1,720,978 research outputs found
Paraoxonase (PON1) and Detoxication of Nerve Agents
No full textParaoxonase (PON1) is a serum and liver enzyme that can hydrolyze in vitro a number of organophosphorus (OP) compounds, including the active metabolites of specific OP insecticides, and certain OP nerve agents such as sarin and soman. PON1 presents several genetic polymorphisms that influence its ability to hydrolyze OPs as well as its level of expression. Studies using animals, including transgenic mice, have shown that PON1 modulates the in vivo acute toxicity of certain OPs, particularly chlorpyrifos oxon and diazoxon. In contrast, because of its low catalytic efficiency toward paraoxon, PON1 does not influence the acute toxicity of this OP in vivo. The catalytic efficiency of PON1 toward nerve agents is similarly low, although some studies have shown that administration of exogenous PON1 can protect against the toxicity of soman and sarin. For use as catalytic bioscavengers, recombinant engineered PON1s need to be developed with an enhanced catalytic efficiency toward nerve agents. Such PON1s would be excellent candidates for prophylactic and therapeutic applications in case of OP poisoning. A parallel strategy would be that of identifying and studying agents that would increase levels of endogenous PON1
Modulation of paraoxonase (PON1) activity
No full textParaoxonase 1 (PON1) is a serum enzyme closely associated with high density lipoprotein (HDL). PON1 hydrolyzes several organophosphorus compounds used as insecticides, as well as nerve agents; it metabolizes toxic oxidized lipids associated with both low density lipoprotein (LDL) and HDL; and it can hydrolyze a number of lactone-containing pharmaceutical compounds, inactivating some, while activating others. Serum PON1 activity in a given population can vary by 40-fold. Though most of this variation can be explained by polymorphisms in the coding region (Q192R) and the 5' regulatory region (T-108C), modulation of PON1 by a variety of other factors should be taken into account, including other polymorphisms recently discovered but not yet characterized. This paper examines the major factors (environmental chemicals, drugs, smoking, alcohol, diet, age, disease conditions) that have been shown to modulate PON1 activity in either direction. As PON1 plays a protective role in organophosphate toxicity, and, because of its antioxidant capacity, in cardiovascular disease, a better understanding of how PON1 can be modulated by environmental factors has potential toxicological and clinical consequence
Behavioral phenotyping for autism spectrum disorders in mice
No full textAutism spectrum disorder (ASD) represents a heterogeneous group of disorders characterized by alterations in three behavioral symptom domains: Social interactions, verbal and nonverbal communication, and repetitive behaviors. Increasing prevalence of ASD in recent years suggests that exposure to environmental toxicants may be critical in modulating etiology of this disease. As clinical diagnosis of autism still relies on behavioral evaluation, it is important to be able to assess similar behavioral traits in animal models, to provide biological plausibility of associations between environmental exposures and ASD. Rodents naturally exhibit a large number of behaviors that can be linked to similar behaviors in human. In this unit, behavioral tests are described that are relevant to the domains affected in ASD. For the repetitive domain, the T-maze spontaneous alternation test and marble burying test are described. For the communication domain, neonatal ultrasonic vocalization and olfactory habituation test toward social and non-social odor are described. Finally, for the sociability domain, the three-chambered social preference test and the reciprocal interaction test are presented
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Perinatal diesel exhaust exposure causes persistent changes in the brains of aged mice: An assessment of behavioral and biochemical endpoints related to neurodegenerative disease
No full textEpidemiological studies support an association between air pollution exposure, specifically particulate matter (PM), and neurodegenerative disease. Diesel exhaust (DE) is a principal component of ambient air pollution and a major contributor of PM. Our study aimed to examine whether early-life perinatal DE exposure is sufficient to affect behavioral and biochemical endpoints related to Alzheimer's disease later in life. To achieve this, mice were perinatally exposed (embryonic day 0-postnatal day 21) to DE (250-300 mu g/m(3)) or filtered air (FA), and allowed to reach aged status (>18 months). Mice underwent behavioral assessment at 6 and 20 months of age, with tissue collected at 22 months for biochemical endpoints. At 6 months, minimal changes were noted in home-cage behavior of DE treated animals. At 20 months, an alternation deficit was noted with the T-maze, although no difference was seen in the object location task or any home-cage metrics. DE exposure did not alter the expression of A beta 42, phosphorylated tau S199, or total tau. However, IBA-1 protein, a microglial activation marker, was significantly higher in DE exposed animals. Further, lipid peroxidation levels were significantly higher in the DE exposed animals compared to FA controls. Cytokine levels were largely unchanged with DE exposure, suggesting a lack of inflammation despite persistent lipid peroxidation. Taken together, the findings of this study support that perinatal exposure alone is sufficient to cause lasting changes in the brain, although the effects appear to be less striking than those previously reported in younger animals, suggesting some effects do not persist over time. These findings are encouraging from a public health standpoint and support the aggressive reduction of DE emissions to reduce lifetime exposure and potentially reduce disease outcome
Neurobehavioral assessment of mice following repeated postnatal exposure to chlorpyrifos-oxon
No full textChlorpyrifos (CPF), one of the most widely-used organophosphorus (OP) insecticides in agriculture, is degraded in the field to its oxon form, chlorpyrifos-oxon (CPO), which can represent a significant contaminant in exposures to adults and children. CPO is also responsible for the acetylcholinesterase (AChE) inhibition associated with CPF exposures; CPF is converted by liver CYP450 enzymes to CPO, which binds to and inhibits AChE and other serine active-site esterases, lipases and proteases. Young children represent a particularly susceptible population for exposure to CPF and CPO, in part because levels of the plasma enzyme, paraoxonase (PON1), which hydrolyzes CPO, are very low during early development. While a number of studies have demonstrated developmental neurotoxicity associated with CPF exposure, including effects at or below the threshold levels for AChE inhibition, it is unclear whether these effects were due directly to CPF or to its active metabolite, CPO. PON1 knockout (PON1(-/-)) mice, which lack PON1, represent a highly sensitive mouse model for toxicity associated with exposure to CPF or CPO. To examine the neurobehavioral consequences of CPO exposure during postnatal development, PON1(-/-) mice were exposed daily from PND 4 to PND 21 to CPO at 0.15, 0.18, or 0.25mg/kg/d. A neurobehavioral test battery did not reveal significant effects of CPO on early reflex development, motor coordination, pre-pulse inhibition of startle, startle amplitude, open field behavior, or learning and memory in the contextual fear conditioning, Morris water maze, or water radial-arm maze tests. However, body weight gain and startle latency were significantly affected by exposure to 0.25mg/kg/d CPO. Additionally, from PNDs 15-20 the mice exposed repeatedly to CPO at all three doses exhibited a dose-related transient hyperkinesis in the 20-min period following CPO administration, suggesting possible effects on catecholaminergic neurotransmission. Our previous study demonstrated wide-ranging effects of neonatal CPO exposure on gene expression in the brain and on brain AChE inhibition, and modulation of both of these effects by the PON1(Q192R) polymorphism. The current study indicates that the neurobehavioral consequences of these effects are more elusive, and suggests that alternative neurobehavioral tests might be warranted, such as tests of social interactions, age-dependent effects on learning and memory, or tests designed specifically to assess dopaminergic or noradrenergic functio
Prenatal and early life diesel exhaust exposure disrupts cortical lamina organization: Evidence for a reelin-related pathogenic pathway induced by interleukin-6
No full textSeveral epidemiological studies have shown associations between developmental exposure to traffic-related air pollution and increased risk for autism spectrum disorders (ASD), a spectrum of neurodevelopmental disorders with increasing prevalence rate in the United States. Though animal studies have provided support for these associations, little is known regarding possible underlying mechanisms. In a previous study we found that exposure of C57BL/6J mice of both sexes to environmentally relevant levels (250–300 μg/m 3 ) of diesel exhaust (DE) from embryonic day 0 to postnatal day 21 (E0 to PND21) caused significant changes in all three characteristic behavioral domains of ASD in the offspring. In the present study we investigated a potential mechanistic pathway that may be of relevance for ASD-like changes associated with developmental DE exposure. Using the same DE exposure protocol (250–300 μg/m 3 DE from E0 to PND21) several molecular markers were examined in the brains of male and female mice at PND3, 21, and 60. Exposure to DE as above increased levels of interleukin-6 (IL-6) in placenta and in neonatal brain. The JAK2/STAT3 pathway, a target for IL-6, was activated by STAT3 phosphorylation, and the expression of DNA methyltransferase 1 (DNMT1), a STAT3 target gene, was increased in DE-exposed neonatal brain. DNMT1 has been reported to down-regulate expression of reelin (RELN), an extracellular matrix glycoprotein important in regulating the processes of neuronal migration. RELN is considered an important modulator for ASD, since there are several polymorphisms in this gene linked to the disease, and since lower levels of RELN have been reported in brains of ASD patients. We observed decreased RELN expression in brains of the DE-exposed mice at PND3. Since disorganized patches in the prefrontal cortex have been reported in ASD patients and disrupted cortical organization has been found in RELN-deficient mice, we also assessed cortical organization, by labeling cells expressing the lamina-specific-markers RELN and calretinin. In DE-exposed mice we found increased cell density in deeper cortex (lamina layers VI–IV) for cells expressing either RELN or calretinin. These findings demonstrate that developmental DE exposure is associated with subtle disorganization of the cerebral cortex at PND60, and suggest a pathway involving IL-6, STAT3, and DNMT1 leading to downregulation of RELN expression that could be contributing to this long-lasting disruption in cortical laminar organization
- …
