Long-term (trophic) purinergic signalling: purinoceptors control cell proliferation, differentiation and death

The purinergic signalling system, which uses purines and pyrimidines as chemical transmitters, and purinoceptors as effectors, is deeply rooted in evolution and development and is a pivotal factor in cell communication. The ATP and its derivatives function as a 'danger signal' in the most primitive forms of life. Purinoceptors are extraordinarily widely distributed in all cell types and tissues and they are involved in the regulation of an even more extraordinary number of biological processes. In addition to fast purinergic signalling in neurotransmission, neuromodulation and secretion, there is long-term (trophic) purinergic signalling involving cell proliferation, differentiation, motility and death in the development and regeneration of most systems of the body. In this article, we focus on the latter in the immune/defence system, in stratified epithelia in visceral organs and skin, embryological development, bone formation and resorption, as well as in cancer. Cell Death and Disease (2010) 1, e9; doi:10.1038/cddis.2009.11; published online 14 January 201

Individualization as driving force of clustering phenomena in humans

One of the most intriguing dynamics in biological systems is the emergence of clustering, the self-organization into separated agglomerations of individuals. Several theories have been developed to explain clustering in, for instance, multi-cellular organisms, ant colonies, bee hives, flocks of birds, schools of fish, and animal herds. A persistent puzzle, however, is clustering of opinions in human populations. The puzzle is particularly pressing if opinions vary continuously, such as the degree to which citizens are in favor of or against a vaccination program. Existing opinion formation models suggest that "monoculture" is unavoidable in the long run, unless subsets of the population are perfectly separated from each other. Yet, social diversity is a robust empirical phenomenon, although perfect separation is hardly possible in an increasingly connected world. Considering randomness did not overcome the theoretical shortcomings so far. Small perturbations of individual opinions trigger social influence cascades that inevitably lead to monoculture, while larger noise disrupts opinion clusters and results in rampant individualism without any social structure. Our solution of the puzzle builds on recent empirical research, combining the integrative tendencies of social influence with the disintegrative effects of individualization. A key element of the new computational model is an adaptive kind of noise. We conduct simulation experiments to demonstrate that with this kind of noise, a third phase besides individualism and monoculture becomes possible, characterized by the formation of metastable clusters with diversity between and consensus within clusters. When clusters are small, individualization tendencies are too weak to prohibit a fusion of clusters. When clusters grow too large, however, individualization increases in strength, which promotes their splitting.Comment: 12 pages, 4 figure

Developing an intervention to facilitate family communication about inherited genetic conditions, and training genetic counsellors in its delivery.

Many families experience difficulty in talking about an inherited genetic condition that affects one or more of them. There have now been a number of studies identifying the issues in detail, however few have developed interventions to assist families. The SPRinG collaborative have used the UK Medical Research Council's guidance on Developing and Evaluating Complex Interventions, to work with families and genetic counsellors (GCs) to co-design a psycho-educational intervention to facilitate family communication and promote better coping and adaptation to living with an inherited genetic condition for parents and their children (<18 years). The intervention is modelled on multi-family discussion groups (MFDGs) used in psychiatric settings. The MFDG was developed and tested over three phases. First focus groups with parents, young people, children and health professionals discussed whether MFDG was acceptable and proposed a suitable design. Using evidence and focus group data, the intervention and a training manual were developed and three GCs were trained in its delivery. Finally, a prototype MFDG was led by a family therapist and co-facilitated by the three GCs. Data analysis showed that families attending the focus groups and intervention thought MFDG highly beneficial, and the pilot sessions had a significant impact on their family' functioning. We also demonstrated that it is possible to train GCs to deliver the MFDG intervention. Further studies are now required to test the feasibility of undertaking a definitive randomised controlled trial to evaluate its effectiveness in improving family outcomes before implementing into genetic counselling practice.The National Institute of Health Research funded the study but any views expressed do not necessarily reflect those of the Authority. Funded by NIHR reference number: RP-DG-1211-10015

Telomere disruption results in non-random formation of de novo dicentric chromosomes involving acrocentric human chromosomes

Copyright: © 2010 Stimpson et al.Genome rearrangement often produces chromosomes with two centromeres (dicentrics) that are inherently unstable because of bridge formation and breakage during cell division. However, mammalian dicentrics, and particularly those in humans, can be quite stable, usually because one centromere is functionally silenced. Molecular mechanisms of centromere inactivation are poorly understood since there are few systems to experimentally create dicentric human chromosomes. Here, we describe a human cell culture model that enriches for de novo dicentrics. We demonstrate that transient disruption of human telomere structure non-randomly produces dicentric fusions involving acrocentric chromosomes. The induced dicentrics vary in structure near fusion breakpoints and like naturally-occurring dicentrics, exhibit various inter-centromeric distances. Many functional dicentrics persist for months after formation. Even those with distantly spaced centromeres remain functionally dicentric for 20 cell generations. Other dicentrics within the population reflect centromere inactivation. In some cases, centromere inactivation occurs by an apparently epigenetic mechanism. In other dicentrics, the size of the alpha-satellite DNA array associated with CENP-A is reduced compared to the same array before dicentric formation. Extrachromosomal fragments that contained CENP-A often appear in the same cells as dicentrics. Some of these fragments are derived from the same alpha-satellite DNA array as inactivated centromeres. Our results indicate that dicentric human chromosomes undergo alternative fates after formation. Many retain two active centromeres and are stable through multiple cell divisions. Others undergo centromere inactivation. This event occurs within a broad temporal window and can involve deletion of chromatin that marks the locus as a site for CENP-A maintenance/replenishment.This work was supported by the Tumorzentrum Heidelberg/Mannheim grant (D.10026941)and by March of Dimes Research Foundation grant #1-FY06-377 and NIH R01 GM069514

SCN1A overexpression, associated with a genomic region marked by a risk variant for a common epilepsy, raises seizure susceptibility

Mesial temporal lobe epilepsy with hippocampal sclerosis and a history of febrile seizures is associated with common variation at rs7587026, located in the promoter region of SCN1A. We sought to explore possible underlying mechanisms. SCN1A expression was analysed in hippocampal biopsy specimens of individuals with mesial temporal lobe epilepsy with hippocampal sclerosis who underwent surgical treatment, and hippocampal neuronal cell loss was quantitatively assessed using immunohistochemistry. In healthy individuals, hippocampal volume was measured using MRI. Analyses were performed stratified by rs7587026 type. To study the functional consequences of increased SCN1A expression, we generated, using transposon-mediated bacterial artificial chromosome transgenesis, a zebrafish line expressing exogenous scn1a, and performed EEG analysis on larval optic tecta at 4 day post-fertilization. Finally, we used an in vitro promoter analysis to study whether the genetic motif containing rs7587026 influences promoter activity. Hippocampal SCN1A expression differed by rs7587026 genotype (Kruskal-Wallis test P = 0.004). Individuals homozygous for the minor allele showed significantly increased expression compared to those homozygous for the major allele (Dunn's test P = 0.003), and to heterozygotes (Dunn's test P = 0.035). No statistically significant differences in hippocampal neuronal cell loss were observed between the three genotypes. Among 597 healthy participants, individuals homozygous for the minor allele at rs7587026 displayed significantly reduced mean hippocampal volume compared to major allele homozygotes (Cohen's D = - 0.28, P = 0.02), and to heterozygotes (Cohen's D = - 0.36, P = 0.009). Compared to wild type, scn1lab-overexpressing zebrafish larvae exhibited more frequent spontaneous seizures [one-way ANOVA F(4,54) = 6.95 (P < 0.001)]. The number of EEG discharges correlated with the level of scn1lab overexpression [one-way ANOVA F(4,15) = 10.75 (P < 0.001]. Finally, we showed that a 50 bp promoter motif containing rs7587026 exerts a strong regulatory role on SCN1A expression, though we could not directly link this to rs7587026 itself. Our results develop the mechanistic link between rs7587026 and mesial temporal lobe epilepsy with hippocampal sclerosis and a history of febrile seizures. Furthermore, we propose that quantitative precision may be important when increasing SCN1A expression in current strategies aiming to treat seizures in conditions involving SCN1A haploinsufficiency, such as Dravet syndrome

Cooperation and virulence in acute Pseudomonas aeruginosa infections

BACKGROUND: Efficient host exploitation by parasites is frequently likely to depend on cooperative behaviour. Under these conditions, mixed-strain infections are predicted to show lower virulence (host mortality) than are single-clone infections, due to competition favouring non-contributing social 'cheats' whose presence will reduce within-host growth. We tested this hypothesis using the cooperative production of iron-scavenging siderophores by the pathogenic bacterium Pseudomonas aeruginosa in an insect host. RESULTS: We found that infection by siderophore-producing bacteria (cooperators) results in more rapid host death than does infection by non-producers (cheats), and that mixtures of both result in intermediate levels of virulence. Within-host bacterial growth rates exhibited the same pattern. Crucially, cheats were more successful in mixed infections compared with single-clone infections, while the opposite was true of cooperators. CONCLUSION: These data demonstrate that mixed clone infections can favour the evolution of social cheats, and thus decrease virulence when parasite growth is dependent on cooperative behaviours

Effectiveness of Biosecurity Measures in Preventing Badger Visits to Farm Buildings

This is the final version of the article. Available from Public Library of Science via the DOI in this record.BACKGROUND: Bovine tuberculosis caused by Mycobacterium bovis is a serious and economically important disease of cattle. Badgers have been implicated in the transmission and maintenance of the disease in the UK since the 1970s. Recent studies have provided substantial evidence of widespread and frequent visits by badgers to farm buildings during which there is the potential for close direct contact with cattle and contamination of cattle feed. METHODOLOGY: Here we evaluated the effectiveness of simple exclusion measures in improving farm biosecurity and preventing badger visits to farm buildings. In the first phase of the study, 32 farms were surveyed using motion-triggered infrared cameras on potential entrances to farm buildings to determine the background level of badger visits experienced by each farm. In the second phase, they were divided into four treatment groups; "Control", "Feed Storage", "Cattle Housing" and "Both", whereby no exclusion measures were installed, exclusion measures were installed on feed storage areas only, cattle housing only or both feed storage and cattle housing, respectively. Badger exclusion measures included sheet metal gates, adjustable metal panels for gates, sheet metal fencing, feed bins and electric fencing. Cameras were deployed for at least 365 nights in each phase on each farm. RESULTS: Badger visits to farm buildings occurred on 19 of the 32 farms in phase one. In phase two, the simple exclusion measures were 100% effective in preventing badger entry into farm buildings, as long as they were appropriately deployed. Furthermore, the installation of exclusion measures also reduced the level of badger visits to the rest of the farmyard. The findings of the present study clearly demonstrate how relatively simple practical measures can substantially reduce the likelihood of badger visits to buildings and reduce some of the potential for contact and disease transmission between badgers and cattle.This work was funded by Defra project number SE3119, http://www.defra.gov.uk/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Sedimentary Environment Influences the Effect of an Infaunal Suspension Feeding Bivalve on Estuarine Ecosystem Function

The suspension feeding bivalve Austrovenus stutchburyi is a key species on intertidal sandflats in New Zealand, affecting the appearance and functioning of these systems, but is susceptible to several environmental stressors including sedimentation. Previous studies into the effect of this species on ecosystem function have been restricted in space and time, limiting our ability to infer the effect of habitat change on functioning. We examined the effect of Austrovenus on benthic primary production and nutrient dynamics at two sites, one sandy, the other composed of muddy-sand to determine whether sedimentary environment alters this key species' role. At each site we established large (16 m2) plots of two types, Austrovenus addition and removal. In winter and summer we deployed light and dark benthic chambers to quantify oxygen and nutrient fluxes and measured sediment denitrification enzyme activity to assess denitrification potential. Rates of gross primary production (GPP) and ammonium uptake were significantly increased when Austrovenus was added, relative to removed, at the sandy site (GPP, 1.5 times greater in winter and summer; ammonium uptake, 8 times greater in summer; 3-factor analysis of variance (ANOVA), p<0.05). Denitrification potential was also elevated in Austrovenus addition plots at the sandy site in summer (by 1.6 times, p<0.1). In contrast, there was no effect of Austrovenus treatment on any of these variables at the muddy-sand site, and overall rates tended to be lower at the muddy-sand site, relative to the sandy site (e.g. GPP was 2.1 to 3.4 times lower in winter and summer, respectively, p<0.001). Our results suggest that the positive effects of Austrovenus on system productivity and denitrification potential is limited at a muddy-sand site compared to a sandy site, and reveal the importance of considering sedimentary environment when examining the effect of key species on ecosystem function

Rutas tróficas en macrozooplancton del Lago de Tota - Boyacá, Colombia

1 recurso en línea (56 páginas) : ilustraciones, figuras, tablas.In aquatic ecosystems inputs of matter and energy present in greater or lesser extent depending on the basin, given the origin and quality of these resources, you can alter the balance in metabolism or interactions in the food web. Using stable isotopes of carbon and nitrogen, the link between potential sources of funds and use established by macrozooplankton species in Lake Big and Lake Fellow the Lake Tota sectors. Trophic possible ways the role of each species in the proposed network, as well. In general, most of this study, most species have a bond with the autotrophic pathway, being the phytoplankton the food resource base for the food web, commonly found impoverished carbon signals. Particularly, the analysis showed a variation in the source or resource for two species (Daphnia laevis and Bosmina (Bosmina) cf. longirostris), with an enrichment in its signal to 19.92 ‰ -20.34 ‰ δ13C, which can be given by plasticity in their food supply, and even if Boeckella gracilis having a signal indicating a specialization in its appeal with carbon impoverished -30 to -26 ‰ values δ13C while nitrogen values are enriched with an average value 20.21 ‰ in δ15N. To set the trophic fractionation means establishing three groups, the first (herbivores) consisting of (D. laevis, B. (Bosmina) and Ceriodaphnia pulchella cf. longirostris), the second (omnivore) which is (Daphnia pulex, Macrocyclops sp. and Cyclopoida), and a third group (secondary consumer) where is the only calanoido B. gracilis. In comparing the temporal variation is observed that there is a significant change in signals δ13C and δ15N of some species in relation to the influence of sources and allochthonous or autochthonous origin, spatial variation was not significant. It is concluded that the macrozooplanton Lake Tota, has a strong link with the autotrophic pathway and pelagic trophic levels have 3 sections, plus the primary producers and the food web in general tends to have an amplitude of trophic niche.En los ecosistemas acuáticos se presentan aportes de materia y energía, en mayor o menor proporción dependiendo de su cuenca, dado el origen y calidad de estos recursos, se puede alterar el balance en el metabolismo o las interacciones en la red trófica. Utilizando los isotopos estables de Carbono y Nitrógeno, se estableció el vínculo entre fuentes potenciales de recursos y el uso por las especies del macrozooplancton en los sectores Lago grande y Lago chico del lago de Tota (Boyacá). Así, se propusieron las posibles vías tróficas y el rol de cada especie en la red. En general, en la mayor parte de este estudio, las especies tuvieron un vínculo marcado con la vía autotrófica, siendo el fitoplancton el recurso alimenticio base para la red trófica, encontrando comúnmente señales empobrecidas de carbono. Particularmente, el análisis mostró una variación en la fuente o recurso para dos especies (Daphnia laevis y Bosmina (Bosmina) cf. longirostris), con un enriquecimiento en su señal de 19.92‰ δ13C a -20.34‰ δ13C, lo que se puede dar por una plasticidad en su fuente alimenticia, e incluso el caso de Boeckella gracilis que tiene una señal que indica una especialización en su recurso con valores empobrecidos de carbono -30 a -26‰ δ13C mientras que los valores de nitrógeno son enriquecidos con un valor promedio de 20.21‰ en δ15N. Para establecer el fraccionamiento trófico medio se formaron tres grupos, el primero (herbívoros) conformado por (D. laevis, B. (Bosmina) cf. longirostris y Ceriodaphnia pulchella), el segundo (omnívoro) en el que se encuentra (Daphnia pulex, Macrocyclops sp. y Cyclopoida), y un tercer grupo (Consumidor secundario) donde esta B. gracilis el único calanoido. En la comparación de la variación temporal, se observa que hay un cambio significativo en las señales de δ13C y δ15N de algunas especies en relación a la influencia de las fuentes y su origen alóctono o autóctono, la variación espacial no fue significativa. Se concluye que el macrozooplanton del lago de Tota, tiene un fuerte vínculo con la vía autotrófica y que los niveles tróficos pelágicos tienen 3 eslabones, más los productores primarios, y la red trófica en general tiende a tener una amplitud del nicho trófico. En los ecosistemas acuáticos se presentan aportes de materia y energía, en mayor o menor proporción dependiendo de su cuenca, dado el origen y calidad de estos recursos, se puede alterar el balance en el metabolismo o las interacciones en la red trófica. Utilizando los isotopos estables de Carbono y Nitrógeno, se estableció el vínculo entre fuentes potenciales de recursos y el uso por las especies del macrozooplancton en los sectores Lago grande y Lago chico del lago de Tota (Boyacá). Así, se propusieron las posibles vías tróficas y el rol de cada especie en la red. En general, en la mayor parte de este estudio, las especies tuvieron un vínculo marcado con la vía autotrófica, siendo el fitoplancton el recurso alimenticio base para la red trófica, encontrando comúnmente señales empobrecidas de carbono. Particularmente, el análisis mostró una variación en la fuente o recurso para dos especies (Daphnia laevis y Bosmina (Bosmina) cf. longirostris), con un enriquecimiento en su señal de 19.92‰ δ13C a -20.34‰ δ13C, lo que se puede dar por una plasticidad en su fuente alimenticia, e incluso el caso de Boeckella gracilis que tiene una señal que indica una especialización en su recurso con valores empobrecidos de carbono -30 a -26‰ δ13C mientras que los valores de nitrógeno son enriquecidos con un valor promedio de 20.21‰ en δ15N. Para establecer el fraccionamiento trófico medio se formaron tres grupos, el primero (herbívoros) conformado por (D. laevis, B. (Bosmina) cf. longirostris y Ceriodaphnia pulchella), el segundo (omnívoro) en el que se encuentra (Daphnia pulex, Macrocyclops sp. y Cyclopoida), y un tercer grupo (Consumidor secundario) donde esta B. gracilis el único calanoido. En la comparación de la variación temporal, se observa que hay un cambio significativo en las señales de δ13C y δ15N de algunas especies en relación a la influencia de las fuentes y su origen alóctono o autóctono, la variación espacial no fue significativa. Se concluye que el macrozooplanton del lago de Tota, tiene un fuerte vínculo con la vía autotrófica y que los niveles tróficos pelágicos tienen 3 eslabones, más los productores primarios, y la red trófica en general tiende a tener una amplitud del nicho trófico.Bibliografía: páginas 46-56.MaestríaMagíster en Ciencias Biológica