Short length-scale variability of hybrid event beds and its applied significance

Hybrid event beds (HEBs) are a type of deep-water sediment gravity flow deposit that generally comprise a basal clean sandstone overlain by a variety of muddier and less-permeable sandy facies. They are thought to be emplaced by combinations of turbidity currents, transitional flows and debris flows, all as part of the same transport event. To date, a number of studies have highlighted the common presence of HEBs mainly in the outer and marginal parts of deep-water systems where they replace beds composed dominantly of clean sand up-dip and/or axially over scales of km to 10s km. In addition to these broad patterns, important yet poorly understood short-length facies changes (over metres to 100s m) occur, modifying the overall texture and reservoir characteristics at or beneath typical spacing of production wells. The nature and origin of the short length-scale transitions is here addressed in four well-exposed HEB-prone outcrops: the Cretaceous-Paleocene Gottero Sandstone and the Miocene Cilento Flysch, both in Italy, the Carboniferous Mam Tor Sandstone in northern England, and the Carboniferous basal Ross Sandstone Formation, Western Ireland. A series of detailed correlation panels show marked lateral variations in internal bed make-up for most of the hybrid event beds studied. This variability typically involves lateral changes in the proportions of the cleaner basal sandstone and the overlying muddy sandstone division that occur without substantial change in the overall event bed thickness. The variability is inferred to reflect the complex fingering between the up-dip sandstone-dominated part of the event bed and the down-dip linked debrite due to internal erosion (ploughing) of the debrite into the basal clean sand. Where the upper part of the bed is dominated by large mudstone rafts, these may have foundered into liquefied sand and been injected and partly fragmented by the sand intrusions. The variable thickness and continuity of the basal clean sandstones have important implications for reservoir characterisation; significant variability in bed character at interwell scale can be anticipated. Rugose contacts between the intra-bed facies divisions may impact on drainage and sweep efficiency during hydrocarbon production

Dissolving microneedles for DNA vaccination: Improving functionality via polymer characterisation and RALA complexation

DNA vaccination holds the potential to treat or prevent nearly any immunogenic disease, including cancer. To date, these vaccines have demonstrated limited immunogenicity in vivo due to the absence of a suitable delivery system which can protect DNA from degradation and improve transfection efficiencies in vivo. Recently, microneedles have been described as a novel physical delivery technology to enhance DNA vaccine immunogenicity. Of these devices, dissolvable microneedles promise a safe, pain-free delivery system which may simultaneously improve DNA stability within a solid matrix and increase DNA delivery compared to solid arrays. However, to date little work has directly compared the suitability of different dissolvable matrices for formulation of DNA-loaded microneedles. Therefore, the current study examined the ability of 4 polymers to formulate mechanically robust, functional DNA loaded dissolvable microneedles. Additionally, complexation of DNA to a cationic delivery peptide, RALA, prior to incorporation into the dissolvable matrix was explored as a means to improve transfection efficacies following release from the polymer matrix. Our data demonstrates that DNA is degraded following incorporation into PVP, but not PVA matrices. The complexation of DNA to RALA prior to incorporation into polymers resulted in higher recovery from dissolvable matrices, and increased transfection efficiencies in vitro. Additionally, RALA/DNA nanoparticles released from dissolvable PVA matrices demonstrated up to 10-fold higher transfection efficiencies than the corresponding complexes released from PVP matrices, indicating that PVA is a superior polymer for this microneedle application

Origin of mud in turbidites and hybrid event beds: Insight from ponded mudstone caps of the Castagnola turbidite system (north‐west Italy)

The partitioning of different grain‐size classes in gravity flow deposits is one of the key characteristics used to infer depositional processes. Turbidites have relatively clean sandstones with most of their clay deposited as part of a mudstone cap or as a distal mudstone layer, whereas sand‐bearing debrites commonly comprise mixtures of sand grains and interstitial clay; hybrid event beds develop alternations of clean and dirty (clay‐rich) sandstones in varying proportions. Analysis of co‐genetic mudstone caps in terms of thickness and composition is a novel approach that can provide new insight into gravity flow depositional processes. Bed thickness data from the ponded Castagnola system show that turbidites contain more clay overall than do hybrid event beds. The Castagnola system is characterized by deposits of two very different petrographic types. Thanks to this duality, analyses of sandstone and mudstones composition allow inference of which proportion of the clay in each of the deposit types was acquired en route. In combination with standard sedimentological observations the new data allow insight into the likely characteristics of their parent flows. Clean turbidites were deposited by lower concentration, long duration, erosive, muddy turbidity currents which were more efficient at fractionating clay particles away from their basal layer. Hybrid event beds were deposited by shorter duration, higher‐concentration, less‐erosive sandier flows which were less efficient at clay fractionation. The results are consistent with data from other turbidite systems (for example, Marnoso‐arenacea). The approach represents a new method to infer the controls on the degree of clay partitioning in gravity flow deposits

Role of deregulated microRNAs in breast cancer progression Using FFPE tissue

MicroRNAs (miRNAs) contribute to cancer initiation and progression by silencing the expression of their target genes, causing either mRNA molecule degradation or translational inhibition. Intraductal epithelial proliferations of the breast are histologically and clinically classified into normal, atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC). To better understand the progression of ductal breast cancer development, we attempt to identify deregulated miRNAs in this process using Formalin-Fixed, Paraffin-Embedded (FFPE) tissues from breast cancer patients. Following tissue microdissection, we obtained 8 normal, 4 ADH, 6 DCIS and 7 IDC samples, which were subject to RNA isolation and miRNA expression profiling analysis. We found that miR-21, miR-200b/c, miR-141, and miR-183 were consistently up-regulated in ADH, DCIS and IDC compared to normal, while miR-557 was uniquely down-regulated in DCIS. Interestingly, the most significant miRNA deregulations occurred during the transition from normal to ADH. However, the data did not reveal a step-wise miRNA alteration among discrete steps along tumor progression, which is in accordance with previous reports of mRNA profiling of different stages of breast cancer. Furthermore, the expression of MSH2 and SMAD7, two important molecules involving TGF-β pathway, was restored following miR-21 knockdown in both MCF-7 and Hs578T breast cancer cells. In this study, we have not only identified a number of potential candidate miRNAs for breast cancer, but also found that deregulation of miRNA expression during breast tumorigenesis might be an early event since it occurred significantly during normal to ADH transition. Consequently, we have demonstrated the feasibility of miRNA expression profiling analysis using archived FFPE tissues, typically with rich clinical information, as a means of miRNA biomarker discovery

Strike-slip influenced stratigraphic and structural development of the Foula Sandstone Group, Shetland: implications for offshore Devonian basin development on the northern UK continental shelf

The island of Foula, located 25 km SW of Shetland, preserves a gently folded, 1.6 km thick sequence of Middle Devonian sandstones spectacularly exposed in kilometre-long cliff sections >350 m high. These rocks unconformably overlie likely Precambrian-age amphibolite facies basement rocks that are intruded by sheeted granites. The onshore succession is similar in age to the nearby Lower Clair Group offshore to the west. New mapping, incorporating the use of drone imagery in the inaccessible cliff sections, uses down-plunge projections to show that growth folding and faulting on Foula were contemporaneous with sedimentation during basin filling. The large-scale structural geometry is consistent with the regional constrictional strain due to the sinistral transtension associated with movements along the Walls Boundary–Great Glen fault zone system during the Mid-Devonian. Detrital zircon provenance studies indicate that the Devonian sequences of Foula (and nearby Melby in western Shetland) show similarities with the Clair Group and Orkney successions. We suggest that NE–SW transtensional fold development contemporaneous with regional subsidence in the Devonian basins of Scotland may be more widespread than previously realized. Large, kilometre-scale folds previously interpreted to be related to Permo-Carboniferous inversion may therefore have initiated earlier in the basin evolution sequence than previously realized

How metaphysical commitments shape the study of psychological mechanisms

The study of psychological mechanisms is an interdisciplinary endeavour, requiring insights from many different domains (from electrophysiology, to psychology, to theoretical neuroscience, to computer science). In this article, I argue that philosophy plays an essential role in this interdisciplinary project, and that effective scientific study of psychological mechanisms requires that working scientists be responsible metaphysicians. This means adopting deliberate metaphysical positions when studying mechanisms that go beyond what is empirically justified regarding the nature of the phenomenon being studied, the conditions of its occurrence, and its boundaries. Such metaphysical commitments are necessary in order to set up experimental protocols, determine which variables to manipulate under experimental conditions, and which conclusions to draw from different scientific models and theories. It is important for scientists to be aware of the metaphysical commitments they adopt, since they can easily be led astray if invoked carelessly

Histone Acetylation-Mediated Regulation of the Hippo Pathway

The Hippo pathway is a signaling cascade recently found to play a key role in tumorigenesis therefore understanding the mechanisms that regulate it should open new opportunities for cancer treatment. Available data indicate that this pathway is controlled by signals from cell-cell junctions however the potential role of nuclear regulation has not yet been described. Here we set out to verify this possibility and define putative mechanism(s) by which it might occur. By using a luciferase reporter of the Hippo pathway, we measured the effects of different nuclear targeting drugs and found that chromatin-modifying agents, and to a lesser extent certain DNA damaging drugs, strongly induced activity of the reporter. This effect was not mediated by upstream core components (i.e. Mst, Lats) of the Hippo pathway, but through enhanced levels of the Hippo transducer TAZ. Investigation of the underlying mechanism led to the finding that cancer cell exposure to histone deacetylase inhibitors induced secretion of growth factors and cytokines, which in turn activate Akt and inhibit the GSK3 beta associated protein degradation complex in drug-affected as well as in their neighboring cells. Consequently, expression of EMT genes, cell migration and resistance to therapy were induced. These processes were suppressed by using pyrvinium, a recently described small molecule activator of the GSK 3 beta associated degradation complex. Overall, these findings shed light on a previously unrecognized phenomenon by which certain anti-cancer agents may paradoxically promote tumor progression by facilitating stabilization of the Hippo transducer TAZ and inducing cancer cell migration and resistance to therapy. Pharmacological targeting of the GSK3 beta associated degradation complex may thus represent a unique approach to treat cancer. © 2013 Basu et al

Practice effects on the modified Concept Shifting Task (mCST): A convenient assessment for treatment effects on prefrontal cognitive function

<p>Abstract</p> <p>Background</p> <p>Trail-making tests, such as the Concept Shifting Task (CST), can be used to test the effects of treatment on cognitive performance over time in various neuropsychological disorders. However, cognitive performance in such experimental designs might improve as a result of the practice obtained during repeated testing rather than the treatment itself. The current study investigated if practice affects the accuracy and duration of performance on the repeatedly administered Concept Shifting Task modified to make it resistant to practice (mCST). The mCST was administered to 54 healthy participants twice a day, before and after a short break, for eight days. Results. The ANOVA and meta-analysis showed that there was no improvement in the mCST accuracy on the last vs. the first trial (Hedges' <it>g </it>= .14, <it>p </it>= .221) or within the session (after vs. before the break on all days; <it>g </it>= .01, <it>p </it>= .922). However, the participants performed the task faster on the last vs. the first trial (<it>g </it>= -.75, <it>p </it>< .001) and after vs. before the break on all days (<it>g </it>= -.12, <it>p </it>= .002). Conclusions. Repeated administration of the mCST does not affect the accuracy of performance on the test. However, practice might contribute to faster performance on the mCST over time and within each session.</p

Blockade of T-cell activation by dithiocarbamates involves novel mechanisms of inhibition of nuclear factor of activated T cells.

Dithiocarbamates (DTCs) have recently been reported as powerful inhibitors of NF-kappaB activation in a number of cell types. Given the role of this transcription factor in the regulation of gene expression in the inflammatory response, NF-kappaB inhibitors have been suggested as potential therapeutic drugs for inflammatory diseases. We show here that DTCs inhibited both interleukin 2 (IL-2) synthesis and membrane expression of antigens which are induced during T-cell activation. This inhibition, which occurred with a parallel activation of c-Jun transactivating functions and expression, was reflected by transfection experiments at the IL-2 promoter level, and involved not only the inhibition of NF-kappaB-driven reporter activation but also that of nuclear factor of activated T cells (NFAT). Accordingly, electrophoretic mobility shift assays (EMSAs) indicated that pyrrolidine DTC (PDTC) prevented NF-kappaB, and NFAT DNA-binding activity in T cells stimulated with either phorbol myristate acetate plus ionophore or antibodies against the CD3-T-cell receptor complex and simultaneously activated the binding of AP-1. Furthermore, PDTC differentially targeted both NFATp and NFATc family members, inhibiting the transactivation functions of NFATp and mRNA induction of NFATc. Strikingly, Western blotting and immunocytochemical experiments indicated that PDTC promoted a transient and rapid shuttling of NFATp and NFATc, leading to their accelerated export from the nucleus of activated T cells. We propose that the activation of an NFAT kinase by PDTC could be responsible for the rapid shuttling of the NFAT, therefore transiently converting the sustained transactivation of this transcription factor that occurs during lymphocyte activation, and show that c-Jun NH2-terminal kinase (JNK) can act by directly phosphorylating NFATp. In addition, the combined inhibitory effects on NFAT and NF-KB support a potential use of DTCs as immunosuppressants