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At least 919 records · Page 51Linked to original sources
PubMed2006

Site-specific health risk assessment of dioxins and furans in an industrial region with numerous emission sources.

While the sources of releasing dioxins have received much attention, the health risks of incinerators are studied considerably more than those of other sources, such as metallurgical industry. Furthermore, risk assessments focus primarily on the effects of single sources; few have addressed the aggregate risks from multiple sources in a region. When many sources of dioxins exist in an area, such as the Industrial Park located in the densely populated district-Siaogang District in southern Taiwan where 17 primary known PCDD/F stationary emission sources are clustered, is the aggregate exposure to these sources imposing high risks even though individual sources comply with emission standards? The study combined the multimedia and multiple pathway exposure modeling and site-specific exposure scenario to assess dioxin risks contributed by the 17 emission sources in the District, including municipal waste incinerators, medical waste incinerators, sinter plants, electric arc furnace, secondary aluminum smelters, cement kilns, etc. The average cancer risk of a resident living in the District was found to be 3.43E-04 under the site-specific exposure scenario. The top emission source is the sinter plant, followed by the electric arc furnace. The information has driven the local government to conduct more complete assessment and at the same time to consider enforcing a stricter local standard of dioxin emissions in the Siaogang District.

Dioxins↗
PubMed2006

Crystal structure of lactaldehyde dehydrogenase from Escherichia coli and inferences regarding substrate and cofactor specificity.

Aldehyde dehydrogenases catalyze the oxidation of aldehyde substrates to the corresponding carboxylic acids. Lactaldehyde dehydrogenase from Escherichia coli (aldA gene product, P25553) is an NAD(+)-dependent enzyme implicated in the metabolism of l-fucose and l-rhamnose. During the heterologous expression and purification of taxadiene synthase from the Pacific yew, lactaldehyde dehydrogenase from E. coli was identified as a minor (</=5%) side-product subsequent to its unexpected crystallization. Accordingly, we now report the serendipitous crystal structure determination of unliganded lactaldehyde dehydrogenase from E. coli determined by the technique of multiple isomorphous replacement using anomalous scattering at 2.2 A resolution. Additionally, we report the crystal structure of the ternary enzyme complex with products lactate and NADH at 2.1 A resolution, and the crystal structure of the enzyme complex with NADPH at 2.7 A resolution. The structure of the ternary complex reveals that the nicotinamide ring of the cofactor is disordered between two conformations: one with the ring positioned in the active site in the so-called hydrolysis conformation, and another with the ring extended out of the active site into the solvent region, designated the out conformation. This represents the first crystal structure of an aldehyde dehydrogenase-product complex. The active site pocket in which lactate binds is more constricted than that of medium-chain dehydrogenases such as the YdcW gene product of E. coli. The structure of the binary complex with NADPH reveals the first view of the structural basis of specificity for NADH: the negatively charged carboxylate group of E179 destabilizes the binding of the 2'-phosphate group of NADPH sterically and electrostatically, thereby accounting for the lack of enzyme activity with this cofactor.

Aldehyde Oxidoreductases↗
PubMed2019

Increased acetylation of H3K14 in the genomic regions that encode trained immunity enzymes in lysophosphatidylcholine-activated human aortic endothelial cells - Novel qualification markers for chronic disease risk factors and conditional DAMPs.

To test our hypothesis that proatherogenic lysophosphatidylcholine (LPC) upregulates trained immunity pathways (TIPs) in human aortic endothelial cells (HAECs), we conducted an intensive analyses on our RNA-Seq data and histone 3 lysine 14 acetylation (H3K14ac)-CHIP-Seq data, both performed on HAEC treated with LPC. Our analysis revealed that: 1) LPC induces upregulation of three TIPs including glycolysis enzymes (GE), mevalonate enzymes (ME), and acetyl-CoA generating enzymes (ACE); 2) LPC induces upregulation of 29% of 31 histone acetyltransferases, three of which acetylate H3K14; 3) LPC induces H3K14 acetylation (H3K14ac) in the genomic DNA that encodes LPC-induced TIP genes (79%) in comparison to that of in LPC-induced effector genes (43%) including ICAM-1; 4) TIP pathways are significantly different from that of EC activation effectors including adhesion molecule ICAM-1; 5) reactive oxygen species generating enzyme NOX2 deficiency decreases, but antioxidant transcription factor Nrf2 deficiency increases, the expressions of a few TIP genes and EC activation effector genes; and 6) LPC induced TIP genes(81%) favor inter-chromosomal long-range interactions (CLRI, trans-chromatin interaction) while LPC induced effector genes (65%) favor intra-chromosomal CLRIs (cis-chromatin interaction). Our findings demonstrated that proatherogenic lipids upregulate TIPs in HAECs, which are a new category of qualification markers for chronic disease risk factors and conditional DAMPs and potential mechanisms for acute inflammation transition to chronic ones. These novel insights may lead to identifications of new cardiovascular risk factors in upregulating TIPs in cardiovascular cells and novel therapeutic targets for the treatment of metabolic cardiovascular diseases, inflammation, and cancers. (total words: 245).

Acetylation↗
PubMed2006

X Chromosomal effects on social cognitive processing and emotion regulation: A study with Klinefelter men (47,XXY).

Studying Klinefelter syndrome (47,XXY), a genetically defined disorder characterized by the presence of an additional X chromosome, can reveal insights into genotype-phenotype associations. Increased vulnerability to psychiatric disorders characterized by difficulties in social interactions, such as schizophrenia and autism, has been reported for this population. The reported social difficulties in 47,XXY men may arise as a consequence of impairments in the processing of social and emotional information. The present study is the first investigation of social-emotional information processing in this X chromosomal disorder. 32 Klinefelter men and 26 men from the general population, with the groups matched for age, educational level and I.Q., participated in the study. Several tasks were included, reflecting aspects of social-emotional information processing on levels of perception, experience and expression: labeling of facial expressions of emotion, emotion-cognition interactions in decision making and emotion regulation, that refers to subjective experience and identification of emotional arousal as well as verbal expression of emotions. A discrepancy between cognitive appraisal of emotions and emotional arousal was observed in Klinefelter syndrome. Taken together, Klinefelter men seem less accurate in perception of socio-emotional cues such as angry facial expressions, they are less able to identify and verbalize their emotions, but experience increased levels of emotional arousal, in comparison to the general population. Besides describing the social-emotional phenotype of this X chromosomal disorder, the present data may prove to be an important contribution to the development of more general models describing pathways to neuropsychiatric disorders characterized by social cognitive disturbances.

Adult↗
PubMed2006

A sense of time: how molecular clocks organize metabolism.

The discovery of an internal temporal clockwork that coordinates behavior and metabolism according to the rising and setting of the sun was first revealed in flies and plants. However, in the past decade, a molecular transcription-translation feedback loop with similar properties has also been identified in mammals. In mammals, this transcriptional oscillator programs 24-hour cycles in sleep, activity and feeding within the master pacemaker neurons of the suprachiasmatic nucleus of the hypothalamus. More recent studies have shown that the core transcription mechanism is also present in other locations within the brain, in addition to many peripheral tissues. Processes ranging from glucose transport to gluconeogenesis, lipolysis, adipogenesis and mitochondrial oxidative phosphorylation are controlled through overlapping transcription networks that are tied to the clock and are thus time sensitive. Because disruption of tissue timing occurs when food intake, activity and sleep are altered, understanding how these many tissue clocks are synchronized to tick at the same time each day, and determining how each tissue 'senses time' set by these molecular clocks might open new insight into human disease, including disorders of sleep, circadian disruption, diabetes and obesity.

Animals↗
PubMed2005

Investigating the light absorption in a single pass through the photoreceptor layer by means of the lipofuscin fluorescence.

Reflection densitometry has been widely used to measure the density difference of the bleachable cone photopigments in human eyes. Most such measurements make a series of assumptions concerning the amount of scattered light to derive an estimate of the true cone photopigment density from the density difference measurements. The current study made three types of measurements of the light returning from the eye before and after bleaching: the amount of light returning in the "directed" reflection, which is a double-pass estimate of the cone photopigment density; the amount of light in undirected or diffuse reflection; and the amount of fluorescence from lipofuscin in the RPE, which provides a single-pass measurement of optical density difference. For a 1 deg foveally fixated field, the density difference estimates for the three measurements were 0.68, 0.21, and 0.22 respectively. The lipofuscin fluorescence was found to be unguided. The background density difference was non-negligible and very close to the single pass estimate from fluorescence. These measurements each involve potentially different pathways of light through the retina, and therefore place different constraints on models of these pathways. A simple model comparing the directional and the fluorescence optical densities produced retinal coverage estimates around 70-75%. Estimates of the shape factor of the single pass optical Stiles-Crawford effect were evaluated from the dark-adapted and bleached fluorescence measurements. The values were closer to those obtained from psychophysical methods than to the double pass optical Stiles-Crawford shape factors obtained directly from retinal reflectometry.

Adult↗
PubMed2003

Primary folding dynamics of sperm whale apomyoglobin: core formation.

The structure, thermodynamics, and kinetics of heat-induced unfolding of sperm whale apomyoglobin core formation have been studied. The most rudimentary core is formed at pH(*) 3.0 and up to 60 mM NaCl. Steady state for ultraviolet circular dichroism and fluorescence melting studies indicate that the core in this acid-destabilized state consists of a heterogeneous composition of structures of approximately 26 residues, two-thirds of the number involved for horse heart apomyoglobin under these conditions. Fluorescence temperature-jump relaxation studies show that there is only one process involved in Trp burial. This occurs in 20 micro s for a 7 degrees jump to 52 degrees C, which is close to the limits placed by diffusion on folding reactions. However, infrared temperature jump studies monitoring native helix burial are biexponential with times of 5 micro s and 56 micro s for a similar temperature jump. Both fluorescence and infrared fast phases are energetically favorable but the slow infrared absorbance phase is highly temperature-dependent, indicating a substantial enthalpic barrier for this process. The kinetics are best understood by a multiple-pathway kinetics model. The rapid phases likely represent direct burial of one or both of the Trp residues and parts of the G- and H-helices. We attribute the slow phase to burial and subsequent rearrangement of a misformed core or to a collapse having a high energy barrier wherein both Trps are solvent-exposed.

Animals↗
PubMed1998

Levamisole inhibits intestinal Cl- secretion via basolateral K+ channel blockade.

BACKGROUND & AIMS: Phenylimidazothiazoles have recently been shown to activate wild-type and mutant cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channels in transfected cells and were proposed as therapy for cystic fibrosis. The aim of this study was to investigate the effects of phenylimidazothiazoles on regulated transepithelial Cl- transport in intact epithelia. METHODS: T84 intestinal epithelial cells grown on permeable supports and stripped human colonic mucosal sheets were studied by conventional current-voltage clamping. Selective permeabilization of apical or basolateral membranes with the monovalent ionophore nystatin was used to isolate basolateral K+ and apical Cl- channel activity, respectively. 86Rb+ uptake was assessed for Na/K/2Cl cotransporter and Na+,K(+)-adenosine triphosphatase activity. RESULTS: In T84 monolayers and human colon, levamisole and its brominated derivative bromotetramisole failed to activate transepithelial secretion. In fact, these compounds dose-dependently inhibited secretory responses to the cyclic adenosine monophosphate agonist forskolin and the Ca2+ agonist carbachol. In permeabilized T84 monolayers, phenylimidazothiazoles weakly activated apical Cl- currents (consistent with their reported action on CFTR) and did not affect bumetanide-sensitive or bumetanide-insensitive 86+Rb+ uptake. Instead, they profoundly inhibited the basolateral Ba(2+)-sensitive and Ba(2+)-insensitive K+ currents. CONCLUSIONS: Phenylimidazothiazoles block K+ channels required for Cl(-)-secretory responses elicited by diverse pathways in model epithelia and native colon, an effect that outweighs their ability to activate apical Cl- channels.

Calcium↗
PubMed1999

An assessment of the environmental fate and exposure of benzene and the chlorobenzenes in Canada.

Systematic modelling of the fate of benzene and the chlorobenzenes is presented which follows a four-stage process of chemical classification, quantifying discharge rates and environmental concentrations, evaluative assessment of fate and regional mass balance modelling has been carried out for the southern Ontario region. The EQC model was applied to determine the principal transport and transformation processes experienced by this group of chemicals, which vary considerably in volatility and hydrophobicity. Observed environmental concentrations are in satisfactory agreement with the predictions of the steady state Level III ChemCAN model of chemical fate. A multiple pathway human exposure model which estimates intake of contaminants by residents of southern Ontario has been developed and applied to these chemicals. A novel method of deducing maximum tolerable environmental concentrations is presented. Results suggest that benzene and 1,4-dichlorobenzene are present in the environment at levels sufficient to cause exposures near allowable daily intake (ADI) levels for the general population, but the other substances are present at levels which result in exposure ranging from 1/10 to 1/1000 of the ADI.

Benzene↗
PubMed2003

G protein-coupled receptors in invertebrates: a state of the art.

G protein-coupled receptors (GPCRs) constitute one of the largest and most ancient superfamilies of membrane-spanning proteins. We focus on neuropeptide GPCRs, in particular on those of invertebrates. In general, such receptors mediate the responses of signaling molecules that constitute the highest hierarchical position in the regulation of physiological processes. Until recently, only a few of these receptors were identified in invertebrates. However, the availability of a plethora of genomic information has boosted the discovery of novel members in several invertebrate species, such as Drosophila, in which 18 neuropeptide GPCRs have been characterized. The finalization of genomic projects in other invertebrates will lead to a similar expansion of GPCR understanding. Many new insights regarding neuropeptide regulation have followed from the discovery of their cognate receptors. Furthermore, information on GPCR signaling is still fragmentary and the elucidation of these pathways in model insects such as Drosophila will lead to further insights in other species, including mammals. In this review we present the current status of what is known about invertebrate GPCRs, discuss some novel perceptions that follow from the identified members, and, finally, present some future prospects.

Amino Acid Sequence↗
PubMed2006

Controversies in ventricular remodelling.

Ventricular remodelling describes structural changes in the left ventricle in response to chronic alterations in loading conditions, with three major patterns: concentric remodelling, when a pressure load leads to growth in cardiomyocyte thickness; eccentric hypertrophy, when a volume load produces myocyte lengthening; and myocardial infarction, an amalgam of patterns in which stretched and dilated infarcted tissue increases left-ventricular volume with a combined volume and pressure load on non-infarcted areas. Whether left-ventricular hypertrophy is adaptive or maladaptive is controversial, as suggested by patterns of signalling pathways, transgenic models, and clinical findings in aortic stenosis. The transition from apparently compensated hypertrophy to the failing heart indicates a changing balance between metalloproteinases and their inhibitors, effects of reactive oxygen species, and death-promoting and profibrotic neurohumoral responses. These processes are evasive therapeutic targets. Here, we discuss potential novel therapies for these disorders, including: sildenafil, an unexpected option for anti-transition therapy; surgery for increased sphericity caused by chronic volume overload of mitral regurgitation; an antifibrotic peptide to inhibit the fibrogenic effects of transforming growth factor beta; mechanical intervention in advanced heart failure; and stem-cell therapy.

Animals↗
PubMed2003

Stacking transgenes in forest trees.

Huge potential exists for improving plant raw materials and foodstuffs via metabolic engineering. To date, progress has mostly been limited to modulating the expression of single genes of well-studied pathways, such as the lignin biosynthetic pathway, in model species. However, a recent report illustrates a new level of sophistication in metabolic engineering by overexpressing one lignin enzyme while simultaneously suppressing the expression of another lignin gene in a tree, aspen. This novel approach to multi-gene manipulation has succeeded in concurrently improving several wood-quality traits.

Biolistics↗
PubMed2006

Dimensional representations of DSM-IV cluster A personality disorders in a population-based sample of Norwegian twins: a multivariate study.

BACKGROUND: The 'odd' or 'Cluster A' personality disorders (PDs) - paranoid, schizoid and schizotypal PDs - were created in DSM-III with little empirical foundation. We have examined the relationship between the genetic and environmental risk factors for dimensional representations of these three personality disorders. METHOD: These personality disorders were assessed using the Structured Interview for DSM-IV Personality (SIDP-IV) in 1386 young adult twin pairs from the Norwegian Institute of Public Health Twin Panel. Using Mx, a single-factor independent pathway twin model was fitted to the number of endorsed criteria for the three disorders. RESULTS: The best-fit model included genetic and unique environmental common factors and genetic and unique environmental effects specific to each personality disorder. Total heritability was modest for these personality disorders and ranged from 21% to 28%. Loadings on the common genetic and unique environmental factors were substantially higher for schizotypal than for paranoid or schizoid PD. The proportion of genetic liability shared with all Cluster A disorders was estimated at 100, 43 and 26% respectively for schizotypal, paranoid and schizoid PDs. CONCLUSION: In support of the validity of the Cluster A construct, dimensional representations of schizotypal, paranoid and schizoid PD are all modestly heritable and share a portion of their genetic and environmental risk factors. No evidence was found for shared environmental or sex effects for these PDs. Schizotypal PD most closely reflects the genetic and environmental liability common to all three Cluster A disorders. These results should be interpreted in the context of the limited power of this sample.

Adult↗
PubMed2006

Genetic and environmental influences on dimensional representations of DSM-IV cluster C personality disorders: a population-based multivariate twin study.

BACKGROUND: The DSM-IV cluster C Axis II disorders include avoidant (AVPD), dependent (DEPD) and obsessive-compulsive (OCPD) personality disorders. We aimed to estimate the genetic and environmental influences on dimensional representations of these disorders and examine the validity of the cluster C construct by determining to what extent common familial factors influence the individual PDs. METHOD: PDs were assessed using the Structured Interview for DSM-IV Personality (SIDP-IV) in a sample of 1386 young adult twin pairs from the Norwegian Institute of Public Health Twin Panel (NIPHTP). A single-factor independent pathway multivariate model was applied to the number of endorsed criteria for the three cluster C disorders, using the statistical modeling program Mx. RESULTS: The best-fitting model included genetic and unique environmental factors only, and equated parameters for males and females. Heritability ranged from 27% to 35%. The proportion of genetic variance explained by a common factor was 83, 48 and 15% respectively for AVPD, DEPD and OCPD. Common genetic and environmental factors accounted for 54% and 64% respectively of the variance in AVPD and DEPD but only 11% of the variance in OCPD. CONCLUSION: Cluster C PDs are moderately heritable. No evidence was found for shared environmental or sex effects. Common genetic and individual environmental factors account for a substantial proportion of the variance in AVPD and DEPD. However, OCPD appears to be largely etiologically distinct from the other two PDs. The results do not support the validity of the DSM-IV cluster C construct in its present form.

Adult↗
PubMed2004

The development of family hierarchies and their relation to children's conduct problems.

Despite the intuitive richness of family systems theory, relatively little research has sought to test the validity of constructs theorized to be critical in the development of children's adjustment. One such cornerstone of structural and strategic family therapy is the family hierarchy. The present study investigated both the development of hierarchical structure in families from infancy to late middle childhood and relations between strong hierarchical structure and children's conduct problems. Using structural equation modeling, direct pathways to low hierarchical structure were evident for early caregiving behavior and parent-child conflict, with indirect associations present for parental adjustment, marital functioning, negative child behavior, and ecological disadvantage. In turn, family hierarchies were associated with youth antisocial behavior, an effect that was moderated by ethnic and neighborhood context. The results are discussed in reference to family systems' theory and implications for prevention and intervention.

Child↗
PubMed2000

Identifying the lipid-protein interface and transmembrane structural transitions of the Torpedo Na,K-ATPase using hydrophobic photoreactive probes.

To identify regions of the Torpedo Na,K-ATPase alpha-subunit that interact with membrane lipid and to characterize conformationally dependent structural changes in the transmembrane domain, we have proteolytically mapped the sites of photoincorporation of the hydrophobic compounds 3-(trifluoromethyl)-3-(m-[(125)I]iodophenyl)diazirine ([(125)I]TID) and the phosphatidylcholine analogue [(125)I]TIDPC/16. The principal sites of [(125)I]TIDPC/16 labeling were identified by amino-terminal sequence analysis of proteolytic fragments of the Na,K-ATPase alpha-subunit and are localized to hydrophobic segments M1, M3, M9, and M10. These membrane-spanning segments have the greatest levels of exposure to the lipid bilayer and constitute the bulk of the lipid-protein interface of the Na,K-ATPase alpha-subunit. The extent of [(125)I]TID and [(125)I]TIDPC/16 photoincorporation into these transmembrane segments was the same in the E(1) and E(2) conformations, indicating that lipid-exposed segments located at the periphery of the transmembrane complex do not undergo large-scale movements during the cation transport cycle. In contrast, for [(125)I]TID but not for [(125)I]TIDPC/16, there was enhanced photoincorporation in the E(2) conformation, and this component of labeling mapped to transmembrane segments M5 and M6. Conformationally sensitive [(125)I]TID photoincorporation into the M5 and M6 segments does not reflect a change in the levels of exposure of these segments to the lipid bilayer as evidenced by the lack of [(125)I]TIDPC/16 labeling of these two segments in either conformation. These results suggest that [(125)I]TID promises to be a useful tool for structural characterization of the cation translocation pathway and for conformationally dependent changes in the pathway. A model of the spatial organization of the transmembrane segments of the Na,K-ATPase alpha- and beta-subunits is presented.

Animals↗
PubMed1978

Energy utilization and RNA transport: their interdependence.

The interdependence of RNA transport and the metabolism of nucleotide additives was investigated. Rat-liver RNA was radioactively labeled in vivo for 45 min before isolation of liver nuclei, and the concentration dependence of RNA transport on nucleotide additives was determined. In a parrallel investigation, using nucleotide additives labeled in the base moiety, the distributions of label in the tri-, di-, and monophosphate forms were examined after various intervals of incubation. Analysis of results revealed that RNA transport was linearly related to the decline in energy charge of nucleotide additives, whith high statistical correlation. Kinetic analysis of labeled-nucleotide metabolism led to a simple schematic model for pathways for the utilization of high-energy phosphate bonds, and predictions of the scheme were confirmed by studies examining the effects of nucleotide analogues upon RNA transport. Data concerning inhibitors and chelators intimated that multiple avenues of inhibition and stimulation may potentially influence RNA transport. On the basis of previous data and the results presented in this communication, we conclude that nucleocytoplasmic RNA transport is dependent upon high-energy phosphate-bond hydrolysis and that nucleotides do not stimulate RNA transport via a simple chelation mechanism.

Adenine Nucleotides↗