Genotoxic Effect of Atrazine, Arsenic, Cadmium and Nitrate, Individually and in Mixtures at Maximum Contaminant Levels on mammalian Breast Cell Lines

There is strong evidence that hormonally active agents (HAAs) such as Atrazine (ATZ), Cadmium (Cd), Arsenic (As) and Nitrate (NO3) have both estrogenic activity and carcinogenic potential. Atrazine has clastogenic effects and may also act as tumor promoter as it induces the aromatase enzyme. Arsenic and Cadmium have been implicated in the etiology of skin, lung, prostate and liver cancers. Nitrate in drinking water has been found to increase the risk of bladder cancer.This study examined the genotoxicity of the aforementioned HAAs alone and in mixtures using mammalian breast cell lines, MCF-7 and MCF-10A, which are estrogen receptorpositive (ER+) and estrogen receptor-negative (ER-), respectively. To study the clastogenic potential by whole cell and flow karyotype damage, cells were exposed to environmentally relevant concentrations of ATZ, Cd, As and NO3 for 4 and 7 days.Results indicated that all treatments induced whole cell clastogenicity in MCF-7 cells; except Cd and NO3 after 4 and 7 days as well as the 10% quaternary As mixture after 1 week. In MCF-10A cells, all treatments except the 10% mixture induced whole cell clastogenicity after 4 days, where flow karyotype damage was detected in all treatments except for the 10% mixture after 1 week. Estrogen caused whole cell damage but not flow karyotype damage in MCF-7. On the other hand, estrogen caused flow karyotype damage and not whole cell damage in MCF-10A cells, suggesting that estrogen receptor modulated the genotoxicity of estrogen. Cd caused flow karyotype damage but not whole cell damage in MCF-7 indicating that Cd’s gentoxicity is not related to its estrogenic activity.Keywords: HAAs, clastogenicity, flow-karyotype, genotoxicity, MCF-7, MCF-10

An apicobasal gradient of Rac activity determines protrusion form and position

Each cell within a polarised epithelial sheet must align and correctly position a wide range of subcellular structures, including actin-based dynamic protrusions. Using in vivo inducible transgenes that can sense or modify Rac activity, we demonstrate an apicobasal gradient of Rac activity that is required to correctly form and position distinct classes of dynamic protrusion along the apicobasal axis of the cell. We show that we can modify the Rac activity gradient in genetic mutants for specific polarity proteins, with consequent changes in protrusion form and position and additionally show, using photoactivatable Rac transgenes, that it is the level of Rac activity that determines protrusion form. Thus, we demonstrate a mechanism by which polarity proteins can spatially regulate Rac activity and the actin cytoskeleton to ensure correct epithelial cell shape and prevent epithelial-to-mesenchymal transitions

Semi-analytical approach to magnetized temperature autocorrelations

The cosmic microwave background (CMB) temperature autocorrelations, induced by a magnetized adiabatic mode of curvature inhomogeneities, are computed with semi-analytical methods. As suggested by the latest CMB data, a nearly scale-invariant spectrum for the adiabatic mode is consistently assumed. In this situation, the effects of a fully inhomogeneous magnetic field are scrutinized and constrained with particular attention to harmonics which are relevant for the region of Doppler oscillations. Depending on the parameters of the stochastic magnetic field a hump may replace the second peak of the angular power spectrum. Detectable effects on the Doppler region are then expected only if the magnetic power spectra have quasi-flat slopes and typical amplitude (smoothed over a comoving scale of Mpc size and redshifted to the epoch of gravitational collapse of the protogalaxy) exceeding 0.1 nG. If the magnetic energy spectra are bluer (i.e. steeper in frequency) the allowed value of the smoothed amplitude becomes, comparatively, larger (in the range of 20 nG). The implications of this investigation for the origin of large-scale magnetic fields in the Universe are discussed. Connections with forthcoming experimental observations of CMB temperature fluctuations are also suggested and partially explored.Comment: 40 pages, 13 figure

Microparticle-mediated transfer of the viral receptors CAR and CD46, and the CFTR channel in a CHO cell model confers new functions to target cells

Cell microparticles (MPs) released in the extracellular milieu can embark plasma membrane and intracellular components which are specific of their cellular origin, and transfer them to target cells. The MP-mediated, cell-to-cell transfer of three human membrane glycoproteins of different degrees of complexity was investigated in the present study, using a CHO cell model system. We first tested the delivery of CAR and CD46, two monospanins which act as adenovirus receptors, to target CHO cells. CHO cells lack CAR and CD46, high affinity receptors for human adenovirus serotype 5 (HAdV5), and serotype 35 (HAdV35), respectively. We found that MPs derived from CHO cells (MP-donor cells) constitutively expressing CAR (MP-CAR) or CD46 (MP-CD46) were able to transfer CAR and CD46 to target CHO cells, and conferred selective permissiveness to HAdV5 and HAdV35. In addition, target CHO cells incubated with MP-CD46 acquired the CD46-associated function in complement regulation. We also explored the MP-mediated delivery of a dodecaspanin membrane glycoprotein, the CFTR to target CHO cells. CFTR functions as a chloride channel in human cells and is implicated in the genetic disease cystic fibrosis. Target CHO cells incubated with MPs produced by CHO cells constitutively expressing GFP-tagged CFTR (MP-GFP-CFTR) were found to gain a new cellular function, the chloride channel activity associated to CFTR. Time-course analysis of the appearance of GFP-CFTR in target cells suggested that MPs could achieve the delivery of CFTR to target cells via two mechanisms: the transfer of mature, membrane-inserted CFTR glycoprotein, and the transfer of CFTR-encoding mRNA. These results confirmed that cell-derived MPs represent a new class of promising therapeutic vehicles for the delivery of bioactive macromolecules, proteins or mRNAs, the latter exerting the desired therapeutic effect in target cells via de novo synthesis of their encoded proteins

Association of MC1R Variants and host phenotypes with melanoma risk in CDKN2A mutation carriers: a GenoMEL study

<p><b>Background</b> Carrying the cyclin-dependent kinase inhibitor 2A (CDKN2A) germline mutations is associated with a high risk for melanoma. Penetrance of CDKN2A mutations is modified by pigmentation characteristics, nevus phenotypes, and some variants of the melanocortin-1 receptor gene (MC1R), which is known to have a role in the pigmentation process. However, investigation of the associations of both MC1R variants and host phenotypes with melanoma risk has been limited.</p> <p><b>Methods</b> We included 815 CDKN2A mutation carriers (473 affected, and 342 unaffected, with melanoma) from 186 families from 15 centers in Europe, North America, and Australia who participated in the Melanoma Genetics Consortium. In this family-based study, we assessed the associations of the four most frequent MC1R variants (V60L, V92M, R151C, and R160W) and the number of variants (1, ≥2 variants), alone or jointly with the host phenotypes (hair color, propensity to sunburn, and number of nevi), with melanoma risk in CDKN2A mutation carriers. These associations were estimated and tested using generalized estimating equations. All statistical tests were two-sided.</p> <p><b>Results</b> Carrying any one of the four most frequent MC1R variants (V60L, V92M, R151C, R160W) in CDKN2A mutation carriers was associated with a statistically significantly increased risk for melanoma across all continents (1.24 × 10−6 ≤ P ≤ .0007). A consistent pattern of increase in melanoma risk was also associated with increase in number of MC1R variants. The risk of melanoma associated with at least two MC1R variants was 2.6-fold higher than the risk associated with only one variant (odds ratio = 5.83 [95% confidence interval = 3.60 to 9.46] vs 2.25 [95% confidence interval = 1.44 to 3.52]; Ptrend = 1.86 × 10−8). The joint analysis of MC1R variants and host phenotypes showed statistically significant associations of melanoma risk, together with MC1R variants (.0001 ≤ P ≤ .04), hair color (.006 ≤ P ≤ .06), and number of nevi (6.9 × 10−6 ≤ P ≤ .02).</p> <p><b>Conclusion</b> Results show that MC1R variants, hair color, and number of nevi were jointly associated with melanoma risk in CDKN2A mutation carriers. This joint association may have important consequences for risk assessments in familial settings.</p&gt

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis

Paediatric palliative home care by general paediatricians: a multimethod study on perceived barriers and incentives

<p>Abstract</p> <p>Background</p> <p>Non-specialist palliative care, as it is delivered by general practitioners, is a basic component of a comprehensive palliative care infrastructure for adult patients with progressive and far advanced disease. Currently palliative care for children and adolescents is recognized as a distinct entity of care, requiring networks of service providers across different settings, including paediatricians working in general practice. In Germany, the medical home care for children and adolescents is to a large extent delivered by general paediatricians working in their own practice. However, these are rarely confronted with children suffering from life-limiting diseases. The aim of this study was therefore to examine potential barriers, incentives, and the professional self-image of general paediatricians with regard to paediatric palliative care.</p> <p>Methods</p> <p>Based on qualitative expert interviews, a questionnaire was designed and a survey among general paediatricians in their own practice (n = 293) was undertaken. The survey has been developed and performed in close cooperation with the regional professional association of paediatricians.</p> <p>Results</p> <p>The results showed a high disposition on part of the paediatricians to engage in palliative care, and the majority of respondents regarded palliative care as part of their profile. Main barriers for the implementation were time restrictions (40.7%) and financial burden (31.6%), sole responsibility without team support (31.1%), as well as formal requirements such as forms and prescriptions (26.6%). Major facilitations were support by local specialist services such as home care nursing service (83.0%), access to a specialist paediatric palliative care consultation team (82.4%), as well as an option of exchange with colleagues (60.1%).</p> <p>Conclusions</p> <p>Altogether, the high commitment to this survey reflects the relevance of the issue for paediatricians working in general practice. Education in basic palliative care competence and communication skills was seen as an important prerequisite for the engagement in paediatric palliative home care. A local network of specialist support on site and a 24/7 on-call service are necessary in order to facilitate the implementation of basic palliative care by paediatricians in their own practice.</p

TRY plant trait database - enhanced coverage and open access

Plant traits-the morphological, anatomical, physiological, biochemical and phenological characteristics of plants-determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait-based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits-almost complete coverage for 'plant growth form'. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait-environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives