Cyclooxygenase-2 (COX-2) expression is normally tightly regulated. However, constitutive overexpression plays a key role in colon carcinogenesis. To understand the molecular nature of enhanced COX-2 ...expression detected in colon cancer, we examined the ability of the AU-rich element-containing (ARE-containing) 3' untranslated region (3'UTR) of COX-2 mRNA to regulate rapid mRNA decay in human colon cancer cells. In tumor cells displaying enhanced growth and tumorigenicity that is correlated with elevated COX-2, vascular endothelial growth factor (VEGF), and IL-8 protein levels, the corresponding mRNAs were transcribed constitutively and turned over slowly. The observed mRNA stabilization is owing to defective recognition of class II-type AREs present within the COX-2, VEGF, and IL-8 3'UTRs; c-myc mRNA, containing a class I ARE decayed rapidly in the same cells. Correlating with cellular defects in mRNA stability, the RNA-binding of trans-acting cellular factors was altered. In particular, we found that the RNA-stability factor HuR binds to the COX-2 ARE, and overexpression of HuR, as detected in tumors, results in elevated expression of COX-2, VEGF, and IL-8. These findings demonstrate the functional significance rapid mRNA decay plays in controlling gene expression and show that dysregulation of these trans-acting factors can lead to overexpression of COX-2 and other angiogenic proteins, as detected in neoplasia.
Sacubitril/valsartan (LCZ696) is indicated for the treatment of patients with heart failure and reduced ejection fraction (HFrEF). Since patients with HFrEF may receive sacubitril/valsartan and ...sildenafil, both increasing cyclic guanosine monophosphate, the present study evaluated the pharmacokinetic and pharmacodynamic drug interaction potential between sacubitril/valsartan and sildenafil. In this open‐label, three‐period, single sequence study, patients with mild‐to‐moderate hypertension (153.8 ± 8.2 mmHg mean systolic blood pressure (SBP)) received a single dose of sildenafil 50 mg, sacubitril/valsartan 400 mg once daily for 5 days, and sacubitril/valsartan and sildenafil coadministration. When coadministered with sildenafil, the AUC and Cmax of valsartan decreased by 29% and 39%, respectively. Coadministration of sacubitril/valsartan and sildenafil resulted in a greater decrease in BP (–5/–4/–4 mmHg mean ambulatory SBP/DBP/MAP (mean arterial pressure)) than with sacubitril/valsartan alone. Both treatments were generally safe and well tolerated in this study; however, the additional BP reduction suggests that sildenafil should be administered cautiously in patients receiving sacubitril/valsartan. Unique identifier: NCT01601470.
We report on a search for new low-surface-brightness galaxies (LSBGs) using Sloan Digital Sky Survey (SDSS) data within the Galaxy And Mass Assembly (GAMA) equatorial fields. The search method ...consisted of masking objects detected with SDSS PHOTO, combining gri images weighted to maximize the expected signal-to-noise ratio, and smoothing the images. The processed images were then run through a detection algorithm that finds all pixels above a set threshold and groups them based on their proximity to one another. The list of detections was cleaned of contaminants such as diffraction spikes and the faint wings of masked objects. From these, selecting potentially the brightest in terms of total flux, a list of 343 LSBGs was produced having been confirmed using VISTA Kilo-degree Infrared Galaxy Survey (VIKING) imaging. The photometry of this sample was refined using the deeper VIKING Z band as the aperture-defining band. Measuring their g - i and J - K colours shows that most are consistent with being at redshifts less than 0.2. The photometry is carried out using an AUTO aperture for each detection giving surface brightnesses of ... mag arcsec-2 and magnitudes of r > 19.8 mag. None of these galaxies are bright enough to be within the GAMA main survey limit but could be part of future deeper surveys to measure the low-mass end of the galaxy stellar mass function. (ProQuest: ... denotes formulae/symbols omitted.)
Since the first mammal was cloned, the idea of using this technique to help endangered species has aroused considerable interest. However, several issues limit this possibility, including the ...relatively low success rate at every stage of the cloning process, and the dearth of usable tissues from these rare animals. iPS cells have been produced from cells from a number of rare mammalian species and this is the method of choice for strategies to improve cloning efficiency and create new gametes by directed differentiation. Nevertheless information about other stem cell/progenitor capabilities of cells from endangered species could prove important for future conservation approaches and adds to the knowledge base about cellular material that can be extremely limited. Multipotent progenitor cells, termed skin-derived precursor (SKP) cells, can be isolated directly from mammalian skin dermis, and human cheek tissue has also been shown to be a good source of SKP-like cells. Recently we showed that structures identical to SKPs termed m-SKPs could be obtained from monolayer/ two dimensional (2D) skin fibroblast cultures. Here we aimed to isolate m-SKPs from cultured cells of three endangered species; giant panda (Ailuropoda melanoleuca); red panda (Ailurus fulgens); and Asiatic lion (Panthera leo persica). m-SKP-like spheres were formed from the giant panda buccal mucosa fibroblasts; whereas dermal fibroblast (DF) cells cultured from abdominal skin of the other two species were unable to generate spheres. Under specific differentiation culture conditions giant panda spheres expressed neural, Schwann, adipogenic and osteogenic cell markers. Furthermore, these buccal mucosa derived spheres were shown to maintain expression of SKP markers: nestin, versican, fibronectin, and P75 and switch on expression of the stem cell marker ABCG2. These results demonstrate that giant panda cheek skin can be a useful source of m-SKP multipotent progenitors. At present lack of sample numbers means that we can only postulate why we were unable to obtain m-SKPs from the lion and red panda cultures. However the giant panda observations point to the value of archiving cells from rare species, and the possibilities for later progenitor cell derivation.
The cyclooxygenase-2 (COX-2) enzyme catalyzes the rate-limiting step of prostaglandin formation in inflammatory states, and COX-2 overexpression plays a key role in carcinogenesis. To understand the ...mechanisms regulating COX-2 expression, we examined its posttranscriptional regulation mediated through the AU-rich element (ARE) within the COX-2 mRNA 3'-untranslated region (3'UTR). RNA binding studies, performed to identify ARE-binding regulatory factors, demonstrated binding of the translational repressor protein TIA-1 to COX-2 mRNA. The significance of TIA-1-mediated regulation of COX-2 expression was observed in TIA-1 null fibroblasts that produced significantly more COX-2 protein than wild-type fibroblasts. However, TIA-1 deficiency did not alter COX-2 transcription or mRNA turnover. Colon cancer cells demonstrated to overexpress COX-2 through increased polysome association with COX-2 mRNA also showed defective TIA-1 binding both in vitro and in vivo. These findings implicate that TIA-1 functions as a translational silencer of COX-2 expression and support the hypothesis that dysregulated RNA-binding of TIA-1 promotes COX-2 expression in neoplasia.
F2-isoprostanes are produced in vivo by nonenzymatic peroxidation of arachidonic acid esterified in phospholipids. Increased urinary and plasma F2-isoprostane levels are associated with a number of ...human diseases. These metabolites are regarded as excellent markers of oxidant stress in vivo. Isoprostanes are initially generated in situ, i.e. when the arachidonate precursor is esterified in phospholipids, and they are subsequently released in free form. Although the mechanism(s) responsible for the release of free isoprostanes after in situ generation in membrane phospholipids is, for the most part, unknown, this process is likely mediated by phospholipase A2 activity(ies). Here we reported that human plasma contains an enzymatic activity that catalyzes this reaction. The activity associates with high density and low density lipoprotein and comigrates with platelet-activating factor (PAF) acetylhydrolase on KBr density gradients. Plasma samples from subjects deficient in PAF acetylhydrolase do not release F2-isoprostanes from esterified precursors. The intracellular PAF acetylhydrolase II, which shares homology to the plasma enzyme, also catalyzes this reaction. We found that both the intracellular and plasma PAF acetylhydrolases have high affinity for esterified F2-isoprostanes. However, the rate of esterified F2-isoprostane hydrolysis is much slower compared with the rate of hydrolysis of other substrates utilized by these enzymes. Studies using PAF acetylhydrolase transgenic mice indicated that these animals have a higher capacity to release F2-isoprostanes compared with nontransgenic littermates. Our results suggested that PAF acetylhydrolases play key roles in the hydrolysis of F2-isoprostanes esterified on phospholipids in vivo.
We defined the bathymetry of Shelikof Strait and the western Gulf of Alaska (WGOA) from the edges of the land masses down to about 7000 m deep in the Aleutian Trench. This map was produced by ...combining soundings from historical National Ocean Service (NOS) smooth sheets (2.7 million soundings); shallow multibeam and LIDAR (light detection and ranging) data sets from the NOS and others (subsampled to 2.6 million soundings); and deep multibeam (subsampled to 3.3 million soundings), single-beam, and underway files from fisheries research cruises (9.1 million soundings). These legacy smooth sheet data, some over a century old, were the best descriptor of much of the shallower and inshore areas, but they are superseded by the newer multibeam and LIDAR, where available. Much of the offshore area is only mapped by non-hydrographic single-beam and underway files. We combined these disparate data sets by proofing them against their source files, where possible, in an attempt to preserve seafloor features for research purposes. We also attempted to minimize bathymetric data errors so that they would not create artificial seafloor features that might impact such analyses. The main result of the bathymetry compilation is that we observe abundant features related to glaciation of the shelf of Alaska during the Last Glacial Maximum including abundant end moraines, some medial moraines, glacial lineations, eskers, iceberg ploughmarks, and two types of pockmarks. We developed an integrated onshore–offshore geomorphic map of the region that includes glacial flow directions, moraines, and iceberg ploughmarks to better define the form and flow of former ice masses.
HELP: the Herschel Extragalactic Legacy Project Shirley, R; Duncan, K; Campos varillas, M ...
Monthly notices of the Royal Astronomical Society,
10/2021, Letnik:
507, Številka:
1
Journal Article
Recenzirano
Odprti dostop
ABSTRACT We present the Herschel Extragalactic Legacy Project (HELP). This project collates, curates, homogenizes, and creates derived data products for most of the premium multiwavelength ...extragalactic data sets. The sky boundaries for the first data release cover 1270 deg2 defined by the Herschel SPIRE extragalactic survey fields; notably the Herschel Multi-tiered Extragalactic Survey (HerMES) and the Herschel Atlas survey (H-ATLAS). Here, we describe the motivation and principal elements in the design of the project. Guiding principles are transparent or ‘open’ methodologies with care for reproducibility and identification of provenance. A key element of the design focuses around the homogenization of calibration, meta data, and the provision of information required to define the selection of the data for statistical analysis. We apply probabilistic methods that extract information directly from the images at long wavelengths, exploiting the prior information available at shorter wavelengths and providing full posterior distributions rather than maximum-likelihood estimates and associated uncertainties as in traditional catalogues. With this project definition paper, we provide full access to the first data release of HELP; Data Release 1 (DR1), including a monolithic map of the largest SPIRE extragalactic field at 385 deg2 and 18 million measurements of PACS and SPIRE fluxes. We also provide tools to access and analyse the full HELP data base. This new data set includes far-infrared photometry, photometric redshifts, and derived physical properties estimated from modelling the spectral energy distributions over the full HELP sky. All the software and data presented is publicly available.
Deep-sea coral and sponge ecosystems are widespread throughout most of Alaska's marine waters, and are associated with many different species of fishes and invertebrates. These ecosystems are ...vulnerable to the effects of commercial fishing activities and climate change. We compared four commonly used species distribution models (general linear models, generalized additive models, boosted regression trees and random forest models) and an ensemble model to predict the presence or absence and abundance of six groups of benthic invertebrate taxa in the Gulf of Alaska. All four model types performed adequately on training data for predicting presence and absence, with regression forest models having the best overall performance measured by the area under the receiver-operating-curve (AUC). The models also performed well on the test data for presence and absence with average AUCs ranging from 0.66 to 0.82. For the test data, ensemble models performed the best. For abundance data, there was an obvious demarcation in performance between the two regression-based methods (general linear models and generalized additive models), and the tree-based models. The boosted regression tree and random forest models out-performed the other models by a wide margin on both the training and testing data. However, there was a significant drop-off in performance for all models of invertebrate abundance (~50%) when moving from the training data to the testing data. Ensemble model performance was between the tree-based and regression-based methods. The maps of predictions from the models for both presence and abundance agreed very well across model types, with an increase in variability in predictions for the abundance data. We conclude that where data conforms well to the modeled distribution (such as the presence-absence data and binomial distribution in this study), the four types of models will provide similar results, although the regression-type models may be more consistent with biological theory. For data with highly zero-inflated distributions and non-normal distributions such as the abundance data from this study, the tree-based methods performed better. Ensemble models that averaged predictions across the four model types, performed better than the GLM or GAM models but slightly poorer than the tree-based methods, suggesting ensemble models might be more robust to overfitting than tree methods, while mitigating some of the disadvantages in predictive performance of regression methods.
•Invertebrate distribution was predicted by four models and an ensemble model.•Models were accurate for presence or absence of six groups of benthic invertebrate taxa.•The models were less accurate in predicting invertebrate abundance.•There were drop-offs in model performance when predicting test data.•Ensemble models are more robust to overfitting than tree models.
Current evidence indicates that dysregulation of the host inflammatory response to infectious agents is central to the mortality of patients with sepsis. Strategies to block inflammatory mediators ...such as PAF have been investigated as adjuvant therapies for sepsis. PAF-AH, the enzyme responsible for PAF degradation, showed positive results in pre-clinical studies and phase II clinical trials, but the results of a phase III study were disappointing. In this study, we investigated the potential protective mechanism of PAF-AH in sepsis using the murine model of cecal ligation and puncture (CLP). Treatment with rPAF-AH increased peritoneal fluid levels of the anti-inflammatory mediators MCP-1/CCL2 after CLP. The numbers of bacteria (CFU) in the peritoneal cavity were decreased in the rPAF-AH-treated group, indicating more efficient bacterial clearance after rPAF-AH treatment. Interestingly, we observed increased levels of nitric oxide (NO) after PAF-AH administration, and rPAF-AH treatment did not decrease CFU numbers either in iNOS-deficient mice or in CCR2-deficient mice. We concluded that administration of exogenous rPAF-AH reduced inflammatory injury, altered cytokine levels and favored bacterial clearance with a clear impact on mortality through modulation of MCP-1/CCL2 and NO levels in a clinically relevant sepsis model.
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