Associations of iron metabolism genes with blood manganese levels: a population-based study with validation data from animal models

<p>Abstract</p> <p>Background</p> <p>Given mounting evidence for adverse effects from excess manganese exposure, it is critical to understand host factors, such as genetics, that affect manganese metabolism.</p> <p>Methods</p> <p>Archived blood samples, collected from 332 Mexican women at delivery, were analyzed for manganese. We evaluated associations of manganese with functional variants in three candidate iron metabolism genes: <it>HFE </it>[hemochromatosis], <it>TF </it>[transferrin], and <it>ALAD </it>[δ-aminolevulinic acid dehydratase]. We used a knockout mouse model to parallel our significant results as a novel method of validating the observed associations between genotype and blood manganese in our epidemiologic data.</p> <p>Results</p> <p>Percentage of participants carrying at least one copy of <it>HFE C282Y</it>, <it>HFE H63D</it>, <it>TF P570S</it>, and <it>ALAD K59N </it>variant alleles was 2.4%, 17.7%, 20.1%, and 6.4%, respectively. Percentage carrying at least one copy of either <it>C282Y </it>or <it>H63D </it>allele in <it>HFE </it>gene was 19.6%. Geometric mean (geometric standard deviation) manganese concentrations were 17.0 (1.5) μg/l. Women with any <it>HFE </it>variant allele had 12% lower blood manganese concentrations than women with no variant alleles (β = -0.12 [95% CI = -0.23 to -0.01]). <it>TF </it>and <it>ALAD </it>variants were not significant predictors of blood manganese. In animal models, <it>Hfe</it>^-/-mice displayed a significant reduction in blood manganese compared with <it>Hfe</it>^+/+mice, replicating the altered manganese metabolism found in our human research.</p> <p>Conclusions</p> <p>Our study suggests that genetic variants in iron metabolism genes may contribute to variability in manganese exposure by affecting manganese absorption, distribution, or excretion. Genetic background may be critical to consider in studies that rely on environmental manganese measurements.</p

C4b Binding Protein Binds to CD154 Preventing CD40 Mediated Cholangiocyte Apoptosis: A Novel Link between Complement and Epithelial Cell Survival

Activation of CD40 on hepatocytes and cholangiocytes is critical for amplifying Fas-mediated apoptosis in the human liver. C4b-Binding Protein (C4BP) has been reported to act as a potential surrogate ligand for CD40, suggesting that it could be involved in modulating liver epithelial cell survival. Using surface plasmon resonance (BiaCore) analysis supported by gel filtration we have shown that C4BP does not bind CD40, but it forms stable high molecular weight complexes with soluble CD40 ligand (sCD154). These C4BP/sCD154 complexes bound efficiently to immobilised CD40, but when applied to cholangiocytes they failed to induce apoptosis or proliferation or to activate NFkB, AP-1 or STAT 3, which are activated by sCD154 alone. Thus C4BP can modulate CD40/sCD154 interactions by presenting a high molecular weight multimeric sCD154/C4BP complex that suppresses critical intracellular signalling pathways, permitting cell survival without inducing proliferation. Immunohistochemistry demonstrated co-localisation and enhanced expression of C4BP and CD40 in human liver cancers. These findings suggest a novel pathway whereby components of the complement system and TNF ligands and receptors might be involved in modulating epithelial cell survival in chronic inflammation and malignant disease

Linear ensemble-coding in midbrain superior colliculus specifies the saccade kinematics

Recently, we proposed an ensemble-coding scheme of the midbrain superior colliculus (SC) in which, during a saccade, each spike emitted by each recruited SC neuron contributes a fixed minivector to the gaze-control motor output. The size and direction of this ‘spike vector’ depend exclusively on a cell’s location within the SC motor map (Goossens and Van Opstal, in J Neurophysiol 95: 2326–2341, 2006). According to this simple scheme, the planned saccade trajectory results from instantaneous linear summation of all spike vectors across the motor map. In our simulations with this model, the brainstem saccade generator was simplified by a linear feedback system, rendering the total model (which has only three free parameters) essentially linear. Interestingly, when this scheme was applied to actually recorded spike trains from 139 saccade-related SC neurons, measured during thousands of eye movements to single visual targets, straight saccades resulted with the correct velocity profiles and nonlinear kinematic relations (‘main sequence properties– and ‘component stretching’) Hence, we concluded that the kinematic nonlinearity of saccades resides in the spatial-temporal distribution of SC activity, rather than in the brainstem burst generator. The latter is generally assumed in models of the saccadic system. Here we analyze how this behaviour might emerge from this simple scheme. In addition, we will show new experimental evidence in support of the proposed mechanism

Standardized metadata for human pathogen/vector genomic sequences

High throughput sequencing has accelerated the determination of genome sequences for thousands of human infectious disease pathogens and dozens of their vectors. The scale and scope of these data are enabling genotype-phenotype association studies to identify genetic determinants of pathogen virulence and drug/insecticide resistance, and phylogenetic studies to track the origin and spread of disease outbreaks. To maximize the utility of genomic sequences for these purposes, it is essential that metadata about the pathogen/vector isolate characteristics be collected and made available in organized, clear, and consistent formats. Here we report the development of the GSCID/BRC Project and Sample Application Standard, developed by representatives of the Genome Sequencing Centers for Infectious Diseases (GSCIDs), the Bioinformatics Resource Centers (BRCs) for Infectious Diseases, and the U.S. National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), informed by interactions with numerous collaborating scientists. It includes mapping to terms from other data standards initiatives, including the Genomic Standards Consortium's minimal information (MIxS) and NCBI's BioSample/BioProjects checklists and the Ontology for Biomedical Investigations (OBI). The standard includes data fields about characteristics of the organism or environmental source of the specimen, spatial-temporal information about the specimen isolation event, phenotypic characteristics of the pathogen/vector isolated, and project leadership and support. By modeling metadata fields into an ontology-based semantic framework and reusing existing ontologies and minimum information checklists, the application standard can be extended to support additional project-specific data fields and integrated with other data represented with comparable standards. The use of this metadata standard by all ongoing and future GSCID sequencing projects will provide a consistent representation of these data in the BRC resources and other repositories that leverage these data, allowing investigators to identify relevant genomic sequences and perform comparative genomics analyses that are both statistically meaningful and biologically relevant

A genetic algorithm for the one-dimensional cutting stock problem with setups

This paper investigates the one-dimensional cutting stock problem considering two conflicting objective functions: minimization of both the number of objects and the number of different cutting patterns used. A new heuristic method based on the concepts of genetic algorithms is proposed to solve the problem. This heuristic is empirically analyzed by solving randomly generated instances and also practical instances from a chemical-fiber company. The computational results show that the method is efficient and obtains positive results when compared to other methods from the literature. © 2014 Brazilian Operations Research Society

Endemic Dengue Associated with the Co-Circulation of Multiple Viral Lineages and Localized Density-Dependent Transmission

Dengue is one of the most important infectious diseases of humans and has spread throughout much of the tropical and subtropical world. Despite this widespread dispersal, the determinants of dengue transmission in endemic populations are not well understood, although essential for virus control. To address this issue we performed a phylogeographic analysis of 751 complete genome sequences of dengue 1 virus (DENV-1) sampled from both rural (Dong Thap) and urban (Ho Chi Minh City) populations in southern Viet Nam during the period 2003–2008. We show that DENV-1 in Viet Nam exhibits strong spatial clustering, with likely importation from Cambodia on multiple occasions. Notably, multiple lineages of DENV-1 co-circulated in Ho Chi Minh City. That these lineages emerged at approximately the same time and dispersed over similar spatial regions suggests that they are of broadly equivalent fitness. We also observed an important relationship between the density of the human host population and the dispersion rate of dengue, such that DENV-1 tends to move from urban to rural populations, and that densely populated regions within Ho Chi Minh City act as major transmission foci. Despite these fluid dynamics, the dispersion rates of DENV-1 are relatively low, particularly in Ho Chi Minh City where the virus moves less than an average of 20 km/year. These low rates suggest a major role for mosquito-mediated dispersal, such that DENV-1 does not need to move great distances to infect a new host when there are abundant susceptibles, and imply that control measures should be directed toward the most densely populated urban environments

Environmental enrichment reduces signs of boredom in caged mink

Animals housed in impoverished cages are often labelled 'bored'. They have also been called 'apathetic' or 'depressed', particularly when profoundly inactive. However, these terms are rarely operationally defined and validated. As a negative state caused by under-stimulation, boredom should increase interest in stimuli of all kinds. Apathy (lack of interest), by contrast, should manifest as decreased interest in all stimuli, while anhedonia (loss of pleasure, a depressive symptom) should specifically decrease interest in normally rewarding stimuli. We tested the hypotheses that mink, a model carnivore, experience more boredom, depression-like apathy, or anhedonia in non-enriched (NE) cages than in complex, enriched (E) cages. We exposed 29 subjects (13 E, 16 NE) to ten stimuli categorized a priori as aversive (e.g. air puffs), rewarding (e.g. evoking chasing) or ambiguous/neutral (e.g. candles). Interest in stimuli was assessed via latencies to contact, contact durations, and durations oriented to stimuli. NE mink contacted all stimuli faster (P = 0.003) than E mink, and spent longer oriented to/in contact with them, albeit only significantly so for ambiguous ones (treatment*type P<0.013). With stimulus category removed from statistical models, interest in all stimuli was consistently higher among NE mink (P<0.0001 for all measures). NE mink also consumed more food rewards (P = 0.037). Finally, we investigated whether lying down while awake and stereotypic behaviour (both increased by NE housing) predicted these responses. Lying awake positively co-varied with certain measures of increased exploration. In contrast, stereotypic 'scrabbling' or locomotion (e.g. pacing) did not. Overall, NE mink showed no evidence of apathy or depression, but instead a heightened investigation of diverse stimuli consistent with boredom. This state was potentially indicated by spending much time lying still but awake (although this result requires replication). Boredom can thus be operationalized and assessed empirically in non-human animals. It can also be reduced by environmental enrichment

The politics of heroes through the prism of popular heroism

This is the author accepted manuscript. The final version is available from Palgrave Macmillan via the DOI in this record.In modern day Britain, the discourse of national heroification is routinely utilised by politicians, educationalists and cultural industry professionals, whilst also being a popular concept to describe deserving ‘do-gooders’ who contribute to British society in a myriad of ways. We argue that although this heroification discourse is enacted as a discursive device of encouraging politically and morally desirable behaviour, it is dissociated from the largely under-explored facets of contemporary popular heroism. To compensate for this gap, this paper explores public preferences for heroes using survey data representative of British adults. This analysis demonstrates a conceptual stretching in the understanding of heroism, and allows identifying age- and gender-linked dynamics which effect public choices of heroes. In particular, we demonstrate that age above all determines the preference for having a hero, but does not explain preferences for specific hero-types. The focus on gender illustrates that the landscape of popular heroism reproduces a male-dominated bias which exists in the wider political and cultural heroification discourse. Simultaneously, our study shows that if national heroification discourse in Britain remains male-centric, the landscape of popular heroism is characterised by a gendered trend towards privatisation of heroes being particularly prominent amongst women. In the conclusion, this paper argues for a conceptual revision and re-gendering of the national heroification discourse as a step towards both empirically grounded, and age- and gender-sensitive politics of heroes and heroines.AHR