Effects of different regions of the developing gut on the migration of enteric neural crest-derived cells: A role for Sema3A, but not Sema3F

AbstractThe enteric nervous system arises from vagal (caudal hindbrain) and sacral level neural crest-derived cells that migrate into and along the developing gut. Data from previous studies have suggested that (i) there may be gradients along the gut that induce the caudally directed migration of vagal enteric neural precursors (ENPs), (ii) exposure to the caecum might alter the migratory ability of vagal ENPs and (iii) Sema3A might regulate the entry into the hindgut of ENPs derived from sacral neural crest. Using co-cultures we show that there is no detectable gradient of chemoattractive molecules along the pre-caecal gut that specifically promotes the caudally directed migration of vagal ENPs, although vagal ENPs migrate faster caudally than rostrally along explants of hindgut. Exposure to the caecum did not alter the rate at which ENPs colonized explants of hindgut, but it did alter the ability of ENPs to colonize the midgut. The co-cultures also revealed that there is localized expression of a repulsive cue in the distal hindgut, which might delay the entry of sacral ENPs. We show that Sema3A is expressed by the hindgut mesenchyme and its receptor, neuropilin-1, is expressed by migrating ENPs. Furthermore, there is premature entry of sacral ENPs and extrinsic axons into the distal hindgut of fetal mice lacking Sema3A. These data show that Sema3A expressed by the distal hindgut regulates the entry of sacral ENPs and extrinsic axons into the hindgut. ENPs did not express neuropilin-2 and there was no detectable change in the timetable by which ENPs colonize the gut in mice lacking neuropilin-2

Inflationary Perturbations: the Cosmological Schwinger Effect

This pedagogical review aims at presenting the fundamental aspects of the theory of inflationary cosmological perturbations of quantum-mechanical origin. The analogy with the well-known Schwinger effect is discussed in detail and a systematic comparison of the two physical phenomena is carried out. In particular, it is demonstrated that the two underlying formalisms differ only up to an irrelevant canonical transformation. Hence, the basic physical mechanisms at play are similar in both cases and can be reduced to the quantization of a parametric oscillator leading to particle creation due to the interaction with a classical source: pair production in vacuum is therefore equivalent to the appearance of a growing mode for the cosmological fluctuations. The only difference lies in the nature of the source: an electric field in the case of the Schwinger effect and the gravitational field in the case of inflationary perturbations. Although, in the laboratory, it is notoriously difficult to produce an electric field such that pairs extracted from the vacuum can be detected, the gravitational field in the early universe can be strong enough to lead to observable effects that ultimately reveal themselves as temperature fluctuations in the Cosmic Microwave Background. Finally, the question of how quantum cosmological perturbations can be considered as classical is discussed at the end of the article.Comment: 49 pages, 6 figures, to appear in a LNP volume "Inflationary Cosmology

Selectivity and functional diversity in arbuscular mycorrhizas of co-occurring fungi and plants from a temperate deciduous woodland

1 The arbuscular mycorrhizal (AM) fungi colonizing plants at a woodland site in North Yorkshire (UK) have been characterized from the roots of five plant species (Rubus fruticosus agg. L., Epilobium angustifolium L., Acer pseudoplatanus L., Ajuga reptans L. and Glechoma hederacea L.), and identified using small-subunit rRNA (SSUrRNA) gene amplification and sequencing. 2 Interactions between five plant species from the site and four co-occurring glomalean fungi were investigated in artificial one-to-one AM symbioses. Three of the fungi were isolated from the site; the fourth was a culture genetically similar to a taxon found at the site. Phosphorus uptake and growth responses were compared with non-mycorrhizal controls. 3 Individual fungi colonized each plant with different spatial distribution and intensity. Some did not colonize at all, indicating incompatibility under the conditions used in the experiments. 4 Glomus hoi consistently occupied a large proportion of root systems and outperformed the other fungi, improving P uptake and enhancing the growth of four out of the five plant species. Only G. hoi colonized and increased P uptake in Acer pseudoplatanus, the host plant with which it associates almost exclusively under field conditions. Colonization of all plant species by Scutellospora dipurpurescens was sparse, and beneficial to only one of the host plants (Teucrium scorodonia). Archaeospora trappei and Glomus sp. UY1225 had variable effects on the host plants, conferring a range of P uptake and growth benefits on Lysimachia nummularia and T. scorodonia, increasing P uptake whilst not affecting biomass in Ajuga reptans and Glechoma hederacea, and failing to form mycorrhizas with A. pseudoplatanus. 5 These experimental mycorrhizas show that root colonization, symbiont compatibility and plant performance vary with each fungus-plant combination, even when the plants and fungi naturally co-exist. 6 We provide evidence of physical and functional selectivity in AM. The small number of described AM fungal species (154) has been ascribed to their supposed lack of host specificity, but if the selectivity we have observed is the general rule, then we may predict that many more, probably hard-to-culture glomalean species await discovery, or that members of species as currently perceived may be physiologically or functionally distinct

Cost-benefit analysis of BIM-enabled design clash detection and resolution

Building Information Modelling (BIM) is increasingly deployed as part of the processes in Architecture, Engineering and Construction (AEC) industry projects. While the benefits of BIM have been extensively proclaimed, explicit justification in terms of direct cost savings for BIM implementation on real-life projects, particularly for clash detection BIM workstream, are not well documented. This paper proposes and demonstrates a methodology to prove how BIM-based clash detection leads to cost savings. A schema is developed based on literature review and industrial expertise to quantify cost savings achieved by the utilisation of BIM-based clash detection and resolution. This paper provides validation of the proposed schema on a major infrastructure project. The developed schema includes the categorisation of identified clashes based on stakeholder involvement and required actions. The validation used the estimated cost of clashes were those not resolved before site operations took place. This schema simplifies both the categorisation and cost estimation of clashes in design. Estimated savings yielded 20% of contract value using the schema, for the multi-million-dollar project case study, thus extending evidence of BIM savings and benefits. The schema improves the existing process and valorises clash detection, thus allowing stakeholders to conduct a cost-benefit analysis. In addition, the categorisation methodology allows prioritising on the most costly clashes, and draw lessons learnt for further projects. This schema opens the path towards a systematic methodology to appraise the benefits of different BIM uses or processes

The TAL1 complex targets the FBXW7 tumor suppressor by activating miR-223 in human T cell acute lymphoblastic leukemia

The oncogenic transcription factor TAL1/SCL is aberrantly expressed in 60% of cases of human T cell acute lymphoblastic leukemia (T-ALL) and initiates T-ALL in mouse models. By performing global microRNA (miRNA) expression profiling after depletion of TAL1, together with genome-wide analysis of TAL1 occupancy by chromatin immunoprecipitation coupled to massively parallel DNA sequencing, we identified the miRNA genes directly controlled by TAL1 and its regulatory partners HEB, E2A, LMO1/2, GATA3, and RUNX1. The most dynamically regulated miRNA was miR-223, which is bound at its promoter and up-regulated by the TAL1 complex. miR-223 expression mirrors TAL1 levels during thymic development, with high expression in early thymocytes and marked down-regulation after the double-negative-2 stage of maturation. We demonstrate that aberrant miR-223 up-regulation by TAL1 is important for optimal growth of TAL1-positive T-ALL cells and that sustained expression of miR-223 partially rescues T-ALL cells after TAL1 knockdown. Overexpression of miR-223 also leads to marked down-regulation of FBXW7 protein expression, whereas knockdown of TAL1 leads to up-regulation of FBXW7 protein levels, with a marked reduction of its substrates MYC, MYB, NOTCH1, and CYCLIN E. We conclude that TAL1-mediated up-regulation of miR-223 promotes the malignant phenotype in T-ALL through repression of the FBXW7 tumor suppressor

Interstitials, Vacancies and Dislocations in Flux-Line Lattices: A Theory of Vortex Crystals, Supersolids and Liquids

We study a three dimensional Abrikosov vortex lattice in the presence of an equilibrium concentration of vacancy, interstitial and dislocation loops. Vacancies and interstitials renormalize the long-wavelength bulk and tilt elastic moduli. Dislocation loops lead to the vanishing of the long-wavelength shear modulus. The coupling to vacancies and interstitials - which are always present in the liquid state - allows dislocations to relax stresses by climbing out of their glide plane. Surprisingly, this mechanism does not yield any further independent renormalization of the tilt and compressional moduli at long wavelengths. The long wavelength properties of the resulting state are formally identical to that of the ``flux-line hexatic'' that is a candidate ``normal'' hexatically ordered vortex liquid state.Comment: 21 RevTeX pgs, 7 eps figures uuencoded; corrected typos, published versio

The purified extract from the medicinal plant Bacopa monnieri, bacopaside II, inhibits growth of colon cancer cells in vitro by inducing cell cycle arrest and apoptosis

Published: 21 July 2018Aquaporin-1 (AQP1), a transmembrane pore-forming molecule, facilitates the rapid movement of water and small solutes across cell membranes. We have previously shown that bacopaside II, an extract from the medicinal herb Bacopa monnieri, blocks the AQP1 water channel and impairs migration of cells that express AQP1. The aim of this study was to further elucidate the anti-tumour potential of bacopaside II in colon cancer cells. Expression of AQP1 in HT-29, SW480, SW620 and HCT116 was determined by quantitative PCR and western immunoblot. Cells were treated with bacopaside II, and morphology, growth, autophagy, cell cycle and apoptosis assessed by time-lapse microscopy, crystal violet, acridine orange, propidium iodide (PI) and annexin V/PI staining respectively. AQP1 expression was significantly higher in HT-29 than SW480, SW620 and HCT116. Bacopaside II significantly reduced growth at ≥20 µM for HT-29 and ≥15 µM for SW480, SW620 and HCT116. Inhibition of HT-29 at 20 µM was primarily mediated by G0/G1 cell cycle arrest, and at 30 µM by G2/M arrest and apoptosis. Inhibition of SW480, SW620 and HCT116 at ≥15 µM was mediated by G2/M arrest and apoptosis. These results are the first to show that bacopaside II inhibits colon cancer cell growth by inducing cell cycle arrest and apoptosis.Eric Smith, Helen M. Palethorpe, Yoko Tomita, Jinxin V. Pei, Amanda R. Townsend, Timothy J. Price, Joanne P. Young, Andrea J. Yool and Jennifer E. Hardingha

Adsorption of mono- and multivalent cat- and anions on DNA molecules

Adsorption of monovalent and multivalent cat- and anions on a deoxyribose nucleic acid (DNA) molecule from a salt solution is investigated by computer simulation. The ions are modelled as charged hard spheres, the DNA molecule as a point charge pattern following the double-helical phosphate strands. The geometrical shape of the DNA molecules is modelled on different levels ranging from a simple cylindrical shape to structured models which include the major and minor grooves between the phosphate strands. The densities of the ions adsorbed on the phosphate strands, in the major and in the minor grooves are calculated. First, we find that the adsorption pattern on the DNA surface depends strongly on its geometrical shape: counterions adsorb preferentially along the phosphate strands for a cylindrical model shape, but in the minor groove for a geometrically structured model. Second, we find that an addition of monovalent salt ions results in an increase of the charge density in the minor groove while the total charge density of ions adsorbed in the major groove stays unchanged. The adsorbed ion densities are highly structured along the minor groove while they are almost smeared along the major groove. Furthermore, for a fixed amount of added salt, the major groove cationic charge is independent on the counterion valency. For increasing salt concentration the major groove is neutralized while the total charge adsorbed in the minor groove is constant. DNA overcharging is detected for multivalent salt. Simulations for a larger ion radii, which mimic the effect of the ion hydration, indicate an increased adsorbtion of cations in the major groove.Comment: 34 pages with 14 figure

Automatic coronary artery calcium scoring on radiotherapy planning CT Scans of breast cancer patients: Reproducibility and association with traditional cardiovascular risk factors

Objectives Coronary artery calcium (CAC) is a strong and independent predictor of cardiovascular disease (CVD) risk. This study assesses reproducibility of automatic CAC scoring on radiotherapy planning computed tomography (CT) scans of breast cancer patients, and examines its association with traditional cardiovascular risk factors. Methods This study included 561 breast cancer patients undergoing radiotherapy between 2013 and 2015. CAC was automatically scored with an algorithm using supervised pattern recognition, expressed as Agatston scores and categorized into five categories (0, 1-10, 11-100, 101-400, >400). Reproducibility between automatic and manual expert scoring was assessed in 79 patients with automatically determined CAC above zero and 84 randomly selected patients without automatically determined CAC. Interscan reproducibility of automatic scoring was assessed in 294 patients having received two scans (82% on the same day). Association between CAC and CVD risk factors was assessed in 36 patients with CAC scores >100, 72 randomly selected patients with scores 1-100, and 72 randomly selected patients without CAC. Reliability was assessed with linearly weighted kappa and agreement with proportional agreement. Results 134 out of 561 (24%) patients had a CAC score above zero. Reliability of CVD risk categorization between automatic and manual scoring was 0.80 (95% Confidence Interval (CI): 0.74-0.87), and slightly higher for scans with breath-hold. Agreement was 0.79 (95% CI: 0.72-0.85). Interscan reliability was 0.61 (95% CI: 0.50-0.72) with an agreement of 0.84 (95% CI: 0.80-0.89). Ten out of 36 (27.8%) patients with CAC scores above 100 did not have other cardiovascular risk factors. Conclusions Automatic CAC scoring on radiotherapy planning CT scans is a reliable method to assess CVD risk based on Agatston scores. One in four breast cancer patients planned for radiotherapy have elevated CAC score. One in three patients with high CAC scores don't have other CVD risk factors and wouldn't have been identified as high risk

White paper on guidelines concerning enteric nervous system stem cell therapy for enteric neuropathies.

Over the last 20 years, there has been increasing focus on the development of novel stem cell based therapies for the treatment of disorders and diseases affecting the enteric nervous system (ENS) of the gastrointestinal tract (so-called enteric neuropathies). Here, the idea is that ENS progenitor/stem cells could be transplanted into the gut wall to replace the damaged or absent neurons and glia of the ENS. This White Paper sets out experts' views on the commonly used methods and approaches to identify, isolate, purify, expand and optimize ENS stem cells, transplant them into the bowel, and assess transplant success, including restoration of gut function. We also highlight obstacles that must be overcome in order to progress from successful preclinical studies in animal models to ENS stem cell therapies in the clinic