The linkage between mercury-caused neuro- and genotoxicity via the inhibition of dna repair machinery: fish brain model

The linkage between mercury-caused neuro- and genotoxicity via the inhibition of DNA repair machinery: fish brain model. Nedzvetsky V.S., Gasso V.Y., Herrmann B., Novitsky R.O. Heavy metals in model conditions as well as industrial pollution launch disturbances in neural cells of different animals and human beings. The neurotoxicity of mercury, which is one of the most toxic heavy metals, has been studied for several decades. However, its low doses chronic exposure effects for neural tissue cells are still poorly understood. Therefore, the basic molecular mechanisms of mercury should be clarified. The purpose of our research is to clarify the mechanism of mercury genotoxicity, the role of the DNA repair protein apurinic/apyrimidinic endonuclease 1 (APE1) in neural tissue cells, and the response to inorganic mercury-induced neurotoxicity. In our model, we used juvenile rainbow trout exposed to mercury chloride with a range of doses 9-36 µg/L for 60 days to study the cytotoxicity of chronic exposure. We detected the reactive oxygen species (ROS) production as an index of oxidative stress and APE1 as a marker of cellular DNA damage response in a neural cell. The ROS level was measured by using the fluorometric method based on 2',7'-dichlorofluorescein diacetate reaction. The analyses of markers of the DNA repair (APE1) and apoptosis (B cell lymphoma-2 anti-apoptotic protein – Bcl-2) were carried out with western blotting. The mercury chloride chronic exposure induced statistically significant upregulation of the ROS production in the fish brain. Contrary, the mercury low doses stimulated the downregulation of APE1 expression in the brain tissue. Furthermore, mercury chronic exposure inhibited the expression of Bcl-2 in the animals treated with 18 and 36 µg/L mercury chloride. The harmful effect of mercury could be promoted by oxidative stress generation. The downregulation of APE1 expression could lead to a lack of DNA damage response efficacy and initiate the decline in neural cell functioning. Obtained data on the APE1 expression have shown that the neurotoxic effect of mercury could be mediated, at least partially, by the decline in cellular DNA damage response in the brain. The evaluation of decrease in DNA repair response via detection of the APE1 expression can be a prospective tool to reveal the deleterious effects of toxicants in terms of their neuro- and genotoxicity

The linkage between mercury-caused neuro- and genotoxicity via the inhibition of dna repair machinery: fish brain modelthe linkage between mercury-caused neuro- and genotoxicity via the inhibition of dna repair machinery: fish brain model

The linkage between mercury-caused neuro- and genotoxicity via the inhibition of DNA repair machinery: fish brain model. Nedzvetsky V.S., Gasso V.Y., Herrmann B., Novitsky R.O. Heavy metals in model conditions as well as industrial pollution launch disturbances in neural cells of different animals and human beings. The neurotoxicity of mercury, which is one of the most toxic heavy metals, has been studied for several decades. However, its low doses chronic exposure effects for neural tissue cells are still poorly understood. Therefore, the basic molecular mechanisms of mercury should be clarified. The purpose of our research is to clarify the mechanism of mercury genotoxicity, the role of the DNA repair protein apurinic/apyrimidinic endonuclease 1 (APE1) in neural tissue cells, and the response to inorganic mercury-induced neurotoxicity. In our model, we used juvenile rainbow trout exposed to mercury chloride with a range of doses 9-36 µg/L for 60 days to study the cytotoxicity of chronic exposure. We detected the reactive oxygen species (ROS) production as an index of oxidative stress and APE1 as a marker of cellular DNA damage response in a neural cell. The ROS level was measured by using the fluorometric method based on 2',7'-dichlorofluorescein diacetate reaction. The analyses of markers of the DNA repair (APE1) and apoptosis (B cell lymphoma-2 anti-apoptotic protein – Bcl-2) were carried out with western blotting. The mercury chloride chronic exposure induced statistically significant upregulation of the ROS production in the fish brain. Contrary, the mercury low doses stimulated the downregulation of APE1 expression in the brain tissue. Furthermore, mercury chronic exposure inhibited the expression of Bcl-2 in the animals treated with 18 and 36 µg/L mercury chloride. The harmful effect of mercury could be promoted by oxidative stress generation. The downregulation of APE1 expression could lead to a lack of DNA damage response efficacy and initiate the decline in neural cell functioning. Obtained data on the APE1 expression have shown that the neurotoxic effect of mercury could be mediated, at least partially, by the decline in cellular DNA damage response in the brain. The evaluation of decrease in DNA repair response via detection of the APE1 expression can be a prospective tool to reveal the deleterious effects of toxicants in terms of their neuro- and genotoxicity

Numerical simulation of spray coalescence in an eulerian framework : direct quadrature method of moments and multi-fluid method

The scope of the present study is Eulerian modeling and simulation of polydisperse liquid sprays undergoing droplet coalescence and evaporation. The fundamental mathematical description is the Williams spray equation governing the joint number density function f(v, u; x, t) of droplet volume and velocity. Eulerian multi-fluid models have already been rigorously derived from this equation in Laurent et al. (2004). The first key feature of the paper is the application of direct quadrature method of moments (DQMOM) introduced by Marchisio and Fox (2005) to the Williams spray equation. Both the multi-fluid method and DQMOM yield systems of Eulerian conservation equations with complicated interaction terms representing coalescence. In order to validate and compare these approaches, the chosen configuration is a self-similar 2D axisymmetrical decelerating nozzle with sprays having various size distributions, ranging from smooth ones up to Dirac delta functions. The second key feature of the paper is a thorough comparison of the two approaches for various test-cases to a reference solution obtained through a classical stochastic Lagrangian solver. Both Eulerian models prove to describe adequately spray coalescence and yield a very interesting alternative to the Lagrangian solver

Curva de anticorpos pós-vacinais em ovinos imunizados com uma ou duas doses de bacterina oleosa anti-leptospirose, produzida com a sorovariedade Hardjo, tipo Hardjoprajitno, estirpe Norma, isolada no Brasil

Foi comparado o nível de anticorpos de ovelhas imunizadas com uma ou duas doses de bacterina oleosa produzida com a sorovariedade Hardjo, tipo Hardjoprajitno, estirpe Norma, isolada da urina de bovino no Brasil. Culturas de 2x10(8) leptospiras/mL foram inativadas com formalina a 0,3%, à concentração final e emulsionada em óleo Emulsigen® 12%. A dose da vacina foi padronizada para a concentração de 1x10(8) leptospiras/mL. Quarenta ovinos adultos, da raça Santa Inês, de um rebanho livre de leptospirose por exames clínicos e sorológicos durante um ano foram escolhidos para o experimento. O grupo A (n=15) recebeu duas doses de 3,0mL da vacina por via subcutânea, com intervalo de 30 dias. O grupo B (n=15) recebeu dose única de 3,0mL, via subcutânea e o grupo C (controle) recebeu uma dose subcutânea de 3,0mL de solução 0,85% de cloreto de sódio. Os títulos de anticorpos pós-vacinação foram mensurados pelo teste de soroaglutinação microscópica (SAM) e um teste imunoenzimático (ELISA) a cada 30 dias durante 120 dias. Os títulos dos grupos A e B na primeira colheita variaram de 80 a 160. No grupo A, após a segunda dose, os títulos aumentaram duas a quatro vezes, até 3.200, enquanto no grupo B os títulos de aglutininas foram menores que 160 e diminuíram uma a duas vezes após 60 dias da vacinação. Utilizando-se dose única, os anticorpos persistiram por somente 30 dias e, com duas doses, com 30 dias de intervalo, os anticorpos foram detectáveis por 60 dias por meio do teste de SAM e 120 dias no teste de ELISA. Assim, o teste de SAM detectou títulos de IgM vacinal somente por 60 dias, enquanto o teste de ELISA foi capaz de detectar anticorpos durante os 120 dias. No grupo controle negativo, ocorreram no ELISA reações inespecíficas de títulos até 80, porém no SAM os títulos dos mesmos animais se mantiveram em zero. O teste de ELISA pode ser utilizado para medir anticorpos vacinais para a sorovariedade Hardjo, tipo Hardjoprajitno, estirpe Norma em ovinos

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Combined radiohormonotherapy in node positive lymph node prostate cancer

Purpose: Pelvic radiation therapy (RT) represents a therapeutic option in the treatment of node-positive prostate cancer but it remains controversial, because of its high rate toxicities. New radiation technique such as IMRT may reduce these complications. In this study, we aimed to assess the rate of toxicities according to CTC-NCI.v3 in such patients treated with either 3DCRT or IMRT (Tomotherapy).Methods and Materials: From January 2008 to December 2010, data were analyzed from 30 consecutive patients including 29 node-positive prostate cancer undergoing definitive or adjuvant RT (IMRT and/or 3DCRT) after radical prostatectomy and lymphadenectomy combined to hormonal therapy. Median age was 66 years (range : 52-83). Median preoperative PSA value was 12 ng/ml (range: 2.72-165). According to the pT-classification, there were 4 pT2, 7 pT3a, 10 pT3b, and 1 pT4 patients. Pathologic positive lymph nodes were found in 23 patients. Radiologic positive lymph nodes were found in 5 patients. Two patients were node negative. Gleason score was ranging between 7 to 10. Twelve patients were treated by Tomotherapy including 4 with simultaneous integrated boost (SIB). Eighteen patients were treated by Tomotherapy including 2 with SIB to the whole pelvis and 3DCRT boost to the prostate. V50% for bladder and rectum were recorded. Acute and late toxicities were assessed according to CTC-NCI.v3 classification.Results: With a median follow-up of 17 months, only one patient presented nodal and metastatic failure. Urinary incontinence was graded 1 after surgery for 6 patients and grade 2 in two. Sexual impuissance was noted in 3 patients. Acute toxicities during RT were proctitis grade 0 in 23 patients (76.5%), grade 1 in 7 (23.5%). Nocturia grade 1 in 9 patients. Interruption of treatment was seen in only case because of grade 3 urinary incontinence. Late effects included erectile dysfunction in 5 patients (83%) and one patient had grade 3proctitis requiring colostomy 3 months after RT. Median Dose-Volume Histogram according to radiation techniques V50% bladder V50% rectum Tomotherapy (IMRT) 36.25 Gy 39 Gy Tomotherapy + 3DCRT 41.26 Gy 39.18 GyConclusion: Based on our above-mentioned findings, there is no a significant difference in morbidity in patients treated with Tomotherapy or Tomotherapy with 3DCRT boost