Penetration and intracellular uptake of poly(glycerol-adipate)nanoparticles into 3-dimensional brain tumour cell culture models

Nanoparticle (NP) drug delivery systems may potentially enhance the efficacy of therapeutic agents. It is difficult to characterise many important properties of NPs in vivo and therefore attempts have been made to use realistic in vitro multicellular spheroids instead. In this paper we have evaluated poly(glycerol-adipate) (PGA) NPs as a potential drug carrier for local brain cancer therapy. Various 3-dimensional (3-D) cell culture models have been used to investigate the delivery properties of PGA NPs. Tumour cells in 3-D culture showed a much higher level of endocytic uptake of NPs than a mixed normal neonatal brain cell population. Differences in endocytic uptake of NPs in 2-D and 3-D models strongly suggest that it is very important to use in vitro 3-D cell culture models for evaluating this parameter. Tumour penetration of NPs is another important parameter which could be studied in 3-D cell models. The penetration of PGA NPs through 3-D cell culture varied between models, which will therefore require further study to develop useful and realistic in vitro models. Further use of 3-D cell culture models will be of benefit in the future development of new drug delivery systems, particularly for brain cancers which are more difficult to study in vivo

Linking marine ecosystems with the services they supply: what are the relevant service providing units?

Marine ecosystems support supply of ecosystem services (ESs) through processes and functions carried out by diverse biological elements. Managing sustainability of ES use requires linking services to the parts of ecosystems supplying them. We specified marine service providing units (SPUs) as plausible combinations of a biotic group (e.g., bacteria, seabirds) with an associated major habitat (e.g., sublittoral sediment). We developed a network model for large marine ecosystems, documenting 2,916 links between 153 SPUs with 31 services. Coastal habitats and their taxa accounted for 48% of links, but all habitats with their taxa contribute to at least 20 ESs. Through network analysis, we showed some services link to certain key habitats, while others are less clearly defined in space, being supported by a variety of habitats and their taxa. Analysis highlighted large‐scale flows across marine habitats that are essential in underpinning continued supply of certain ESs, for example, seed dispersal. If we only protect habitats where services are used, we will not fully protect the supply of services reliant on mobile taxa moving between habitats. This emerged because we considered habitats and their taxa together. We recommend using combinations of habitats and taxa as SPUs when informing marine ecosystem management and conservation

Letters and records of the dissenting congregations: David Crosley, Cripplegate and Baptist Church life

The original publication is available at www.springerlink.comInternational audienceThis chapter examines the status and function of letters in manuscript records of dissenting Churches of the post-Toleration years, concentrating on the correspondence of the Baptist Church of Cripplegate. The letters are placed in the context of controversies about Church government and discipline and the rhetoric used during the scandal caused by the excommunication of its Northern minister David Crosley for drinking, lying and adultery is assessed. In doing so, the chapter pays particular attention to the epistolary exchanges between metropolitan and provincial congregations and to what they reveal about conceptions of the Baptist ministry

Association of FCGR2A and FCGR2A-FCGR3A haplotypes with susceptibility to giant cell arteritis

The Fc gamma receptors have been shown to play important roles in the initiation and regulation of many immunological and inflammatory processes and to amplify and refine the immune response to an infection. We have investigated the hypothesis that polymorphism within the FCGR genetic locus is associated with giant cell arteritis (GCA). Biallelic polymorphisms in FCGR2A, FCGR3A, FCGR3B and FCGR2B were examined for association with biopsy-proven GCA (n = 85) and healthy ethnically matched controls (n = 132) in a well-characterised cohort from Lugo, Spain. Haplotype frequencies and linkage disequilibrium (D') were estimated across the FCGR locus and a model-free analysis performed to determine association with GCA. There was a significant association between FCGR2A-131RR homozygosity (odds ratio (OR) 2.10, 95% confidence interval (CI) 1.12 to 3.77, P = 0.02, compared with all others) and carriage of FCGR3A-158F (OR 3.09, 95% CI 1.10 to 8.64, P = 0.03, compared with non-carriers) with susceptibility to GCA. FCGR haplotypes were examined to refine the extent of the association. The haplotype showing the strongest association with GCA susceptibility was the FCGR2A-FCGR3A 131R-158F haplotype (OR 2.84, P = 0.01 for homozygotes compared with all others). There was evidence of a multiplicative joint effect between homozygosity for FCGR2A-131R and HLA-DRB1*04 positivity, consistent with both of these two genetic factors contributing to the risk of disease. The risk of GCA in HLA-DRB1*04 positive individuals homozygous for the FCGR2A-131R allele is increased almost six-fold compared with those with other FCGR2A genotypes who are HLA-DRB1*04 negative. We have demonstrated that FCGR2A may contribute to the 'susceptibility' of GCA in this Spanish population. The increased association observed with a FCGR2A-FCGR3A haplotype suggests the presence of additional genetic polymorphisms in linkage disequilibrium with this haplotype that may contribute to disease susceptibility. These findings may ultimately provide new insights into disease pathogenesis

Compression of Structured High-Throughput Sequencing Data

Large biological datasets are being produced at a rapid pace and create substantial storage challenges, particularly in the domain of high-throughput sequencing (HTS). Most approaches currently used to store HTS data are either unable to quickly adapt to the requirements of new sequencing or analysis methods (because they do not support schema evolution), or fail to provide state of the art compression of the datasets. We have devised new approaches to store HTS data that support seamless data schema evolution and compress datasets substantially better than existing approaches. Building on these new approaches, we discuss and demonstrate how a multi-tier data organization can dramatically reduce the storage, computational and network burden of collecting, analyzing, and archiving large sequencing datasets. For instance, we show that spliced RNA-Seq alignments can be stored in less than 4% the size of a BAM file with perfect data fidelity. Compared to the previous compression state of the art, these methods reduce dataset size more than 40% when storing exome, gene expression or DNA methylation datasets. The approaches have been integrated in a comprehensive suite of software tools (http://goby.campagnelab.org) that support common analyses for a range of high-throughput sequencing assays.National Center for Research Resources (U.S.) (Grant UL1 RR024996)Leukemia & Lymphoma Society of America (Translational Research Program Grant LLS 6304-11)National Institute of Mental Health (U.S.) (R01 MH086883

Thalamic inputs to dorsomedial striatum are involved in inhibitory control: evidence from the five-choice serial reaction time task in rats

Rationale Corticostriatal circuits are widely implicated in the top-down control of attention including inhibitory control and behavioural flexibility. However, recent neurophysiological evidence also suggests a role for thalamic inputs to striatum in behaviours related to salient, reward-paired cues. Objectives Here, we used designer receptors exclusively activated by designer drugs (DREADDs) to investigate the role of parafascicular (Pf) thalamic inputs to the dorsomedial striatum (DMS) using the five-choice serial reaction time task (5CSRTT) in rats. Methods The 5CSRTT requires sustained attention in order to detect spatially and temporally distributed visual cues and provides measures of inhibitory control related to impulsivity (premature responses) and compulsivity (perseverative responses). Rats underwent bilateral Pf injections of the DREADD vector, AAV2-CaMKIIa-HA-hM4D(Gi)-IRES-mCitrine. The DREADD agonist, clozapine N-oxide (CNO; 1 μl bilateral; 3 μM) or vehicle, was injected into DMS 1 h before behavioural testing. Task parameters were manipulated to increase attention load or reduce stimulus predictability respectively. Results We found that inhibition of the Pf-DMS projection significantly increased perseverative responses when stimulus predictability was reduced but had no effect on premature responses or response accuracy, even under increased attentional load. Control experiments showed no effects on locomotor activity in an open field. Conclusions These results complement previous lesion work in which the DMS and orbitofrontal cortex were similarly implicated in perseverative responses and suggest a specific role for thalamostriatal inputs in inhibitory control

How Ubiquitin Unfolds after Transfer into the Gas Phase

The structural evolution of ubiquitin after transfer into the gas phase was studied by electron capture dissociation. Site-specific fragment yields show that ubiquitin’s solution fold is overall unstable in the gas phase, but unfolding caused by loss of solvent is slowest in regions stabilized by salt bridges

Complexity reduction and policy consensus: asylum seekers, the right to work, and the ‘pull factor’ thesis in the UK context

Since the early 2000s, asylum policy in Western states has become increasingly dominated by the concept of the ‘pull factor’—the idea that the economic rights afforded to asylum seekers can act as a migratory pull, and will have a bearing on the numbers of asylum applications received. The pull factor thesis has been widely discredited by researchers but remains powerful among policymakers. Through an analysis of the pull factor in the UK context, and drawing on insights from Cultural Political Economy, this article argues that the hegemony of the pull factor thesis is best understood as a ‘policy imaginary’ which has become sedimented through both discursive and extra-discursive practices and processes. The article offers a means of understanding how a common sense assumption—which is challenged by a large body of evidence—has come to dominate policymaking in a key area of concern for politicians and policymakers

Two rapid assays for screening of patulin biodegradation

Artículo sobre distintos ensayos para comprobar la biodegradación de la patulinaThe mycotoxin patulin is produced by the blue mould pathogen Penicillium expansum in rotting apples during postharvest storage. Patulin is toxic to a wide range of organisms, including humans, animals, fungi and bacteria. Wash water from apple packing and processing houses often harbours patulin and fungal spores, which can contaminate the environment. Ubiquitous epiphytic yeasts, such as Rhodosporidium kratochvilovae strain LS11 which is a biocontrol agent of P. expansum in apples, have the capacity to resist the toxicity of patulin and to biodegrade it. Two non-toxic products are formed. One is desoxypatulinic acid. The aim of the work was to develop rapid, high-throughput bioassays for monitoring patulin degradation in multiple samples. Escherichia coli was highly sensitive to patulin, but insensitive to desoxypatulinic acid. This was utilized to develop a detection test for patulin, replacing time-consuming thin layer chromatography or high-performance liquid chromatography. Two assays for patulin degradation were developed, one in liquid medium and the other in semi-solid medium. Both assays allow the contemporary screening of a large number of samples. The liquid medium assay utilizes 96-well microtiter plates and was optimized for using a minimum of patulin. The semisolid medium assay has the added advantage of slowing down the biodegradation, which allows the study and isolation of transient degradation products. The two assays are complementary and have several areas of utilization, from screening a bank of microorganisms for biodegradation ability to the study of biodegradation pathways