Dependence receptor involvement in subtilisin-induced long-term depression and in long-term potentiation

The serine protease subtilisin induces a form of long-term depression (LTD) which is accompanied by a reduced expression of the axo-dendritic guidance molecule Unco-ordinated-5C (Unc-5C). One objective of the present work was to determine whether a loss of Unc-5C function contributed to subtilisin-induced LTD by using Unc-5C antibodies in combination with the pore-forming agents Triton X-100 (0.005%) or streptolysin O in rat hippocampal slices. In addition we have assessed the effect of subtilisin on the related dependence receptor Deleted in Colorectal Cancer (DCC) and used antibodies to this protein for functional studies. Field excitatory postsynaptic potentials (fEPSPs) were analysed in rat hippocampal slices and protein extracts were used for Western blotting. Subtilisin produced a greater loss of DCC than of Unc-5C, but the antibodies had no effect on resting excitability or fEPSPs and did not modify subtilisin-induced LTD. However, antibodies to DCC but not Unc-5C did reduce the amplitude of theta-burst long-term potentiation (LTP). In addition, two inhibitors of endocytosis – dynasore and tat-gluR2(3Y) – were tested and, although the former compound had no effect on neurophysiological responses, tat-gluR2(3Y) did reduce the amplitude of subtilisin-induced LTD without affecting the expression of DCC or Unc-5C but with some loss of PostSynaptic Density Protein-95. The results support the view that the dependence receptor DCC may be involved in LTP and suggest that the endocytotic removal of a membrane protein or proteins may contribute to subtilisin-induced LTD, although it appears that neither Unc-5C nor DCC are involved in this process. (220)

Prenatal inhibition of the tryptophan–kynurenine pathway alters synaptic plasticity and protein expression in the rat hippocampus

Glutamate receptors sensitive to N-methyl-d-aspartate (NMDA) are important in early brain development, influencing cell proliferation and migration, neuritogenesis, axon guidance and synapse formation. The kynurenine pathway of tryptophan metabolism includes an agonist (quinolinic acid) and an antagonist (kynurenic acid) at these receptors. Rats were treated in late gestation with 3,4-dimethoxy-N-[4-(3-nitrophenyl)thiazol-2-yl]-benzene-sulphonamide (Ro61-8048), an inhibitor of kynurenine-3-monoxygenase which diverts kynurenine metabolism to kynurenic acid. Within 5 h of drug administration, there was a significant decrease in GluN2A expression and increased GluN2B in the embryo brains, with changes in sonic hedgehog at 24 h. When injected dams were allowed to litter normally, the brains of offspring were removed at postnatal day 21 (P21). Recordings of hippocampal field excitatory synaptic potentials (fEPSPs) showed that prenatal exposure to Ro61-8048 increased neuronal excitability and paired-pulse facilitation. Long-term potentiation was also increased, with no change in long-term depression. At this time, levels of GluN2A, GluN2B and postsynaptic density protein PSD-95 were all increased. Among several neurodevelopmental proteins, the expression of sonic hedgehog was increased, but DISC1 and dependence receptors were unaffected, while raised levels of doublecortin and Proliferating Cell Nuclear Antigen (PCNA) suggested increased neurogenesis. The results reveal that inhibiting the kynurenine pathway in utero leads to molecular and functional synaptic changes in the embryos and offspring, indicating that the pathway is active during gestation and plays a significant role in the normal early development of the embryonic and neonatal nervous system

Selective depletion of tumour suppressors Deleted in Colorectal Cancer (DCC) and neogenin by environmental and endogenous serine proteases: linking diet, obesity and cancer

Background: The related tumour suppressor proteins Deleted in Colorectal Cancer (DCC) and neogenin are absent or weakly expressed in many cancers, whereas their insertion into cells suppresses oncogenic behaviour. Serine proteases influence the initiation and progression of cancers although the mechanisms are unknown. Methods: The effects of environmental (bacterial subtilisin) and endogenous mammalian (chymotrypsin) serine proteases were examined on protein expression in fresh, normal tissue and human neuroblastoma and mammary adenocarcinoma lines. Cell proliferation and migration assays (chemoattraction and wound closure) were used to examine cell function. Cells lacking DCC were transfected with an ectopic dcc plasmid. Results: Subtilisin and chymotrypsin selectively depleted DCC and neogenin from cells at nanomolar concentrations without affecting related proteins. Cells showed reduced adherence and increased migration, but after washing they re-attached within 24 h, with recovery of protein expression. These effects are induced by chymotryptic activity as they are prevented by chymostatin and the soybean Bowman-Birk inhibitor typical of many plant protease inhibitors. Conclusions: Bacillus subtilis, which secretes subtilisin is widely present in soil, the environment and the intestinal contents, while subtilisin itself is used in meat processing, animal feed probiotics and many household cleaning agents. With chymotrypsin present in chyme, blood and tissues, these proteases may contribute to cancer development by depleting DCC and neogenin. Blocking their activity by Bowman-Birk inhibitors may explain the protective effects of a plant diet. Our findings identify a potential non-genetic contribution to cancer cell behaviour which may explain both the association of processed meats and other factors with cancer incidence and the protection afforded by plant-rich diets, with significant implications for cancer prevention

On the Biological Importance of the 3-hydroxyanthranilic Acid: Anthranilic Acid Ratio

Of the major components of the kynurenine pathway for the oxidative metabolism of tryptophan, most attention has focussed on the N-methyl-D-aspartate (NMDA) receptor agonist quinolinic acid, and the glutamate receptor blocker kynurenic acid. However, there is increasing evidence that the redox-active compound 3-hydroxyanthranilic acid may also have potent actions on cell function in the nervous and immune systems, and recent clinical data show marked changes in the levels of this compound, associated with changes in anthranilic acid levels, in patients with a range of neurological and other disorders including osteoporosis, chronic brain injury, Huntington’s disease, coronary heart disease, thoracic disease, stroke and depression. In most cases, there is a decrease in 3-hydroxyanthranilic acid levels and an increase in anthranilic acid levels. In this paper, we summarise the range of data obtained to date, and hypothesise that the levels of 3-hydroxyanthranilic acid or the ratio of 3-hydroxyanthranilic acid to anthranilic acid levels, may contribute to disorders with an inflammatory component, and may represent a novel marker for the assessment of inflammation and its progression. Data are presented which suggest that the ratio between these two compounds is not a simple determinant of neuronal viability. Finally, a hypothesis is presented to account for the development of the observed changes in 3-hydroxyanthranilic acid and anthranilate levels in inflammation and it is suggested that the change of the 3HAA:AA ratio, particularly in the brain, could possibly be a protective response to limit primary and secondary damage

ZFOURGE: Using Composite Spectral Energy Distributions to Characterize Galaxy Populations at 1<z<4

We investigate the properties of galaxies as they shut off star formation over the 4 billion years surrounding peak cosmic star formation. To do this we categorize $\sim7000$ galaxies from $1<z<4$ into $90$ groups based on the shape of their spectral energy distributions (SEDs) and build composite SEDs with $R\sim 50$ resolution. These composite SEDs show a variety of spectral shapes and also show trends in parameters such as color, mass, star formation rate, and emission line equivalent width. Using emission line equivalent widths and strength of the 4000\AA\ break, $D(4000)$, we categorize the composite SEDs into five classes: extreme emission line, star-forming, transitioning, post-starburst, and quiescent galaxies. The transitioning population of galaxies show modest H$\alpha$ emission ($EW_{\rm REST}\sim40$\AA) compared to more typical star-forming composite SEDs at $\log_{10}(M/M_\odot)\sim10.5$ ($EW_{\rm REST}\sim80$\AA). Together with their smaller sizes (3 kpc vs. 4 kpc) and higher S\'ersic indices (2.7 vs. 1.5), this indicates that morphological changes initiate before the cessation of star formation. The transitional group shows a strong increase of over one dex in number density from $z\sim3$ to $z\sim1$, similar to the growth in the quiescent population, while post-starburst galaxies become rarer at $z\lesssim1.5$. We calculate average quenching timescales of 1.6 Gyr at $z\sim1.5$ and 0.9 Gyr at $z\sim2.5$ and conclude that a fast quenching mechanism producing post-starbursts dominated the quenching of galaxies at early times, while a slower process has become more common since $z\sim2$.Comment: Accepted for publication in The Astrophysical Journa

Modelling changing population distributions: an example of the Kenyan Coast, 1979–2009

Large-scale gridded population datasets are usually produced for the year of input census data using a top-down approach and projected backward and forward in time using national growth rates. Such temporal projections do not include any subnational variation in population distribution trends and ignore changes in geographical covariates such as urban land cover changes. Improved predictions of population distribution changes over time require the use of a limited number of covariates that are time-invariant or temporally explicit. Here we make use of recently released multi-temporal high-resolution global settlement layers, historical census data and latest developments in population distribution modelling methods to reconstruct population distribution changes over 30 years across the Kenyan Coast. We explore the methodological challenges associated with the production of gridded population distribution time-series in data-scarce countries and show that trade-offs have to be found between spatial and temporal resolutions when selecting the best modelling approach. Strategies used to fill data gaps may vary according to the local context and the objective of the study. This work will hopefully serve as a benchmark for future developments of population distribution time-series that are increasingly required for population-at-risk estimations and spatial modelling in various fields

Effect of local environment and stellar mass on galaxy quenching and morphology at 0.5<z<2.00.5<z<2.0

We study galactic star-formation activity as a function of environment and stellar mass over 0.5<z<2.0 using the FourStar Galaxy Evolution (ZFOURGE) survey. We estimate the galaxy environment using a Bayesian-motivated measure of the distance to the third nearest neighbor for galaxies to the stellar mass completeness of our survey, $\log(M/M_\odot)>9 (9.5)$ at z=1.3 (2.0). This method, when applied to a mock catalog with the photometric-redshift precision ($\sigma_z / (1+z) \lesssim 0.02$), recovers galaxies in low- and high-density environments accurately. We quantify the environmental quenching efficiency, and show that at z> 0.5 it depends on galaxy stellar mass, demonstrating that the effects of quenching related to (stellar) mass and environment are not separable. In high-density environments, the mass and environmental quenching efficiencies are comparable for massive galaxies ($\log (M/M_\odot)\gtrsim$ 10.5) at all redshifts. For lower mass galaxies ($\log (M/M)_\odot) \lesssim$ 10), the environmental quenching efficiency is very low at $z\gtrsim$ 1.5, but increases rapidly with decreasing redshift. Environmental quenching can account for nearly all quiescent lower mass galaxies ($\log(M/M_\odot) \sim$ 9-10), which appear primarily at $z\lesssim$ 1.0. The morphologies of lower mass quiescent galaxies are inconsistent with those expected of recently quenched star-forming galaxies. Some environmental process must transform the morphologies on similar timescales as the environmental quenching itself. The evolution of the environmental quenching favors models that combine gas starvation (as galaxies become satellites) with gas exhaustion through star-formation and outflows ("overconsumption"), and additional processes such as galaxy interactions, tidal stripping and disk fading to account for the morphological differences between the quiescent and star-forming galaxy populations.Comment: 29 pages, 15 figure, accepted for publication in Ap

Computer-assisted mammographic imaging

Computer-assisted mammography imaging comprises computer-based analysis of digitized images resulting in prompts aiding mammographic interpretation and computerized stereotactic localization devices which improve location accuracy. The commercial prompting systems available are designed to draw attention to mammographic abnormalities detected by algorithms based on symptomatic practise in North America. High sensitivity rates are important commercially but result in increased false prompt rates, which are known to distract radiologists. A national shortage of breast radiologists in the UK necessitates evaluation of such systems in a population breast screening programme to determine effectiveness in increasing cancer detection and feasibility of implementation

High-throughput analysis of candidate imprinted genes and allele-specific gene expression in the human term placenta.

BACKGROUND: Imprinted genes show expression from one parental allele only and are important for development and behaviour. This extreme mode of allelic imbalance has been described for approximately 56 human genes. Imprinting status is often disrupted in cancer and dysmorphic syndromes. More subtle variation of gene expression, that is not parent-of-origin specific, termed 'allele-specific gene expression' (ASE) is more common and may give rise to milder phenotypic differences. Using two allele-specific high-throughput technologies alongside bioinformatics predictions, normal term human placenta was screened to find new imprinted genes and to ascertain the extent of ASE in this tissue. RESULTS: Twenty-three family trios of placental cDNA, placental genomic DNA (gDNA) and gDNA from both parents were tested for 130 candidate genes with the Sequenom MassArray system. Six genes were found differentially expressed but none imprinted. The Illumina ASE BeadArray platform was then used to test 1536 SNPs in 932 genes. The array was enriched for the human orthologues of 124 mouse candidate genes from bioinformatics predictions and 10 human candidate imprinted genes from EST database mining. After quality control pruning, a total of 261 informative SNPs (214 genes) remained for analysis. Imprinting with maternal expression was demonstrated for the lymphocyte imprinted gene ZNF331 in human placenta. Two potential differentially methylated regions (DMRs) were found in the vicinity of ZNF331. None of the bioinformatically predicted candidates tested showed imprinting except for a skewed allelic expression in a parent-specific manner observed for PHACTR2, a neighbour of the imprinted PLAGL1 gene. ASE was detected for two or more individuals in 39 candidate genes (18%). CONCLUSIONS: Both Sequenom and Illumina assays were sensitive enough to study imprinting and strong allelic bias. Previous bioinformatics approaches were not predictive of new imprinted genes in the human term placenta. ZNF331 is imprinted in human term placenta and might be a new ubiquitously imprinted gene, part of a primate-specific locus. Demonstration of partial imprinting of PHACTR2 calls for re-evaluation of the allelic pattern of expression for the PHACTR2-PLAGL1 locus. ASE was common in human term placenta.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are