Physiological concentrations of bile acids down-regulate agonist induced secretion in colonic epithelial cells

In patients with bile acid malabsorption, high concentrations of bile acids enter the colon and stimulate Cl− and fluid secretion, thereby causing diarrhoea. However, deoxycholic acid (DCA), the predominant colonic bile acid, is normally present at lower concentrations where its role in regulating transport is unclear. Thus, the current study set out to investigate the effects of physiologically relevant DCA concentrations on colonic epithelial secretory function. Cl− secretion was measured as changes in short-circuit current across voltage-clamped T84 cell monolayers. At high concentrations (0.5–1 mM), DCA acutely stimulated Cl− secretion but this effect was associated with cell injury, as evidenced by decreased transepithelial resistance (TER) and increased lactate dehydrogenase (LDH) release. In contrast, chronic (24 hrs) exposure to lower DCA concentrations (10–200 μM) inhibited responses to Ca2+ and cAMP-dependent secretagogues without altering TER, LDH release, or secretagogue-induced increases in intracellular second messengers. Other bile acids – taurodeoxycholic acid, chenodeoxycholic acid and cholic acid – had similar antisecretory effects. DCA (50 μM) rapidly stimulated phosphorylation of the epidermal growth factor receptor (EGFr) and both ERK and p38 MAPKs (mitogen-activated protein kinases). The EGFr inhibitor, AG1478, and the protein synthesis inhibitor, cycloheximide, reversed the antisecretory effects of DCA, while the MAPK inhibitors, PD98059 and SB203580, did not. In summary, our studies suggest that, in contrast to its acute prosecretory effects at pathophysiological concentrations, lower, physiologically relevant, levels of DCA chronically down-regulate colonic epithelial secretory function. On the basis of these data, we propose a novel role for bile acids as physiological regulators of colonic secretory capacity

SGAS 143845.1+145407: A Big, Cool Starburst at Redshift 0.816

We present the discovery and a detailed multi-wavelength study of a strongly-lensed luminous infrared galaxy at z=0.816. Unlike most known lensed galaxies discovered at optical or near-infrared wavelengths this lensed source is red, r-Ks = 3.9 [AB], which the data presented here demonstrate is due to ongoing dusty star formation. The overall lensing magnification (a factor of 17) facilitates observations from the blue optical through to 500micron, fully capturing both the stellar photospheric emission as well as the re-processed thermal dust emission. We also present optical and near-IR spectroscopy. These extensive data show that this lensed galaxy is in many ways typical of IR-detected sources at z~1, with both a total luminosity and size in accordance with other (albeit much less detailed) measurements in samples of galaxies observed in deep fields with the Spitzer telescope. Its far-infrared spectral energy distribution is well-fit by local templates that are an order of magnitude less luminous than the lensed galaxy; local templates of comparable luminosity are too hot to fit. Its size (D~7kpc) is much larger than local luminous infrared galaxies, but in line with sizes observed for such galaxies at z~1. The star formation appears uniform across this spatial scale. In this source, the luminosity of which is typical of sources that dominate the cosmic infrared background, we find that star formation is spatially extended and well organised, quite unlike the compact merger-driven starbursts which are typical for sources of this luminosity at z~0.Comment: 18 pages, 10 figure

The Secondary Bile acids, Ursodeoxycholic acid and Lithocholic Acid, Protect Against Intestinal Inflammation by Inhibition of Epithelial Apoptosis

Increased epithelial permeability is a key feature of IBD pathogenesis and it has been proposed that agents which promote barrier function may be of therapeutic benefit. We have previously reported the secondary bile acid, ursodeoxycholic acid (UDCA), to be protective in a mouse model of colonic inflammation and that its bacterial metabolism is required for its beneficial effects. The current study aimed to compare the effects of UDCA, LCA, and a non-metabolizable analog of UDCA, 6-methyl-UDCA (6-MUDCA), on colonic barrier function and mucosal inflammation in a mouse model of colonic inflammation. Bile acids were administered daily to C57Bl6 mice by intraperitoneal injection. Colonic inflammation, induced by addition of DSS (2.5%) to the drinking water, was measured as disease activity index (DAI) and histological score. Epithelial permeability and apoptosis were assessed by measuring FITC-dextran uptake and caspase-3 cleavage, respectively. Cecal bile acids were measured by HPLC-MS/MS. UDCA and LCA, but not 6-MUDCA, were protective against DSS-induced increases in epithelial permeability and colonic inflammation. Furthermore, UDCA and LCA inhibited colonic epithelial caspase-3 cleavage both in DSS-treated mice and in an in vitro model of cytokine-induced epithelial injury. HPLC-MS/MS analysis revealed UDCA administration to increase colonic LCA levels, whereas LCA administration did not alter UDCA levels. UDCA, and its primary metabolite, LCA, protect against intestinal inflammation in vivo, at least in part, by inhibition of epithelial apoptosis and promotion of barrier function. These data suggest that clinical trials of UDCA in IBD patients are warranted

Genetic variation in Pneumocystis carinii isolates from different geographic regions: implications for transmission.

To study transmission patterns of Pneumocystis carinii pneumonia (PCP) in persons with AIDS, we evaluated P. carinii isolates from patients in five U.S. cities for variation at two independent genetic loci, the mitochondrial large subunit rRNA and dihydropteroate synthase. Fourteen unique multilocus genotypes were observed in 191 isolates that were examined at both loci. Mixed infections, accounting for 17.8% of cases, were associated with primary PCP. Genotype frequency distribution patterns varied by patients' place of diagnosis but not by place of birth. Genetic variation at the two loci suggests three probable characteristics of transmission: that most cases of PCP do not result from infections acquired early in life, that infections are actively acquired from a relatively common source (humans or the environment), and that humans, while not necessarily involved in direct infection of other humans, are nevertheless important in the transmission cycle of P. carinii f. sp. hominis

What impact do posters have on academic knowledge transfer? A pilot survey on author attitudes and experiences

<p>Abstract</p> <p>Background</p> <p>Research knowledge is commonly facilitated at conferences via oral presentations, poster presentations and workshops. Current literature exploring the efficacy of academic posters is however limited. The purpose of this initial study was to explore the perceptions of academic poster presentation, together with its benefits and limitations as an effective mechanism for academic knowledge transfer and contribute to the available academic data.</p> <p>Methods</p> <p>A survey was distributed to 88 delegates who presented academic posters at two Releasing Research and Enterprise Potential conferences in June 2007 and June 2008 at Bournemouth University. This survey addressed attitude and opinion items, together with their general experiences of poster presentations. Descriptive statistics were performed on the responses.</p> <p>Results</p> <p>A 39% return was achieved with the majority of respondents believing that posters are a good medium for transferring knowledge and a valid form of academic publication. Visual appeal was cited as more influential than subject content, with 94% agreeing that poster imagery is most likely to draw viewer's attention. Respondents also believed that posters must be accompanied by their author in order to effectively communicate the academic content.</p> <p>Conclusion</p> <p>This pilot study is the first to explore perceptions of the academic poster as a medium for knowledge transfer. Given that academic posters rely heavily on visual appeal and direct author interaction, the medium requires greater flexibility in their design to promote effective knowledge transfer. This paper introduces the concept of the IT-based 'MediaPoster' so as to address the issues raised within published literature and subsequently enhance knowledge-transfer within the field of academic medicine.</p

Collagen reorganization at the tumor-stromal interface facilitates local invasion

BACKGROUND: Stromal-epithelial interactions are of particular significance in breast tissue as misregulation of these interactions can promote tumorigenesis and invasion. Moreover, collagen-dense breast tissue increases the risk of breast carcinoma, although the relationship between collagen density and tumorigenesis is not well understood. As little is known about epithelial-stromal interactions in vivo, it is necessary to visualize the stroma surrounding normal epithelium and mammary tumors in intact tissues to better understand how matrix organization, density, and composition affect tumor formation and progression. METHODS: Epithelial-stromal interactions in normal mammary glands, mammary tumors, and tumor explants in three-dimensional culture were studied with histology, electron microscopy, and nonlinear optical imaging methodologies. Imaging of the tumor-stromal interface in live tumor tissue ex vivo was performed with multiphoton laser-scanning microscopy (MPLSM) to generate multiphoton excitation (MPE) of endogenous fluorophores and second harmonic generation (SHG) to image stromal collagen. RESULTS: We used both laser-scanning multiphoton and second harmonic generation microscopy to determine the organization of specific collagen structures around ducts and tumors in intact, unfixed and unsectioned mammary glands. Local alterations in collagen density were clearly seen, allowing us to obtain three-dimensional information regarding the organization of the mammary stroma, such as radiating collagen fibers that could not have been obtained using classical histological techniques. Moreover, we observed and defined three tumor-associated collagen signatures (TACS) that provide novel markers to locate and characterize tumors. In particular, local cell invasion was found predominantly to be oriented along certain aligned collagen fibers, suggesting that radial alignment of collagen fibers relative to tumors facilitates invasion. Consistent with this observation, primary tumor explants cultured in a randomly organized collagen matrix realigned the collagen fibers, allowing individual tumor cells to migrate out along radially aligned fibers. CONCLUSION: The presentation of these tumor-associated collagen signatures allowed us to identify pre-palpable tumors and see cells at the tumor-stromal boundary invading into the stroma along radially aligned collagen fibers. As such, TACS should provide indications that a tumor is, or could become, invasive, and may serve as part of a strategy to help identify and characterize breast tumors in animal and human tissues

Using Dark Energy Explorers and Machine Learning to Enhance the Hobby-Eberly Telescope Dark Energy Experiment

We present analysis using a citizen science campaign to improve the cosmological measures from the Hobby-Eberly Telescope Dark Energy Experiment (HETDEX). The goal of HETDEX is to measure the Hubble expansion rate, $H(z)$, and angular diameter distance, $D_A(z)$, at $z =$ 2.4, each to percent-level accuracy. This accuracy is determined primarily from the total number of detected Lyman-$\alpha$ emitters (LAEs), the false positive rate due to noise, and the contamination due to [O II] emitting galaxies. This paper presents the citizen science project, Dark Energy Explorers, with the goal of increasing the number of LAEs, decreasing the number of false positives due to noise and the [O II] galaxies. Initial analysis shows that citizen science is an efficient and effective tool for classification most accurately done by the human eye, especially in combination with unsupervised machine learning. Three aspects from the citizen science campaign that have the most impact are 1) identifying individual problems with detections, 2) providing a clean sample with 100% visual identification above a signal-to-noise cut, and 3) providing labels for machine learning efforts. Since the end of 2022, Dark Energy Explorers has collected over three and a half million classifications by 11,000 volunteers in over 85 different countries around the world. By incorporating the results of the Dark Energy Explorers we expect to improve the accuracy on the $D_A(z)$ and $H(z)$ parameters at $z =$ 2.4 by 10 - 30%. While the primary goal is to improve on HETDEX, Dark Energy Explorers has already proven to be a uniquely powerful tool for science advancement and increasing accessibility to science worldwide.Comment: 14 pages, 6 figures, accepted for publication in The Astrophysical Journa

Dietary Supplementation with Soluble Plantain Non-Starch Polysaccharides Inhibits Intestinal Invasion of Salmonella Typhimurium in the Chicken

Soluble fibres (non-starch polysaccharides, NSP) from edible plants but particularly plantain banana (Musa spp.), have been shown in vitro and ex vivo to prevent various enteric pathogens from adhering to, or translocating across, the human intestinal epithelium, a property that we have termed contrabiotic. Here we report that dietary plantain fibre prevents invasion of the chicken intestinal mucosa by Salmonella. In vivo experiments were performed with chicks fed from hatch on a pellet diet containing soluble plantain NSP (0 to 200 mg/d) and orally infected with S.Typhimurium 4/74 at 8 d of age. Birds were sacrificed 3, 6 and 10 d post-infection. Bacteria were enumerated from liver, spleen and caecal contents. In vitro studies were performed using chicken caecal crypts and porcine intestinal epithelial cells infected with Salmonella enterica serovars following pre-treatment separately with soluble plantain NSP and acidic or neutral polysaccharide fractions of plantain NSP, each compared with saline vehicle. Bacterial adherence and invasion were assessed by gentamicin protection assay. In vivo dietary supplementation with plantain NSP 50 mg/d reduced invasion by S.Typhimurium, as reflected by viable bacterial counts from splenic tissue, by 98.9% (95% CI, 98.1–99.7; P<0.0001). In vitro studies confirmed that plantain NSP (5–10 mg/ml) inhibited adhesion of S.Typhimurium 4/74 to a porcine epithelial cell-line (73% mean inhibition (95% CI, 64–81); P<0.001) and to primary chick caecal crypts (82% mean inhibition (95% CI, 75–90); P<0.001). Adherence inhibition was shown to be mediated via an effect on the epithelial cells and Ussing chamber experiments with ex-vivo human ileal mucosa showed that this effect was associated with increased short circuit current but no change in electrical resistance. The inhibitory activity of plantain NSP lay mainly within the acidic/pectic (homogalacturonan-rich) component. Supplementation of chick feed with plantain NSP was well tolerated and shows promise as a simple approach for reducing invasive salmonellosis

Hubble Space Telescope Imaging of Lyman Alpha Emission at z=4.4

We present the highest redshift detections of resolved Lyman alpha emission, using Hubble Space Telescope/ACS F658N narrowband-imaging data taken in parallel with the Wide Field Camera 3 Early Release Science program in the GOODS CDF-S. We detect Lyman alpha emission from three spectroscopically confirmed z = 4.4 Lyman alpha emitting galaxies (LAEs), more than doubling the sample of LAEs with resolved Lyman alpha emission. Comparing the light distribution between the rest-frame ultraviolet continuum and narrowband images, we investigate the escape of Lyman alpha photons at high redshift. While our data do not support a positional offset between the Lyman alpha and rest-frame ultraviolet (UV) continuum emission, the half-light radii in two out of the three galaxies are significantly larger in Lyman alpha than in the rest-frame UV continuum. This result is confirmed when comparing object sizes in a stack of all objects in both bands. Additionally, the narrowband flux detected with HST is significantly less than observed in similar filters from the ground. These results together imply that the Lyman alpha emission is not strictly confined to its indigenous star-forming regions. Rather, the Lyman alpha emission is more extended, with the missing HST flux likely existing in a diffuse outer halo. This suggests that the radiative transfer of Lyman alpha photons in high-redshift LAEs is complicated, with the interstellar-medium geometry and/or outflows playing a significant role in galaxies at these redshifts.Comment: Submitted to the Astrophysical Journal. 11 pages, 10 figure

Loss of the integrin-activating transmembrane protein Fam38A (Piezo1) promotes a switch to a reduced integrin-dependent mode of cell migration

Lung cancer is one of the most common fatal diseases in the developed world. The disease is rarely cured by currently available therapies, with an overall survival rate of ∼10%. Characterizing novel proteins that offer crucial insights into the processes of lung tumour invasion and metastasis may therefore provide much-needed prognostic markers, and influence therapeutic strategies. Aberrant function of the integrin family of heterodimeric cell surface receptors is a common theme in cancer--investigation into novel integrin activity regulators may offer crucial insights into the processes of tumour invasion and metastasis and may reveal insights into potential therapeutic targets. We previously described that depletion of the novel multi-transmembrane domain protein Fam38A, located at the endoplasmic reticulum (ER), inactivates endogenous beta1 integrin affinity, reducing cell adhesion. We now show that depletion of Fam38A, also now known as Piezo1, causes anchorage independence and a switch to a reduced integrin-dependent mode of cell migration/invasion, a novel phenotype for this integrin-regulating protein. Normal lung epithelial cells show increased rates of migration by 2D time-lapse microscopy and increased capacity to invade into matrigel, despite having decreased integrin affinity. We confirm greatly depleted Fam38A expression in small cell lung cancer (SCLC) lines where a form of reduced integrin-dependent migration, i.e. amoeboid migration, is a known phenotype. We propose that loss of Fam38A expression may cause increased cell migration and metastasis in lung tumours