM com insuficiência cardíaca (n=13). Arritmias e VFC foram determinadas pelo Holter. Animais portadores de DVM, quando comparados ao controle, apresentaram diminuição significativa da potência total, a qual é representativa de toda a VFC. Somente cães doentes e com insuficiência cardíaca apresentaram incidência elevada de arritmias supraventriculares, frequência cardíaca aumentada, pequena quantidade de pausas superiores a 2,0s entre batimentos consecutivos, permanência por mais tempo em taquicardia do que em bradicardia, diminuído índice de alta frequência (indicativo de controle parassimpático) e elevado índice de baixa frequência (indicativo de controle simpático e parassimpático), quando comparados ao controle (p<0,05). Assim, conclui-se que, em cães portadores de DVM, as variáveis obtidas com o Holter apresentam-se alteradas devido ao desenvolvimento de insuficiência cardíaca...

Heart rate variability parameters of myxomatous mitral valve disease in dogs with and without heart failure obtained using 24-hour Holter electrocardiography.

Time-domain heart rate variability (HRV) parameters and the correlation between echocardiography and Holter examinations in dogs with myxomatous mitral valve disease (MMVD) were determined. Holter examination was also performed at different time frames: an entire 24-hour period, a four-hour period during sleep, and a four-hour period while awake. Ten healthy (control group) and 28 MMVD dogs, 15 with and 13 without heart failure, were evaluated. The SDANN (sd of the mean normal RR intervals for all five-minute segments during 24-hour Holter) and pNN(50) (percentage of differences between adjacent normal RR intervals that are >50 ms computed over 24-hour Holter) variables were significantly lower in the dogs with MMVD heart failure. The differences in HRV between the groups were only detected during the 24-hour evaluation period (P<0.05). There were high correlations (canonical analysis) between Holter and echocardiography examinations when considering pNN(50), SDANN, and LA/AO (left atrial to aortic root ratio) (r=0.92; P<0.05), indicating that both are important in evaluating MMVD dogs. SDANN and pNN(50) are measures of parasympathetic control of the heart, and thus, it is possible to infer that the MMVD dogs exhibit parasympathetic withdrawal during the development of heart failure.

Effect of monensin on Mayaro virus replication in monkey kidney and Aedes albopictus cells.

The effect of a cationic ionophore, monensin, on the replication of Mayaro virus in monkey kidney TC7 and Aedes albopictus cells has been studied. Treatment of these cells with 1 micromol/l monensin during infection did not affect the virus protein synthesis but inhibited severely the virus replication. Electron microscopy of the cells infected with Mayaro virus and treated with monensin revealed that the morphogenesis of Mayaro virus was impaired in TC7 but not in A. albopictus cells.

Weak bases affect late stages of Mayaro virus replication cycle in vertebrate cells.

This paper describes the effect of two weak bases (ammonium chloride and chloroquine) on the morphogenesis of Mayaro virus. When Mayaro virus-infected TC7 (monkey kidney) cells were treated with these agents it was observed that weak bases caused a significant reduction in virus yield. Also, cellular protein synthesis, which is inhibited by Mayaro virus infection, recovered to nearly normal levels. However, the synthesis of Mayaro virus proteins was affected. These phenomena were dose-dependent. The process of Mayaro virus infection in vertebrate cells is very rapid. Virus precursors are not observed in cell cytoplasm and budding through the plasma membrane seems to be the only way of virus release. Electron microscopy of cells infected with Mayaro virus and treated with weak bases revealed an accumulation of virus structures in cell cytoplasm. The study also noted an inhibition of budding through the plasma membrane and the appearance of virus particles inside intracytoplasmic vacuoles. These observations indicate an impairment at the final stages of the virus replication cycle.

Angiographic and electrophysiologic substrates of ventricular tachycardia in chronic Chagasic myocarditis.

Forty-three consecutive symptomatic patients with chronic Chagasic myocarditis and ventricular tachycardia (VT) underwent clinical evaluation, 24-hour Holter monitoring, left ventricular angiography and electrophysiologic testing including programmed ventricular stimulation at 3 drive cycle lengths at 2 sites in the right ventricle. The mean ejection fraction was 42 +/- 10%. Sixteen patients had clinical sustained VT and 27 nonsustained VT. VT was reproducibly initiated in 13 of 16 (81%) patients with sustained VT and in 14 of 27 (52%) patients with nonsustained VT. Electrocardiographic conduction disturbances were seen in 15 of 16 (94%) patients with sustained VT and in 17 of 27 (63%) patients with nonsustained VT (p less than 0.05). Five of 16 (31%) sustained VT and none of nonsustained VT patients had left ventricular aneurysms (p less than 0.05). These data indicate that VT is frequently inducible in patients with sustained VT and nonsustained VT and chronic Chagasic myocarditis. An association appears to be present between conduction disturbances on the electrocardiogram, left ventricular aneurysms and development of sustained ventricular arrhythmias.