Investigation of molecular mechanisms and regulatory pathways of pro-angiogenic nanorods

NASA Astrophysics Data System (ADS)

Nethi, Susheel Kumar; Veeriah, Vimal; Barui, Ayan Kumar; Rajendran, Saranya; Mattapally, Saidulu; Misra, Sanjay; Chatterjee, Suvro; Patra, Chitta Ranjan

2015-05-01

Angiogenesis, a process involving the growth of new blood vessels from the pre-existing vasculature, plays a crucial role in various pathophysiological conditions. We have previously demonstrated that europium hydroxide [EuIII(OH)3] nanorods (EHNs) exhibit pro-angiogenic properties through the generation of reactive oxygen species (ROS) and mitogen activated protein kinase (MAPK) activation. Considering the enormous implication of angiogenesis in cardiovascular diseases (CVDs) and cancer, it is essential to understand in-depth molecular mechanisms and signaling pathways in order to develop the most efficient and effective alternative treatment strategy for CVDs. However, the exact underlying mechanism and cascade signaling pathways behind the pro-angiogenic properties exhibited by EHNs still remain unclear. Herein, we report for the first time that the hydrogen peroxide (H2O2), a redox signaling molecule, generated by these EHNs activates the endothelial nitric oxide synthase (eNOS) that promotes the nitric oxide (NO) production in a PI3K (phosphoinositide 3-kinase)/Akt dependent manner, eventually triggering angiogenesis. We intensely believe that the investigation and understanding of the in-depth molecular mechanism and signaling pathways of EHNs induced angiogenesis will help us in developing an effective alternative treatment strategy for cardiovascular related and ischemic diseases where angiogenesis plays an important role.Angiogenesis, a process involving the growth of new blood vessels from the pre-existing vasculature, plays a crucial role in various pathophysiological conditions. We have previously demonstrated that europium hydroxide [EuIII(OH)3] nanorods (EHNs) exhibit pro-angiogenic properties through the generation of reactive oxygen species (ROS) and mitogen activated protein kinase (MAPK) activation. Considering the enormous implication of angiogenesis in cardiovascular diseases (CVDs) and cancer, it is essential to understand in-depth molecular mechanisms and signaling pathways in order to develop the most efficient and effective alternative treatment strategy for CVDs. However, the exact underlying mechanism and cascade signaling pathways behind the pro-angiogenic properties exhibited by EHNs still remain unclear. Herein, we report for the first time that the hydrogen peroxide (H2O2), a redox signaling molecule, generated by these EHNs activates the endothelial nitric oxide synthase (eNOS) that promotes the nitric oxide (NO) production in a PI3K (phosphoinositide 3-kinase)/Akt dependent manner, eventually triggering angiogenesis. We intensely believe that the investigation and understanding of the in-depth molecular mechanism and signaling pathways of EHNs induced angiogenesis will help us in developing an effective alternative treatment strategy for cardiovascular related and ischemic diseases where angiogenesis plays an important role. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr01327e

Coordinate regulation of cytochrome and alternative pathway respiration in tobacco.

PubMed

Vanlerberghe, G C; McIntosh, L

1992-12-01

In suspension cells of NT1 tobacco (Nicotiana tabacum L. cv bright yellow), inhibition of the cytochrome pathway of respiration with antimycin A induced a large increase in the capacity of the alternative pathway over a period of approximately 12 h, as confirmed in both whole cells and isolated mitochondria. The increase in alternative pathway capacity required de novo RNA and protein synthesis and correlated closely with the increase of a 35-kD alternative oxidase protein. When the cytochrome pathway of intact cells was inhibited by antimycin A, respiration proceeded exclusively through the alternative pathway, reached rates significantly higher than before antimycin A addition, and was not stimulated by p-trifluoromethoxycarbonylcyanide (FCCP). When inhibition of the cytochrome pathway was relieved, alternative pathway capacity and the level of the 35-kD alternative oxidase protein declined. Respiration rate also declined and could once again be stimulated by FCCP. These observations show that the capacities of the mitochondrial electron transport pathways can be regulated in a coordinate fashion.

Unconventional Transport Routes of Soluble and Membrane Proteins and Their Role in Developmental Biology

PubMed Central

Pompa, Andrea; De Marchis, Francesca; Pallotta, Maria Teresa; Benitez-Alfonso, Yoselin; Jones, Alexandra; Schipper, Kerstin; Moreau, Kevin; Žárský, Viktor; Di Sansebastiano, Gian Pietro; Bellucci, Michele

2017-01-01

Many proteins and cargoes in eukaryotic cells are secreted through the conventional secretory pathway that brings proteins and membranes from the endoplasmic reticulum to the plasma membrane, passing through various cell compartments, and then the extracellular space. The recent identification of an increasing number of leaderless secreted proteins bypassing the Golgi apparatus unveiled the existence of alternative protein secretion pathways. Moreover, other unconventional routes for secretion of soluble or transmembrane proteins with initial endoplasmic reticulum localization were identified. Furthermore, other proteins normally functioning in conventional membrane traffic or in the biogenesis of unique plant/fungi organelles or in plasmodesmata transport seem to be involved in unconventional secretory pathways. These alternative pathways are functionally related to biotic stress and development, and are becoming more and more important in cell biology studies in yeast, mammalian cells and in plants. The city of Lecce hosted specialists working on mammals, plants and microorganisms for the inaugural meeting on “Unconventional Protein and Membrane Traffic” (UPMT) during 4–7 October 2016. The main aim of the meeting was to include the highest number of topics, summarized in this report, related to the unconventional transport routes of protein and membranes. PMID:28346345

Design and analysis of synthetic carbon fixation pathways

PubMed Central

Bar-Even, Arren; Noor, Elad; Lewis, Nathan E.; Milo, Ron

2010-01-01

Carbon fixation is the process by which CO2 is incorporated into organic compounds. In modern agriculture in which water, light, and nutrients can be abundant, carbon fixation could become a significant growth-limiting factor. Hence, increasing the fixation rate is of major importance in the road toward sustainability in food and energy production. There have been recent attempts to improve the rate and specificity of Rubisco, the carboxylating enzyme operating in the Calvin–Benson cycle; however, they have achieved only limited success. Nature employs several alternative carbon fixation pathways, which prompted us to ask whether more efficient novel synthetic cycles could be devised. Using the entire repertoire of approximately 5,000 metabolic enzymes known to occur in nature, we computationally identified alternative carbon fixation pathways that combine existing metabolic building blocks from various organisms. We compared the natural and synthetic pathways based on physicochemical criteria that include kinetics, energetics, and topology. Our study suggests that some of the proposed synthetic pathways could have significant quantitative advantages over their natural counterparts, such as the overall kinetic rate. One such cycle, which is predicted to be two to three times faster than the Calvin–Benson cycle, employs the most effective carboxylating enzyme, phosphoenolpyruvate carboxylase, using the core of the naturally evolved C4 cycle. Although implementing such alternative cycles presents daunting challenges related to expression levels, activity, stability, localization, and regulation, we believe our findings suggest exciting avenues of exploration in the grand challenge of enhancing food and renewable fuel production via metabolic engineering and synthetic biology. PMID:20410460

Aromatic sulfonation with sulfur trioxide: mechanism and kinetic model.

PubMed

Moors, Samuel L C; Deraet, Xavier; Van Assche, Guy; Geerlings, Paul; De Proft, Frank

2017-01-01

Electrophilic aromatic sulfonation of benzene with sulfur trioxide is studied with ab initio molecular dynamics simulations in gas phase, and in explicit noncomplexing (CCl 3 F) and complexing (CH 3 NO 2 ) solvent models. We investigate different possible reaction pathways, the number of SO 3 molecules participating in the reaction, and the influence of the solvent. Our simulations confirm the existence of a low-energy concerted pathway with formation of a cyclic transition state with two SO 3 molecules. Based on the simulation results, we propose a sequence of elementary reaction steps and a kinetic model compatible with experimental data. Furthermore, a new alternative reaction pathway is proposed in complexing solvent, involving two SO 3 and one CH 3 NO 2 .

Exploring Robust and Resilient Pathways to Water Security (Invited)

NASA Astrophysics Data System (ADS)

Brown, C. M.

2013-12-01

Lack of water security and the resultant cumulative effects of water-related hazards are understood to hinder economic growth throughout the world. Traditional methods for achieving water security as exemplified in the industrialized world have exerted negative externalities such as degradation of aquatic ecosystems. There is also growing concern that such methods may not be robust to climate variability change. It has been proposed that alternative pathways to water security must be followed in the developing world. However, it is not clear such pathways currently exist and there is an inherent moral hazard in such recommendations. This presentation will present a multidimensional definition of water security, explore the conflict in norms between engineering and ecologically oriented communities, and present a framework synthesizing those norms for assessing and innovating robust and resilient pathways to water security.

Tamoxifen resistance: from cell culture experiments towards novel biomarkers.

PubMed

Nass, Norbert; Kalinski, Thomas

2015-03-01

Tamoxifen is still the most frequently used antiestrogen for the treatment of patients with premenopausal, estrogen receptor positive breast cancer. However, in 20-30% of these cases, tamoxifen therapy fails due to an existing or developing resistance. The prediction of tamoxifen resistance by appropriate biomarker analysis and the development of novel therapies for tamoxifen resistance in premenopausal breast cancer is, therefore, an important goal of ongoing research. Tamoxifen resistance is associated with altered estrogen receptor expression especially on the plasma membrane, including the alternative G-protein coupled receptor GPR-30 (GPER) and estrogen receptor splice products, such as ERα36. Tamoxifen resistant cells often use alternative pathways to promote proliferation in the absence of genomic estrogen signaling. These pathways involve the epidermal growth factor EGF, the inflammation associated transcription factor NF-κB- and the IGF-1 pathway. Tamoxifen resistant mamma carcinoma cell lines are useful models to understand tamoxifen resistance in-vitro and to search for prognostic or predictive biomarkers. Furthermore, such cell lines can be used to identify potential targets for therapy. Copyright © 2015 Elsevier GmbH. All rights reserved.

Prioritizing biological pathways by recognizing context in time-series gene expression data.

PubMed

Lee, Jusang; Jo, Kyuri; Lee, Sunwon; Kang, Jaewoo; Kim, Sun

2016-12-23

The primary goal of pathway analysis using transcriptome data is to find significantly perturbed pathways. However, pathway analysis is not always successful in identifying pathways that are truly relevant to the context under study. A major reason for this difficulty is that a single gene is involved in multiple pathways. In the KEGG pathway database, there are 146 genes, each of which is involved in more than 20 pathways. Thus activation of even a single gene will result in activation of many pathways. This complex relationship often makes the pathway analysis very difficult. While we need much more powerful pathway analysis methods, a readily available alternative way is to incorporate the literature information. In this study, we propose a novel approach for prioritizing pathways by combining results from both pathway analysis tools and literature information. The basic idea is as follows. Whenever there are enough articles that provide evidence on which pathways are relevant to the context, we can be assured that the pathways are indeed related to the context, which is termed as relevance in this paper. However, if there are few or no articles reported, then we should rely on the results from the pathway analysis tools, which is termed as significance in this paper. We realized this concept as an algorithm by introducing Context Score and Impact Score and then combining the two into a single score. Our method ranked truly relevant pathways significantly higher than existing pathway analysis tools in experiments with two data sets. Our novel framework was implemented as ContextTRAP by utilizing two existing tools, TRAP and BEST. ContextTRAP will be a useful tool for the pathway based analysis of gene expression data since the user can specify the context of the biological experiment in a set of keywords. The web version of ContextTRAP is available at http://biohealth.snu.ac.kr/software/contextTRAP .

ALTERNATE ROUTES FOR DRUG DELIVERY TO THE CELL INTERIOR

PubMed Central

Tarragó-Trani, Maria Teresa; Storrie, Brian

2007-01-01

The targeted delivery of drugs to the cell interior can be accomplished by taking advantage of the various receptor-mediated endocytic pathways operating in a particular cell. Among these pathways, the retrograde trafficking pathway from endosomes to the Golgi apparatus, and endoplasmic reticulum is of special importance since it provides a route to deliver drugs bypassing the acid pH, hydrolytic environment of the lysosome. The existence of pathways for drug or antigen delivery to the endoplasmic reticulum and Golgi apparatus has been to a large extent an outcome of research on the trafficking of A/B type-bacterial or plant toxins such as Shiga toxin within the cell. The targeting properties of these toxins reside in their B subunit. In this article we present an overview of the multiplicity of pathways to deliver drugs intracellularly. We highlight the retrograde trafficking pathway illustrated by Shiga toxin and Shiga-like toxin, and the potential role of the B subunit of these toxins as carriers of drugs, antigens and imaging agents. PMID:17669543

Dependence of prevalence of contiguous pathways in proteins on structural complexity.

PubMed

Thayer, Kelly M; Galganov, Jesse C; Stein, Avram J

2017-01-01

Allostery is a regulatory mechanism in proteins where an effector molecule binds distal from an active site to modulate its activity. Allosteric signaling may occur via a continuous path of residues linking the active and allosteric sites, which has been suggested by large conformational changes evident in crystal structures. An alternate possibility is that the signal occurs in the realm of ensemble dynamics via an energy landscape change. While the latter was first proposed on theoretical grounds, increasing evidence suggests that such a control mechanism is plausible. A major difficulty for testing the two methods is the ability to definitively determine that a residue is directly involved in allosteric signal transduction. Statistical Coupling Analysis (SCA) is a method that has been successful at predicting pathways, and experimental tests involving mutagenesis or domain substitution provide the best available evidence of signaling pathways. However, ascertaining energetic pathways which need not be contiguous is far more difficult. To date, simple estimates of the statistical significance of a pathway in a protein remain to be established. The focus of this work is to estimate such benchmarks for the statistical significance of contiguous pathways for the null model of selecting residues at random. We found that when 20% of residues in proteins are randomly selected, contiguous pathways at the 6 Å cutoff level were found with success rates of 51% in PDZ, 30% in p53, and 3% in MutS. The results suggest that the significance of pathways may have system specific factors involved. Furthermore, the possible existence of false positives for contiguous pathways implies that signaling could be occurring via alternate routes including those consistent with the energetic landscape model.

Composition Influences the Pathway but not the Outcome of the Metabolic Response of Bacterioplankton to Resource Shifts

PubMed Central

Comte, Jérôme; del Giorgio, Paul A.

2011-01-01

Bacterioplankton community metabolism is central to the functioning of aquatic ecosystems, and strongly reactive to changes in the environment, yet the processes underlying this response remain unclear. Here we explore the role that community composition plays in shaping the bacterial metabolic response to resource gradients that occur along aquatic ecotones in a complex watershed in Québec. Our results show that the response is mediated by complex shifts in community structure, and structural equation analysis confirmed two main pathways, one involving adjustments in the level of activity of existing phylotypes, and the other the replacement of the dominant phylotypes. These contrasting response pathways were not determined by the type or the intensity of the gradients involved, as we had hypothesized, but rather it would appear that some compositional configurations may be intrinsically more plastic than others. Our results suggest that community composition determines this overall level of community plasticity, but that composition itself may be driven by factors independent of the environmental gradients themselves, such that the response of bacterial communities to a given type of gradient may alternate between the adjustment and replacement pathways. We conclude that community composition influences the pathways of response in these bacterial communities, but not the metabolic outcome itself, which is driven by the environment, and which can be attained through multiple alternative configurations. PMID:21980410

Fast Identification of Biological Pathways Associated with a Quantitative Trait Using Group Lasso with Overlaps

PubMed Central

Silver, Matt; Montana, Giovanni

2012-01-01

Where causal SNPs (single nucleotide polymorphisms) tend to accumulate within biological pathways, the incorporation of prior pathways information into a statistical model is expected to increase the power to detect true associations in a genetic association study. Most existing pathways-based methods rely on marginal SNP statistics and do not fully exploit the dependence patterns among SNPs within pathways. We use a sparse regression model, with SNPs grouped into pathways, to identify causal pathways associated with a quantitative trait. Notable features of our “pathways group lasso with adaptive weights” (P-GLAW) algorithm include the incorporation of all pathways in a single regression model, an adaptive pathway weighting procedure that accounts for factors biasing pathway selection, and the use of a bootstrap sampling procedure for the ranking of important pathways. P-GLAW takes account of the presence of overlapping pathways and uses a novel combination of techniques to optimise model estimation, making it fast to run, even on whole genome datasets. In a comparison study with an alternative pathways method based on univariate SNP statistics, our method demonstrates high sensitivity and specificity for the detection of important pathways, showing the greatest relative gains in performance where marginal SNP effect sizes are small. PMID:22499682

Lower growth temperature increases alternative pathway capacity and alternative oxidase protein in tobacco.

PubMed

Vanlerberghe, G C; McIntosh, L

1992-09-01

Suspension cells of NT1 tobacco (Nicotiana tabacum L. cv bright yellow) have been used to study the effect of growth temperature on the CN-resistant, salicylhydroxamic acid-sensitive alternative pathway of respiration. Mitochondria isolated from cells maintained at 30 degrees C had a low capacity to oxidize succinate via the alternative pathway, whereas mitochondria isolated from cells 24 h after transfer to 18 degrees C displayed, on average, a 5-fold increase in this capacity (from 7 to 32 nanoatoms oxygen per milligram protein per minute). This represented an increase in alternative pathway capacity from 18 to 45% of the total capacity of electron transport. This increased capacity was lost upon transfer of cells back to 30 degrees C. A monoclonal antibody to the terminal oxidase of the alternative pathway (the alternative oxidase) from Sauromatum guttatum (T.E. Elthon, R.L. Nickels, L. McIntosh [1989] Plant Physiology 89: 1311-1317) recognized a 35-kilodalton mitochondrial protein in tobacco. There was an excellent correlation between the capacity of the alternative path in isolated tobacco mitochondria and the levels of this 35-kilodalton alternative oxidase protein. Cycloheximide could inhibit both the increased level of the 35-kilodalton alternative oxidase protein and the increased alternative pathway capacity normally seen upon transfer to 18 degrees C. We conclude that transfer of tobacco cells to the lower temperature increases the capacity of the alternative pathway due, at least in part, to de novo synthesis of the 35-kilodalton alternative oxidase protein.

Deficiency in the mitochondrial apoptotic pathway reveals the toxic potential of autophagy under ER stress conditions.

PubMed

Deegan, Shane; Saveljeva, Svetlana; Logue, Susan E; Pakos-Zebrucka, Karolina; Gupta, Sanjeev; Vandenabeele, Peter; Bertrand, Mathieu J M; Samali, Afshin

2014-01-01

Endoplasmic reticulum (ER) stress-induced cell death is normally associated with activation of the mitochondrial apoptotic pathway, which is characterized by CYCS (cytochrome c, somatic) release, apoptosome formation, and caspase activation, resulting in cell death. In this study, we demonstrate that under conditions of ER stress cells devoid of CASP9/caspase-9 or BAX and BAK1, and therefore defective in the mitochondrial apoptotic pathway, still undergo a delayed form of cell death associated with the activation of caspases, therefore revealing the existence of an alternative stress-induced caspase activation pathway. We identified CASP8/caspase-8 as the apical protease in this caspase cascade, and found that knockdown of either of the key autophagic genes, ATG5 or ATG7, impacted on CASP8 activation and cell death induction, highlighting the crucial role of autophagy in the activation of this novel ER stress-induced death pathway. In line with this, we identified a protein complex composed of ATG5, FADD, and pro-CASP8 whose assembly coincides with caspase activation and cell death induction. Together, our results reveal the toxic potential of autophagy in cells undergoing ER stress that are defective in the mitochondrial apoptotic pathway, and suggest a model in which the autophagosome functions as a platform facilitating pro-CASP8 activation. Chemoresistance, a common problem in the treatment of cancer, is frequently caused by the downregulation of key mitochondrial death effector proteins. Alternate stress-induced apoptotic pathways, such as the one described here, may become of particular relevance for tackling the problem of chemoresistance in cancer cells.

Role of AMACR (α-methylacyl-CoA racemase) and MFE-1 (peroxisomal multifunctional enzyme-1) in bile acid synthesis in mice.

PubMed

Autio, Kaija J; Schmitz, Werner; Nair, Remya R; Selkälä, Eija M; Sormunen, Raija T; Miinalainen, Ilkka J; Crick, Peter J; Wang, Yuqin; Griffiths, William J; Reddy, Janardan K; Baes, Myriam; Hiltunen, J Kalervo

2014-07-01

Cholesterol is catabolized to bile acids by peroxisomal β-oxidation in which the side chain of C27-bile acid intermediates is shortened by three carbon atoms to form mature C24-bile acids. Knockout mouse models deficient in AMACR (α-methylacyl-CoA racemase) or MFE-2 (peroxisomal multifunctional enzyme type 2), in which this β-oxidation pathway is prevented, display a residual C24-bile acid pool which, although greatly reduced, implies the existence of alternative pathways of bile acid synthesis. One alternative pathway could involve Mfe-1 (peroxisomal multifunctional enzyme type 1) either with or without Amacr. To test this hypothesis, we generated a double knockout mouse model lacking both Amacr and Mfe-1 activities and studied the bile acid profiles in wild-type, Mfe-1 and Amacr single knockout mouse line and Mfe-1 and Amacr double knockout mouse lines. The total bile acid pool was decreased in Mfe-1-/- mice compared with wild-type and the levels of mature C24-bile acids were reduced in the double knockout mice when compared with Amacr-deficient mice. These results indicate that Mfe-1 can contribute to the synthesis of mature bile acids in both Amacr-dependent and Amacr-independent pathways.

Lower Growth Temperature Increases Alternative Pathway Capacity and Alternative Oxidase Protein in Tobacco 1

PubMed Central

Vanlerberghe, Greg C.; McIntosh, Lee

1992-01-01

Suspension cells of NT1 tobacco (Nicotiana tabacum L. cv bright yellow) have been used to study the effect of growth temperature on the CN-resistant, salicylhydroxamic acid-sensitive alternative pathway of respiration. Mitochondria isolated from cells maintained at 30°C had a low capacity to oxidize succinate via the alternative pathway, whereas mitochondria isolated from cells 24 h after transfer to 18°C displayed, on average, a 5-fold increase in this capacity (from 7 to 32 nanoatoms oxygen per milligram protein per minute). This represented an increase in alternative pathway capacity from 18 to 45% of the total capacity of electron transport. This increased capacity was lost upon transfer of cells back to 30°C. A monoclonal antibody to the terminal oxidase of the alternative pathway (the alternative oxidase) from Sauromatum guttatum (T.E. Elthon, R.L. Nickels, L. McIntosh [1989] Plant Physiology 89: 1311-1317) recognized a 35-kilodalton mitochondrial protein in tobacco. There was an excellent correlation between the capacity of the alternative path in isolated tobacco mitochondria and the levels of this 35-kilodalton alternative oxidase protein. Cycloheximide could inhibit both the increased level of the 35-kilodalton alternative oxidase protein and the increased alternative pathway capacity normally seen upon transfer to 18°C. We conclude that transfer of tobacco cells to the lower temperature increases the capacity of the alternative pathway due, at least in part, to de novo synthesis of the 35-kilodalton alternative oxidase protein. Images Figure 3 Figure 4 PMID:16652932

Involvement of alternative oxidase in the regulation of sensitivity of Sclerotinia sclerotiorum to the fungicides azoxystrobin and procymidone.

PubMed

Xu, Ting; Wang, Ya-Ting; Liang, Wu-Sheng; Yao, Fei; Li, Yong-Hong; Li, Dian-Rong; Wang, Hao; Wang, Zheng-Yi

2013-06-01

Sclerotinia sclerotiorum is a filamentous fungal pathogen that can infect many economically important crops and vegetables. Alternative oxidase is the terminal oxidase of the alternative respiratory pathway in fungal mitochondria. The function of alternative oxidase was investigated in the regulation of sensitivity of S. sclerotiorum to two commercial fungicides, azoxystrobin and procymidone which have different fungitoxic mechanisms. Two isolates of S. sclerotiorum were sensitive to both fungicides. Application of salicylhydroxamic acid, a specific inhibitor of alternative oxidase, significantly increased the values of effective concentration causing 50% mycelial growth inhibition (EC50) of azoxystrobin to both S. sclerotiorum isolates, whereas notably decreased the EC50 values of procymidone. In mycelial respiration assay azoxystrobin displayed immediate inhibitory effect on cytochrome pathway capacity, but had no immediate effect on alternative pathway capacity. In contrast, procymidone showed no immediate impact on capacities of both cytochrome and alternative pathways in the mycelia. However, alternative oxidase encoding gene (aox) transcript and protein levels, alternative respiration pathway capacity of the mycelia were obviously increased by pre-treatment for 24 h with both azoxystrobin and procymidone. These results indicate that alternative oxidase was involved in the regulation of sensitivity of S. sclerotiorum to the fungicides azoxystrobin and procymidone, and that both fungicides could affect aox gene expression and the alternative respiration pathway capacity development in mycelia of this fungal pathogen.

Genes and proteins of the alternative steroid backdoor pathway for dihydrotestosterone synthesis are expressed in the human ovary and seem enhanced in the polycystic ovary syndrome.

PubMed

Marti, Nesa; Galván, José A; Pandey, Amit V; Trippel, Mafalda; Tapia, Coya; Müller, Michel; Perren, Aurel; Flück, Christa E

2017-02-05

Recently, dihydrotestosterone biosynthesis through the backdoor pathway has been implicated for the human testis in addition to the classic pathway for testosterone (T) synthesis. In the human ovary, androgen precursors are crucial for estrogen synthesis and hyperandrogenism in pathologies such as the polycystic ovary syndrome is partially due to ovarian overproduction. However, a role for the backdoor pathway is only established for the testis and the adrenal, but not for the human ovary. To investigate whether the backdoor pathway exists in normal and PCOS ovaries, we performed specific gene and protein expression studies on ovarian tissues. We found aldo-keto reductases (AKR1C1-1C4), 5α-reductases (SRD5A1/2) and retinol dehydrogenase (RoDH) expressed in the human ovary, indicating that the ovary might produce dihydrotestosterone via the backdoor pathway. Immunohistochemical studies showed specific localization of these proteins to the theca cells. PCOS ovaries show enhanced expression, what may account for the hyperandrogenism. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

t4 Workshop Report

PubMed Central

Silbergeld, Ellen K.; Contreras, Elizabeth Q.; Hartung, Thomas; Hirsch, Cordula; Hogberg, Helena; Jachak, Ashish C.; Jordan, William; Landsiedel, Robert; Morris, Jeffery; Patri, Anil; Pounds, Joel G.; de Vizcaya Ruiz, Andrea; Shvedova, Anna; Tanguay, Robert; Tatarazako, Norihasa; van Vliet, Erwin; Walker, Nigel J.; Wiesner, Mark; Wilcox, Neil; Zurlo, Joanne

2014-01-01

Summary In October 2010, a group of experts met as part of the transatlantic think tank for toxicology (t4) to exchange ideas about the current status and future of safety testing of nanomaterials. At present, there is no widely accepted path forward to assure appropriate and effective hazard identification for engineered nanomaterials. The group discussed needs for characterization of nanomaterials and identified testing protocols that incorporate the use of innovative alternative whole models such as zebrafish or C. elegans, as well as in vitro or alternative methods to examine specific functional pathways and modes of action. The group proposed elements of a potential testing scheme for nanomaterials that works towards an integrated testing strategy, incorporating the goals of the NRC report Toxicity Testing in the 21st Century: A Vision and a Strategy by focusing on pathways of toxic response, and utilizing an evidence-based strategy for developing the knowledge base for safety assessment. Finally, the group recommended that a reliable, open, curated database be developed that interfaces with existing databases to enable sharing of information. PMID:21993959

TRANSAT-- method for detecting the conserved helices of functional RNA structures, including transient, pseudo-knotted and alternative structures.

PubMed

Wiebe, Nicholas J P; Meyer, Irmtraud M

2010-06-24

The prediction of functional RNA structures has attracted increased interest, as it allows us to study the potential functional roles of many genes. RNA structure prediction methods, however, assume that there is a unique functional RNA structure and also do not predict functional features required for in vivo folding. In order to understand how functional RNA structures form in vivo, we require sophisticated experiments or reliable prediction methods. So far, there exist only a few, experimentally validated transient RNA structures. On the computational side, there exist several computer programs which aim to predict the co-transcriptional folding pathway in vivo, but these make a range of simplifying assumptions and do not capture all features known to influence RNA folding in vivo. We want to investigate if evolutionarily related RNA genes fold in a similar way in vivo. To this end, we have developed a new computational method, Transat, which detects conserved helices of high statistical significance. We introduce the method, present a comprehensive performance evaluation and show that Transat is able to predict the structural features of known reference structures including pseudo-knotted ones as well as those of known alternative structural configurations. Transat can also identify unstructured sub-sequences bound by other molecules and provides evidence for new helices which may define folding pathways, supporting the notion that homologous RNA sequence not only assume a similar reference RNA structure, but also fold similarly. Finally, we show that the structural features predicted by Transat differ from those assuming thermodynamic equilibrium. Unlike the existing methods for predicting folding pathways, our method works in a comparative way. This has the disadvantage of not being able to predict features as function of time, but has the considerable advantage of highlighting conserved features and of not requiring a detailed knowledge of the cellular environment.

Thiamin (Vitamin B1) Biosynthesis and Regulation: A Rich Source of Antimicrobial Drug Targets?

PubMed Central

Du, Qinglin; Wang, Honghai; Xie, Jianping

2011-01-01

Drug resistance of pathogens has necessitated the identification of novel targets for antibiotics. Thiamin (vitamin B1) is an essential cofactor for all organisms in its active form thiamin diphosphate (ThDP). Therefore, its metabolic pathways might be one largely untapped source of antibiotics targets. This review describes bacterial thiamin biosynthetic, salvage, and transport pathways. Essential thiamin synthetic enzymes such as Dxs and ThiE are proposed as promising drug targets. The regulation mechanism of thiamin biosynthesis by ThDP riboswitch is also discussed. As drug targets of existing antimicrobial compound pyrithiamin, the ThDP riboswitch might serves as alternative targets for more antibiotics. PMID:21234302

Education Direct: An Alternative Entry Pathway to Pre-Service Teacher Education

ERIC Educational Resources Information Center

Pilkington, Kevin; Lock, Graeme

2012-01-01

Universities in Australia are offering alternative entrance pathways to attract students from a range of backgrounds. These alternative pathways will undoubtedly be reviewed due to the recommendation in the Review of Australian Higher Education (Bradley, Noonan, Nugent & Scales, 2008) concerning increasing the diversity of university entrants.…

Value-Based Payment Reform and the Medicare Access and Children's Health Insurance Program Reauthorization Act of 2015: A Primer for Plastic Surgeons.

PubMed

Squitieri, Lee; Chung, Kevin C

2017-07-01

In 2015, the U.S. Congress passed the Medicare Access and Children's Health Insurance Program Reauthorization Act, which effectively repealed the Centers for Medicare and Medicaid Services sustainable growth rate formula and established the Centers for Medicare and Medicaid Services Quality Payment Program. The Medicare Access and Children's Health Insurance Program Reauthorization Act represents an unparalleled acceleration toward value-based payment models and a departure from traditional volume-driven fee-for-service reimbursement. The Quality Payment Program includes two paths for provider participation: the Merit-Based Incentive Payment System and Advanced Alternative Payment Models. The Merit-Based Incentive Payment System pathway replaces existing quality reporting programs and adds several new measures to create a composite performance score for each provider (or provider group) that will be used to adjust reimbursed payment. The advanced alternative payment model pathway is available to providers who participate in qualifying Advanced Alternative Payment Models and is associated with an initial 5 percent payment incentive. The first performance period for the Merit-Based Incentive Payment System opens January 1, 2017, and closes on December 31, 2017, and is associated with payment adjustments in January of 2019. The Centers for Medicare and Medicaid Services estimates that the majority of providers will begin participation in 2017 through the Merit-Based Incentive Payment System pathway, but aims to have 50 percent of payments tied to quality or value through Advanced Alternative Payment Models by 2018. In this article, the authors describe key components of the Medicare Access and Children's Health Insurance Program Reauthorization Act to providers navigating through the Quality Payment Program and discuss how plastic surgeons may optimize their performance in this new value-based payment program.

Partitioning of electron flux between the respiratory chains of the yeast Candida parapsilosis: parallel working of the two chains.

PubMed

Guerin, M G; Camougrand, N M

1994-02-08

Partitioning of the electron flux between the classical and the alternative respiratory chains of the yeast Candida parapsilosis, was measured as a function of the oxidation rate and of the Q-pool redox poise. At low respiration rate, electrons from external NADH travelled preferentially through the alternative pathway as indicated by the antimycin A-insensitivity of electron flow. Inhibition of the alternative pathway by SHAM restored full antimycin A-sensitivity to the remaining electro flow. The dependence of the respiratory rate on the redox poise of the quinone pool was investigated when the electron flux was mediated either by the main respiratory chain (growth in the absence of antimycin A) or by the second respiratory chain (growth in the presence of antimycin A). In the former case, a linear relationship was found between these two parameters. In contrast, in the latter case, the relationship between Q-pool reduction level and electron flux was non-linear, but it could be resolved into two distinct curves. This second quinone is not reducible in the presence of antimycin A but only in the presence of high concentrations of myxothiazol or cyanide. Since two quinone species exist in C. parapsilosis, UQ9 and Qx (C33H54O4), we hypothesized that these two curves could correspond to the functioning of the second quinone engaged during the alternative pathway activity. Partitioning of electrons between both respiratory chains could occur upstream of complex III with the second chain functioning in parallel to the main one, and with the additional possibility of merging into the main one at the complex IV level.

Cytochrome and Alternative Pathway Respiration in Green Algae 1

PubMed Central

Weger, Harold G.; Guy, Robert D.; Turpin, David H.

1990-01-01

Inhibitor titration curves and discrimination against 18O2 by mitochondrial respiration in three strains of green algae (Selenastrum minutum [Naeg.] Collins, and two strains of Chlamydomonas reinhardtii Dangeard) with differing respiratory capabilities were determined. Discrimination for cytochrome pathway respiration ranged from 19.89 to 20.43%. Discrimination for alternative pathway respiration by wild-type C. reinhardtii (measured in the presence of KCN) was 25.46%, while discrimination values for a cytochrome oxidase deficient mutant of C. reinhardtii ranged from 24.24 to 24.96%. In the absence of KCN, the alternative pathway was not engaged in wild-type C. reinhardtii, the only algal strain that possessed both cytochrome and alternative pathway capacities. PMID:16667462

Estimating environmental co-benefits of U.S. low-carbon pathways using an integrated assessment model with state-level resolution.

PubMed

Ou, Yang; Shi, Wenjing; Smith, Steven J; Ledna, Catherine M; West, J Jason; Nolte, Christopher G; Loughlin, Daniel H

2018-04-15

There are many technological pathways that can lead to reduced carbon dioxide emissions. However, these pathways can have substantially different impacts on other environmental endpoints, such as air quality and energy-related water demand. This study uses an integrated assessment model with state-level resolution of the energy system to compare environmental impacts of alternative low-carbon pathways for the United States. One set of pathways emphasizes nuclear energy and carbon capture and storage, while another set emphasizes renewable energy, including wind, solar, geothermal power, and bioenergy. These are compared with pathways in which all technologies are available. Air pollutant emissions, mortality costs attributable to particulate matter smaller than 2.5 μm in diameter, and energy-related water demands are evaluated for 50% and 80% carbon dioxide reduction targets in 2050. The renewable low-carbon pathways require less water withdrawal and consumption than the nuclear and carbon capture pathways. However, the renewable low-carbon pathways modeled in this study produce higher particulate matter-related mortality costs due to greater use of biomass in residential heating. Environmental co-benefits differ among states because of factors such as existing technology stock, resource availability, and environmental and energy policies.

Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development.

PubMed

Fukami, Maki; Homma, Keiko; Hasegawa, Tomonobu; Ogata, Tsutomu

2013-04-01

We review the current knowledge about the "backdoor" pathway for the biosynthesis of dihydrotestosterone (DHT). While DHT is produced from cholesterol through the conventional "frontdoor" pathway via testosterone, recent studies have provided compelling evidence for the presence of an alternative "backdoor" pathway to DHT without testosterone intermediacy. This backdoor pathway is known to exist in the tammar wallaby pouch young testis and the immature mouse testis, and has been suggested to be present in the human as well. Indeed, molecular analysis has identified pathologic mutations of genes involved in the backdoor pathway in genetic male patients with undermasculinized external genitalia, and urine steroid profile analysis has argued for the relevance of the activated backdoor pathway to abnormal virilization in genetic females with cytochrome P450 oxidoreductase deficiency and 21-hydroxylase deficiency. It is likely that the backdoor pathway is primarily operating in the fetal testis in a physiological condition to produce a sufficient amount of DHT for male sex development, and that the backdoor pathway is driven with a possible interaction between fetal and permanent adrenals in pathologic conditions with increased 17-hydroxyprogesterone levels. These findings provide novel insights into androgen biosynthesis in both physiological and pathological conditions. Copyright © 2012 Wiley Periodicals, Inc., a Wiley company.

Metabolic plasticity for isoprenoid biosynthesis in bacteria.

PubMed

Pérez-Gil, Jordi; Rodríguez-Concepción, Manuel

2013-05-15

Isoprenoids are a large family of compounds synthesized by all free-living organisms. In most bacteria, the common precursors of all isoprenoids are produced by the MEP (methylerythritol 4-phosphate) pathway. The MEP pathway is absent from archaea, fungi and animals (including humans), which synthesize their isoprenoid precursors using the completely unrelated MVA (mevalonate) pathway. Because the MEP pathway is essential in most bacterial pathogens (as well as in the malaria parasites), it has been proposed as a promising new target for the development of novel anti-infective agents. However, bacteria show a remarkable plasticity for isoprenoid biosynthesis that should be taken into account when targeting this metabolic pathway for the development of new antibiotics. For example, a few bacteria use the MVA pathway instead of the MEP pathway, whereas others possess the two full pathways, and some parasitic strains lack both the MVA and the MEP pathways (probably because they obtain their isoprenoids from host cells). Moreover, alternative enzymes and metabolic intermediates to those of the canonical MVA or MEP pathways exist in some organisms. Recent work has also shown that resistance to a block of the first steps of the MEP pathway can easily be developed because several enzymes unrelated to isoprenoid biosynthesis can produce pathway intermediates upon spontaneous mutations. In the present review, we discuss the major advances in our knowledge of the biochemical toolbox exploited by bacteria to synthesize the universal precursors for their essential isoprenoids.

A Method for Finding Metabolic Pathways Using Atomic Group Tracking.

PubMed

Huang, Yiran; Zhong, Cheng; Lin, Hai Xiang; Wang, Jianyi

2017-01-01

A fundamental computational problem in metabolic engineering is to find pathways between compounds. Pathfinding methods using atom tracking have been widely used to find biochemically relevant pathways. However, these methods require the user to define the atoms to be tracked. This may lead to failing to predict the pathways that do not conserve the user-defined atoms. In this work, we propose a pathfinding method called AGPathFinder to find biochemically relevant metabolic pathways between two given compounds. In AGPathFinder, we find alternative pathways by tracking the movement of atomic groups through metabolic networks and use combined information of reaction thermodynamics and compound similarity to guide the search towards more feasible pathways and better performance. The experimental results show that atomic group tracking enables our method to find pathways without the need of defining the atoms to be tracked, avoid hub metabolites, and obtain biochemically meaningful pathways. Our results also demonstrate that atomic group tracking, when incorporated with combined information of reaction thermodynamics and compound similarity, improves the quality of the found pathways. In most cases, the average compound inclusion accuracy and reaction inclusion accuracy for the top resulting pathways of our method are around 0.90 and 0.70, respectively, which are better than those of the existing methods. Additionally, AGPathFinder provides the information of thermodynamic feasibility and compound similarity for the resulting pathways.

A Method for Finding Metabolic Pathways Using Atomic Group Tracking

PubMed Central

Zhong, Cheng; Lin, Hai Xiang; Wang, Jianyi

2017-01-01

A fundamental computational problem in metabolic engineering is to find pathways between compounds. Pathfinding methods using atom tracking have been widely used to find biochemically relevant pathways. However, these methods require the user to define the atoms to be tracked. This may lead to failing to predict the pathways that do not conserve the user-defined atoms. In this work, we propose a pathfinding method called AGPathFinder to find biochemically relevant metabolic pathways between two given compounds. In AGPathFinder, we find alternative pathways by tracking the movement of atomic groups through metabolic networks and use combined information of reaction thermodynamics and compound similarity to guide the search towards more feasible pathways and better performance. The experimental results show that atomic group tracking enables our method to find pathways without the need of defining the atoms to be tracked, avoid hub metabolites, and obtain biochemically meaningful pathways. Our results also demonstrate that atomic group tracking, when incorporated with combined information of reaction thermodynamics and compound similarity, improves the quality of the found pathways. In most cases, the average compound inclusion accuracy and reaction inclusion accuracy for the top resulting pathways of our method are around 0.90 and 0.70, respectively, which are better than those of the existing methods. Additionally, AGPathFinder provides the information of thermodynamic feasibility and compound similarity for the resulting pathways. PMID:28068354

In vitro C3 Deposition on Cryptococcus Capsule Occurs Via Multiple Complement Activation Pathways

PubMed Central

Mershon-Shier, Kileen L.; Vasuthasawat, Alex; Takahashi, Kazue; Morrison, Sherie L.; Beenhouwer, David O.

2011-01-01

Complement can be activated via three pathways: classical, alternative, and lectin. Cryptococcus gattii and C. neoformans are closely related fungal pathogens possessing a polysaccharide capsule composed mainly of glucuronoxylomannan (GXM), which serves as a site for complement activation and deposition of complement components. We determined C3 deposition on Cryptococcus spp. by flow cytometry and confocal microscopy after incubation with serum from C57BL/6J mice as well as mice deficient in complement components C4, C3, factor B, and mannose binding lectin (MBL). C. gattii and C. neoformans activate complement in EGTA-treated serum indicating that they can activate the alternative pathway. However, complement activation was seen with factor B−/− serum suggesting activation could also take place in the absence of a functional alternative pathway. Furthermore, we uncovered a role for C4 in the alternative pathway activation by Cryptococcus spp. We also identified an unexpected and complex role for MBL in complement activation by Cryptococcus spp. No complement activation occurred in the absence of MBL-A and -C proteins although activation took place when the lectin binding activity of MBL was disrupted by calcium chelation. In addition, alternative pathway activation by C. neoformans required both MBL-A and -C, while either MBL-A or -C was sufficient for alternative pathway activation by C. gattii. Thus, complement activation by Cryptococcus spp. can take place through multiple pathways and complement activation via the alternative pathway requires the presence of C4 and MBL proteins. PMID:21723612

Alternative pathway regulation by factor H modulates Streptococcus pneumoniae induced proinflammatory cytokine responses by decreasing C5a receptor crosstalk.

PubMed

van der Maten, Erika; de Bont, Cynthia M; de Groot, Ronald; de Jonge, Marien I; Langereis, Jeroen D; van der Flier, Michiel

2016-12-01

Bacterial pathogens not only stimulate innate immune receptors, but also activate the complement system. Crosstalk between complement C5a receptor (C5aR) and other innate immune receptors is known to enhance the proinflammatory cytokine response. An important determinant of the magnitude of complement activation is the activity of the alternative pathway, which serves as an amplification mechanism for complement activation. Both alternative pathway activity as well as plasma levels of factor H, a key inhibitor of the alternative pathway, show large variation within the human population. Here, we studied the effect of factor H-mediated regulation of the alternative pathway on bacterial-induced proinflammatory cytokine responses. We used the human pathogen Streptococcus pneumoniae as a model stimulus to induce proinflammatory cytokine responses in human peripheral blood mononuclear cells. Serum containing active complement enhanced pneumococcal induced proinflammatory cytokine production through C5a release and C5aR crosstalk. We found that inhibition of the alternative pathway by factor H, with a concentration equivalent to a high physiological level, strongly reduced C5a levels and decreased proinflammatory cytokine production in human peripheral blood mononuclear cells. This suggests that variation in alternative pathway activity due to variation in factor H plasma levels affects individual cytokine responses during infection. Copyright © 2016 Elsevier Ltd. All rights reserved.

Exploring metabolic pathways in genome-scale networks via generating flux modes.

PubMed

Rezola, A; de Figueiredo, L F; Brock, M; Pey, J; Podhorski, A; Wittmann, C; Schuster, S; Bockmayr, A; Planes, F J

2011-02-15

The reconstruction of metabolic networks at the genome scale has allowed the analysis of metabolic pathways at an unprecedented level of complexity. Elementary flux modes (EFMs) are an appropriate concept for such analysis. However, their number grows in a combinatorial fashion as the size of the metabolic network increases, which renders the application of EFMs approach to large metabolic networks difficult. Novel methods are expected to deal with such complexity. In this article, we present a novel optimization-based method for determining a minimal generating set of EFMs, i.e. a convex basis. We show that a subset of elements of this convex basis can be effectively computed even in large metabolic networks. Our method was applied to examine the structure of pathways producing lysine in Escherichia coli. We obtained a more varied and informative set of pathways in comparison with existing methods. In addition, an alternative pathway to produce lysine was identified using a detour via propionyl-CoA, which shows the predictive power of our novel approach. The source code in C++ is available upon request.

Insulation of a synthetic hydrogen metabolism circuit in bacteria

PubMed Central

2010-01-01

Background The engineering of metabolism holds tremendous promise for the production of desirable metabolites, particularly alternative fuels and other highly reduced molecules. Engineering approaches must redirect the transfer of chemical reducing equivalents, preventing these electrons from being lost to general cellular metabolism. This is especially the case for high energy electrons stored in iron-sulfur clusters within proteins, which are readily transferred when two such clusters are brought in close proximity. Iron sulfur proteins therefore require mechanisms to ensure interaction between proper partners, analogous to many signal transduction proteins. While there has been progress in the isolation of engineered metabolic pathways in recent years, the design of insulated electron metabolism circuits in vivo has not been pursued. Results Here we show that a synthetic hydrogen-producing electron transfer circuit in Escherichia coli can be insulated from existing cellular metabolism via multiple approaches, in many cases improving the function of the pathway. Our circuit is composed of heterologously expressed [Fe-Fe]-hydrogenase, ferredoxin, and pyruvate-ferredoxin oxidoreductase (PFOR), allowing the production of hydrogen gas to be coupled to the breakdown of glucose. We show that this synthetic pathway can be insulated through the deletion of competing reactions, rational engineering of protein interaction surfaces, direct protein fusion of interacting partners, and co-localization of pathway components on heterologous protein scaffolds. Conclusions Through the construction and characterization of a synthetic metabolic circuit in vivo, we demonstrate a novel system that allows for predictable engineering of an insulated electron transfer pathway. The development of this system demonstrates working principles for the optimization of engineered pathways for alternative energy production, as well as for understanding how electron transfer between proteins is controlled. PMID:20184755

Agrobacterium Mediated Transient Gene Silencing (AMTS) in Stevia rebaudiana: Insights into Steviol Glycoside Biosynthesis Pathway

PubMed Central

Guleria, Praveen; Yadav, Sudesh Kumar

2013-01-01

Background Steviol glycoside biosynthesis pathway has emerged as bifurcation from ent-kaurenoic acid, substrate of methyl erythritol phosphate pathway that also leads to gibberellin biosynthesis. However, the genetic regulation of steviol glycoside biosynthesis has not been studied. So, in present study RNA interference (RNAi) based Agrobacterium mediated transient gene silencing (AMTS) approach was followed. SrKA13H and three SrUGTs (SrUGT85C2, SrUGT74G1 and SrUGT76G1) genes encoding ent-kaurenoic acid-13 hydroxylase and three UDP glycosyltransferases of steviol glycoside biosynthesis pathway were silenced in Stevia rebaudiana to understand its molecular mechanism and association with gibberellins. Methodology/Principal Findings RNAi mediated AMTS of SrKA13H and three SrUGTs has significantly reduced the expression of targeted endogenous genes as well as total steviol glycoside accumulation. While gibberellins (GA3) content was significantly enhanced on AMTS of SrUGT85C2 and SrKA13H. Silencing of SrKA13H and SrUGT85C2 was found to block the metabolite flux of steviol glycoside pathway and shifted it towards GA3 biosynthesis. Further, molecular docking of three SrUGT proteins has documented highest affinity of SrUGT76G1 for the substrates of alternate pathways synthesizing steviol glycosides. This could be a plausible reason for maximum reduction in steviol glycoside content on silencing of SrUGT76G1 than other genes. Conclusions SrKA13H and SrUGT85C2 were identified as regulatory genes influencing carbon flux between steviol glycoside and gibberellin biosynthesis. This study has also documented the existence of alternate steviol glycoside biosynthesis route. PMID:24023961

Cytochrome and alternative pathway respiration in green algae : measurements using inhibitors and o(2) discrimination.

PubMed

Weger, H G; Guy, R D; Turpin, D H

1990-05-01

Inhibitor titration curves and discrimination against (18)O(2) by mitochondrial respiration in three strains of green algae (Selenastrum minutum [Naeg.] Collins, and two strains of Chlamydomonas reinhardtii Dangeard) with differing respiratory capabilities were determined. Discrimination for cytochrome pathway respiration ranged from 19.89 to 20.43%. Discrimination for alternative pathway respiration by wild-type C. reinhardtii (measured in the presence of KCN) was 25.46%, while discrimination values for a cytochrome oxidase deficient mutant of C. reinhardtii ranged from 24.24 to 24.96%. In the absence of KCN, the alternative pathway was not engaged in wild-type C. reinhardtii, the only algal strain that possessed both cytochrome and alternative pathway capacities.

Dual Catalytic Activity of a Cytochrome P450 Controls Bifurcation at a Metabolic Branch Point of Alkaloid Biosynthesis in Rauwolfia serpentina

PubMed Central

Dang, Thu‐Thuy T.; Franke, Jakob; Tatsis, Evangelos

2017-01-01

Abstract Plants create tremendous chemical diversity from a single biosynthetic intermediate. In plant‐derived ajmalan alkaloid pathways, the biosynthetic intermediate vomilenine can be transformed into the anti‐arrhythmic compound ajmaline, or alternatively, can isomerize to form perakine, an alkaloid with a structurally distinct scaffold. Here we report the discovery and characterization of vinorine hydroxylase, a cytochrome P450 enzyme that hydroxylates vinorine to form vomilenine, which was found to exist as a mixture of rapidly interconverting epimers. Surprisingly, this cytochrome P450 also catalyzes the non‐oxidative isomerization of the ajmaline precursor vomilenine to perakine. This unusual dual catalytic activity of vinorine hydroxylase thereby provides a control mechanism for the bifurcation of these alkaloid pathway branches. This discovery highlights the unusual catalytic functionality that has evolved in plant pathways. PMID:28654178

Dual Catalytic Activity of a Cytochrome P450 Controls Bifurcation at a Metabolic Branch Point of Alkaloid Biosynthesis in Rauwolfia serpentina.

PubMed

Dang, Thu-Thuy T; Franke, Jakob; Tatsis, Evangelos; O'Connor, Sarah E

2017-08-01

Plants create tremendous chemical diversity from a single biosynthetic intermediate. In plant-derived ajmalan alkaloid pathways, the biosynthetic intermediate vomilenine can be transformed into the anti-arrhythmic compound ajmaline, or alternatively, can isomerize to form perakine, an alkaloid with a structurally distinct scaffold. Here we report the discovery and characterization of vinorine hydroxylase, a cytochrome P450 enzyme that hydroxylates vinorine to form vomilenine, which was found to exist as a mixture of rapidly interconverting epimers. Surprisingly, this cytochrome P450 also catalyzes the non-oxidative isomerization of the ajmaline precursor vomilenine to perakine. This unusual dual catalytic activity of vinorine hydroxylase thereby provides a control mechanism for the bifurcation of these alkaloid pathway branches. This discovery highlights the unusual catalytic functionality that has evolved in plant pathways. © 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.

Theorizing a model information pathway to mitigate the menstrual taboo.

PubMed

Yagnik, Arpan

2017-12-13

The impact of menstruation on the society is directly seen in the educational opportunities, quality of life and professional endeavors of females. However, lack of menstrual hygiene management has indirect implication on the balance and development of the society and nation. This study is set in the Indian context. The researcher identifies actors with a potential of mitigating menstrual taboo and then theorizes an optimal information pathway to mitigate menstrual taboo. Diffusion of innovation, framing and agenda setting theories contribute as frameworks in the creation of an optimal pathway to dissolve the menstrual taboo. The actors identified in this model are scholars, health activists, students, NGOs, media, government, corporations and villages or communities. The determinants for the direction and the order of the pathway to diffuse knowledge and confidence among these actors are the ultimate goal and sustainability of the model, strengths and weaknesses of actors, and actors' extent of influence. Considering the absence of an existing alternate, this model pathway provides a solid framework purely from a theoretical perspective. Theoretically, this model pathway is possible, practical and optimal. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Cytochrome and Alternative Pathway Respiration in Tobacco (Effects of Salicylic Acid).

PubMed

Rhoads, D. M.; McIntosh, L.

1993-11-01

In suspension cultures of NT1 tobacco (Nicotiana tabacum L. cv Bright Yellow) cells the cytochrome pathway capacity increased between d 3 and d 4 following subculturing and reached the highest level observed on d 7. The capacity decreased significantly by d 10 and was at the same level on d 14. Both alternative pathway capacity and the amount of the 35-kD alternative oxidase protein increased significantly between d 5 and d 6, reached the highest point observed on d 7, remained constant until d 10, and decreased by d 14. The highest capacities of the alternative and cytochrome pathways and the highest amount of the 35-kD protein were attained on the day that cell cultures reached a stationary phase of growth. Addition of salicylic acid to cell cultures on d 4 caused a significant increase in alternative pathway capacity and a dramatic accumulation of the 35-kD protein by 12 h. The alternative pathway capacity and the protein level reached the highest level observed by 16 h after salicylic acid addition, and the cytochrome pathway capacity was at about the same level at each time point. The accumulation of the 35-kD alternative oxidase protein was significantly decreased by addition of actinomycin D 1 h before salicylic acid and was blocked by addition of cycloheximide. These results indicate that de novo transcription and translation were necessary for salicylic acid to cause the maximum accumulation of the 35-kD protein.

Cytochrome and Alternative Pathway Respiration in Tobacco (Effects of Salicylic Acid).

PubMed Central

Rhoads, D. M.; McIntosh, L.

1993-01-01

In suspension cultures of NT1 tobacco (Nicotiana tabacum L. cv Bright Yellow) cells the cytochrome pathway capacity increased between d 3 and d 4 following subculturing and reached the highest level observed on d 7. The capacity decreased significantly by d 10 and was at the same level on d 14. Both alternative pathway capacity and the amount of the 35-kD alternative oxidase protein increased significantly between d 5 and d 6, reached the highest point observed on d 7, remained constant until d 10, and decreased by d 14. The highest capacities of the alternative and cytochrome pathways and the highest amount of the 35-kD protein were attained on the day that cell cultures reached a stationary phase of growth. Addition of salicylic acid to cell cultures on d 4 caused a significant increase in alternative pathway capacity and a dramatic accumulation of the 35-kD protein by 12 h. The alternative pathway capacity and the protein level reached the highest level observed by 16 h after salicylic acid addition, and the cytochrome pathway capacity was at about the same level at each time point. The accumulation of the 35-kD alternative oxidase protein was significantly decreased by addition of actinomycin D 1 h before salicylic acid and was blocked by addition of cycloheximide. These results indicate that de novo transcription and translation were necessary for salicylic acid to cause the maximum accumulation of the 35-kD protein. PMID:12231986

Businesses Partner with Schools, Community to Create Alternative Career Pathways

ERIC Educational Resources Information Center

Overman, Stephenie

2012-01-01

Business, education and community leaders are working together to create alternative career pathways for young people who are not profiting from the four-year college track. The new Pathways to Prosperity Network brings together the Pathways to Prosperity Project at Harvard Graduate School of Education (HGSE), Jobs for the Future (JFF) and six…

Calcium-independent haemolysis via the lectin pathway of complement activation in the guinea-pig and other *

PubMed Central

Zhang, Y; Suankratay, C; Zhang, X-H; Jones, D R; Lint, T F; Gewurz, H

1999-01-01

We previously reported that complement-dependent haemolysis of sheep erythrocytes (E) coated with mannan (M) and sensitized with human mannan-binding lectin (MBL) via the lectin pathway in man occurs in Mg-EGTA and requires alternative pathway amplification. Calcium was required for MBL binding to E-M, but once the E-M-MBL intermediate was formed, MBL was retained and haemolysis occurred in the absence of calcium. Comparable or greater lectin pathway haemolysis in the absence of calcium was observed upon incubation of E-M-MBL in guinea-pig, rat, dog and pig sera, and was further investigated in the guinea-pig, in which titres were much higher (∼14-fold) than in man, and in contrast to humans, greater than classical pathway haemolytic activity. As in human serum, no lysis was observed in C4- or C2-deficient guinea-pig serum until purified C4 or C2, respectively, were restored. However, lectin pathway haemolytic activity in the guinea-pig did not require the alternative pathway. Removal (>98%) of factor D activity by three sequential passages through Sephadex G-75, resulting in serum which retained a normal classical pathway but no alternative pathway haemolytic activity, did not reduce the ability of guinea-pig serum to mediate haemolysis via the lectin pathway. Further, the C3-convertase formed via the lectin pathway (E-M-MBL-C4,2) lysed in C2-deficient guinea-pig but not human serum chelated with EDTA, a condition which precludes alternative pathway amplification. Thus, lectin pathway haemolysis occurs efficiently in guinea-pig serum, in the absence of calcium and without requirement for alternative pathway amplification. The guinea-pig provides a model for studying the assembly and haemolytic function of a lectin pathway which contrasts with the lectin pathway of man, and allows for comparisons that may help clarify the role of this pathway in complement biology. PMID:10457224

Lifecycle analysis of renewable natural gas and hydrocarbon fuels from wastewater treatment plants’ sludge

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Uisung; Han, Jeongwoo; Urgun Demirtas, Meltem

Wastewater treatment plants (WWTPs) produce sludge as a byproduct when they treat wastewater. In the United States, over 8 million dry tons of sludge are produced annually just from publicly owned WWTPs. Sludge is commonly treated in anaerobic digesters, which generate biogas; the biogas is then largely flared to reduce emissions of methane, a potent greenhouse gas. Because sludge is quite homogeneous and has a high energy content, it is a good potential feedstock for other conversion processes that make biofuels, bioproducts, and power. For example, biogas from anaerobic digesters can be used to generate renewable natural gas (RNG), whichmore » can be further processed to produce compressed natural gas (CNG) and liquefied natural gas (LNG). Sludge can be directly converted into hydrocarbon liquid fuels via thermochemical processes such as hydrothermal liquefaction (HTL). Currently, the environmental impacts of converting sludge into energy are largely unknown, and only a few studies have focused on the environmental impacts of RNG produced from existing anaerobic digesters. As biofuels from sludge generate high interest, however, existing anaerobic digesters could be upgraded to technology with more economic potential and more environmental benefits. The environmental impacts of using a different anaerobic digestion (AD) technology to convert sludge into energy have yet to be analyzed. In addition, no studies are available about the direct conversion of sludge into liquid fuels. In order to estimate the energy consumption and greenhouse gas (GHG) emissions impacts of these alternative pathways (sludge-to-RNG and sludge-to-liquid), this study performed a lifecycle analysis (LCA) using the Greenhouse gases, Regulated Emissions, and Energy use in Transportation (GREET®) model. The energy uses and GHG emissions associated with the RNG and hydrocarbon liquid are analyzed relative to the current typical sludge management case, which consists of a single-stage mesophilic digester with biogas flaring. Along with the alternative HTL process, four types of AD technologies with fuel production—single-stage mesophilic, mesophilic 2-stage, single-stage mesophilic with thermohydrolysis treatment, and mesophilicmesophilic acid/gas phase—are studied. Results show that the sludge-to-CNG pathway via AD and the sludge-to-liquid pathway via HTL reduce GHG emissions consumptions significantly. When we compare the GHG emissions of the alternative fuel production pathways to that of the counterfactual case in terms of the amount of sludge treated, reductions in GHG emissions are 39%–80% and 87% for alternative AD and HTL, respectively. Compared to petroleum gasoline and diesel GHG emission results in terms of MJ, the renewable CNG production pathway via AD and the renewable diesel production pathway via HTL reduce GHG emissions by 193% and 46%, respectively. These large reductions are mainly due to GHG credits from avoiding GHGs under the counterfactual scenario, and/or fertilizer displacement credits. Similarly, reductions in fossil fuel use for sludge-based fuels are huge. However, well-defined counterfactual scenarios are needed because the results of the study depend on the counterfactual scenario, which might vary over time.« less

Shifting from clonal to sexual reproduction in aphids: physiological and developmental aspects.

PubMed

Le Trionnaire, Gaël; Hardie, Jim; Jaubert-Possamai, Stéphanie; Simon, Jean-Christophe; Tagu, Denis

2008-08-01

Developmental biology is one of the fastest growing and fascinating research fields in life sciences. Among the wide range of embryonic development, a fundamental difference exists between organisms with sexual or asexual development. Aphids are unusual organisms which display alternative pathways of sexual and asexual development, the orientation of the pathway being determined by environmental conditions. These insects offer an adapted system in which to study developmental plasticity, because a side-by-side comparison of sexual and asexual development can be made in individuals with the same genotype. In this review, we describe the developmental mechanisms that have evolved in aphids for alternative sexual and asexual reproduction. In particular, we discuss how environmental cues orientate the reproductive mode of aphids from signal perception to endocrine regulation, and propose a comparative analysis of sexual and asexual gametogenesis and embryogenesis, which has been possible due to the development of molecular methods. As a result of the recent development of genomic resources in aphids, we expect these species will permit major advances in the study of the genomic basis underlying the choice of developmental fate and multiple reproduction strategies.

The costs of production of alternative jet fuel: A harmonized stochastic assessment.

PubMed

Bann, Seamus J; Malina, Robert; Staples, Mark D; Suresh, Pooja; Pearlson, Matthew; Tyner, Wallace E; Hileman, James I; Barrett, Steven

2017-03-01

This study quantifies and compares the costs of production for six alternative jet fuel pathways using consistent financial and technical assumptions. Uncertainty was propagated through the analysis using Monte Carlo simulations. The six processes assessed were HEFA, advanced fermentation, Fischer-Tropsch, aqueous phase processing, hydrothermal liquefaction, and fast pyrolysis. The results indicate that none of the six processes would be profitable in the absence of government incentives, with HEFA using yellow grease, HEFA using tallow, and FT revealing the lowest mean jet fuel prices at $0.91/liter ($0.66/liter-$1.24/liter), $1.06/liter ($0.79/liter-$1.42/liter), and $1.15/liter ($0.95/liter-$1.39/liter), respectively. This study also quantifies plant performance in the United States with a Renewable Fuel Standard policy analysis. Results indicate that some pathways could achieve positive NPV with relatively high likelihood under existing policy supports, with HEFA and FPH revealing the highest probability of positive NPV at 94.9% and 99.7%, respectively, in the best-case scenario. Copyright © 2016 Elsevier Ltd. All rights reserved.

TGFβ1-mediated PI3K/Akt and p38 MAP kinase dependent alternative splicing of fibronectin extra domain A in human podocyte culture.

PubMed

Madne, Tarunkumar Hemraj; Dockrell, Mark Edward Carl

2018-04-30

Alternative splicing is an important gene regulation process to distribute proteins in health and diseases. Extra Domain A+ Fibronectin (EDA+Fn) is an alternatively spliced form of fibronectin (Fn) protein, present in the extra cellular matrix (ECM) and a recognised marker of various pathologies. TGFβ1 has been shown to induce alternative splicing of EDA+Fn in many cell types. Podocytes are spectacular cell type and play a key role in filtration and synthesise ECM proteins in renal physiology and pathology. In our previous study we have demonstrated expression and alternative splicing of EDA+Fn in basal condition in human podocytes culture. TGFβ1 further induced the basal expression and alternative splicing of EDA+Fn through Alk5 receptor and SR proteins. In this study, we have investigated TGFβ1 mediated signalling involved in alternative splicing of EDA+Fn in human podocytes. We have performed western blotting to characterise the expression of the EDA+Fn protein and other signalling proteins and RT-PCR to look for signalling pathways involved in regulation of alternative splicing of EDA+Fn in conditionally immortalised human podocytes culture.We have used TGFβ1 as a stimulator and SB431542, SB202190 and LY294002 for inhibitory studies. In this work, we have demonstrated in human podocytes culture TGFβ1 2.5ng/ml induced phosphorylation of Smad1/5/8, Smad2 and Smad3 via the ALK5 receptor. TGFβ1 significantly induced the PI3K/Akt pathway and the PI3K/Akt pathway inhibitor LY294002 significantly downregulated basal as well as TGFβ1 induced alternative splicing of EDA+Fn in human podocytes. In addition to this, TGFβ1 significantly induced the p38 MAP kinase signalling pathway and p38 MAP kinase signalling pathway inhibitor SB202190 downregulated the TGFβ1-mediated alternative splicing of EDA+Fn in human podocytes. The results with PI3K and p38 MAP kinase signalling pathway suggest that inhibiting PI3K signalling pathway downregulated the basal alternative splicing of EDA+Fn in human podocytes and its the inhibition of p38 Map Kinase signalling pathway which had specifically downregulated the TGFβ1 mediated alternative splicing of EDA+Fn in human podocytes culture. Activation of TGFβ1-mediated Smad1/5/8 via Alk5 receptor suggests that TGFβ1 signalling pathway involved Alk5/Alk1 receptor axis signalling in human podocytes.

Alternative Routes to Teacher Certification. Occasional Paper Series 20

ERIC Educational Resources Information Center

Silin, Jonathan G., Ed.; Snyder, Jon; Barry, Miranda; Samuels, Sarah; Sacks, Ariel; Ellenzweig, Allen

2008-01-01

Alternative routes to teacher preparation are clearly here to stay. A growing research literature on non-traditional pathways suggests the complexity of the task ahead. This report offers new teachers the opportunity to tell their own stories in their own words. In "Alternative Certification and Alternative Pathways: A Personal Take on a Core…

Supramolecular organization of cytochrome c oxidase- and alternative oxidase-dependent respiratory chains in the filamentous fungus Podospora anserina.

PubMed

Krause, Frank; Scheckhuber, Christian Q; Werner, Alexandra; Rexroth, Sascha; Reifschneider, Nicole H; Dencher, Norbert A; Osiewacz, Heinz D

2004-06-18

To elucidate the molecular basis of the link between respiration and longevity, we have studied the organization of the respiratory chain of a wild-type strain and of two long-lived mutants of the filamentous fungus Podospora anserina. This established aging model is able to respire by either the standard or the alternative pathway. In the latter pathway, electrons are directly transferred from ubiquinol to the alternative oxidase and thus bypass complexes III and IV. We show that the cytochrome c oxidase pathway is organized according to the mammalian "respirasome" model (Schägger, H., and Pfeiffer, K. (2000) EMBO J. 19, 1777-1783). In contrast, the alternative pathway is composed of distinct supercomplexes of complexes I and III (i.e. I(2) and I(2)III(2)), which have not been described so far. Enzymatic analysis reveals distinct functional properties of complexes I and III belonging to either cytochrome c oxidase- or alternative oxidase-dependent pathways. By a gentle colorless-native PAGE, almost all of the ATP synthases from mitochondria respiring by either pathway were preserved in the dimeric state. Our data are of significance for the understanding of both respiratory pathways as well as lifespan control and aging.

Unbalanced Activation of Glutathione Metabolic Pathways Suggests Potential Involvement in Plant Defense against the Gall Midge Mayetiola destructor in Wheat

PubMed Central

Liu, Xuming; Zhang, Shize; Whitworth, R. Jeff; Stuart, Jeffrey J.; Chen, Ming-Shun

2015-01-01

Glutathione, γ-glutamylcysteinylglycine, exists abundantly in nearly all organisms. Glutathione participates in various physiological processes involved in redox reactions by serving as an electron donor/acceptor. We found that the abundance of total glutathione increased up to 60% in resistant wheat plants within 72 hours following attack by the gall midge Mayetiola destructor, the Hessian fly. The increase in total glutathione abundance, however, is coupled with an unbalanced activation of glutathione metabolic pathways. The activity and transcript abundance of glutathione peroxidases, which convert reduced glutathione (GSH) to oxidized glutathione (GSSG), increased in infested resistant plants. However, the enzymatic activity and transcript abundance of glutathione reductases, which convert GSSG back to GSH, did not change. This unbalanced regulation of the glutathione oxidation/reduction cycle indicates the existence of an alternative pathway to regenerate GSH from GSSG to maintain a stable GSSG/GSH ratio. Our data suggest the possibility that GSSG is transported from cytosol to apoplast to serve as an oxidant for class III peroxidases to generate reactive oxygen species for plant defense against Hessian fly larvae. Our results provide a foundation for elucidating the molecular processes involved in glutathione-mediated plant resistance to Hessian fly and potentially other pests as well. PMID:25627558

[Regulation effects of short sunlight on two electron transport pathways in nectarine flower bud during dormancy induction].

PubMed

Li, Dong-Mei; Zhang, Hai-Sen; Tan, Qiu-Ping; Li, Ling; Yu, Qin; Gao, Dong-Sheng

2011-11-01

Taking the nectarine variety 'Shuguang' (Prunus persica var. nectariana cv. Shuguang) as test material, and by using respiration inhibitors KCN and SHAM, this paper studied the cytochrome electron transport pathway and the alternative respiration pathway in nectarine flower bud during dormancy induction under the effects of short sunlight. Both the total respiration rate (V(t)) and the cytochrome electron transport pathway respiration rate (rho' V(cyt)) presented double hump-shaped variation. Short sunlight brought the first-hump of V(t) and rho' V(cyt), forward and delayed the second-hump synchronously, inhibited the rho' V(cyt), but had no significant effects on the V(t). The capacity (V(alt)) and activity (rho V (alt)) of alternative respiration pathway also varied in double hump-shape, and the variation was basically in synchronous. Short sunlight made the first climax of V(alt) and rhoV(alt) advanced, but had little effects on the later period climax. The inhibition of cytochrome electron transport pathway and the enhancement of alternative respiration pathway were the important features of nectarine flower bud during dormancy induction, and according to the respective contributions of the two electron transport pathways to the total respiration rate, the cytochrome electron transport pathway was still the main pathway of electron transport, whereas the alternative respiration pathway played an auxiliary and branched role.

Alternative splicing regulation in tumor necrosis factor-mediated inflammation.

PubMed

López-Urrutia, Eduardo; Campos-Parra, Alma; Herrera, Luis Alonso; Pérez-Plasencia, Carlos

2017-11-01

It is generally accepted that alternative splicing has an effect on disease when it leads to conspicuous changes in relevant proteins, but that the combinatorial effect of several small modifications can have marked outcomes as well. Inflammation is a complex process involving numerous signaling pathways, among which the tumor necrosis factor (TNF) pathway is one of the most studied. Signaling pathways are commonly represented as intricate cascades of molecular interactions that eventually lead to the activation of one or several genes. Alternative splicing is a common means of controlling protein expression in time and space; therefore, it can modulate the outcome of signaling pathways through small changes in their elements. Notably, the overall process is tightly regulated, which is easily overlooked when analyzing the pathway as a whole. The present review summarizes recent studies of the alternative splicing of key players of the TNF pathway leading to inflammation, and hypothesizes on the cumulative results of those modifications and the impact on cancer development.

Alternative splicing regulation in tumor necrosis factor-mediated inflammation

PubMed Central

López-Urrutia, Eduardo; Campos-Parra, Alma; Herrera, Luis Alonso; Pérez-Plasencia, Carlos

2017-01-01

It is generally accepted that alternative splicing has an effect on disease when it leads to conspicuous changes in relevant proteins, but that the combinatorial effect of several small modifications can have marked outcomes as well. Inflammation is a complex process involving numerous signaling pathways, among which the tumor necrosis factor (TNF) pathway is one of the most studied. Signaling pathways are commonly represented as intricate cascades of molecular interactions that eventually lead to the activation of one or several genes. Alternative splicing is a common means of controlling protein expression in time and space; therefore, it can modulate the outcome of signaling pathways through small changes in their elements. Notably, the overall process is tightly regulated, which is easily overlooked when analyzing the pathway as a whole. The present review summarizes recent studies of the alternative splicing of key players of the TNF pathway leading to inflammation, and hypothesizes on the cumulative results of those modifications and the impact on cancer development. PMID:29113151

2,3-Butanediol Production by Acetogenic Bacteria, an Alternative Route to Chemical Synthesis, Using Industrial Waste Gas ▿ †

PubMed Central

Köpke, Michael; Mihalcea, Christophe; Liew, FungMin; Tizard, Joseph H.; Ali, Mohammed S.; Conolly, Joshua J.; Al-Sinawi, Bakir; Simpson, Séan D.

2011-01-01

2,3-Butanediol (23BD) is a high-value chemical usually produced petrochemically but which can also be synthesized by some bacteria. To date, the best microbial 23BD production rates have been observed using pathogenic bacteria in fermentation systems that depend on sugars as the carbon and energy sources for product synthesis. Here we present evidence of 23BD production by three nonpathogenic acetogenic Clostridium species—Clostridium autoethanogenum, C. ljungdahlii, and C. ragsdalei—using carbon monoxide-containing industrial waste gases or syngas as the sole source of carbon and energy. Through an analysis of the C. ljungdahlii genome, the complete pathway from carbon monoxide to 23BD has been proposed. Homologues of the genes involved in this pathway were also confirmed for the other two species investigated. A gene expression study demonstrates a correlation between mRNA accumulation from 23BD biosynthetic genes and the onset of 23BD production, while a broader expression study of Wood-Ljungdahl pathway genes provides a transcription-level view of one of the oldest existing biochemical pathways. PMID:21685168

Small-molecule factor D inhibitors selectively block the alternative pathway of complement in paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome.

PubMed

Yuan, Xuan; Gavriilaki, Eleni; Thanassi, Jane A; Yang, Guangwei; Baines, Andrea C; Podos, Steven D; Huang, Yongqing; Huang, Mingjun; Brodsky, Robert A

2017-03-01

Paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome are diseases of excess activation of the alternative pathway of complement that are treated with eculizumab, a humanized monoclonal antibody against the terminal complement component C5. Eculizumab must be administered intravenously, and moreover some patients with paroxysmal nocturnal hemoglobinuria on eculizumab have symptomatic extravascular hemolysis, indicating an unmet need for additional therapeutic approaches. We report the activity of two novel small-molecule inhibitors of the alternative pathway component Factor D using in vitro correlates of both paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. Both compounds bind human Factor D with high affinity and effectively inhibit its proteolytic activity against purified Factor B in complex with C3b. When tested using the traditional Ham test with cells from paroxysmal nocturnal hemoglobinuria patients, the Factor D inhibitors significantly reduced complement-mediated hemolysis at concentrations as low as 0.01 μM. Additionally the compound ACH-4471 significantly decreased C3 fragment deposition on paroxysmal nocturnal hemoglobinuria erythrocytes, indicating a reduced potential relative to eculizumab for extravascular hemolysis. Using the recently described modified Ham test with serum from patients with atypical hemolytic uremic syndrome, the compounds reduced the alternative pathway-mediated killing of PIGA -null reagent cells, thus establishing their potential utility for this disease of alternative pathway of complement dysregulation and validating the modified Ham test as a system for pre-clinical drug development for atypical hemolytic uremic syndrome. Finally, ACH-4471 blocked alternative pathway activity when administered orally to cynomolgus monkeys. In conclusion, the small-molecule Factor D inhibitors show potential as oral therapeutics for human diseases driven by the alternative pathway of complement, including paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. Copyright© Ferrata Storti Foundation.

A Method of Accounting for Enzyme Costs in Flux Balance Analysis Reveals Alternative Pathways and Metabolite Stores in an Illuminated Arabidopsis Leaf.

PubMed

Cheung, C Y Maurice; Ratcliffe, R George; Sweetlove, Lee J

2015-11-01

Flux balance analysis of plant metabolism is an established method for predicting metabolic flux phenotypes and for exploring the way in which the plant metabolic network delivers specific outcomes in different cell types, tissues, and temporal phases. A recurring theme is the need to explore the flexibility of the network in meeting its objectives and, in particular, to establish the extent to which alternative pathways can contribute to achieving specific outcomes. Unfortunately, predictions from conventional flux balance analysis minimize the simultaneous operation of alternative pathways, but by introducing flux-weighting factors to allow for the variable intrinsic cost of supporting each flux, it is possible to activate different pathways in individual simulations and, thus, to explore alternative pathways by averaging thousands of simulations. This new method has been applied to a diel genome-scale model of Arabidopsis (Arabidopsis thaliana) leaf metabolism to explore the flexibility of the network in meeting the metabolic requirements of the leaf in the light. This identified alternative flux modes in the Calvin-Benson cycle revealed the potential for alternative transitory carbon stores in leaves and led to predictions about the light-dependent contribution of alternative electron flow pathways and futile cycles in energy rebalancing. Notable features of the analysis include the light-dependent tradeoff between the use of carbohydrates and four-carbon organic acids as transitory storage forms and the way in which multiple pathways for the consumption of ATP and NADPH can contribute to the balancing of the requirements of photosynthetic metabolism with the energy available from photon capture. © 2015 American Society of Plant Biologists. All Rights Reserved.

Seasonal induction of alternative principal pathway for rose flower scent

PubMed Central

Hirata, Hiroshi; Ohnishi, Toshiyuki; Tomida, Kensuke; Ishida, Haruka; Kanda, Momoyo; Sakai, Miwa; Yoshimura, Jin; Suzuki, Hideyuki; Ishikawa, Takamasa; Dohra, Hideo; Watanabe, Naoharu

2016-01-01

Ecological adaptations to seasonal changes are often observed in the phenotypic traits of plants and animals, and these adaptations are usually expressed through the production of different biochemical end products. In this study, ecological adaptations are observed in a biochemical pathway without alteration of the end products. We present an alternative principal pathway to the characteristic floral scent compound 2-phenylethanol (2PE) in roses. The new pathway is seasonally induced in summer as a heat adaptation that uses rose phenylpyruvate decarboxylase (RyPPDC) as a novel enzyme. RyPPDC transcript levels and the resulting production of 2PE are increased time-dependently under high temperatures. The novel summer pathway produces levels of 2PE that are several orders of magnitude higher than those produced by the previously known pathway. Our results indicate that the alternative principal pathway identified here is a seasonal adaptation for managing the weakened volatility of summer roses. PMID:26831950

GM-CSF in murine psoriasiform dermatitis: Redundant and pathogenic roles uncovered by antibody-induced neutralization and genetic deficiency

PubMed Central

Scholz, Tatjana; Weigert, Andreas; Brüne, Bernhard; Sadik, Christian D.; Böhm, Beate

2017-01-01

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pleiotropic, Th17-derived cytokine thought to critically contribute to the pathogenesis of diverse autoimmune diseases, including rheumatoid arthritis and psoriasis. Treatment with monoclonal antibodies that block GM-CSF activity is associated with favorable therapeutic effects in patients with rheumatoid arthritis. We evaluated the role of GM-CSF as a potential target for therapeutic interference in psoriasis using a combined pharmacologic and genetic approach and the mouse model of imiquimod-induced psoriasiform dermatitis (IMQPD). Neutralization of murine GM-CSF by an anti-GM-CSF antibody ameliorated IMQPD. In contrast, genetic deficiency in GM-CSF did not alter the course of IMQPD, suggesting the existence of mechanisms compensating for chronic, but not acute, absence of GM-CSF. Further investigation uncovered an alternative pathogenic pathway for IMQPD in the absence of GM-CSF characterized by an expanded plasmacytoid dendritic cell population and release of IFNα and IL-22. This pathway was not activated in wild-type mice during short-term anti-GM-CSF treatment. Our investigations support the potential value of GM-CSF as a therapeutic target in psoriatic disease. The discovery of an alternative pathogenic pathway for psoriasiform dermatitis in the permanent absence of GM-CSF, however, suggests the need for monitoring during therapeutic use of long-term GM-CSF blockade. PMID:28777803

Alternative Certification Pathways: Filling a Gap?

ERIC Educational Resources Information Center

Ludlow, Carlyn

2013-01-01

The purpose of this article is to examine the proliferation of alternative certification pathways through an analysis of the role and history of teacher certification and supply followed by a synthesis of national, regional, and state research studies on alternative routes to certification programs and a review of studies conducted on well-known…

Effect of gravity on vertical eye position.

PubMed

Pierrot-Deseilligny, C

2009-05-01

There is growing evidence that gravity markedly influences vertical eye position and movements. A new model for the organization of brainstem upgaze pathways is presented in this review. The crossing ventral tegmental tract (CVTT) could be the efferent tract of an "antigravitational" pathway terminating at the elevator muscle motoneurons in the third nerve nuclei and comprising, upstream, the superior vestibular nucleus and y-group, the flocculus, and the otoliths. This pathway functions in parallel to the medial longitudinal fasciculus pathways, which control vertical eye movements made to compensate for all vertical head movements and may also comprise the "gravitational" vestibular pathways, involved in the central reflection of the gravity effect. The CVTT could provide the upgaze system with the supplement of tonic activity required to counteract the gravity effect expressed in the gravitational pathway, being permanently modulated according to the static positions of the head (i.e., the instantaneous gravity vector) between a maximal activity in the upright position and a minimal activity in horizontal positions. Different types of arguments support this new model. The permanent influence of gravity on vertical eye position is strongly suggested by the vertical slow phases and nystagmus observed after rapid changes in hypo- or hypergravity. The chin-beating nystagmus, existing in normal subjects with their head in the upside-down position, suggests that gravity is not compensated for in the downgaze system. Upbeat nystagmus due to brainstem lesions, most likely affecting the CVTT circuitry, is improved when the head is in the horizontal position, suggesting that this circuitry is involved in the counteraction of gravity between the upright and horizontal positions of the head. In downbeat nystagmus due to floccular damage, in which a permanent hyperexcitation of the CVTT could exist, a marked influence of static positions of the head is also observed. Finally, the strongest argument supporting a marked role of gravity in vertical eye position is that the eye movement alterations observed in the main, typical physiological and pathological conditions are precisely those that would be expected from a direct effect of gravity on the eyeballs, with, moreover, no single alternative interpretation existing so far that could account for all these different types of findings.

Regulation of alternative splicing by the circadian clock and food related cues

PubMed Central

2012-01-01

Background The circadian clock orchestrates daily rhythms in metabolism, physiology and behaviour that allow organisms to anticipate regular changes in their environment, increasing their adaptation. Such circadian phenotypes are underpinned by daily rhythms in gene expression. Little is known, however, about the contribution of post-transcriptional processes, particularly alternative splicing. Results Using Affymetrix mouse exon-arrays, we identified exons with circadian alternative splicing in the liver. Validated circadian exons were regulated in a tissue-dependent manner and were present in genes with circadian transcript abundance. Furthermore, an analysis of circadian mutant Vipr2-/- mice revealed the existence of distinct physiological pathways controlling circadian alternative splicing and RNA binding protein expression, with contrasting dependence on Vipr2-mediated physiological signals. This view was corroborated by the analysis of the effect of fasting on circadian alternative splicing. Feeding is an important circadian stimulus, and we found that fasting both modulates hepatic circadian alternative splicing in an exon-dependent manner and changes the temporal relationship with transcript-level expression. Conclusions The circadian clock regulates alternative splicing in a manner that is both tissue-dependent and concurrent with circadian transcript abundance. This adds a novel temporal dimension to the regulation of mammalian alternative splicing. Moreover, our results demonstrate that circadian alternative splicing is regulated by the interaction between distinct physiological cues, and illustrates the capability of single genes to integrate circadian signals at different levels of regulation. PMID:22721557

Backbone N xH compounds at high pressures

DOE PAGES

Goncharov, Alexander F.; Holtgrewe, Nicholas; Qian, Guangrui; ...

2015-06-05

Optical and synchrotron x-ray diffraction diamond anvil cell experiments have been combined with first principles theoretical structure predictions to investigate mixtures of N 2 and H 2 up to 55 GPa. Our experiments show the formation of structurally complex van der Waals compounds above 10 GPa. However, we found that these N xH (0.52, H 2, and NH 3 above approximately 40 GPa. Lastly, our results suggest new pathways for synthesis of environmentally benign high energy-density materials. These materials could also exist as alternative planetary ices.

Arginine decarboxylase (ADC) and agmatinase (AGMAT): an alternative pathway for synthesis of polyamines in pig conceptuses and uteri

USDA-ARS?s Scientific Manuscript database

Arginine, a precursor for the synthesis of nitric oxide (NO) and polyamines, is critical for implantation and development of the conceptus. We first reported that the arginine decarboxylase (ADC)/agmatinase(AGMAT) pathway as an alternative pathway for synthesis of polyamines in the ovine conceptuses...

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hiser, C.; Herdies, L.; McIntosh, L.

Higher plant mitochondria posses a cyanide-resistant, hydroxamate-sensitive alternative pathway of electron transport that does not conserve energy. Aging of potato tuber slices for 24 hours leads to the development of an alternative pathway capacity. We have shown that a monoclonal antibody raised against the alternative pathway terminal oxidase of Sauromatum guttatum crossreacts with a protein of similar size in aged potato slice mitochondria. This protein was partially purified and characterized by two-dimensional gel electrophoresis, and its relative levels parallel the rise in cyanide-resistant respiration. We are using a putative clone of the S. guttatum alternative oxidase gene to isolate themore » equivalent gene from potato and to examine its expression.« less

PathwaySplice: An R package for unbiased pathway analysis of alternative splicing in RNA-Seq data.

PubMed

Yan, Aimin; Ban, Yuguang; Gao, Zhen; Chen, Xi; Wang, Lily

2018-04-24

Pathway analysis of alternative splicing would be biased without accounting for the different number of exons or junctions associated with each gene, because genes with higher number of exons or junctions are more likely to be included in the "significant" gene list in alternative splicing. We present PathwaySplice, an R package that (1) Performs pathway analysis that explicitly adjusts for the number of exons or junctions associated with each gene; (2) Visualizes selection bias due to different number of exons or junctions for each gene and formally tests for presence of bias using logistic regression; (3) Supports gene sets based on the Gene Ontology terms, as well as more broadly defined gene sets (e.g. MSigDB) or user defined gene sets; (4) Identifies the significant genes driving pathway significance and (5) Organizes significant pathways with an enrichment map, where pathways with large number of overlapping genes are grouped together in a network graph. https://bioconductor.org/packages/release/bioc/html/PathwaySplice.html. lily.wangg@gmail.com, xi.steven.chen@gmail.com.

SASD: the Synthetic Alternative Splicing Database for identifying novel isoform from proteomics

PubMed Central

2013-01-01

Background Alternative splicing is an important and widespread mechanism for generating protein diversity and regulating protein expression. High-throughput identification and analysis of alternative splicing in the protein level has more advantages than in the mRNA level. The combination of alternative splicing database and tandem mass spectrometry provides a powerful technique for identification, analysis and characterization of potential novel alternative splicing protein isoforms from proteomics. Therefore, based on the peptidomic database of human protein isoforms for proteomics experiments, our objective is to design a new alternative splicing database to 1) provide more coverage of genes, transcripts and alternative splicing, 2) exclusively focus on the alternative splicing, and 3) perform context-specific alternative splicing analysis. Results We used a three-step pipeline to create a synthetic alternative splicing database (SASD) to identify novel alternative splicing isoforms and interpret them at the context of pathway, disease, drug and organ specificity or custom gene set with maximum coverage and exclusive focus on alternative splicing. First, we extracted information on gene structures of all genes in the Ensembl Genes 71 database and incorporated the Integrated Pathway Analysis Database. Then, we compiled artificial splicing transcripts. Lastly, we translated the artificial transcripts into alternative splicing peptides. The SASD is a comprehensive database containing 56,630 genes (Ensembl gene IDs), 95,260 transcripts (Ensembl transcript IDs), and 11,919,779 Alternative Splicing peptides, and also covering about 1,956 pathways, 6,704 diseases, 5,615 drugs, and 52 organs. The database has a web-based user interface that allows users to search, display and download a single gene/transcript/protein, custom gene set, pathway, disease, drug, organ related alternative splicing. Moreover, the quality of the database was validated with comparison to other known databases and two case studies: 1) in liver cancer and 2) in breast cancer. Conclusions The SASD provides the scientific community with an efficient means to identify, analyze, and characterize novel Exon Skipping and Intron Retention protein isoforms from mass spectrometry and interpret them at the context of pathway, disease, drug and organ specificity or custom gene set with maximum coverage and exclusive focus on alternative splicing. PMID:24267658

The training of a 'stone doctor'.

PubMed

Talati, Jamsheer J

2012-09-01

To propose alternative models of training for doctors treating patients with stones, and to identify their relative value, as such doctors are trained through urology programmes which sometimes cannot be expanded to meet the need, are short of teachers, too comprehensive and lengthy. This review explores new pathways for training to provide competence in the care of patients with stones. Previous reports were identified and existing training models collectively categorised as Model 1. Three alternative models were constructed and compared in the context of advantages, acceptability, feasibility, educational impact and applicability in different geosocio-political contexts. In Model 2, urological and stone training diverge as options after common basic courses and experience. In Model 3, individuals access training through a common educational matrix (EM) for nurses, physicians, etc., according to the match between their capacities, entry requirements, personal desires and willingness for further responsibility. Stone doctors with no urological background cannot fulfil other service and educational commitments, and might create unwelcome dependence on other colleagues for complex situations. Programmes involving a common EM affect professional boundaries and are not easily acceptable. There is a lack of clarity on methods for medical certification and re-certification. However, the lack of technically competent stone experts in developing worlds requires an exploration of alternative models of training and practice. The ability to provide exemplary care after abbreviated training makes alternative models attractive. Worldwide debate, further exploration and pilot implementation are required, perhaps first in the developing world, in which much of the 'stone belt' exists.

Isoflurane is a suitable alternative to ether for anesthetizing rats prior to euthanasia for gene expression analysis.

PubMed

Nakatsu, Noriyuki; Igarashi, Yoshinobu; Aoshi, Taiki; Hamaguchi, Isao; Saito, Masumichi; Mizukami, Takuo; Momose, Haruka; Ishii, Ken J; Yamada, Hiroshi

2017-01-01

Diethyl ether (ether) had been widely used in Japan for anesthesia, despite its explosive properties and toxicity to both humans and animals. We also had used ether as an anesthetic for euthanizing rats for research in the Toxicogenomics Project (TGP). Because the use of ether for these purposes will likely cease, it is required to select an alternative anesthetic which is validated for consistency with existing TGP data acquired under ether anesthesia. We therefore compared two alternative anesthetic candidates, isoflurane and pentobarbital, with ether in terms of hematological findings, serum biochemical parameters, and gene expressions. As a result, few differences among the three agents were observed. In hematological and serum biochemistry analysis, no significant changes were found. In gene expression analysis, four known genes were extracted as differentially expressed genes in the liver of rats anesthetized with ether, isoflurane, or pentobarbital. However, no significant relationships were detected using gene ontology, pathway, or gene enrichment analyses by DAVID and TargetMine. Surprisingly, although it was expected that the lung would be affected by administration via inhalation, only one differentially expressed gene was extracted in the lung. Taken together, our data indicate that there are no significant differences among ether, isoflurane, and pentobarbital with respect to effects on hematological parameters, serum biochemistry parameters, and gene expression. Based on its smallest affect to existing data and its safety profile for humans and animals, we suggest isoflurane as a suitable alternative anesthetic for use in rat euthanasia in toxicogenomics analysis.

COS Spectroscopy of White Dwarf Companions to Blue Stragglers

NASA Astrophysics Data System (ADS)

Gosnell, Natalie M.; Geller, Aaron M.; Knigge, Christian; Mathieu, Robert D.; Sills, Alison; Leiner, Emily; Leigh, Nathan

2017-01-01

Complete membership studies of open stellar clusters reveal that 25% of the evolved stars follow alternative pathways in stellar evolution, meaning something in the history of these stars changed their composition or mass (or both). In order to draw a complete picture of stellar evolution we must include these canonically "strange" stars in our definition of standard stellar populations. The formation mechanism of blue straggler stars, traditionally defined to be brighter and bluer than the main sequence turnoff in a star cluster, has been an outstanding question for almost six decades. Recent Hubble Space Telescope (HST) far-ultraviolet (far-UV) observations directly reveal that the blue straggler stars in the old (7 Gyr) open cluster NGC 188 are predominantly formed through mass transfer. We will present HST far-UV COS spectroscopy of white dwarf companions to blue stragglers. These white dwarfs are the remnants of the mass transfer formation process. The effective temperatures and surface gravities of the white dwarfs delineate the timeline of blue straggler formation in this cluster. The existence of these binaries in a well-studied cluster environment provides an unprecedented opportunity to observationally constrain mass transfer models and inform our understanding of many other alternative pathway stellar products.

Repair of Double-Strand Breaks by End Joining

PubMed Central

Chiruvella, Kishore K.; Liang, Zhuobin; Wilson, Thomas E.

2013-01-01

Nonhomologous end joining (NHEJ) refers to a set of genome maintenance pathways in which two DNA double-strand break (DSB) ends are (re)joined by apposition, processing, and ligation without the use of extended homology to guide repair. Canonical NHEJ (c-NHEJ) is a well-defined pathway with clear roles in protecting the integrity of chromosomes when DSBs arise. Recent advances have revealed much about the identity, structure, and function of c-NHEJ proteins, but many questions exist regarding their concerted action in the context of chromatin. Alternative NHEJ (alt-NHEJ) refers to more recently described mechanism(s) that repair DSBs in less-efficient backup reactions. There is great interest in defining alt-NHEJ more precisely, including its regulation relative to c-NHEJ, in light of evidence that alt-NHEJ can execute chromosome rearrangements. Progress toward these goals is reviewed. PMID:23637284

21 CFR 866.5320 - Properdin factor B immuno-logical test system.

Code of Federal Regulations, 2012 CFR

2012-04-01

... involvement of the alternative to the classical pathway of activation of complement (a group of plasma... the skin). Other diseases in which the alternate pathway of complement activation has been implicated...

21 CFR 866.5320 - Properdin factor B immuno-logical test system.

Code of Federal Regulations, 2014 CFR

2014-04-01

... involvement of the alternative to the classical pathway of activation of complement (a group of plasma... the skin). Other diseases in which the alternate pathway of complement activation has been implicated...

21 CFR 866.5320 - Properdin factor B immuno-logical test system.

Code of Federal Regulations, 2013 CFR

2013-04-01

... involvement of the alternative to the classical pathway of activation of complement (a group of plasma... the skin). Other diseases in which the alternate pathway of complement activation has been implicated...

Evidence-based process for decision-making in the analysis of legal demands for medicines in Brazil.

PubMed

Figueiredo, Tatiana Aragão; Osorio-de-Castro, Claudia Garcia Serpa; Pepe, Vera Lúcia Edais

2013-11-01

Legal actions have been playing a significant role as an alternative pathway to access to medicines in Brazil. These lawsuits demand medicines used in Primary Health Care as well as medicines that are still in clinical research and have not been market approved by the Brazilian National Agency for Sanitary Surveillance (ANVISA). The goal was to analyze medicines demanded through lawsuits brought to the judicial district which includes the city of Rio de Janeiro, Brazil, from July/2007 to June/2008. The medicines in 281 lawsuits were examined for their respective indications, classified according to their presence in publicly-funded lists, market approval by ANVISA, compliance with national clinical guidelines, existence of alternative therapies in lists and support of indication by scientific evidence. Six different categories were described, which are deemed useful to managers and the Judiciary in decision-making. The support of evidence is of utmost importance for medicines that are not included in public funding lists and also for those with no available therapeutic alternatives.

Estimating environmental co-benefits of U.S. low-carbon pathways using an integrated assessment model with state-level resolution

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ou, Yang; Shi, Wenjing; Smith, Steven J.

There are many technological pathways that can lead to reduced carbon dioxide (CO 2) emissions. However, these pathways can have substantially different impacts on other environmental endpoints, such as air quality and energy-related water demand. This study uses an integrated assessment model with state-level resolution of the U.S. energy system to compare environmental impacts of alternative low-carbon pathways. One set of pathways emphasizes nuclear energy and carbon capture and storage (NUC/CCS), while another set emphasizes renewable energy (RE). These are compared with pathways in which all technologies are available. Air pollutant emissions, mortality costs attributable to particulate matter less thanmore » 2.5 microns in diameter (PM2.5), and energy-related water demands are evaluated for 50% and 80% CO 2 reduction targets in the U.S. in 2050. The RE low-carbon pathways require less water withdrawal and consumption than the NUC/CCS pathways because of the large cooling demands of nuclear power and CCS. However, the NUC/CCS low-carbon pathways produce greater health benefits, mainly because the NUC/CCS assumptions result in less primary PM2.5 emissions from residential wood combustion. Environmental co-benefits differ among states because of factors such as existing technology stock, resource availability, and environmental and energy policies. An important finding is that biomass in the building sector can offset some of the health co-benefits of the low-carbon pathways even though it plays only a minor role in reducing CO 2 emissions.« less

A European perspective on alternatives to animal testing for environmental hazard identification and risk assessment.

PubMed

Scholz, Stefan; Sela, Erika; Blaha, Ludek; Braunbeck, Thomas; Galay-Burgos, Malyka; García-Franco, Mauricio; Guinea, Joaquin; Klüver, Nils; Schirmer, Kristin; Tanneberger, Katrin; Tobor-Kapłon, Marysia; Witters, Hilda; Belanger, Scott; Benfenati, Emilio; Creton, Stuart; Cronin, Mark T D; Eggen, Rik I L; Embry, Michelle; Ekman, Drew; Gourmelon, Anne; Halder, Marlies; Hardy, Barry; Hartung, Thomas; Hubesch, Bruno; Jungmann, Dirk; Lampi, Mark A; Lee, Lucy; Léonard, Marc; Küster, Eberhard; Lillicrap, Adam; Luckenbach, Till; Murk, Albertinka J; Navas, José M; Peijnenburg, Willie; Repetto, Guillermo; Salinas, Edward; Schüürmann, Gerrit; Spielmann, Horst; Tollefsen, Knut Erik; Walter-Rohde, Susanne; Whale, Graham; Wheeler, James R; Winter, Matthew J

2013-12-01

Tests with vertebrates are an integral part of environmental hazard identification and risk assessment of chemicals, plant protection products, pharmaceuticals, biocides, feed additives and effluents. These tests raise ethical and economic concerns and are considered as inappropriate for assessing all of the substances and effluents that require regulatory testing. Hence, there is a strong demand for replacement, reduction and refinement strategies and methods. However, until now alternative approaches have only rarely been used in regulatory settings. This review provides an overview on current regulations of chemicals and the requirements for animal tests in environmental hazard and risk assessment. It aims to highlight the potential areas for alternative approaches in environmental hazard identification and risk assessment. Perspectives and limitations of alternative approaches to animal tests using vertebrates in environmental toxicology, i.e. mainly fish and amphibians, are discussed. Free access to existing (proprietary) animal test data, availability of validated alternative methods and a practical implementation of conceptual approaches such as the Adverse Outcome Pathways and Integrated Testing Strategies were identified as major requirements towards the successful development and implementation of alternative approaches. Although this article focusses on European regulations, its considerations and conclusions are of global relevance. Copyright © 2013 Elsevier Inc. All rights reserved.

Discontinuation of dialysis with eculizumab therapy in a pediatric patient with dense deposit disease.

PubMed

Tran, Cheryl L; Sethi, Sanjeev; Murray, David; Cramer, Carl H; Sas, David J; Willrich, Maria; Smith, Richard J; Fervenza, Fernando C

2016-04-01

Dense deposit disease (DDD) is a rare glomerular disease caused by an uncontrolled activation of the alternative complement pathway leading to end-stage renal disease in 50 % of patients. As such, DDD has been classified within the spectrum of complement component 3 (C3) glomerulopathies due to its pathogenesis from alternative pathway dysregulation. Conventional immunosuppressive therapies have no proven effectiveness. Eculizumab, a terminal complement inhibitor, has been reported to mitigate disease in some cases. We report on the efficacy of eculizumab in a pediatric patient who failed to respond to cyclophosphamide, corticosteroids, and plasma exchange. Complement biomarker profiling was remarkable for low serum C3, low properdin, and elevated soluble C5b-9. Consistent with these findings, the alternative pathway functional assay was abnormally low, indicative of alternative pathway activity, although neither C3-nephritic factors nor Factor H autoantibodies were detected. Eculizumab therapy was associated with significant improvement in proteinuria and renal function allowing discontinuation of hemodialysis (HD). Repeat C3 and soluble C5b-9 levels normalized, showing that terminal complement pathway activity was successfully blocked while the patient was receiving eculizumab therapy. Repeat testing for alternative pathway activation allowed for a successful decrease in eculizumab dosing. The case reported here demonstrates the successful recovery of renal function in a pediatric patient on HD following the use of eculizumab.

Diabetic Neuropathy: Update on Pathophysiological Mechanism and the Possible Involvement of Glutamate Pathways.

PubMed

Hussain, Nadia; Adrian, Thomas E

2017-01-01

Diabetic neuropathy is a common complication of diabetes. It adversely affects the lives of most diabetics. It is the leading cause of non-traumatic limb amputation. Diabetic autonomic neuropathy can target any system and increases morbidity and mortality. Treatment begins with adequate glycemic control but despite this, many patients go on to develop neuropathy which suggests there are additional and unidentified, as yet, pathological mechanisms in place. Although several theories exist, the exact mechanisms are not yet established. Disease modifying treatment requires a more complete understanding of the mechanisms of disease. Pathways Involved: This review discusses the potential pathological mechanisms of diabetic neuropathy, including the polyol pathway, hexosamine pathway, protein kinase C, advanced glycation end product formation, polyADP ribose polymerase, and the role of oxidative stress, inflammation, growth factors and lipid abnormalities. Finally it focuses on how possible changes in glutamate signaling pathways fit into the current theories. Insights into the mechanisms involving gene expression in diabetic neuropathy can help pinpoint genes with altered expression. This will help in the development of novel alternative therapeutic strategies to significantly slow the progression of neuropathy in susceptible individuals and perhaps even prevention. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Out of sight but not out of mind: alternative means of communication in plants.

PubMed

Gagliano, Monica; Renton, Michael; Duvdevani, Nili; Timmins, Matthew; Mancuso, Stefano

2012-01-01

Current knowledge suggests that the mechanisms by which plants communicate information take numerous forms. Previous studies have focussed their attention on communication via chemicals, contact and light; other methods of interaction between plants have remained speculative. In this study we tested the ability of young chilli plants to sense their neighbours and identify their relatives using alternative mechanism(s) to recognised plant communication pathways. We found that the presence of a neighbouring plant had a significant influence on seed germination even when all known sources of communication signals were blocked. Furthermore, despite the signalling restriction, seedlings allocated energy to their stem and root systems differently depending on the identity of the neighbour. These results provide clear experimental evidence for the existence of communication channels between plants beyond those that have been recognized and studied thus far.

Chaperonin GroEL-GroES Functions as both Alternating and Non-Alternating Engines.

PubMed

Yamamoto, Daisuke; Ando, Toshio

2016-07-31

A double ring-shaped GroEL consisting of 14 ATPase subunits assists protein folding, together with co-chaperonin GroES. The dynamic GroEL-GroES interaction is actively involved in the chaperonin reaction. Therefore, revealing this dynamic interaction is a key to understanding the operation principle of GroEL. Nevertheless, how this interaction proceeds in the reaction cycle has long been controversial. Here, we directly imaged GroEL-GroES interaction in the presence of disulfide-reduced α-lactalbumin as a substrate protein using high-speed atomic force microscopy. This real-time imaging revealed the occurrence of primary, symmetric GroEL:GroES2 and secondary, asymmetric GroEL:GroES1 complexes. Remarkably, the reaction was observed to often branch into main and side pathways. In the main pathway, alternate binding and release of GroES occurs at the two rings, indicating tight cooperation between the two rings. In the side pathway, however, this cooperation is disrupted, resulting in the interruption of alternating rhythm. From various properties observed for both pathways, we provide mechanistic insight into the alternate and non-alternate operations of the two-engine system. Copyright © 2016 Elsevier Ltd. All rights reserved.

An Alternative Avenue to Teacher Certification: A Cost Analysis of the Pathways to Teaching Careers Program.

ERIC Educational Resources Information Center

Rice, Jennifer King; Brent, Brian O.

2002-01-01

Analyzes cost effectiveness of the Pathways to Teaching Careers, a program that supports an alternative route to university-based teacher certification primarily for noncertified teachers, paraprofessionals, and Peace Corps volunteers. (PKP)

An Exportin-1–dependent microRNA biogenesis pathway during human cell quiescence

PubMed Central

Martinez, Ivan; Hayes, Karen E.; Barr, Jamie A.; Harold, Abby D.; Xie, Mingyi; Bukhari, Syed I. A.; Vasudevan, Shobha; Steitz, Joan A.; DiMaio, Daniel

2017-01-01

The reversible state of proliferative arrest known as “cellular quiescence” plays an important role in tissue homeostasis and stem cell biology. By analyzing the expression of miRNAs and miRNA-processing factors during quiescence in primary human fibroblasts, we identified a group of miRNAs that are induced during quiescence despite markedly reduced expression of Exportin-5, a protein required for canonical miRNA biogenesis. The biogenesis of these quiescence-induced miRNAs is independent of Exportin-5 and depends instead on Exportin-1. Moreover, these quiescence-induced primary miRNAs (pri-miRNAs) are modified with a 2,2,7-trimethylguanosine (TMG)-cap, which is known to bind Exportin-1, and knockdown of Exportin-1 or trimethylguanosine synthase 1, responsible for (TMG)-capping, inhibits their biogenesis. Surprisingly, in quiescent cells Exportin-1–dependent pri-miR-34a is present in the cytoplasm together with a small isoform of Drosha, implying the existence of a different miRNA processing pathway in these cells. Our findings suggest that during quiescence the canonical miRNA biogenesis pathway is down-regulated and specific miRNAs are generated by an alternative pathway to regulate genes involved in cellular growth arrest. PMID:28584122

Presence or Absence of mlr Genes and Nutrient Concentrations Co-Determine the Microcystin Biodegradation Efficiency of a Natural Bacterial Community

PubMed Central

Lezcano, María Ángeles; Morón-López, Jesús; Agha, Ramsy; López-Heras, Isabel; Nozal, Leonor; Quesada, Antonio; El-Shehawy, Rehab

2016-01-01

The microcystin biodegradation potential of a natural bacterial community coexisting with a toxic cyanobacterial bloom was investigated in a water reservoir from central Spain. The biodegradation capacity was confirmed in all samples during the bloom and an increase of mlrA gene copies was found with increasing microcystin concentrations. Among the 24 microcystin degrading strains isolated from the bacterial community, only 28% showed presence of mlrA gene, strongly supporting the existence and abundance of alternative microcystin degradation pathways in nature. In vitro degradation assays with both mlr+ and mlr− bacterial genotypes (with presence and absence of the complete mlr gene cluster, respectively) were performed with four isolated strains (Sphingopyxis sp. IM-1, IM-2 and IM-3; Paucibacter toxinivorans IM-4) and two bacterial degraders from the culture collection (Sphingosinicella microcystinivorans Y2; Paucibacter toxinivorans 2C20). Differences in microcystin degradation efficiencies between genotypes were found under different total organic carbon and total nitrogen concentrations. While mlr+ strains significantly improved microcystin degradation rates when exposed to other carbon and nitrogen sources, mlr− strains showed lower degradation efficiencies. This suggests that the presence of alternative carbon and nitrogen sources possibly competes with microcystins and impairs putative non-mlr microcystin degradation pathways. Considering the abundance of the mlr− bacterial population and the increasing frequency of eutrophic conditions in aquatic systems, further research on the diversity of this population and the characterization and conditions affecting non-mlr degradation pathways deserves special attention. PMID:27827872

Differential mechanisms of complement-mediated neutralization of the closely related paramyxoviruses simian virus 5 and mumps virus

DOE Office of Scientific and Technical Information (OSTI.GOV)

Johnson, John B.; Capraro, Gerald A.; Parks, Griffith D.

2008-06-20

The complement system is an important component of the innate immune response to virus infection. The role of human complement pathways in the in vitro neutralization of three closely related paramyxoviruses, Simian Virus 5 (SV5), Mumps virus (MuV) and Human Parainfluenza virus type 2 (HPIV2) was investigated. Sera from ten donors showed high levels of neutralization against HPIV2 that was largely complement-independent, whereas nine of ten donor sera were found to neutralize SV5 and MuV only in the presence of active complement pathways. SV5 and MuV neutralization proceeded through the alternative pathway of the complement cascade. Electron microscopy studies andmore » biochemical analyses showed that treatment of purified SV5 with human serum resulted in C3 deposition on virions and the formation of massive aggregates, but there was relatively little evidence of virion lysis. Treatment of MuV with human serum also resulted in C3 deposition on virions, however in contrast to SV5, MuV particles were lysed by serum complement and there was relatively little aggregation. Assays using serum depleted of complement factors showed that SV5 and MuV neutralization in vitro was absolutely dependent on complement factor C3, but was not dependent on downstream complement factors C5 or C8. Our results indicate that even though antibodies exist that recognize both SV5 and MuV, they are mostly non-neutralizing and viral inactivation in vitro occurs through the alternative pathway of complement. The implications of our work for development of paramyxovirus vectors and vaccines are discussed.« less

Revealing the Bacterial Butyrate Synthesis Pathways by Analyzing (Meta)genomic Data

PubMed Central

Vital, Marius; Howe, Adina Chuang

2014-01-01

ABSTRACT Butyrate-producing bacteria have recently gained attention, since they are important for a healthy colon and when altered contribute to emerging diseases, such as ulcerative colitis and type II diabetes. This guild is polyphyletic and cannot be accurately detected by 16S rRNA gene sequencing. Consequently, approaches targeting the terminal genes of the main butyrate-producing pathway have been developed. However, since additional pathways exist and alternative, newly recognized enzymes catalyzing the terminal reaction have been described, previous investigations are often incomplete. We undertook a broad analysis of butyrate-producing pathways and individual genes by screening 3,184 sequenced bacterial genomes from the Integrated Microbial Genome database. Genomes of 225 bacteria with a potential to produce butyrate were identified, including many previously unknown candidates. The majority of candidates belong to distinct families within the Firmicutes, but members of nine other phyla, especially from Actinobacteria, Bacteroidetes, Fusobacteria, Proteobacteria, Spirochaetes, and Thermotogae, were also identified as potential butyrate producers. The established gene catalogue (3,055 entries) was used to screen for butyrate synthesis pathways in 15 metagenomes derived from stool samples of healthy individuals provided by the HMP (Human Microbiome Project) consortium. A high percentage of total genomes exhibited a butyrate-producing pathway (mean, 19.1%; range, 3.2% to 39.4%), where the acetyl-coenzyme A (CoA) pathway was the most prevalent (mean, 79.7% of all pathways), followed by the lysine pathway (mean, 11.2%). Diversity analysis for the acetyl-CoA pathway showed that the same few firmicute groups associated with several Lachnospiraceae and Ruminococcaceae were dominating in most individuals, whereas the other pathways were associated primarily with Bacteroidetes. PMID:24757212

Isolation and purification of C3 from human plasma.

PubMed

O'Rear, L D; Ross, G D

2001-05-01

The alternative pathway of complement shares its terminal components (C3 and C5 through 9) with the classical pathway, but has several unique components, including factors D, B, and P (properdin). This unit presents methods for assaying total alternative pathway activity and the activity of factors B and D. Radial immunodiffusion (RID) can also be used to measure factor D, B, and P concentrations.

Alteration of respiration capacity and transcript accumulation level of alternative oxidase genes in necrosis lines of common wheat.

PubMed

Sugie, Atsushi; Murai, Koji; Takumi, Shigeo

2007-06-01

Mitochondrial alternative oxidase (AOX) is the terminal oxidase responsible for cyanide-insensitive and salicylhydroxamic acid-sensitive respiration in plants. AOX is a key enzyme of the alternative respiration pathway. To study the effects of necrotic cell death on the mitochondrial function, production of reactive oxygen species (ROS), respiration capacities and accumulation patterns of mitochondria-targeted protein-encoding gene transcripts were compared between wild-type, lesion-mimic mutant and hybrid necrosis wheat plants. Around cells with the necrosis symptom, ROS accumulated abundantly in the intercellular spaces. The ratio of the alternative pathway to the cytochrome pathway was markedly enhanced in the necrotic leaves. Transcripts of a wheat AOX gene, Waox1a, were more abundant in a novel lesion-mimic mutant of common wheat than in the wild-type plants. An increased level of the Waox1a transcripts was also observed in hybrid plants containing Ne1 and Ne2 genes. These results indicated that an increase of the wheat AOX transcript level resulted in enhancement of respiration capacity of the alternative pathway in the necrotic cells.

Alternative Splicing in the Hippo Pathway—Implications for Disease and Potential Therapeutic Targets

PubMed Central

Porazinski, Sean; Ladomery, Michael

2018-01-01

Alternative splicing is a well-studied gene regulatory mechanism that produces biological diversity by allowing the production of multiple protein isoforms from a single gene. An involvement of alternative splicing in the key biological signalling Hippo pathway is emerging and offers new therapeutic avenues. This review discusses examples of alternative splicing in the Hippo pathway, how deregulation of these processes may contribute to disease and whether these processes offer new potential therapeutic targets. PMID:29534050

Construction of an alternative glycerol-utilization pathway for improved β-carotene production in Escherichia coli.

PubMed

Guo, Jin-Ying; Hu, Kun-Le; Bi, Chang-Hao; Li, Qing-Yan; Zhang, Xue-Li

2018-05-11

Glycerol, which is an inevitable by-product of biodiesel production, is an ideal carbon source for the production of carotenoids due to its low price, good availability and chemically reduced status, which results in a low requirement for additional reducing equivalents. In this study, an alternative carbon-utilization pathway was constructed in Escherichia coli to enable more efficient β-carotene production from glycerol. An aldehyde reductase gene (alrd) and an aldehyde dehydrogenase gene (aldH) from Ralstonia eutropha H16 were integrated into the E. coli chromosome to form a novel glycerol-utilization pathway. The β-carotene specific production value was increased by 50% after the introduction of alrd and aldH. It was found that the glycerol kinase gene (garK), alrd and aldH were the bottleneck of the alternative glycerol metabolic pathway, and modulation of garK gene with an mRS library further increased the β-carotene specific production value by 13%. Finally, co-modulation of genes in the introduced aldH-alrd operon led to 86% more of β-carotene specific production value than that of the strain without the alternative glycerol-utilization pathway and the glycerol-utilization rate was also increased. In this work, β-carotene production of E. coli was significantly improved by constructing and optimizing an alternative glycerol-utilization pathway. This strategy can potentially be used to improve the production of other isoprenoids using glycerol as a cheap and abundant substrate, and therefore has industrial relevance.

Bioprospecting and evolving alternative xylose and arabinose pathway enzymes for use in Saccharomyces cerevisiae.

PubMed

Lee, Sun-Mi; Jellison, Taylor; Alper, Hal S

2016-03-01

Bioprospecting is an effective way to find novel enzymes from strains with desirable phenotypes. Such bioprospecting has enabled organisms such as Saccharomyces cerevisiae to utilize nonnative pentose sugars. Yet, the efficiency of this pentose catabolism (especially for the case of arabinose) remains suboptimal. Thus, further pathway optimization or identification of novel, optimal pathways is needed. Previously, we identified a novel set of xylan catabolic pathway enzymes from a superior pentose-utilizing strain of Ustilago bevomyces. These enzymes were used to successfully engineer a xylan-utilizing S. cerevisiae through a blended approach of bioprospecting and evolutionary engineering. Here, we expanded this approach to xylose and arabinose catabolic pathway engineering and demonstrated that bioprospected xylose and arabinose catabolic pathways from U. bevomyces offer alternative choices for enabling efficient pentose catabolism in S. cerevisiae. By introducing a novel set of xylose catabolic genes from U. bevomyces, growth rates were improved up to 85 % over a set of traditional Scheffersomyces stipitis pathway genes. In addition, we suggested an alternative arabinose catabolic pathway which, after directed evolution and pathway engineering, enabled S. cerevisiae to grow on arabinose as a sole carbon source in minimal medium with growth rates upwards of 0.05 h(-1). This pathway represents the most efficient growth of yeast on pure arabinose minimal medium. These pathways provide great starting points for further strain development and demonstrate the utility of bioprospecting from U. bevomyces.

Energy sources, self-organization, and the origin of life.

PubMed

Boiteau, Laurent; Pascal, Robert

2011-02-01

The emergence and early developments of life are considered from the point of view that contingent events that inevitably marked evolution were accompanied by deterministic driving forces governing the selection between different alternatives. Accordingly, potential energy sources are considered for their propensity to induce self-organization within the scope of the chemical approach to the origin of life. Requirements in terms of quality of energy locate thermal or photochemical activation in the atmosphere as highly likely processes for the formation of activated low-molecular weight organic compounds prone to induce biomolecular self-organization through their ability to deliver quanta of energy matching the needs of early biochemical pathways or the reproduction of self-replicating entities. These lines of reasoning suggest the existence of a direct connection between the free energy content of intermediates of early pathways and the quanta of energy delivered by available sources of energy.

A New Look at the Impact of Maximizing on Unhappiness: Two Competing Mediating Effects

PubMed Central

Peng, Jiaxi; Zhang, Jiaxi; Zhang, Yan; Gong, Pinjia; Han, Bing; Sun, Hao; Cao, Fei; Miao, Danmin

2018-01-01

The current study aims to explore how the decision-making style of maximizing affects subjective well-being (SWB), which mainly focuses on the confirmation of the mediator role of regret and suppressing role of achievement motivation. A total of 402 Chinese undergraduate students participated in this study, in which they responded to the maximization, regret, and achievement motivation scales and SWB measures. Results suggested that maximizing significantly predicted SWB. Moreover, regret and achievement motivation (hope for success dimension) could completely mediate and suppress this effect. That is, two competing indirect pathways exist between maximizing and SWB. One pathway is through regret. Maximizing typically leads one to regret, which could negatively predict SWB. Alternatively, maximizing could lead to high levels of hope for success, which were positively correlated with SWB. Findings offered a complex method of thinking about the relationship between maximizing and SWB. PMID:29467694

Growth of organic crystals via attachment and transformation of nanoscopic precursors

NASA Astrophysics Data System (ADS)

Jiang, Yuan; Kellermeier, Matthias; Gebaue, Denis; Lu, Zihao; Rosenberg, Rose; Moise, Adrian; Przybylski, Michael; Cölfen, Helmut

2017-06-01

A key requirement for the understanding of crystal growth is to detect how new layers form and grow at the nanoscale. Multistage crystallization pathways involving liquid-like, amorphous or metastable crystalline precursors have been predicted by theoretical work and have been observed experimentally. Nevertheless, there is no clear evidence that any of these precursors can also be relevant for the growth of crystals of organic compounds. Herein, we present a new growth mode for crystals of DL-glutamic acid monohydrate that proceeds through the attachment of preformed nanoscopic species from solution, their subsequent decrease in height at the surface and final transformation into crystalline 2D nuclei that eventually build new molecular layers by further monomer incorporation. This alternative mechanism provides a direct proof for the existence of multistage pathways in the crystallization of molecular compounds and the relevance of precursor units larger than the monomeric constituents in the actual stage of growth.

Review: transport of tRNA out of the nucleus-direct channeling to the ribosome?

PubMed

Grosshans, H; Simos, G; Hurt, E

2000-04-01

Although tRNA was the first substrate whose export from the nuclei of eukaryotic cells had been shown to be carrier-mediated and active, it has only been in the last 2 years that the first mechanistic details of this nucleocytoplasmic transport pathway have begun to emerge. A member of the importin/karyopherin beta superfamily, Los1p in yeast and Xpo-t in vertebrates, has been shown to export tRNA in cooperation with the small GTPase Ran (Gsp1p) from the nucleus into the cytoplasm, where tRNA becomes available for translation. However, Los1p is not essential for viability in yeast cells, suggesting that alternative tRNA export pathways exist. Recent results show that aminoacylation and a translation factor are also required for efficient nuclear tRNA export. Thus, protein translation and nuclear export of tRNA appear to be coupled processes. Copyright 2000 Academic Press.

Reduced mycorrhizal colonization (rmc) tomato mutant lacks expression of SymRK signaling pathway genes

PubMed Central

Nair, Aswathy; Bhargava, Sujata

2012-01-01

Comparison of the expression of 13 genes involved in arbuscular mycorrhizal (AM) symbiosis was performed in a wild type tomato (Solanum lycopersicum cv 76R) and its reduced mycorrhizal colonization mutant rmc in response to colonization with Glomus fasiculatum. Four defense-related genes were induced to a similar extent in the mutant and wild type AM colonized plants, indicating a systemic response to AM colonization. Genes related to nutrient exchange between the symbiont partners showed higher expression in the AM roots of wild type plants than the mutant plants, which correlated with their arbuscular frequency. A symbiosis receptor kinase that is involved in both nodulation and AM symbiosis was not expressed in the rmc mutant. The fact that some colonization was observed in rmc was suggestive of the existence of an alternate colonization signaling pathway for AM symbiosis in this mutant. PMID:23221680

Biodegradation of p-nitrophenol via 1,2,4-benzenetriol by an Arthrobacter sp.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jain, R.K.; Spain, J.C.; Dreisbach, J.H.

1994-08-01

The degradation of p-nitrophenol (PNP) by Moraxella and Pseudomonas spp. involves an initial monooxygenase-catalyzed removal of the nitro group. The resultant hydroquinone is subject to ring fission catalyzed by a dioxygenase enzyme. A strain of an Arthrobacter sp. JS443, capable of degrading PNP with stoichiometric release of nitrite has been isolated. During induction of the enzymes required for growth on PNP, 1,2,4-benzenetriol was identified as an intermediate by gas chromatography-mass spectroscopy and radiotracer studies. 1,2,4-Benzenetriol was converted to maleylacetic acid, which was further degraded by the beta-ketoadipate pathway. Conversion of PNP to 1,2,4-benzenetriol is catalyzed by a monooxygenase system inmore » strain JS443 through the formation of 4-nitrocatechol, 4-nitroresorcinol, or both. Results clearly indicate the existence of an alternative pathway for the biodegradation of PNP. 15 refs, 2 figs., 2 tabs.« less

A cochlear-bone wave can yield a hearing sensation as well as otoacoustic emission

PubMed Central

Tchumatchenko, Tatjana; Reichenbach, Tobias

2014-01-01

A hearing sensation arises when the elastic basilar membrane inside the cochlea vibrates. The basilar membrane is typically set into motion through airborne sound that displaces the middle ear and induces a pressure difference across the membrane. A second, alternative pathway exists, however: stimulation of the cochlear bone vibrates the basilar membrane as well. This pathway, referred to as bone conduction, is increasingly used in headphones that bypass the ear canal and the middle ear. Furthermore, otoacoustic emissions, sounds generated inside the cochlea and emitted therefrom, may not involve the usual wave on the basilar membrane, suggesting that additional cochlear structures are involved in their propagation. Here we describe a novel propagation mode within the cochlea that emerges through deformation of the cochlear bone. Through a mathematical and computational approach we demonstrate that this propagation mode can explain bone conduction as well as numerous properties of otoacoustic emissions. PMID:24954736

Energy Sources, Self-organization, and the Origin of Life

NASA Astrophysics Data System (ADS)

Boiteau, Laurent; Pascal, Robert

2011-02-01

The emergence and early developments of life are considered from the point of view that contingent events that inevitably marked evolution were accompanied by deterministic driving forces governing the selection between different alternatives. Accordingly, potential energy sources are considered for their propensity to induce self-organization within the scope of the chemical approach to the origin of life. Requirements in terms of quality of energy locate thermal or photochemical activation in the atmosphere as highly likely processes for the formation of activated low-molecular weight organic compounds prone to induce biomolecular self-organization through their ability to deliver quanta of energy matching the needs of early biochemical pathways or the reproduction of self-replicating entities. These lines of reasoning suggest the existence of a direct connection between the free energy content of intermediates of early pathways and the quanta of energy delivered by available sources of energy.

Parallel evolution of Nitric Oxide signaling: Diversity of synthesis & memory pathways

PubMed Central

Moroz, Leonid L.; Kohn, Andrea B.

2014-01-01

The origin of NO signaling can be traceable back to the origin of life with the large scale of parallel evolution of NO synthases (NOSs). Inducible-like NOSs may be the most basal prototype of all NOSs and that neuronal-like NOS might have evolved several times from this prototype. Other enzymatic and non-enzymatic pathways for NO synthesis have been discovered using reduction of nitrites, an alternative source of NO. Diverse synthetic mechanisms can co-exist within the same cell providing a complex NO-oxygen microenvironment tightly coupled with cellular energetics. The dissection of multiple sources of NO formation is crucial in analysis of complex biological processes such as neuronal integration and learning mechanisms when NO can act as a volume transmitter within memory-forming circuits. In particular, the molecular analysis of learning mechanisms (most notably in insects and gastropod molluscs) opens conceptually different perspectives to understand the logic of recruiting evolutionarily conserved pathways for novel functions. Giant uniquely identified cells from Aplysia and related species precent unuque opportunities for integrative analysis of NO signaling at the single cell level. PMID:21622160

Alternative Pathways to Apprenticeships. Good Practice Guide

ERIC Educational Resources Information Center

National Centre for Vocational Education Research (NCVER), 2015

2015-01-01

Apprenticeships are changing. The increasing proportions of people entering apprenticeships at various levels of ability and backgrounds are stimulating demand for alternative pathways to completions. This good practice guide assembles the key findings for education practitioners and workplace supervisors from three related research reports on…

Aligning Metabolic Pathways Exploiting Binary Relation of Reactions.

PubMed

Huang, Yiran; Zhong, Cheng; Lin, Hai Xiang; Huang, Jing

2016-01-01

Metabolic pathway alignment has been widely used to find one-to-one and/or one-to-many reaction mappings to identify the alternative pathways that have similar functions through different sets of reactions, which has important applications in reconstructing phylogeny and understanding metabolic functions. The existing alignment methods exhaustively search reaction sets, which may become infeasible for large pathways. To address this problem, we present an effective alignment method for accurately extracting reaction mappings between two metabolic pathways. We show that connected relation between reactions can be formalized as binary relation of reactions in metabolic pathways, and the multiplications of zero-one matrices for binary relations of reactions can be accomplished in finite steps. By utilizing the multiplications of zero-one matrices for binary relation of reactions, we efficiently obtain reaction sets in a small number of steps without exhaustive search, and accurately uncover biologically relevant reaction mappings. Furthermore, we introduce a measure of topological similarity of nodes (reactions) by comparing the structural similarity of the k-neighborhood subgraphs of the nodes in aligning metabolic pathways. We employ this similarity metric to improve the accuracy of the alignments. The experimental results on the KEGG database show that when compared with other state-of-the-art methods, in most cases, our method obtains better performance in the node correctness and edge correctness, and the number of the edges of the largest common connected subgraph for one-to-one reaction mappings, and the number of correct one-to-many reaction mappings. Our method is scalable in finding more reaction mappings with better biological relevance in large metabolic pathways.

Patterns of threshold evolution in polyphenic insects under different developmental models.

PubMed

Tomkins, Joseph L; Moczek, Armin P

2009-02-01

Two hypotheses address the evolution of polyphenic traits in insects. Under the developmental reprogramming model, individuals exceeding a threshold follow a different developmental pathway from individuals below the threshold. This decoupling is thought to free selection to independently hone alternative morphologies, increasing phenotypic plasticity and morphological diversity. Under the alternative model, extreme positive allometry explains the existence of alternative phenotypes and divergent phenotypes are developmentally coupled by a continuous reaction norm, such that selection on either morph acts on both. We test the hypothesis that continuous reaction norm polyphenisms, evolve through changes in the allometric parameters of even the smallest males with minimal trait expression, whereas threshold polyphenisms evolve independent of the allometric parameters of individuals below the threshold. We compare two polyphenic species; the dung beetle Onthophagus taurus, whose allometry has been modeled both as a threshold polyphenism and a continuous reaction norm and the earwig Forficula auricularia, whose allometry is best modeled with a discontinuous threshold. We find that across populations of both species, variation in forceps or horn allometry in minor males are correlated to the population's threshold. These findings suggest that regardless of developmental mode, alternative morphs do not evolve independently of one another.

Out of Sight but Not out of Mind: Alternative Means of Communication in Plants

PubMed Central

Gagliano, Monica; Renton, Michael; Duvdevani, Nili; Timmins, Matthew; Mancuso, Stefano

2012-01-01

Current knowledge suggests that the mechanisms by which plants communicate information take numerous forms. Previous studies have focussed their attention on communication via chemicals, contact and light; other methods of interaction between plants have remained speculative. In this study we tested the ability of young chilli plants to sense their neighbours and identify their relatives using alternative mechanism(s) to recognised plant communication pathways. We found that the presence of a neighbouring plant had a significant influence on seed germination even when all known sources of communication signals were blocked. Furthermore, despite the signalling restriction, seedlings allocated energy to their stem and root systems differently depending on the identity of the neighbour. These results provide clear experimental evidence for the existence of communication channels between plants beyond those that have been recognized and studied thus far. PMID:22629387

Distinct Contributions of the Magnocellular and Parvocellular Visual Streams to Perceptual Selection

PubMed Central

Denison, Rachel N.; Silver, Michael A.

2014-01-01

During binocular rivalry, conflicting images presented to the two eyes compete for perceptual dominance, but the neural basis of this competition is disputed. In interocular switch (IOS) rivalry, rival images periodically exchanged between the two eyes generate one of two types of perceptual alternation: 1) a fast, regular alternation between the images that is time-locked to the stimulus switches and has been proposed to arise from competition at lower levels of the visual processing hierarchy, or 2) a slow, irregular alternation spanning multiple stimulus switches that has been associated with higher levels of the visual system. The existence of these two types of perceptual alternation has been influential in establishing the view that rivalry may be resolved at multiple hierarchical levels of the visual system. We varied the spatial, temporal, and luminance properties of IOS rivalry gratings and found, instead, an association between fast, regular perceptual alternations and processing by the magnocellular stream and between slow, irregular alternations and processing by the parvocellular stream. The magnocellular and parvocellular streams are two early visual pathways that are specialized for the processing of motion and form, respectively. These results provide a new framework for understanding the neural substrates of binocular rivalry that emphasizes the importance of parallel visual processing streams, and not only hierarchical organization, in the perceptual resolution of ambiguities in the visual environment. PMID:21861685

49 CFR 451.7 - Alternative approval of existing containers.

Code of Federal Regulations, 2013 CFR

2013-10-01

..., DEPARTMENT OF HOMELAND SECURITY SAFETY APPROVAL OF CARGO CONTAINERS TESTING AND APPROVAL OF CONTAINERS Approval of Existing Containers § 451.7 Alternative approval of existing containers. (a) Existing... 49 Transportation 6 2013-10-01 2013-10-01 false Alternative approval of existing containers. 451.7...

49 CFR 451.7 - Alternative approval of existing containers.

Code of Federal Regulations, 2011 CFR

2011-10-01

..., DEPARTMENT OF HOMELAND SECURITY SAFETY APPROVAL OF CARGO CONTAINERS TESTING AND APPROVAL OF CONTAINERS Approval of Existing Containers § 451.7 Alternative approval of existing containers. (a) Existing... 49 Transportation 6 2011-10-01 2011-10-01 false Alternative approval of existing containers. 451.7...

49 CFR 451.7 - Alternative approval of existing containers.

Code of Federal Regulations, 2012 CFR

2012-10-01

..., DEPARTMENT OF HOMELAND SECURITY SAFETY APPROVAL OF CARGO CONTAINERS TESTING AND APPROVAL OF CONTAINERS Approval of Existing Containers § 451.7 Alternative approval of existing containers. (a) Existing... 49 Transportation 6 2012-10-01 2012-10-01 false Alternative approval of existing containers. 451.7...

49 CFR 451.7 - Alternative approval of existing containers.

Code of Federal Regulations, 2014 CFR

2014-10-01

..., DEPARTMENT OF HOMELAND SECURITY SAFETY APPROVAL OF CARGO CONTAINERS TESTING AND APPROVAL OF CONTAINERS Approval of Existing Containers § 451.7 Alternative approval of existing containers. (a) Existing... 49 Transportation 6 2014-10-01 2014-10-01 false Alternative approval of existing containers. 451.7...

49 CFR 451.7 - Alternative approval of existing containers.

Code of Federal Regulations, 2010 CFR

2010-10-01

..., DEPARTMENT OF HOMELAND SECURITY SAFETY APPROVAL OF CARGO CONTAINERS TESTING AND APPROVAL OF CONTAINERS Approval of Existing Containers § 451.7 Alternative approval of existing containers. (a) Existing... 49 Transportation 6 2010-10-01 2010-10-01 false Alternative approval of existing containers. 451.7...

Isolation and Characterization of the Z-ISO Gene Encoding a Missing Component of Carotenoid Biosynthesis in Plants1[C][W][OA

PubMed Central

Chen, Yu; Li, Faqiang; Wurtzel, Eleanore T.

2010-01-01

Metabolic engineering of plant carotenoids in food crops has been a recent focus for improving human health. Pathway manipulation is predicated on comprehensive knowledge of this biosynthetic pathway, which has been extensively studied. However, there existed the possibility of an additional biosynthetic step thought to be dispensable because it could be compensated for by light. This step, mediated by a putative Z-ISO, was predicted to occur in the sequence of redox reactions that are coupled to an electron transport chain and convert the colorless 15-cis-phytoene to the red-colored all-trans-lycopene. The enigma of carotenogenesis in the absence of light (e.g. in endosperm, a target for improving nutritional content) argued for Z-ISO as a pathway requirement. Therefore, understanding of plant carotenoid biosynthesis was obviously incomplete. To prove the existence of Z-ISO, maize (Zea mays) and Arabidopsis (Arabidopsis thaliana) mutants were isolated and the gene identified. Functional testing of the gene product in Escherichia coli showed isomerization of the 15-cis double bond in 9,15,9′-tri-cis-ζ-carotene, proving that Z-ISO encoded the missing step. Z-ISO was found to be important for both light-exposed and “dark” tissues. Comparative genomics illuminated the origin of Z-ISO found throughout higher and lower plants, algae, diatoms, and cyanobacteria. Z-ISO evolved from an ancestor related to the NnrU (for nitrite and nitric oxide reductase U) gene required for bacterial denitrification, a pathway that produces nitrogen oxides as alternate electron acceptors for anaerobic growth. Therefore, plant carotenogenesis evolved by recruitment of genes from noncarotenogenic bacteria. PMID:20335404

Alternative Pathways into University: Are Tertiary Preparation Programs a Viable Option?

ERIC Educational Resources Information Center

Chesters, Jenny; Rutter, Kerry; Nelson, Karen; Watson, Louis

2018-01-01

During the past three decades, the student populations of Australian universities have become more heterogeneous as the higher education sector expanded and new alternative entry pathways were established. Broadening access to university study and, therefore, to professional and semi-professional occupations, provides avenues for social mobility.…

Alternative complement pathway activation increases mortality in a model of burn injury in mice.

PubMed Central

Gelfand, J A; Donelan, M; Hawiger, A; Burke, J F

1982-01-01

We have studied the role of the complement system in burn injury in an experimental model in mice. A 25% body surface area, full-thickness scald wound was produced in anesthetized animals. Massive activation of the alternative complement pathway, but not the classical pathway, was seen. This activation was associated with the generation of neutrophil aggregating activity in the plasma, neutrophil aggregates in the lungs, increased pulmonary vascular permeability, and increased lung edema formation. Decomplementation with cobra venom factor (CVF) or genetic C5 deficiency diminished these pathologic changes, and CVF pretreatment substantially reduced burn mortality in the first 24 h. Preliminary data show that human burn patients have a similar pattern of complement activation involving predominantly the alternative pathway, indicating the possible relevance of the murine model to human disease. Images PMID:7174787

The "Mevalonate hypothesis": a cholesterol-independent alternative for the etiology of atherosclerosis.

PubMed

Keizer, Hiskias G

2012-11-05

The "cholesterol hypothesis" is the leading theory to explain the cause of atherosclerosis. The "cholesterol hypothesis" assumes that plasma (LDL) cholesterol is an important causal factor for atherosclerosis.However, data of at least seven placebo controlled randomized prospective trials with various cholesterol lowering drugs show that plasma cholesterol lowering does not necessarily lead to protection against cardiovascular disease. Therefore an alternative hypothesis for the etiology of cardiovascular disease is formulated. This alternative hypothesis, the "mevalonate hypothesis", assumes that after stimulation of the mevalonate pathway in endothelial cells by inflammatory factors, these cells start producing cholesterol and free radicals. In this hypothesis, only the latter play a role in the etiology of atherosclerosis by contributing to the formation of oxidized cholesterol which is a widely accepted causal factor for atherosclerosis.Regardless of how the mevalonate pathway is activated (by withdrawal of statin drugs, by inflammatory factors or indirectly by reduced intracellular cholesterol levels) in all these cases free radical production is observed as well as cardiovascular disease. Since in the "mevalonate hypothesis" cholesterol is produced at the same time as the free radicals causing atherosclerosis, this hypothesis provides an explanation for the correlation which exists between cardiovascular disease and plasma cholesterol levels. From an evolutionary perspective, concomitant cholesterol production and free radical production in response to inflammatory factors makes sense if one realizes that both activities potentially protect cells and organisms from infection by gram-negative bacteria.In conclusion, data have been collected which suggest that activation of the mevalonate pathway in endothelial cells is likely to be a causal factor for atherosclerosis. This "mevalonate hypothesis" provides a better explanation for results obtained from recent clinical studies with cholesterol lowering drugs than the "cholesterol hypothesis". Furthermore, this hypothesis explains how cholesterol can be correlated with cardiovascular disease without being a causal factor for it. Finally it provides a logical explanation for the etiology of this disease.

Appearance of an Alternate Pathway Cyanide-resistant during Germination of Seeds of Cicer arietinum

PubMed Central

Burguillo, Placido De La Fuente; Nicolás, Gregorio

1977-01-01

The combined action of the inhibitors antimycin A and cyanide with benzohydroxamic acid indicates the presence of a cyanide-resistant pathway of respiration in chick pea (Cicer arietinum L.) seeds. The appearance of this pathway takes place during germination. During the first 12 hours of germination, the respiration is predominantly cyanide-sensitive, showing after this time a shift to an “alternate” respiration which is sensitive to benzohydroxamic acid, reaching the maximal cyanide resistance between 72 and 96 hours of germination. The appearance of the alternate pathway is initiated by high O2 concentrations and depends on cytoplasmic protein synthesis, since its appearance is inhibited by cycloheximide but not by chloramphenicol. Actinomycin D has no effect on the appearance of the alternate pathway. Our results indicate, in agreement with other authors, that the branching point is located between the flavoproteins and cytochromes b, probably at the level of ubiquinone, but the possibility of more than one branching point of the electron flow is also considered. PMID:16660130

Specific Inhibition of the Cyanide-insensitive Respiratory Pathway in Plant Mitochondria by Hydroxamic Acids

PubMed Central

Schonbaum, Gregory R.; Bonner, Walter D.; Storey, Bayard T.; Bahr, James T.

1971-01-01

Hydroxamic acids, R-CONHOH, are inhibitors specific to the respiratory pathway through the alternate, cyanide-insensitive terminal oxidase of plant mitochondria. The nature of the R group in these compounds affects the concentration at which the hydroxamic acids are effective, but it appears that all hydroxamic acids inhibit if high enough concentrations are used. The benzhydroxamic acids are effective at relatively low concentrations; of these, the most effective are m-chlorobenzhydroxamic acid and m-iodobenzhydroxamic acid. The concentrations required for half-maximal inhibition of the alternate oxidase pathway in mung bean (Phaseolus aureus) mitochondria are 0.03 mm for m-chlorobenzhydroxamic acid and 0.02 mm for m-iodobenzhydroxamic acid. With skunk cabbage (Symplocarpus foetidus) mitochondria, the required concentrations are 0.16 for m-chlorobenzhydroxamic acid and 0.05 for m-iodobenzhydroxamic acid. At concentrations which inhibit completely the alternate oxidase pathway, these two compounds have no discernible effect on either the respiratory pathway through cytochrome oxidase, or on the energy coupling reactions of these mitochondria. These inhibitors make it possible to isolate the two respiratory pathways and study their mode of action separately. These inhibitors also enhance an electron paramagnetic resonance signal near g = 2 in anaerobic, submitochondrial particles from skunk cabbage, which appears to be specific to the alternate oxidase and thus provides a means for its assay. PMID:5543780

The influence of alternative pathways of respiration that utilize branched-chain amino acids following water shortage in Arabidopsis.

PubMed

Pires, Marcel V; Pereira Júnior, Adilson A; Medeiros, David B; Daloso, Danilo M; Pham, Phuong Anh; Barros, Kallyne A; Engqvist, Martin K M; Florian, Alexandra; Krahnert, Ina; Maurino, Veronica G; Araújo, Wagner L; Fernie, Alisdair R

2016-06-01

During dark-induced senescence isovaleryl-CoA dehydrogenase (IVDH) and D-2-hydroxyglutarate dehydrogenase (D-2HGDH) act as alternate electron donors to the ubiquinol pool via the electron-transfer flavoprotein/electron-transfer flavoprotein:ubiquinone oxidoreductase (ETF/ETFQO) pathway. However, the role of this pathway in response to other stresses still remains unclear. Here, we demonstrated that this alternative pathway is associated with tolerance to drought in Arabidopsis. In comparison with wild type (WT) and lines overexpressing D-2GHDH, loss-of-function etfqo-1, d2hgdh-2 and ivdh-1 mutants displayed compromised respiration rates and were more sensitive to drought. Our results demonstrated that an operational ETF/ETFQO pathway is associated with plants' ability to withstand drought and to recover growth once water becomes replete. Drought-induced metabolic reprogramming resulted in an increase in tricarboxylic acid (TCA) cycle intermediates and total amino acid levels, as well as decreases in protein, starch and nitrate contents. The enhanced levels of the branched-chain amino acids in loss-of-function mutants appear to be related to their increased utilization as substrates for the TCA cycle under water stress. Our results thus show that mitochondrial metabolism is highly active during drought stress responses and provide support for a role of alternative respiratory pathways within this response. © 2015 John Wiley & Sons Ltd.

Presence or Absence of mlr Genes and Nutrient Concentrations Co-Determine the Microcystin Biodegradation Efficiency of a Natural Bacterial Community.

PubMed

Lezcano, María Ángeles; Morón-López, Jesús; Agha, Ramsy; López-Heras, Isabel; Nozal, Leonor; Quesada, Antonio; El-Shehawy, Rehab

2016-11-03

The microcystin biodegradation potential of a natural bacterial community coexisting with a toxic cyanobacterial bloom was investigated in a water reservoir from central Spain. The biodegradation capacity was confirmed in all samples during the bloom and an increase of mlr A gene copies was found with increasing microcystin concentrations. Among the 24 microcystin degrading strains isolated from the bacterial community, only 28% showed presence of mlr A gene, strongly supporting the existence and abundance of alternative microcystin degradation pathways in nature. In vitro degradation assays with both mlr ⁺ and mlr - bacterial genotypes (with presence and absence of the complete mlr gene cluster, respectively) were performed with four isolated strains ( Sphingopyxis sp. IM-1, IM-2 and IM-3; Paucibacter toxinivorans IM-4) and two bacterial degraders from the culture collection ( Sphingosinicella microcystinivorans Y2; Paucibacter toxinivorans 2C20). Differences in microcystin degradation efficiencies between genotypes were found under different total organic carbon and total nitrogen concentrations. While mlr ⁺ strains significantly improved microcystin degradation rates when exposed to other carbon and nitrogen sources, mlr - strains showed lower degradation efficiencies. This suggests that the presence of alternative carbon and nitrogen sources possibly competes with microcystins and impairs putative non- mlr microcystin degradation pathways. Considering the abundance of the mlr - bacterial population and the increasing frequency of eutrophic conditions in aquatic systems, further research on the diversity of this population and the characterization and conditions affecting non- mlr degradation pathways deserves special attention.

Lessons and challenges from adaptation pathways planning applications

NASA Astrophysics Data System (ADS)

Haasnoot, M.; Lawrence, J.; Kwakkel, J. H.; Walker, W.; Timmermans, J.; Bloemen, P.; Thissen, W.

2015-12-01

Planning for adaptation to dynamic risks (e.g., because of climate change) is a critical need. The concept of 'adaptive policies' is receiving increasing attention as a way of performing strategic planning that is able to address many of the inherent challenges of uncertainty and dynamic change. Several approaches for developing adaptive policies are available in the literature. One approach, for which several applications already exist, is Dynamic Adaptive Policy Pathways (DAPP). Pathway maps enable policy analysts, decision makers, and stakeholders to recognize potential 'locked-in' situations and to assess the flexibility, robustness, and efficacy of decision alternatives. Most of the applications of DAPP have been in deltas, coastal cities, or floodplains, often within the context of climate change adaptation. In this talk, we describe the DAPP approach and present a framework for designing signposts as adaptation signals, together with an illustrative application for the Rhine River in the Netherlands. We also draw lessons and challenges from pathways applications that differ in environment, culture, and institutional context. For example, the Dutch Delta Programme has used pathways to identify short-term decisions and long-term policy options. In Bangladesh, an application is in its early phase. Steps before generating pathways - such as long- term thinking in multiple possible futures and acknowledging uncertainties - are already a big challenge there. In New Zealand, the 'Sustainable Delta Game' has been used as the catalyst for pathways thinking by two local councils. This has led to its application in decision making for coastal and flood risk management and economic analysis of policy options.

Fault tolerance in protein interaction networks: stable bipartite subgraphs and redundant pathways.

PubMed

Brady, Arthur; Maxwell, Kyle; Daniels, Noah; Cowen, Lenore J

2009-01-01

As increasing amounts of high-throughput data for the yeast interactome become available, more system-wide properties are uncovered. One interesting question concerns the fault tolerance of protein interaction networks: whether there exist alternative pathways that can perform some required function if a gene essential to the main mechanism is defective, absent or suppressed. A signature pattern for redundant pathways is the BPM (between-pathway model) motif, introduced by Kelley and Ideker. Past methods proposed to search the yeast interactome for BPM motifs have had several important limitations. First, they have been driven heuristically by local greedy searches, which can lead to the inclusion of extra genes that may not belong in the motif; second, they have been validated solely by functional coherence of the putative pathways using GO enrichment, making it difficult to evaluate putative BPMs in the absence of already known biological annotation. We introduce stable bipartite subgraphs, and show they form a clean and efficient way of generating meaningful BPMs which naturally discard extra genes included by local greedy methods. We show by GO enrichment measures that our BPM set outperforms previous work, covering more known complexes and functional pathways. Perhaps most importantly, since our BPMs are initially generated by examining the genetic-interaction network only, the location of edges in the protein-protein physical interaction network can then be used to statistically validate each candidate BPM, even with sparse GO annotation (or none at all). We uncover some interesting biological examples of previously unknown putative redundant pathways in such areas as vesicle-mediated transport and DNA repair.

Fault Tolerance in Protein Interaction Networks: Stable Bipartite Subgraphs and Redundant Pathways

PubMed Central

Brady, Arthur; Maxwell, Kyle; Daniels, Noah; Cowen, Lenore J.

2009-01-01

As increasing amounts of high-throughput data for the yeast interactome become available, more system-wide properties are uncovered. One interesting question concerns the fault tolerance of protein interaction networks: whether there exist alternative pathways that can perform some required function if a gene essential to the main mechanism is defective, absent or suppressed. A signature pattern for redundant pathways is the BPM (between-pathway model) motif, introduced by Kelley and Ideker. Past methods proposed to search the yeast interactome for BPM motifs have had several important limitations. First, they have been driven heuristically by local greedy searches, which can lead to the inclusion of extra genes that may not belong in the motif; second, they have been validated solely by functional coherence of the putative pathways using GO enrichment, making it difficult to evaluate putative BPMs in the absence of already known biological annotation. We introduce stable bipartite subgraphs, and show they form a clean and efficient way of generating meaningful BPMs which naturally discard extra genes included by local greedy methods. We show by GO enrichment measures that our BPM set outperforms previous work, covering more known complexes and functional pathways. Perhaps most importantly, since our BPMs are initially generated by examining the genetic-interaction network only, the location of edges in the protein-protein physical interaction network can then be used to statistically validate each candidate BPM, even with sparse GO annotation (or none at all). We uncover some interesting biological examples of previously unknown putative redundant pathways in such areas as vesicle-mediated transport and DNA repair. PMID:19399174

Cerebral Gluconeogenesis and Diseases.

PubMed

Yip, James; Geng, Xiaokun; Shen, Jiamei; Ding, Yuchuan

2016-01-01

The gluconeogenesis pathway, which has been known to normally present in the liver, kidney, intestine, or muscle, has four irreversible steps catalyzed by the enzymes: pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose 1,6-bisphosphatase, and glucose 6-phosphatase. Studies have also demonstrated evidence that gluconeogenesis exists in brain astrocytes but no convincing data have yet been found in neurons. Astrocytes exhibit significant 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 activity, a key mechanism for regulating glycolysis and gluconeogenesis. Astrocytes are unique in that they use glycolysis to produce lactate, which is then shuttled into neurons and used as gluconeogenic precursors for reduction. This gluconeogenesis pathway found in astrocytes is becoming more recognized as an important alternative glucose source for neurons, specifically in ischemic stroke and brain tumor. Further studies are needed to discover how the gluconeogenesis pathway is controlled in the brain, which may lead to the development of therapeutic targets to control energy levels and cellular survival in ischemic stroke patients, or inhibit gluconeogenesis in brain tumors to promote malignant cell death and tumor regression. While there are extensive studies on the mechanisms of cerebral glycolysis in ischemic stroke and brain tumors, studies on cerebral gluconeogenesis are limited. Here, we review studies done to date regarding gluconeogenesis to evaluate whether this metabolic pathway is beneficial or detrimental to the brain under these pathological conditions.

A comparative analysis of well-to-wheel primary energy demand and greenhouse gas emissions for the operation of alternative and conventional vehicles in Switzerland, considering various energy carrier production pathways

NASA Astrophysics Data System (ADS)

Yazdanie, Mashael; Noembrini, Fabrizio; Dossetto, Lionel; Boulouchos, Konstantinos

2014-03-01

This study provides a comprehensive analysis of well-to-wheel (WTW) primary energy demand and greenhouse gas (GHG) emissions for the operation of conventional and alternative passenger vehicle drivetrains. Results are determined based on a reference vehicle, drivetrain/production process efficiencies, and lifecycle inventory data specific to Switzerland. WTW performance is compared to a gasoline internal combustion engine vehicle (ICEV). Both industrialized and novel hydrogen and electricity production pathways are evaluated. A strong case is presented for pluggable electric vehicles (PEVs) due to their high drivetrain efficiency. However, WTW performance strongly depends on the electricity source. A critical electricity mix can be identified which divides optimal drivetrain performance between the EV, ICEV, and plug-in hybrid vehicle. Alternative drivetrain and energy carrier production pathways are also compared by natural resource. Fuel cell vehicle (FCV) performance proves to be on par with PEVs for energy carrier (EC) production via biomass and natural gas resources. However, PEVs outperform FCVs via solar energy EC production pathways. ICE drivetrains using alternative fuels, particularly biogas and CNG, yield remarkable WTW energy and emission reductions as well, indicating that alternative fuels, and not only alternative drivetrains, play an important role in the transition towards low-emission vehicles in Switzerland.

Continuing Development of Alternative High-Throughput Screens to Determine Endocrine Disruption, Focusing on Androgen Receptor, Steroidogenesis, and Thyroid Pathways

EPA Science Inventory

The focus of this meeting is the SAP's review and comment on the Agency's proposed high-throughput computational model of androgen receptor pathway activity as an alternative to the current Tier 1 androgen receptor assay (OCSPP 890.1150: Androgen Receptor Binding Rat Prostate Cyt...

Targeting pro-resolution pathways to combat chronic inflammation in COPD

PubMed Central

Anthony, Desiree; Vlahos, Ross

2014-01-01

Chronic obstructive pulmonary disease (COPD) is an inflammatory lung condition that is associated with irreversible airflow obstruction as a consequence of small airways disease, excessive mucus production and emphysema. Paradoxically, excessive inflammation fails to control microbial pathogens that not only colonise COPD airways, but also trigger acute exacerbations, which markedly increase inflammation underlying host tissue damage. Excessive production of leukocyte mobilising cytokines such as CXCL8 (IL-8) and leukotriene B4 (LTB4) in response to environmental stimuli (cigarette smoke and microbial products) are thought to maintain chronic inflammation, in conjunction with inefficient macrophage clearance of microbes and apoptotic neutrophils. In this perspective, we discuss an alternative view on why inflammation persists with a focus on why pro-resolution mediators such as lipoxin A4 (LXA4), D-series resolving and Annexin A1 fail to effectively switch off inflammation in COPD. These pro-resolving mediators converge on the G-protein coupled receptor, ALX/FPR2. This receptor is particularly relevant to COPD as the complex milieu of exogenous and host-derived mediators within the inflamed airways include agonists that potently activate ALX/FPR2, including Serum Amyloid A (SAA) and the cathelicidin, LL-37. There is emerging evidence to suggest that ALX/FPR2 can exist in alternative receptor conformations in an agonist-biased manner, which facilitates alternate functional receptor behaviors. Hence, the development of more stable pro-resolving analogs provides therapeutic opportunities to address ALX/FPR2 conformations to counteract pathogenic signaling and promote non-phlogistic clearance pathways essential for resolution of inflammation. PMID:25478196

Targeting pro-resolution pathways to combat chronic inflammation in COPD.

PubMed

Bozinovski, Steven; Anthony, Desiree; Vlahos, Ross

2014-11-01

Chronic obstructive pulmonary disease (COPD) is an inflammatory lung condition that is associated with irreversible airflow obstruction as a consequence of small airways disease, excessive mucus production and emphysema. Paradoxically, excessive inflammation fails to control microbial pathogens that not only colonise COPD airways, but also trigger acute exacerbations, which markedly increase inflammation underlying host tissue damage. Excessive production of leukocyte mobilising cytokines such as CXCL8 (IL-8) and leukotriene B4 (LTB4) in response to environmental stimuli (cigarette smoke and microbial products) are thought to maintain chronic inflammation, in conjunction with inefficient macrophage clearance of microbes and apoptotic neutrophils. In this perspective, we discuss an alternative view on why inflammation persists with a focus on why pro-resolution mediators such as lipoxin A4 (LXA4), D-series resolving and Annexin A1 fail to effectively switch off inflammation in COPD. These pro-resolving mediators converge on the G-protein coupled receptor, ALX/FPR2. This receptor is particularly relevant to COPD as the complex milieu of exogenous and host-derived mediators within the inflamed airways include agonists that potently activate ALX/FPR2, including Serum Amyloid A (SAA) and the cathelicidin, LL-37. There is emerging evidence to suggest that ALX/FPR2 can exist in alternative receptor conformations in an agonist-biased manner, which facilitates alternate functional receptor behaviors. Hence, the development of more stable pro-resolving analogs provides therapeutic opportunities to address ALX/FPR2 conformations to counteract pathogenic signaling and promote non-phlogistic clearance pathways essential for resolution of inflammation.

Respiration, oxidative phosphorylation, and uncoupling protein in Candida albicans.

PubMed

Cavalheiro, R A; Fortes, F; Borecký, J; Faustinoni, V C; Schreiber, A Z; Vercesi, A E

2004-10-01

The respiration, membrane potential (Deltapsi), and oxidative phosphorylation of mitochondria in situ were determined in spheroplasts obtained from Candida albicans control strain ATCC 90028 by lyticase treatment. Mitochondria in situ were able to phosphorylate externally added ADP (200 microM) in the presence of 0.05% BSA. Mitochondria in situ generated and sustained stable mitochondrial Deltapsi respiring on 5 mM NAD-linked substrates, 5 mM succinate, or 100 microM N,N,N',N'-tetramethyl-p-phenylenediamine dihydrochloride plus 1 mM ascorbate. Rotenone (4 microM) inhibited respiration by 30% and 2 micro M antimycin A or myxothiazole and 1 mM cyanide inhibited it by 85%. Cyanide-insensitive respiration was partially blocked by 2 mM benzohydroxamic acid, suggesting the presence of an alternative oxidase. Candida albicans mitochondria in situ presented a carboxyatractyloside-insensitive increase of Deltapsi induced by 5 mM ATP and 0.5% BSA, and Deltapsi decrease induced by 10 microM linoleic acid, both suggesting the existence of an uncoupling protein. The presence of this protein was subsequently confirmed by immunodetection and respiration experiments with isolated mitochondria. In conclusion, Candida albicans ATCC 90028 possesses an alternative electron transfer chain and alternative oxidase, both absent in animal cells. These pathways can be exceptional targets for the design of new chemotherapeutic agents. Blockage of these respiratory pathways together with inhibition of the uncoupling protein (another potential target for drug design) could lead to increased production of reactive oxygen species, dysfunction of Candida mitochondria, and possibly to oxidative cell death.

Structural and functional identification of vasculogenic mimicry in vitro.

PubMed

Racordon, Dusan; Valdivia, Andrés; Mingo, Gabriel; Erices, Rafaela; Aravena, Raúl; Santoro, Felice; Bravo, Maria Loreto; Ramirez, Carolina; Gonzalez, Pamela; Sandoval, Alejandra; González, Alfonso; Retamal, Claudio; Kogan, Marcelo J; Kato, Sumie; Cuello, Mauricio A; Osorio, German; Nualart, Francisco; Alvares, Pedro; Gago-Arias, Araceli; Fabri, Daniella; Espinoza, Ignacio; Sanchez, Beatriz; Corvalán, Alejandro H; Pinto, Mauricio P; Owen, Gareth I

2017-08-01

Vasculogenic mimicry (VM) describes a process by which cancer cells establish an alternative perfusion pathway in an endothelial cell-free manner. Despite its strong correlation with reduced patient survival, controversy still surrounds the existence of an in vitro model of VM. Furthermore, many studies that claim to demonstrate VM fail to provide solid evidence of true hollow channels, raising concerns as to whether actual VM is actually being examined. Herein, we provide a standardized in vitro assay that recreates the formation of functional hollow channels using ovarian cancer cell lines, cancer spheres and primary cultures derived from ovarian cancer ascites. X-ray microtomography 3D-reconstruction, fluorescence confocal microscopy and dye microinjection conclusively confirm the existence of functional glycoprotein-rich lined tubular structures in vitro and demonstrate that many of structures reported in the literature may not represent VM. This assay may be useful to design and test future VM-blocking anticancer therapies.

Neutrophil extracellular traps can activate alternative complement pathways.

PubMed

Wang, H; Wang, C; Zhao, M-H; Chen, M

2015-09-01

The interaction between neutrophils and activation of alternative complement pathway plays a pivotal role in the pathogenesis of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). ANCAs activate primed neutrophils to release neutrophil extracellular traps (NETs), which have recently gathered increasing attention in the development of AAV. The relationship between NETs and alternative complement pathway has not been elucidated. The current study aimed to investigate the relationship between NETs and alternative complement pathway. Detection of components of alternative complement pathway on NETs in vitro was assessed by immunostain and confocal microscopy. Complement deposition on NETs were detected after incubation with magnesium salt ethyleneglycol tetraacetic acid (Mg-EGTA)-treated human serum. After incubation of serum with supernatants enriched in ANCA-induced NETs, levels of complement components in supernatants were measured by enzyme-linked immunosorbent assay (ELISA). Complement factor B (Bb) and properdin deposited on NETs in vitro. The deposition of C3b and C5b-9 on NETs incubated with heat-inactivated normal human serum (Hi-NHS) or EGTA-treated Hi-NHS (Mg-EGTA-Hi-NHS) were significantly less than that on NETs incubated with NHS or EGTA-treated NHS (Mg-EGTA-NHS). NETs induced by ANCA could activate the alternative complement cascade in the serum. In the presence of EGTA, C3a, C5a and SC5b-9 concentration decreased from 800·42 ± 244·81 ng/ml, 7·68 ± 1·50 ng/ml, 382·15 ± 159·75 ng/ml in the supernatants enriched in ANCA induced NETs to 479·07 ± 156·2 ng/ml, 4·86 ± 1·26 ng/ml, 212·65 ± 44·40 ng/ml in the supernatants of DNase I-degraded NETs (P < 0·001, P = 0·008, P < 0·001, respectively). NETs could activate the alternative complement pathway, and might thus participate in the pathogenesis of AAV. © 2015 British Society for Immunology.

Phenylbutyrate improves nitrogen disposal via alternative pathway without eliciting an increase in protein breakdown and catabolism in control and ornithine transcarbamylace-deficient patients

USDA-ARS?s Scientific Manuscript database

Phenylbutyrate (PB) is a drug used in urea cycle disorder patients to elicit alternative pathways for nitrogen disposal. However, PB decreases plasma branched chain amino acid (BCAA) concentrations and prior research suggests that PB may increase leucine oxidation, indicating increased protein degra...

ALTERNATE PATHWAY TO LUNG CANCER INDICATED BY KRAS AND P53 MUTATIONS IN NONSMOKERS EXPOSED TO INDOOR SMOKY COAL EMISSIONS

EPA Science Inventory

Alternate Pathway to Lung Cancer Indicated by KRAS and P53 Mutations in Nonsmokers Exposed to Indoor Smoky Coal Emissions

Use of smoky coal in unvented homes in Xuan Wei County, Yunnan Province, China, is
associated with lung cancer among nonsmoking females. Such wome...

A Novel Method to Identify Differential Pathways in Hippocampus Alzheimer's Disease.

PubMed

Liu, Chun-Han; Liu, Lian

2017-05-08

BACKGROUND Alzheimer's disease (AD) is the most common type of dementia. The objective of this paper is to propose a novel method to identify differential pathways in hippocampus AD. MATERIAL AND METHODS We proposed a combined method by merging existed methods. Firstly, pathways were identified by four known methods (DAVID, the neaGUI package, the pathway-based co-expressed method, and the pathway network approach), and differential pathways were evaluated through setting weight thresholds. Subsequently, we combined all pathways by a rank-based algorithm and called the method the combined method. Finally, common differential pathways across two or more of five methods were selected. RESULTS Pathways obtained from different methods were also different. The combined method obtained 1639 pathways and 596 differential pathways, which included all pathways gained from the four existing methods; hence, the novel method solved the problem of inconsistent results. Besides, a total of 13 common pathways were identified, such as metabolism, immune system, and cell cycle. CONCLUSIONS We have proposed a novel method by combining four existing methods based on a rank product algorithm, and identified 13 significant differential pathways based on it. These differential pathways might provide insight into treatment and diagnosis of hippocampus AD.

Short linear motif acquisition, exon formation and alternative splicing determine a pathway to diversity for NCoR-family co-repressors

PubMed Central

Short, Stephen; Peterkin, Tessa; Guille, Matthew; Patient, Roger; Sharpe, Colin

2015-01-01

Vertebrate NCoR-family co-repressors play central roles in the timing of embryo and stem cell differentiation by repressing the activity of a range of transcription factors. They interact with nuclear receptors using short linear motifs (SLiMs) termed co-repressor for nuclear receptor (CoRNR) boxes. Here, we identify the pathway leading to increasing co-repressor diversity across the deuterostomes. The final complement of CoRNR boxes arose in an ancestral cephalochordate, and was encoded in one large exon; the urochordates and vertebrates then split this region between 10 and 12 exons. In Xenopus, alternative splicing is prevalent in NCoR2, but absent in NCoR1. We show for one NCoR1 exon that alternative splicing can be recovered by a single point mutation, suggesting NCoR1 lost the capacity for alternative splicing. Analyses in Xenopus and zebrafish identify that cellular context, rather than gene sequence, predominantly determines species differences in alternative splicing. We identify a pathway to diversity for the NCoR family beginning with the addition of a SLiM, followed by gene duplication, the generation of alternatively spliced isoforms and their differential deployment. PMID:26289800

Human Stem Cell Derived Cardiomyocytes: An Alternative ...

EPA Pesticide Factsheets

Chemical spills and associated deaths in the US has increased 2.6-fold and 16-fold from 1983 to 2012, respectfully. In addition, the number of chemicals to which humans are exposed to in the environment has increased almost 10-fold from 2001 to 2013 within the US. Internationally, a WHO report on the global composite impact of chemicals on health reported that 16% of the total burden of cardiovascular disease was attributed to environmental chemical exposure with 2.5 million deaths per year. Clearly, the cardiovascular system, at all its various developmental and life stages, represents a critical target organ system that can be adversely affected by existing and emerging chemicals (e.g., engineered nanomaterials) in a variety of environmental media. The ability to assess chemical cardiac risk and safety is critically needed but extremely challenging due to the number and categories of chemicals in commerce, as indicated. This presentation\\session will evaluate the use of adult human stem cell derived cardiomyocytes, and existing platforms, as an alternative model to evaluate environmental chemical cardiac toxicity as well as provide key information for the development of predictive adverse outcomes pathways associated with environmental chemical exposures. (This abstract does not represent EPA policy) Rapid and translatable chemical safety screening models for cardiotoxicity current status for informing regulatory decisions, a workshop sponsored by the Society

Identification and characterization of properdin in amphioxus: Implications for a functional alternative complement pathway in the basal chordate.

PubMed

Gao, Zhan; Ma, Zengyu; Qu, Baozhen; Jiao, Deyan; Zhang, Shicui

2017-06-01

A complement system operating via the alternative pathway similar to that of vertebrates has been demonstrated in the primitive chordate amphioxus. However, the factor P (fP), a positive regulator of the alternative pathway, remains elusive in amphioxus to date. In this study, we identified and characterized a properdin gene in the amphioxus B. japonicum, BjfP, which represents an archetype of vertebrate properdins. Real-time PCR analysis showed that the BjfP was ubiquitously expressed and its expression was significantly up-regulated following the challenge with bacteria or lipopolysaccharide (LPS) and lipoteichoic acid (LTA). Recombinant BjfP (rBjfP) and its truncated proteins including rTSR1-3, rTSR4-6 and rTSR7-8, were all capable of interacting with both Gram-negative and positive bacteria as well as LPS and LTA. Moreover, rBjfP, rTSR1-3 and rTSR4-6 could also specifically bind to C3b. Importantly, both rTSR1-3 and rTSR4-6 could inhibit the binding of rBjfP to C3b, and thus suppress the activation of the alternative pathway of complement, suggesting the involvement of BjfP in the alternative pathway. This is the first report showing that a properdin protein in invertebrates plays similar roles to vertebrate properdins. Collectively, these data suggest that BjfP might represent the ancient molecule from which vertebrate properdins evolved. Copyright © 2017 Elsevier Ltd. All rights reserved.

Genetic control of the alternative pathway of complement in humans and age-related macular degeneration

PubMed Central

Hecker, Laura A.; Edwards, Albert O.; Ryu, Euijung; Tosakulwong, Nirubol; Baratz, Keith H.; Brown, William L.; Issa, Peter Charbel; Scholl, Hendrik P.; Pollok-Kopp, Beatrix; Schmid-Kubista, Katharina E.; Bailey, Kent R.; Oppermann, Martin

2010-01-01

Activation of the alternative pathway of complement is implicated in common neurodegenerative diseases including age-related macular degeneration (AMD). We explored the impact of common variation in genes encoding proteins of the alternative pathway on complement activation in human blood and in AMD. Genetic variation across the genes encoding complement factor H (CFH), factor B (CFB) and component 3 (C3) was determined. The influence of common haplotypes defining transcriptional and translational units on complement activation in blood was determined in a quantitative genomic association study. Individual haplotypes in CFH and CFB were associated with distinct and novel effects on plasma levels of precursors, regulators and activation products of the alternative pathway of complement in human blood. Further, genetic variation in CFH thought to influence cell surface regulation of complement did not alter plasma complement levels in human blood. Plasma markers of chronic activation (split-products Ba and C3d) and an activating enzyme (factor D) were elevated in AMD subjects. Most of the elevation in AMD was accounted for by the genetic variation controlling complement activation in human blood. Activation of the alternative pathway of complement in blood is under genetic control and increases with age. The genetic variation associated with increased activation of complement in human blood also increased the risk of AMD. Our data are consistent with a disease model in which genetic variation in the complement system increases the risk of AMD by a combination of systemic complement activation and abnormal regulation of complement activation in local tissues. PMID:19825847

Taenia crassiceps: fatty acids oxidation and alternative energy source in in vitro cysticerci exposed to anthelminthic drugs.

PubMed

Vinaud, Marina Clare; Ferreira, Cirlane Silva; Lino Junior, Ruy de Souza; Bezerra, José Clecildo Barreto

2009-07-01

Cysticerci metabolic studies demonstrate alternative pathways responsible for its survival, such as energy sources, fatty acids oxidation and excretion of beta-hydroxybutyrate, which indicates the capability of energy production from proteins. The aim of this study was to detect alternative metabolic pathways for energy production and its end products in Taenia crassiceps cysticerci in vitro exposed to praziquantel and albendazole, in sub-lethal doses. Spectrophotometer and chromatographic analysis were performed to detect: propionate, acetate, beta-hydroxybutyrate, total proteins, urea and creatinine, SE by cysticerci in vitro exposed to praziquantel and albendazole. The drugs influenced the metabolism by inducing the creatinine phosphate phosphorylation as an alternative energy source, inhibiting the use of proteins and amino acids in the acid nucleic synthesis; and preventing the budding and replication of the cysticerci. This study also highlights the description of urea excretion, which is an important metabolic pathway to excrete toxic products such as ammonia, and the fatty acid oxidation as an alternative energy source in cysticerci exposed to anthelmintic drugs.

Pluripotency and a secretion mechanism of Drosophila transglutaminase.

PubMed

Shibata, Toshio; Kawabata, Shun-Ichiro

2018-03-01

Transglutaminase (TG) catalyses the formation of an isopeptide bond between glutamine and lysine residues and amine incorporation into specific glutamine residues. TG is conserved in all metazoans and functions both intracellularly and extracellularly. Here we review the existing knowledge of Drosophila TG with an emphasis on its pluripotency: Drosophila TG (i) plays a key role in cuticular morphogenesis, haemolymph coagulation, and entrapment against invading pathogens, (ii) suppresses the immune deficiency pathway to enable immune tolerance against commensal bacteria through the incorporation of polyamines into the nuclear factor-κB-like transcription factor Relish as well as through the protein-protein cross-linking of Relish, (iii) forms a physical matrix in the gut through cross-linking of chitin-binding proteins and (iv) is involved in the maintenance of homeostasis in microbiota in the gut. Moreover, we review the evidence that TG-A, one of alternative splicing-derived isoforms of Drosophila TG, is secreted through an endoplasmic reticulum/Golgi-independent pathway involving exosomes and fatty acylations.

Ultralow-power switching via defect engineering in germanium telluride phase-change memory devices.

PubMed

Nukala, Pavan; Lin, Chia-Chun; Composto, Russell; Agarwal, Ritesh

2016-01-25

Crystal-amorphous transformation achieved via the melt-quench pathway in phase-change memory involves fundamentally inefficient energy conversion events; and this translates to large switching current densities, responsible for chemical segregation and device degradation. Alternatively, introducing defects in the crystalline phase can engineer carrier localization effects enhancing carrier-lattice coupling; and this can efficiently extract work required to introduce bond distortions necessary for amorphization from input electrical energy. Here, by pre-inducing extended defects and thus carrier localization effects in crystalline GeTe via high-energy ion irradiation, we show tremendous improvement in amorphization current densities (0.13-0.6 MA cm(-2)) compared with the melt-quench strategy (∼50 MA cm(-2)). We show scaling behaviour and good reversibility on these devices, and explore several intermediate resistance states that are accessible during both amorphization and recrystallization pathways. Existence of multiple resistance states, along with ultralow-power switching and scaling capabilities, makes this approach promising in context of low-power memory and neuromorphic computation.

Ultralow-power switching via defect engineering in germanium telluride phase-change memory devices

PubMed Central

Nukala, Pavan; Lin, Chia-Chun; Composto, Russell; Agarwal, Ritesh

2016-01-01

Crystal–amorphous transformation achieved via the melt-quench pathway in phase-change memory involves fundamentally inefficient energy conversion events; and this translates to large switching current densities, responsible for chemical segregation and device degradation. Alternatively, introducing defects in the crystalline phase can engineer carrier localization effects enhancing carrier–lattice coupling; and this can efficiently extract work required to introduce bond distortions necessary for amorphization from input electrical energy. Here, by pre-inducing extended defects and thus carrier localization effects in crystalline GeTe via high-energy ion irradiation, we show tremendous improvement in amorphization current densities (0.13–0.6 MA cm−2) compared with the melt-quench strategy (∼50 MA cm−2). We show scaling behaviour and good reversibility on these devices, and explore several intermediate resistance states that are accessible during both amorphization and recrystallization pathways. Existence of multiple resistance states, along with ultralow-power switching and scaling capabilities, makes this approach promising in context of low-power memory and neuromorphic computation. PMID:26805748

The VTAC Committee: developing guidance for an alternative regulatory pathway to the anadromous salmonid protection rules

Treesearch

Michael Liquori; Peter Cafferata; Kevin Boston; Richard Gienger; David Hope

2012-01-01

In recent decades, riparian protection standards have been guided by generalized prescriptive rules. With the passage of the Anadromous Salmonid Protection rules in 2009, the Board of Forestry and Fire Protection (Board) established a regulatory pathway that provides an alternative approach for riparian protection based on site-specific criteria (14 CCR § 916....

Alternative Pathways to Talent Development in Music: The Narrative of an Eminent Filipino Singer-Songwriter

ERIC Educational Resources Information Center

Garces-Bacsal, Rhoda Myra

2014-01-01

The narrative of an eminent Filipino singer-songwriter, Noel Cabangon, provides a description of an alternative pathway to musical talent development. Most theories on talent development assume that a young artist would have access to the resources required for one to advance in the domain. The results of multiple in-depth interviews suggested…

Targeting the PI3K/Akt pathway in murine MDS/MPN driven by hyperactive Ras.

PubMed

Akutagawa, J; Huang, T Q; Epstein, I; Chang, T; Quirindongo-Crespo, M; Cottonham, C L; Dail, M; Slusher, B S; Friedman, L S; Sampath, D; Braun, B S

2016-06-01

Chronic and juvenile myelomonocytic leukemias (CMML and JMML) are myelodysplastic/myeloproliferative neoplasia (MDS/MPN) overlap syndromes that respond poorly to conventional treatments. Aberrant Ras activation because of NRAS, KRAS, PTPN11, CBL and NF1 mutations is common in CMML and JMML. However, no mechanism-based treatments currently exist for cancers with any of these mutations. An alternative therapeutic strategy involves targeting Ras-regulated effector pathways that are aberrantly activated in CMML and JMML, which include the Raf/MEK/ERK and phosphoinositide-3'-OH kinase (PI3K)/Akt cascades. Mx1-Cre, Kras(D12) and Mx1-Cre, Nf1(flox/)(-) mice accurately model many aspects of CMML and JMML. Treating Mx1-Cre, Kras(D12) mice with GDC-0941 (also referred to as pictilisib), an orally bioavailable inhibitor of class I PI3K isoforms, reduced leukocytosis, anemia and splenomegaly while extending survival. However, GDC-0941 treatment attenuated activation of both PI3K/Akt and Raf/MEK/ERK pathways in primary hematopoietic cells, suggesting it could be acting through suppression of Raf/MEK/ERK signals. To interrogate the importance of the PI3K/Akt pathway specifically, we treated mice with the allosteric Akt inhibitor MK-2206. This compound had no effect on Raf/MEK/ERK signaling, yet it also induced robust hematologic responses in Kras and Nf1 mice with MPN. These data support investigating PI3K/Akt pathway inhibitors as a therapeutic strategy in JMML and CMML patients.

The G2 block induced by DNA damage: a caffeine-resistant component independent of Cdc25C, MPM-2 phosphorylation, and H1 kinase activity.

PubMed

Barratt, R A; Kao, G; McKenna, W G; Kuang, J; Muschel, R J

1998-06-15

Treatment of cells with agents that cause DNA damage often results in a delay in G2. There is convincing evidence showing that inhibition of p34cdc2 kinase activation is involved in the DNA damage-induced G2 delay. In this study, we have demonstrated the existence of an additional pathway, independent of the p34cdc2 kinase activation pathway, that leads to a G2 arrest in etoposide-treated cells. Both the X-ray-induced and the etoposide-induced G2 arrest were associated with inhibition of the p34cdc2 H1 kinase activation pathway as judged by p34cdc2 H1 kinase activity and phosphorylation of cdc25C. Caffeine treatment restored these activities after either of the treatments. However, the etoposide-treated cells did not resume cycling, revealing the presence of an alternative pathway leading to a G2 arrest. To explore the possibility that this additional pathway involved phosphorylation of the MPM-2 epitope that is shared by a large family of mitotic phosphoproteins, we monitored the phosphorylation status of the MPM-2 epitope after DNA damage and after treatment with caffeine. Phosphorylation of the MPM-2 epitope was depressed in both X-ray and etoposide-treated cells, and the depression was reversed by caffeine in both cases. The results indicate that the pathway affecting MPM-2 epitope phosphorylation is involved in the G2 delay caused by DNA damage. However, it is not part of the caffeine-insensitive pathway leading to a G2 block seen in etoposide-treated cells.

Pinpointing retrovirus entry sites in cells expressing alternatively spliced receptor isoforms by single virus imaging.

PubMed

Padilla-Parra, Sergi; Marin, Mariana; Kondo, Naoyuki; Melikyan, Gregory B

2014-06-16

The majority of viruses enter host cells via endocytosis. Current knowledge of viral entry pathways is largely based upon infectivity measurements following genetic and/or pharmacological interventions that disrupt vesicular trafficking and maturation. Imaging of single virus entry in living cells provides a powerful means to delineate viral trafficking pathways and entry sites under physiological conditions. Here, we visualized single avian retrovirus co-trafficking with markers for early (Rab5) and late (Rab7) endosomes, acidification of endosomal lumen and the resulting viral fusion measured by the viral content release into the cytoplasm. Virus-carrying vesicles either merged with the existing Rab5-positive early endosomes or slowly accumulated Rab5. The Rab5 recruitment to virus-carrying endosomes correlated with acidification of their lumen. Viral fusion occurred either in early (Rab5-positive) or intermediate (Rab5- and Rab7-positive) compartments. Interestingly, different isoforms of the cognate receptor directed virus entry from distinct endosomes. In cells expressing the transmembrane receptor, viruses preferentially entered and fused with slowly maturing early endosomes prior to accumulation of Rab7. By comparison, in cells expressing the GPI-anchored receptor, viruses entered both slowly and quickly maturing endosomes and fused with early (Rab5-positive) and intermediate (Rab5- and Rab7-positive) compartments. Since the rate of low pH-triggered fusion was independent of the receptor isoform, we concluded that the sites of virus entry are determined by the kinetic competition between endosome maturation and viral fusion. Our findings demonstrate the ability of this retrovirus to enter cells via alternative endocytic pathways and establish infection by releasing its content from distinct endosomal compartments.

Two Alternative Pathways for the Synthesis of the Rare Compatible Solute Mannosylglucosylglycerate in Petrotoga mobilis▿

PubMed Central

Fernandes, Chantal; Mendes, Vitor; Costa, Joana; Empadinhas, Nuno; Jorge, Carla; Lamosa, Pedro; Santos, Helena; da Costa, Milton S.

2010-01-01

The compatible solute mannosylglucosylglycerate (MGG), recently identified in Petrotoga miotherma, also accumulates in Petrotoga mobilis in response to hyperosmotic conditions and supraoptimal growth temperatures. Two functionally connected genes encoding a glucosyl-3-phosphoglycerate synthase (GpgS) and an unknown glycosyltransferase (gene Pmob_1143), which we functionally characterized as a mannosylglucosyl-3-phosphoglycerate synthase and designated MggA, were identified in the genome of Ptg. mobilis. This enzyme used the product of GpgS, glucosyl-3-phosphoglycerate (GPG), as well as GDP-mannose to produce mannosylglucosyl-3-phosphoglycerate (MGPG), the phosphorylated precursor of MGG. The MGPG dephosphorylation was determined in cell extracts, and the native enzyme was partially purified and characterized. Surprisingly, a gene encoding a putative glucosylglycerate synthase (Ggs) was also identified in the genome of Ptg. mobilis, and an active Ggs capable of producing glucosylglycerate (GG) from ADP-glucose and d-glycerate was detected in cell extracts and the recombinant enzyme was characterized, as well. Since GG has never been identified in this organism nor was it a substrate for the MggA, we anticipated the existence of a nonphosphorylating pathway for MGG synthesis. We putatively identified the corresponding gene, whose product had some sequence homology with MggA, but it was not possible to recombinantly express a functional enzyme from Ptg. mobilis, which we named mannosylglucosylglycerate synthase (MggS). In turn, a homologous gene from Thermotoga maritima was successfully expressed, and the synthesis of MGG was confirmed from GDP-mannose and GG. Based on the measurements of the relevant enzyme activities in cell extracts and on the functional characterization of the key enzymes, we propose two alternative pathways for the synthesis of the rare compatible solute MGG in Ptg. mobilis. PMID:20061481

Autotaxin activity increases locally following lung injury, but is not required for pulmonary lysophosphatidic acid production or fibrosis.

PubMed

Black, Katharine E; Berdyshev, Evgeny; Bain, Gretchen; Castelino, Flavia V; Shea, Barry S; Probst, Clemens K; Fontaine, Benjamin A; Bronova, Irina; Goulet, Lance; Lagares, David; Ahluwalia, Neil; Knipe, Rachel S; Natarajan, Viswanathan; Tager, Andrew M

2016-06-01

Lysophosphatidic acid (LPA) is an important mediator of pulmonary fibrosis. In blood and multiple tumor types, autotaxin produces LPA from lysophosphatidylcholine (LPC) via lysophospholipase D activity, but alternative enzymatic pathways also exist for LPA production. We examined the role of autotaxin (ATX) in pulmonary LPA production during fibrogenesis in a bleomycin mouse model. We found that bleomycin injury increases the bronchoalveolar lavage (BAL) fluid levels of ATX protein 17-fold. However, the LPA and LPC species that increase in BAL of bleomycin-injured mice were discordant, inconsistent with a substrate-product relationship between LPC and LPA in pulmonary fibrosis. LPA species with longer chain polyunsaturated acyl groups predominated in BAL fluid after bleomycin injury, with 22:5 and 22:6 species accounting for 55 and 16% of the total, whereas the predominant BAL LPC species contained shorter chain, saturated acyl groups, with 16:0 and 18:0 species accounting for 56 and 14% of the total. Further, administration of the potent ATX inhibitor PAT-048 to bleomycin-challenged mice markedly decreased ATX activity systemically and in the lung, without effect on pulmonary LPA or fibrosis. Therefore, alternative ATX-independent pathways are likely responsible for local generation of LPA in the injured lung. These pathways will require identification to therapeutically target LPA production in pulmonary fibrosis.-Black, K. E., Berdyshev, E., Bain, G., Castelino, F. V., Shea, B. S., Probst, C. K., Fontaine, B. A., Bronova, I., Goulet, L., Lagares, D., Ahluwalia, N., Knipe, R. S., Natarajan, V., Tager, A. M. Autotaxin activity increases locally following lung injury, but is not required for pulmonary lysophosphatidic acid production or fibrosis. © FASEB.

Application of Adverse Outcome Pathways to U.S. EPA’s Endocrine Disruptor Screening Program

PubMed Central

Noyes, Pamela D.; Casey, Warren M.; Dix, David J.

2017-01-01

Background: The U.S. EPA’s Endocrine Disruptor Screening Program (EDSP) screens and tests environmental chemicals for potential effects in estrogen, androgen, and thyroid hormone pathways, and it is one of the only regulatory programs designed around chemical mode of action. Objectives: This review describes the EDSP’s use of adverse outcome pathway (AOP) and toxicity pathway frameworks to organize and integrate diverse biological data for evaluating the endocrine activity of chemicals. Using these frameworks helps to establish biologically plausible links between endocrine mechanisms and apical responses when those end points are not measured in the same assay. Results: Pathway frameworks can facilitate a weight of evidence determination of a chemical’s potential endocrine activity, identify data gaps, aid study design, direct assay development, and guide testing strategies. Pathway frameworks also can be used to evaluate the performance of computational approaches as alternatives for low-throughput and animal-based assays and predict downstream key events. In cases where computational methods can be validated based on performance, they may be considered as alternatives to specific assays or end points. Conclusions: A variety of biological systems affect apical end points used in regulatory risk assessments, and without mechanistic data, an endocrine mode of action cannot be determined. Because the EDSP was designed to consider mode of action, toxicity pathway and AOP concepts are a natural fit. Pathway frameworks have diverse applications to endocrine screening and testing. An estrogen pathway example is presented, and similar approaches are being used to evaluate alternative methods and develop predictive models for androgen and thyroid pathways. https://doi.org/10.1289/EHP1304 PMID:28934726

Cerebral Gluconeogenesis and Diseases

PubMed Central

Yip, James; Geng, Xiaokun; Shen, Jiamei; Ding, Yuchuan

2017-01-01

The gluconeogenesis pathway, which has been known to normally present in the liver, kidney, intestine, or muscle, has four irreversible steps catalyzed by the enzymes: pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose 1,6-bisphosphatase, and glucose 6-phosphatase. Studies have also demonstrated evidence that gluconeogenesis exists in brain astrocytes but no convincing data have yet been found in neurons. Astrocytes exhibit significant 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 activity, a key mechanism for regulating glycolysis and gluconeogenesis. Astrocytes are unique in that they use glycolysis to produce lactate, which is then shuttled into neurons and used as gluconeogenic precursors for reduction. This gluconeogenesis pathway found in astrocytes is becoming more recognized as an important alternative glucose source for neurons, specifically in ischemic stroke and brain tumor. Further studies are needed to discover how the gluconeogenesis pathway is controlled in the brain, which may lead to the development of therapeutic targets to control energy levels and cellular survival in ischemic stroke patients, or inhibit gluconeogenesis in brain tumors to promote malignant cell death and tumor regression. While there are extensive studies on the mechanisms of cerebral glycolysis in ischemic stroke and brain tumors, studies on cerebral gluconeogenesis are limited. Here, we review studies done to date regarding gluconeogenesis to evaluate whether this metabolic pathway is beneficial or detrimental to the brain under these pathological conditions. PMID:28101056

Functional Toxicogenomic Assessment of Triclosan in Human HepG2 Cells Using Genome-Wide CRISPR-Cas9 Screening.

PubMed

Xia, Pu; Zhang, Xiaowei; Xie, Yuwei; Guan, Miao; Villeneuve, Daniel L; Yu, Hongxia

2016-10-04

There are thousands of chemicals used by humans and detected in the environment for which limited or no toxicological data are available. Rapid and cost-effective approaches for assessing the toxicological properties of chemicals are needed. We used CRISPR-Cas9 functional genomic screening to identify the potential molecular mechanism of a widely used antimicrobial triclosan (TCS) in HepG2 cells. Resistant genes at IC50 (the concentration causing a 50% reduction in cell viability) were significantly enriched in the adherens junction pathway, MAPK signaling pathway, and PPAR signaling pathway, suggesting a potential role in the molecular mechanism of TCS-induced cytotoxicity. Evaluation of the top-ranked resistant genes, FTO (encoding an mRNA demethylase) and MAP2K3 (a MAP kinase kinase family gene), revealed that their loss conferred resistance to TCS. In contrast, sensitive genes at IC10 and IC20 were specifically enriched in pathways involved with immune responses, which was concordant with transcriptomic profiling of TCS at concentrations of

Development and application of the adverse outcome pathway framework for understanding and predicting chronic toxicity: II. A focus on growth impairment in fish.

PubMed

Groh, Ksenia J; Carvalho, Raquel N; Chipman, James K; Denslow, Nancy D; Halder, Marlies; Murphy, Cheryl A; Roelofs, Dick; Rolaki, Alexandra; Schirmer, Kristin; Watanabe, Karen H

2015-02-01

Adverse outcome pathways (AOPs) organize knowledge on the progression of toxicity through levels of biological organization. By determining the linkages between toxicity events at different levels, AOPs lay the foundation for mechanism-based alternative testing approaches to hazard assessment. Here, we focus on growth impairment in fish to illustrate the initial stages in the process of AOP development for chronic toxicity outcomes. Growth is an apical endpoint commonly assessed in chronic toxicity tests for which a replacement is desirable. Based on several criteria, we identified reduction in food intake to be a suitable key event for initiation of middle-out AOP development. To start exploring the upstream and downstream links of this key event, we developed three AOP case studies, for pyrethroids, selective serotonin reuptake inhibitors (SSRIs) and cadmium. Our analysis showed that the effect of pyrethroids and SSRIs on food intake is strongly linked to growth impairment, while cadmium causes a reduction in growth due to increased metabolic demands rather than changes in food intake. Locomotion impairment by pyrethroids is strongly linked to their effects on food intake and growth, while for SSRIs their direct influence on appetite may play a more important role. We further discuss which alternative tests could be used to inform on the predictive key events identified in the case studies. In conclusion, our work demonstrates how the AOP concept can be used in practice to assess critically the knowledge available for specific chronic toxicity cases and to identify existing knowledge gaps and potential alternative tests. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

FOXO3 Modulates Endothelial Gene Expression and Function by Classical and Alternative Mechanisms*

PubMed Central

Czymai, Tobias; Viemann, Dorothee; Sticht, Carsten; Molema, Grietje; Goebeler, Matthias; Schmidt, Marc

2010-01-01

FOXO transcription factors represent targets of the phosphatidylinositol 3-kinase/protein kinase B survival pathway controlling important biological processes, such as cell cycle progression, apoptosis, vascular remodeling, stress responses, and metabolism. Recent studies suggested the existence of alternative mechanisms of FOXO-dependent gene expression beyond classical binding to a FOXO-responsive DNA-binding element (FRE). Here we analyzed the relative contribution of those mechanisms to vascular function by comparing the transcriptional and cellular responses to conditional activation of FOXO3 and a corresponding FRE-binding mutant in human primary endothelial cells. We demonstrate that FOXO3 controls expression of vascular remodeling genes in an FRE-dependent manner. In contrast, FOXO3-induced cell cycle arrest and apoptosis occurs independently of FRE binding, albeit FRE-dependent gene expression augments the proapoptotic response. These findings are supported by bioinformatical analysis, which revealed a statistical overrepresentation of cell cycle regulators and apoptosis-related genes in the group of co-regulated genes. Molecular analysis of FOXO3-induced endothelial apoptosis excluded modulators of the extrinsic death receptor pathway and demonstrated important roles for the BCL-2 family members BIM and NOXA in this process. Although NOXA essentially contributed to FRE-dependent apoptosis, BIM was effectively induced in the absence of FRE-binding, and small interfering RNA-mediated BIM depletion could rescue apoptosis induced by both FOXO3 mutants. These data suggest BIM as a critical cell type-specific mediator of FOXO3-induced endothelial apoptosis, whereas NOXA functions as an amplifying factor. Our study provides the first comprehensive analysis of alternatively regulated FOXO3 targets in relevant primary cells and underscores the importance of such genes for endothelial function and integrity. PMID:20123982

Alternative Mating Type Configurations (a/α versus a/a or α/α) of Candida albicans Result in Alternative Biofilms Regulated by Different Pathways

PubMed Central

Srikantha, Thyagarajan; Huang, Guanghua; Garnaas, Adam M.; Soll, David R.

2011-01-01

Similar multicellular structures can evolve within the same organism that may have different evolutionary histories, be controlled by different regulatory pathways, and play similar but nonidentical roles. In the human fungal pathogen Candida albicans, a quite extraordinary example of this has occurred. Depending upon the configuration of the mating type locus (a/α versus a/a or α/α), C. albicans forms alternative biofilms that appear similar morphologically, but exhibit dramatically different characteristics and are regulated by distinctly different signal transduction pathways. Biofilms formed by a/α cells are impermeable to molecules in the size range of 300 Da to 140 kDa, are poorly penetrated by human polymorphonuclear leukocytes (PMNs), and are resistant to antifungals. In contrast, a/a or α/α biofilms are permeable to molecules in this size range, are readily penetrated by PMNs, and are susceptible to antifungals. By mutational analyses, a/α biofilms are demonstrated to be regulated by the Ras1/cAMP pathway that includes Ras1→Cdc35→cAMP(Pde2—|)→Tpk2(Tpk1)→Efg1→Tec1→Bcr1, and a/a biofilms by the MAP kinase pathway that includes Mfα→Ste2→ (Ste4, Ste18, Cag1)→Ste11→Hst7→Cek2(Cek1)→Tec1. These observations suggest the hypothesis that while the upstream portion of the newly evolved pathway regulating a/a and α/α cell biofilms was derived intact from the upstream portion of the conserved pheromone-regulated pathway for mating, the downstream portion was derived through modification of the downstream portion of the conserved pathway for a/α biofilm formation. C. albicans therefore forms two alternative biofilms depending upon mating configuration. PMID:21829325

Exploiting differential RNA splicing patterns: a potential new group of therapeutic targets in cancer.

PubMed

Jyotsana, Nidhi; Heuser, Michael

2018-02-01

Mutations in genes associated with splicing have been found in hematologic malignancies, but also in solid cancers. Aberrant cancer specific RNA splicing either results from mutations or misexpression of the spliceosome genes directly, or from mutations in splice sites of oncogenes or tumor suppressors. Areas covered: In this review, we present molecular targets of aberrant splicing in various malignancies, information on existing and emerging therapeutics against such targets, and strategies for future drug development. Expert opinion: Alternative splicing is an important mechanism that controls gene expression, and hence pharmacologic and genetic control of aberrant alternative RNA splicing has been proposed as a potential therapy in cancer. To identify and validate aberrant RNA splicing patterns as therapeutic targets we need to (1) characterize the most common genetic aberrations of the spliceosome and of splice sites, (2) understand the dysregulated downstream pathways and (3) exploit in-vivo disease models of aberrant splicing. Antisense oligonucleotides show promising activity, but will benefit from improved delivery tools. Inhibitors of mutated splicing factors require improved specificity, as alternative and aberrant splicing are often intertwined like two sides of the same coin. In summary, targeting aberrant splicing is an early but emerging field in cancer treatment.

"Which Pathway Am I?" Using a Game Approach to Teach Students about Biochemical Pathways

ERIC Educational Resources Information Center

Ooi, Beng Guat; Sanger, Michael J.

2009-01-01

This game was designed to provide students with an alternative way to learn biochemical pathways through an interactive approach. In this game, students worked in pairs to help each other identify pathways taped to each other's backs by asking simple "yes or no" questions related to these pathways. This exercise was conducted after the traditional…

Use of navigation channels by Lake Sturgeon: Does channelization increase vulnerability of fish to ship strikes?

PubMed

Hondorp, Darryl W; Bennion, David H; Roseman, Edward F; Holbrook, Christopher M; Boase, James C; Chiotti, Justin A; Thomas, Michael V; Wills, Todd C; Drouin, Richard G; Kessel, Steven T; Krueger, Charles C

2017-01-01

Channelization for navigation and flood control has altered the hydrology and bathymetry of many large rivers with unknown consequences for fish species that undergo riverine migrations. In this study, we investigated whether altered flow distributions and bathymetry associated with channelization attracted migrating Lake Sturgeon (Acipenser fulvescens) into commercial navigation channels, potentially increasing their exposure to ship strikes. To address this question, we quantified and compared Lake Sturgeon selection for navigation channels vs. alternative pathways in two multi-channel rivers differentially affected by channelization, but free of barriers to sturgeon movement. Acoustic telemetry was used to quantify Lake Sturgeon movements. Under the assumption that Lake Sturgeon navigate by following primary flow paths, acoustic-tagged Lake Sturgeon in the more-channelized lower Detroit River were expected to choose navigation channels over alternative pathways and to exhibit greater selection for navigation channels than conspecifics in the less-channelized lower St. Clair River. Consistent with these predictions, acoustic-tagged Lake Sturgeon in the more-channelized lower Detroit River selected the higher-flow and deeper navigation channels over alternative migration pathways, whereas in the less-channelized lower St. Clair River, individuals primarily used pathways alternative to navigation channels. Lake Sturgeon selection for navigation channels as migratory pathways also was significantly higher in the more-channelized lower Detroit River than in the less-channelized lower St. Clair River. We speculated that use of navigation channels over alternative pathways would increase the spatial overlap of commercial vessels and migrating Lake Sturgeon, potentially enhancing their vulnerability to ship strikes. Results of our study thus demonstrated an association between channelization and the path use of migrating Lake Sturgeon that could prove important for predicting sturgeon-vessel interactions in navigable rivers as well as for understanding how fish interact with their habitat in landscapes altered by human activity.

Use of navigation channels by Lake Sturgeon: Does channelization increase vulnerability of fish to ship strikes?

PubMed Central

Bennion, David H.; Roseman, Edward F.; Holbrook, Christopher M.; Boase, James C.; Chiotti, Justin A.; Thomas, Michael V.; Wills, Todd C.; Drouin, Richard G.; Kessel, Steven T.; Krueger, Charles C.

2017-01-01

Channelization for navigation and flood control has altered the hydrology and bathymetry of many large rivers with unknown consequences for fish species that undergo riverine migrations. In this study, we investigated whether altered flow distributions and bathymetry associated with channelization attracted migrating Lake Sturgeon (Acipenser fulvescens) into commercial navigation channels, potentially increasing their exposure to ship strikes. To address this question, we quantified and compared Lake Sturgeon selection for navigation channels vs. alternative pathways in two multi-channel rivers differentially affected by channelization, but free of barriers to sturgeon movement. Acoustic telemetry was used to quantify Lake Sturgeon movements. Under the assumption that Lake Sturgeon navigate by following primary flow paths, acoustic-tagged Lake Sturgeon in the more-channelized lower Detroit River were expected to choose navigation channels over alternative pathways and to exhibit greater selection for navigation channels than conspecifics in the less-channelized lower St. Clair River. Consistent with these predictions, acoustic-tagged Lake Sturgeon in the more-channelized lower Detroit River selected the higher-flow and deeper navigation channels over alternative migration pathways, whereas in the less-channelized lower St. Clair River, individuals primarily used pathways alternative to navigation channels. Lake Sturgeon selection for navigation channels as migratory pathways also was significantly higher in the more-channelized lower Detroit River than in the less-channelized lower St. Clair River. We speculated that use of navigation channels over alternative pathways would increase the spatial overlap of commercial vessels and migrating Lake Sturgeon, potentially enhancing their vulnerability to ship strikes. Results of our study thus demonstrated an association between channelization and the path use of migrating Lake Sturgeon that could prove important for predicting sturgeon-vessel interactions in navigable rivers as well as for understanding how fish interact with their habitat in landscapes altered by human activity. PMID:28678798

SFK-STAT pathway: an alternative and important way to malignancies.

PubMed

Hayakawa, Fumihiko; Naoe, Tomoki

2006-11-01

Signal transducers and activators of transcription (STAT) proteins play a crucial role in mediating signals from a diverse spectrum of cytokine receptors. STAT is thought to be activated by JAK family kinases (JFK) in many cytokine receptor signal pathways; however, recent studies have demonstrated an alternative pathway to activate STAT by Src family kinases (SFK) in growth factor receptor signal. We also observed STAT5 phosphorylation by Lyn, a member of SFK, in our two recent studies. We introduce these studies and review the literature of STAT activation by SFK and aberrant activation of STAT by oncogenic signals.

Sustainable and efficient pathways for bioenergy recovery from low-value process streams via bioelectrochemical systems in biorefineries

DOE PAGES

Borole, Abhijeet P.

2015-08-25

Conversion of biomass into bioenergy is possible via multiple pathways resulting in production of biofuels, bioproducts and biopower. Efficient and sustainable conversion of biomass, however, requires consideration of many environmental and societal parameters in order to minimize negative impacts. Integration of multiple conversion technologies and inclusion of upcoming alternatives such as bioelectrochemical systems can minimize these impacts and improve conservation of resources such as hydrogen, water and nutrients via recycle and reuse. This report outlines alternate pathways integrating microbial electrolysis in biorefinery schemes to improve energy efficiency while evaluating environmental sustainability parameters.

Glycolytic strategy as a tradeoff between energy yield and protein cost

PubMed Central

Flamholz, Avi; Noor, Elad; Bar-Even, Arren; Liebermeister, Wolfram; Milo, Ron

2013-01-01

Contrary to the textbook portrayal of glycolysis as a single pathway conserved across all domains of life, not all sugar-consuming organisms use the canonical Embden–Meyerhoff–Parnass (EMP) glycolytic pathway. Prokaryotic glucose metabolism is particularly diverse, including several alternative glycolytic pathways, the most common of which is the Entner–Doudoroff (ED) pathway. The prevalence of the ED pathway is puzzling as it produces only one ATP per glucose—half as much as the EMP pathway. We argue that the diversity of prokaryotic glucose metabolism may reflect a tradeoff between a pathway’s energy (ATP) yield and the amount of enzymatic protein required to catalyze pathway flux. We introduce methods for analyzing pathways in terms of thermodynamics and kinetics and show that the ED pathway is expected to require several-fold less enzymatic protein to achieve the same glucose conversion rate as the EMP pathway. Through genomic analysis, we further show that prokaryotes use different glycolytic pathways depending on their energy supply. Specifically, energy-deprived anaerobes overwhelmingly rely upon the higher ATP yield of the EMP pathway, whereas the ED pathway is common among facultative anaerobes and even more common among aerobes. In addition to demonstrating how protein costs can explain the use of alternative metabolic strategies, this study illustrates a direct connection between an organism’s environment and the thermodynamic and biochemical properties of the metabolic pathways it employs. PMID:23630264

Traditional or Alternative--Finding New Teachers along Different Pathways

ERIC Educational Resources Information Center

Reese, Susan

2010-01-01

In 2009, the National Center for Policy Analysis (NCPA) brief, "Alternative Certification Programs: Meeting the Demand for Effective Teachers," noted that each state had its own requirements for alternative certification, and while some states and school districts have become more open to alternative certification, other states are very…

Identification of the alternative terminal oxidase of higher plant mitochondria

PubMed Central

Elthon, Thomas E.; McIntosh, Lee

1987-01-01

In addition to cytochrome oxidase, plant mitochondria have a second terminal oxidase called the alternative oxidase. The alternative oxidase is of great interest in that energy is not conserved when electrons flow through it. The potential energy of the system is thus lost as heat, and, in plants with high levels of the alternative oxidase, this results in thermogenesis. We have purified the alternative oxidase from mitochondria of the thermogenic spadix of Sauromatum guttatum and have identified its polypeptide constituents by using polyclonal antibodies. A 166-fold purification was achieved through a combination of cation-exchange (carboxymethyl-Sepharose) and hydrophobic-interaction (phenyl-Sepharose) chromatography. Polyclonal antibodies raised to the CM-Sepharose fractions readily immunoprecipitated alternative oxidase activity and immunoprecipitated four of the proteins that copurify with the activity. These proteins have apparent molecular masses of 37, 36, 35.5, and 35 kDa. Polyclonal antibodies raised individually to the 37-, 36-, and 35.5- plus 35-kDa proteins cross-reacted with all of these proteins, indicating the presence of common antigenic sites. The 37-kDa protein appears to be constitutive in Sauromatum, whereas expression of the 36- and 35-kDa proteins was correlated with presence of alternative pathway activity. The 35.5-kDa protein appears with loss of alternative pathway activity during senescence, indicating that this protein may be a degradation product of the 36-kDa protein. Binding of anti-36-kDa protein antibodies to total mitochondrial protein blots of five plant species indicated that similar proteins were always present when alternative pathway activity was observed. Images PMID:16593898

Understanding alternative fluxes/effluxes through comparative metabolic pathway analysis of phylum actinobacteria using a simplified approach.

PubMed

Verma, Mansi; Lal, Devi; Saxena, Anjali; Anand, Shailly; Kaur, Jasvinder; Kaur, Jaspreet; Lal, Rup

2013-12-01

Actinobacteria are known for their diverse metabolism and physiology. Some are dreadful human pathogens whereas some constitute the natural flora for human gut. Therefore, the understanding of metabolic pathways is a key feature for targeting the pathogenic bacteria without disturbing the symbiotic ones. A big challenge faced today is multiple drug resistance by Mycobacterium and other pathogens that utilize alternative fluxes/effluxes. With the availability of genome sequence, it is now feasible to conduct the comparative in silico analysis. Here we present a simplified approach to compare metabolic pathways so that the species specific enzyme may be traced and engineered for future therapeutics. The analyses of four key carbohydrate metabolic pathways, i.e., glycolysis, pyruvate metabolism, tri carboxylic acid cycle and pentose phosphate pathway suggest the presence of alternative fluxes. It was found that the upper pathway of glycolysis was highly variable in the actinobacterial genomes whereas lower glycolytic pathway was highly conserved. Likewise, pentose phosphate pathway was well conserved in contradiction to TCA cycle, which was found to be incomplete in majority of actinobacteria. The clustering based on presence and absence of genes of these metabolic pathways clearly revealed that members of different genera shared identical pathways and, therefore, provided an easy method to identify the metabolic similarities/differences between pathogenic and symbiotic organisms. The analyses could identify isoenzymes and some key enzymes that were found to be missing in some pathogenic actinobacteria. The present work defines a simple approach to explore the effluxes in four metabolic pathways within the phylum actinobacteria. The analysis clearly reflects that actinobacteria exhibit diverse routes for metabolizing substrates. The pathway comparison can help in finding the enzymes that can be used as drug targets for pathogens without effecting symbiotic organisms within the same host. This may help to prevail over the multiple drug resistance, for designing broad spectrum drugs, in food industries and other clinical research areas. © 2013.

77 FR 61633 - Information Collection: Renewable Energy and Alternate Uses of Existing Facilities on the Outer...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-10-10

...] Information Collection: Renewable Energy and Alternate Uses of Existing Facilities on the Outer Continental... requirements in the regulations under ``Renewable Energy and Alternate Uses of Existing Facilities on the Outer..., transportation, or transmission of energy from sources other than oil and gas (renewable energy). Specifically...

CORRECTIVE ACTION DECISION DOCUMENT FOR AREA 9 UXO LANDFILL, TONOPAH TEST RNGE, CAU 453, REVISION 0, MARCH 1998

DOE Office of Scientific and Technical Information (OSTI.GOV)

none

1998-03-01

This Corrective Action Decision Document (CADD) has been prepared for the Area 9 Unexploded Ordnance (UXO) Landfill (Corrective Action Unit [CAU] 453) in accordance with the Federal Facility Agreement and Consent Order (FFACO) of 1996. Corrective Action Unit 453 is located at the Tonopah Test Range (TTR), Nevada, and is comprised of three individual landfill cells located northwest of Area 9. The cells are listed as one Corrective Action Site (CAS) 09-55-001-0952. The landfill cells have been designated as: � Cell A9-1 � Cell A9-2 � Cell A9-3 The purpose of this CADD is to identify and provide a rationalemore » for the selection of a recommended corrective action alternative for CAU 453. The scope of this CADD consists of the following tasks: � Develop corrective action objectives. � Identify corrective action alternative screening criteria. � Develop corrective action alternatives. � Perform detailed and comparative evaluations of the corrective action alternatives in relation to the corrective action objectives and screening criteria. � Recommend and justify a preferred corrective action alternative for the CAU. In June and July 1997, a corrective action investigation was performed that consisted of activities set forth in the Corrective Action Investigation Plan (CAIP) (DOE/NV, 1997). Subsurface investigation of the soils surrounding the cells revealed no contaminants of concern (COCs) above preliminary action levels. The cell contents were not investigated due to the potential for live UXO. Details concerning the analytical and investigation results can be found in Appendix A of this CADD. Based on the potential exposure pathways, the following corrective action objectives have been identified for CAU 453: � Prevent or mitigate human exposure to subsurface soils containing COCs, solid waste, and/or UXO. � Prevent adverse impacts to groundwater quality. Based on the review of existing data, future land use, and current operations at the TTR, the following alternatives have been developed for consideration at the Area 9 UXO Landfill CAU: � Alternative 1 - No Further Action � Alternative 2 - Closure in Place by Administrative Controls � Alternative 3 - Closure in Place by Capping � Alternative 4 - Clean Closure by Removal The corrective action alternatives were evaluated based on four general corrective action standards and five remedy selection decision factors. Based on the results of this evaluation, Alternative 2, Closure in Place by Administrative Controls, was selected as the preferred corrective action alternative. The preferred corrective action alternative was evaluated on its technical merits, focusing on performance, reliability, feasibility, and safety. The alternative was judged to meet all requirements for the technical components evaluated and to represent the most cost-effective corrective action. The alternative meets all applicable state and federal regulations for closure of the site and will reduce potential future exposure pathways to the contents of the landfill. During corrective action implementation, this alternative will present minimal potential threat to site workers. However, appropriate health and safety procedures will be developed and implemented.« less

Pathways of topological rank analysis (PoTRA): a novel method to detect pathways involved in hepatocellular carcinoma.

PubMed

Li, Chaoxing; Liu, Li; Dinu, Valentin

2018-01-01

Complex diseases such as cancer are usually the result of a combination of environmental factors and one or several biological pathways consisting of sets of genes. Each biological pathway exerts its function by delivering signaling through the gene network. Theoretically, a pathway is supposed to have a robust topological structure under normal physiological conditions. However, the pathway's topological structure could be altered under some pathological condition. It is well known that a normal biological network includes a small number of well-connected hub nodes and a large number of nodes that are non-hubs. In addition, it is reported that the loss of connectivity is a common topological trait of cancer networks, which is an assumption of our method. Hence, from normal to cancer, the process of the network losing connectivity might be the process of disrupting the structure of the network, namely, the number of hub genes might be altered in cancer compared to that in normal or the distribution of topological ranks of genes might be altered. Based on this, we propose a new PageRank-based method called Pathways of Topological Rank Analysis (PoTRA) to detect pathways involved in cancer. We use PageRank to measure the relative topological ranks of genes in each biological pathway, then select hub genes for each pathway, and use Fisher's exact test to test if the number of hub genes in each pathway is altered from normal to cancer. Alternatively, if the distribution of topological ranks of gene in a pathway is altered between normal and cancer, this pathway might also be involved in cancer. Hence, we use the Kolmogorov-Smirnov test to detect pathways that have an altered distribution of topological ranks of genes between two phenotypes. We apply PoTRA to study hepatocellular carcinoma (HCC) and several subtypes of HCC. Very interestingly, we discover that all significant pathways in HCC are cancer-associated generally, while several significant pathways in subtypes of HCC are HCC subtype-associated specifically. In conclusion, PoTRA is a new approach to explore and discover pathways involved in cancer. PoTRA can be used as a complement to other existing methods to broaden our understanding of the biological mechanisms behind cancer at the system-level.

UNC-108/Rab2 Regulates Postendocytic Trafficking in Caenorhabditis elegans

PubMed Central

Chun, Denise K.; McEwen, Jason M.; Burbea, Michelle

2008-01-01

After endocytosis, membrane proteins are often sorted between two alternative pathways: a recycling pathway and a degradation pathway. Relatively little is known about how trafficking through these alternative pathways is differentially regulated. Here, we identify UNC-108/Rab2 as a regulator of postendocytic trafficking in both neurons and coelomocytes. Mutations in the Caenorhabditis elegans Rab2 gene unc-108, caused the green fluorescent protein (GFP)-tagged glutamate receptor GLR-1 (GLR-1::GFP) to accumulate in the ventral cord and in neuronal cell bodies. In neuronal cell bodies of unc-108/Rab2 mutants, GLR-1::GFP was found in tubulovesicular structures that colocalized with markers for early and recycling endosomes, including Syntaxin-13 and Rab8. GFP-tagged Syntaxin-13 also accumulated in the ventral cord of unc-108/Rab2 mutants. UNC-108/Rab2 was not required for ubiquitin-mediated sorting of GLR-1::GFP into the multivesicular body (MVB) degradation pathway. Mutations disrupting the MVB pathway and unc-108/Rab2 mutations had additive effects on GLR-1::GFP levels in the ventral cord. In coelomocytes, postendocytic trafficking of the marker Texas Red-bovine serum albumin was delayed. These results demonstrate that UNC-108/Rab2 regulates postendocytic trafficking, most likely at the level of early or recycling endosomes, and that UNC-108/Rab2 and the MVB pathway define alternative postendocytic trafficking mechanisms that operate in parallel. These results define a new function for Rab2 in protein trafficking. PMID:18434599

Pathway enrichment analysis approach based on topological structure and updated annotation of pathway.

PubMed

Yang, Qian; Wang, Shuyuan; Dai, Enyu; Zhou, Shunheng; Liu, Dianming; Liu, Haizhou; Meng, Qianqian; Jiang, Bin; Jiang, Wei

2017-08-16

Pathway enrichment analysis has been widely used to identify cancer risk pathways, and contributes to elucidating the mechanism of tumorigenesis. However, most of the existing approaches use the outdated pathway information and neglect the complex gene interactions in pathway. Here, we first reviewed the existing widely used pathway enrichment analysis approaches briefly, and then, we proposed a novel topology-based pathway enrichment analysis (TPEA) method, which integrated topological properties and global upstream/downstream positions of genes in pathways. We compared TPEA with four widely used pathway enrichment analysis tools, including database for annotation, visualization and integrated discovery (DAVID), gene set enrichment analysis (GSEA), centrality-based pathway enrichment (CePa) and signaling pathway impact analysis (SPIA), through analyzing six gene expression profiles of three tumor types (colorectal cancer, thyroid cancer and endometrial cancer). As a result, we identified several well-known cancer risk pathways that could not be obtained by the existing tools, and the results of TPEA were more stable than that of the other tools in analyzing different data sets of the same cancer. Ultimately, we developed an R package to implement TPEA, which could online update KEGG pathway information and is available at the Comprehensive R Archive Network (CRAN): https://cran.r-project.org/web/packages/TPEA/. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Distinct transcriptional networks in quiescent myoblasts: a role for Wnt signaling in reversible vs. irreversible arrest.

PubMed

Subramaniam, Sindhu; Sreenivas, Prethish; Cheedipudi, Sirisha; Reddy, Vatrapu Rami; Shashidhara, Lingadahalli Subrahmanya; Chilukoti, Ravi Kumar; Mylavarapu, Madhavi; Dhawan, Jyotsna

2014-01-01

Most cells in adult mammals are non-dividing: differentiated cells exit the cell cycle permanently, but stem cells exist in a state of reversible arrest called quiescence. In damaged skeletal muscle, quiescent satellite stem cells re-enter the cell cycle, proliferate and subsequently execute divergent programs to regenerate both post-mitotic myofibers and quiescent stem cells. The molecular basis for these alternative programs of arrest is poorly understood. In this study, we used an established myogenic culture model (C2C12 myoblasts) to generate cells in alternative states of arrest and investigate their global transcriptional profiles. Using cDNA microarrays, we compared G0 myoblasts with post-mitotic myotubes. Our findings define the transcriptional program of quiescent myoblasts in culture and establish that distinct gene expression profiles, especially of tumour suppressor genes and inhibitors of differentiation characterize reversible arrest, distinguishing this state from irreversibly arrested myotubes. We also reveal the existence of a tissue-specific quiescence program by comparing G0 C2C12 myoblasts to isogenic G0 fibroblasts (10T1/2). Intriguingly, in myoblasts but not fibroblasts, quiescence is associated with a signature of Wnt pathway genes. We provide evidence that different levels of signaling via the canonical Wnt pathway characterize distinct cellular states (proliferation vs. quiescence vs. differentiation). Moderate induction of Wnt signaling in quiescence is associated with critical properties such as clonogenic self-renewal. Exogenous Wnt treatment subverts the quiescence program and negatively affects clonogenicity. Finally, we identify two new quiescence-induced regulators of canonical Wnt signaling, Rgs2 and Dkk3, whose induction in G0 is required for clonogenic self-renewal. These results support the concept that active signal-mediated regulation of quiescence contributes to stem cell properties, and have implications for pathological states such as cancer and degenerative disease.

Operational integration in primary health care: patient encounters and workflows.

PubMed

Sifaki-Pistolla, Dimitra; Chatzea, Vasiliki-Eirini; Markaki, Adelais; Kritikos, Kyriakos; Petelos, Elena; Lionis, Christos

2017-11-29

Despite several countrywide attempts to strengthen and standardise the primary healthcare (PHC) system, Greece is still lacking a sustainable, policy-based model of integrated services. The aim of our study was to identify operational integration levels through existing patient care pathways and to recommend an alternative PHC model for optimum integration. The study was part of a large state-funded project, which included 22 randomly selected PHC units located across two health regions of Greece. Dimensions of operational integration in PHC were selected based on the work of Kringos and colleagues. A five-point Likert-type scale, coupled with an algorithm, was used to capture and transform theoretical framework features into measurable attributes. PHC services were grouped under the main categories of chronic care, urgent/acute care, preventive care, and home care. A web-based platform was used to assess patient pathways, evaluate integration levels and propose improvement actions. Analysis relied on a comparison of actual pathways versus optimal, the latter ones having been identified through literature review. Overall integration varied among units. The majority (57%) of units corresponded to a basic level. Integration by type of PHC service ranged as follows: basic (86%) or poor (14%) for chronic care units, poor (78%) or basic (22%) for urgent/acute care units, basic (50%) for preventive care units, and partial or basic (50%) for home care units. The actual pathways across all four categories of PHC services differed from those captured in the optimum integration model. Certain similarities were observed in the operational flows between chronic care management and urgent/acute care management. Such similarities were present at the highest level of abstraction, but also in common steps along the operational flows. Existing patient care pathways were mapped and analysed, and recommendations for an optimum integration PHC model were made. The developed web platform, based on a strong theoretical framework, can serve as a robust integration evaluation tool. This could be a first step towards restructuring and improving PHC services within a financially restrained environment.

Development of a digital clinical pathway for emergency medicine: Lessons from usability testing and implementation failure.

PubMed

Gutenstein, Marc; Pickering, John W; Than, Martin

2018-06-01

Clinical pathways are used to support the management of patients in emergency departments. An existing document-based clinical pathway was used as the foundation on which to design and build a digital clinical pathway for acute chest pain, with the aim of improving clinical calculations, clinician decision-making, documentation, and data collection. Established principles of decision support system design were used to build an application within the existing electronic health record, before testing with a multidisciplinary team of doctors using a think-aloud protocol. Technical authoring was successful, however, usability testing revealed that the user experience and the flexibility of workflow within the application were critical barriers to implementation. Emergency medicine and acute care decision support systems face particular challenges to existing models of linear workflow that should be deliberately addressed in digital pathway design. We make key recommendations regarding digital pathway design in emergency medicine.

Clathrin-independent pathways do not contribute significantly to endocytic flux.

PubMed

Bitsikas, Vassilis; Corrêa, Ivan R; Nichols, Benjamin J

2014-09-17

Several different endocytic pathways have been proposed to function in mammalian cells. Clathrin-coated pits are well defined, but the identity, mechanism and function of alternative pathways have been controversial. Here we apply universal chemical labelling of plasma membrane proteins to define all primary endocytic vesicles, and labelling of specific proteins with a reducible SNAP-tag substrate. These approaches provide high temporal resolution and stringent discrimination between surface-connected and intracellular membranes. We find that at least 95% of the earliest detectable endocytic vesicles arise from clathrin-coated pits. GPI-anchored proteins, candidate cargoes for alternate pathways, are also found to enter the cell predominantly via coated pits. Experiments employing a mutated clathrin adaptor reveal distinct mechanisms for sorting into coated pits, and thereby explain differential effects on the uptake of transferrin and GPI-anchored proteins. These data call for a revision of models for the activity and diversity of endocytic pathways in mammalian cells.

30 CFR 285.1013 - Is an Alternate Use RUE assignable?

Code of Federal Regulations, 2010 CFR

2010-07-01

... RENEWABLE ENERGY ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS Facilities Alternate Use Rue...

Development and Validation of a Computational Model for Androgen Receptor Activity

PubMed Central

2016-01-01

Testing thousands of chemicals to identify potential androgen receptor (AR) agonists or antagonists would cost millions of dollars and take decades to complete using current validated methods. High-throughput in vitro screening (HTS) and computational toxicology approaches can more rapidly and inexpensively identify potential androgen-active chemicals. We integrated 11 HTS ToxCast/Tox21 in vitro assays into a computational network model to distinguish true AR pathway activity from technology-specific assay interference. The in vitro HTS assays probed perturbations of the AR pathway at multiple points (receptor binding, coregulator recruitment, gene transcription, and protein production) and multiple cell types. Confirmatory in vitro antagonist assay data and cytotoxicity information were used as additional flags for potential nonspecific activity. Validating such alternative testing strategies requires high-quality reference data. We compiled 158 putative androgen-active and -inactive chemicals from a combination of international test method validation efforts and semiautomated systematic literature reviews. Detailed in vitro assay information and results were compiled into a single database using a standardized ontology. Reference chemical concentrations that activated or inhibited AR pathway activity were identified to establish a range of potencies with reproducible reference chemical results. Comparison with existing Tier 1 AR binding data from the U.S. EPA Endocrine Disruptor Screening Program revealed that the model identified binders at relevant test concentrations (<100 μM) and was more sensitive to antagonist activity. The AR pathway model based on the ToxCast/Tox21 assays had balanced accuracies of 95.2% for agonist (n = 29) and 97.5% for antagonist (n = 28) reference chemicals. Out of 1855 chemicals screened in the AR pathway model, 220 chemicals demonstrated AR agonist or antagonist activity and an additional 174 chemicals were predicted to have potential weak AR pathway activity. PMID:27933809

Pathways of topological rank analysis (PoTRA): a novel method to detect pathways involved in hepatocellular carcinoma

PubMed Central

Liu, Li; Dinu, Valentin

2018-01-01

Complex diseases such as cancer are usually the result of a combination of environmental factors and one or several biological pathways consisting of sets of genes. Each biological pathway exerts its function by delivering signaling through the gene network. Theoretically, a pathway is supposed to have a robust topological structure under normal physiological conditions. However, the pathway’s topological structure could be altered under some pathological condition. It is well known that a normal biological network includes a small number of well-connected hub nodes and a large number of nodes that are non-hubs. In addition, it is reported that the loss of connectivity is a common topological trait of cancer networks, which is an assumption of our method. Hence, from normal to cancer, the process of the network losing connectivity might be the process of disrupting the structure of the network, namely, the number of hub genes might be altered in cancer compared to that in normal or the distribution of topological ranks of genes might be altered. Based on this, we propose a new PageRank-based method called Pathways of Topological Rank Analysis (PoTRA) to detect pathways involved in cancer. We use PageRank to measure the relative topological ranks of genes in each biological pathway, then select hub genes for each pathway, and use Fisher’s exact test to test if the number of hub genes in each pathway is altered from normal to cancer. Alternatively, if the distribution of topological ranks of gene in a pathway is altered between normal and cancer, this pathway might also be involved in cancer. Hence, we use the Kolmogorov–Smirnov test to detect pathways that have an altered distribution of topological ranks of genes between two phenotypes. We apply PoTRA to study hepatocellular carcinoma (HCC) and several subtypes of HCC. Very interestingly, we discover that all significant pathways in HCC are cancer-associated generally, while several significant pathways in subtypes of HCC are HCC subtype-associated specifically. In conclusion, PoTRA is a new approach to explore and discover pathways involved in cancer. PoTRA can be used as a complement to other existing methods to broaden our understanding of the biological mechanisms behind cancer at the system-level. PMID:29666752

Assessment of the risk of introduction of Anoplophora glabripennis (Coleoptera: Cerambycidae) in municipal solid waste from the quarantine area of New York City to landfills outside of the quarantine area: a pathway analysis of the risk of spread and establishment.

PubMed

Auclair, Allan N D; Fowler, G; Hennessey, M K; Hogue, A T; Keena, M; Lance, D R; McDowell, R M; Oryang, D O; Sawyer, A J

2005-02-01

The risk associated with spread of Asian longhorned beetle, Anoplophora glabripennis (Motschulsky), from infested areas in New York City to the wide array of landfills across the eastern United States contracted by the city since 1997 was unknown, but of great concern. Landfills, some as far as South Carolina, Virginia, and Ohio, occupied forest types and climates at high risk of Asian longhorned beetle establishment. The city proposed a separate waste wood collection known as the "311 System;" this was estimated to cost federal and state agencies $6.1 to $9.1 million per year, including the cost of processing and disposal of the wood. Pathway analysis was used to quantify the probability that Asian longhorned beetle present in wood waste collected at curbside would survive transport, compaction, and burial to form a mated pair. The study found that in seven alternate management scenarios, risks with most pathways are very low, especially given existing mitigations. Mitigations included chemical control, removal of infested trees, and burial of wood waste in managed landfills that involved multiple-layering, compaction, and capping of dumped waste with a 15-cm soil cover at the end of each day. Although the risk of business-as-usual collection and disposal practices was virtually nil, any changes of policy or practice such as illegal dumping or disposal at a single landfill increased the risk many thousandfold. By rigorously maintaining and monitoring existing mitigations, it was estimated that taxpayers would save $75 to $122 million dollars over the next decade.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wellman, Dawn M.; Freshley, Mark D.; Truex, Michael J.

Current requirements for site remediation and closure are standards-based and are often overly conservative, costly, and in some cases, technically impractical to achieve. Use of risk-informed alternate endpoints provide a means to achieve remediation goals that are permitted by regulations and are protective of human health and the environment. Alternate endpoints enable establishing a path for cleanup that may include intermediate remedial milestones and transition points and/or regulatory alternatives to standards-based remediation. A framework is presented that is centered around developing and refining conceptual models in conjunction with assessing risks and potential endpoints as part of a system-based assessment thatmore » integrates site data with scientific understanding of processes that control the distribution and transport of contaminants in the subsurface and pathways to receptors. This system based assessment and subsequent implementation of the remediation strategy with appropriate monitoring are targeted at providing a holistic approach to addressing risks to human health and the environment. This holistic approach also enables effective predictive analysis of contaminant behavior to provide defensible criteria and data for making long-term decisions. Developing and implementing an alternate endpoint-based approach for remediation and waste site closure presents a number of challenges and opportunities. Categories of these challenges include scientific and technical, regulatory, institutional, and budget and resource allocation issues. Opportunities exist for developing and implementing systems-based approaches with respect to supportive characterization, monitoring, predictive modeling, and remediation approaches.« less

Alternative Sigma Factor Over-Expression Enables Heterologous Expression of a Type II Polyketide Biosynthetic Pathway in Escherichia coli

PubMed Central

Stevens, David Cole; Conway, Kyle R.; Pearce, Nelson; Villegas-Peñaranda, Luis Roberto; Garza, Anthony G.; Boddy, Christopher N.

2013-01-01

Background Heterologous expression of bacterial biosynthetic gene clusters is currently an indispensable tool for characterizing biosynthetic pathways. Development of an effective, general heterologous expression system that can be applied to bioprospecting from metagenomic DNA will enable the discovery of a wealth of new natural products. Methodology We have developed a new Escherichia coli-based heterologous expression system for polyketide biosynthetic gene clusters. We have demonstrated the over-expression of the alternative sigma factor σ54 directly and positively regulates heterologous expression of the oxytetracycline biosynthetic gene cluster in E. coli. Bioinformatics analysis indicates that σ54 promoters are present in nearly 70% of polyketide and non-ribosomal peptide biosynthetic pathways. Conclusions We have demonstrated a new mechanism for heterologous expression of the oxytetracycline polyketide biosynthetic pathway, where high-level pleiotropic sigma factors from the heterologous host directly and positively regulate transcription of the non-native biosynthetic gene cluster. Our bioinformatics analysis is consistent with the hypothesis that heterologous expression mediated by the alternative sigma factor σ54 may be a viable method for the production of additional polyketide products. PMID:23724102

Untangling the Web: The Diverse Functions of the PIWI/piRNA Pathway

PubMed Central

Mani, Sneha Ramesh; Juliano, Celina E.

2014-01-01

SUMMARY Small RNAs impact several cellular processes through gene regulation. Argonaute proteins bind small RNAs to form effector complexes that control transcriptional and post-transcriptional gene expression. PIWI proteins belong to the Argonaute protein family, and bind PIWI-interacting RNAs (piRNAs). They are highly abundant in the germline, but are also expressed in some somatic tissues. The PIWI/piRNA pathway has a role in transposon repression in Drosophila, which occurs both by epigenetic regulation and post-transcriptional degradation of transposon mRNAs. These functions are conserved, but clear differences in the extent and mechanism of transposon repression exist between species. Mutations in piwi genes lead to the upregulation of transposon mRNAs. It is hypothesized that this increased transposon mobilization leads to genomic instability and thus sterility, although no causal link has been established between transposon upregulation and genome instability. An alternative scenario could be that piwi mutations directly affect genomic instability, and thus lead to increased transposon expression. We propose that the PIWI/piRNA pathway controls genome stability in several ways: suppression of transposons, direct regulation of chromatin architecture and regulation of genes that control important biological processes related to genome stability. The PIWI/piRNA pathway also regulates at least some, if not many, protein-coding genes, which further lends support to the idea that piwi genes may have broader functions beyond transposon repression. An intriguing possibility is that the PIWI/piRNA pathway is using transposon sequences to coordinate the expression of large groups of genes to regulate cellular function. PMID:23712694

Targeting the PI3K/Akt pathway in murine MDS/MPN driven by hyperactive Ras

PubMed Central

Akutagawa, Jon; Huang, Tannie Q.; Epstein, Inbal; Chang, Tiffany; Quirindongo-Crespo, Maricel; Cottonham, Charisa L.; Dail, Monique; Slusher, Barbara S.; Friedman, Lori S.; Sampath, Deepak; Braun, Benjamin S.

2016-01-01

Chronic and juvenile myelomonocytic leukemias (CMML and JMML) are myelodysplastic/myeloproliferative neoplasia (MDS/MPN) overlap syndromes that respond poorly to conventional treatments. Aberrant Ras activation due to NRAS, KRAS, PTPN11, CBL, and NF1 mutations is common in CMML and JMML. However, no mechanism-based treatments currently exist for cancers with any of these mutations. An alternative therapeutic strategy involves targeting Ras-regulated effector pathways that are aberrantly activated in CMML and JMML, which include the Raf/MEK/ERK and phosphoinositide-3´-OH kinase (PI3K)/Akt cascades. Mx1-Cre, KrasD12 and Mx1-Cre, Nf1flox/− mice accurately model many aspects of CMML and JMML. Treating Mx1-Cre, KrasD12 mice with GDC-0941 (also referred to as pictilisib), an orally bioavailable inhibitor of class I PI3K isoforms, reduced leukocytosis, anemia, and splenomegaly while extending survival. However, GDC-0941 treatment attenuated activation of both PI3K/Akt and Raf/MEK/ERK pathways in primary hematopoietic cells, suggesting it could be acting through suppression of Raf/MEK/ERK signals. To interrogate the importance of the PI3K/Akt pathway specifically, we treated mice with the allosteric Akt inhibitor MK-2206. This compound had no effect on Raf/MEK/ERK signaling, yet it also induced robust hematologic responses in Kras and Nf1 mice with MPN. These data support investigating PI3K/Akt pathway inhibitors as a therapeutic strategy in JMML and CMML patients. PMID:26965285

30 CFR 285.1015 - How do I relinquish an Alternate Use RUE?

Code of Federal Regulations, 2010 CFR

2010-07-01

... OFFSHORE RENEWABLE ENERGY ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS Facilities Alternate Use...

30 CFR 285.1005 - How do I request an Alternate Use RUE?

Code of Federal Regulations, 2010 CFR

2010-07-01

... RENEWABLE ENERGY ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS Facilities Requesting An Alternate...

Pathways for School Finance in California. Technical Appendix

ERIC Educational Resources Information Center

Rose, Heather; Sonstelie, Jon; Weston, Margaret

2010-01-01

This is a technical appendix for the report, "Pathways for School Finance in California" (ED515651). "Pathways for School Finance in California" simulates alternatives to California's current school finance system. This appendix provides more information about the revenues used in those simulations. The first section describes…

Physics Teacher Preparation as a Means for Growth

NASA Astrophysics Data System (ADS)

Henderson, Ron

2013-03-01

Physics departments across the country are experiencing pressures to increase the number of graduates. One response is to improve marketing and recruiting efforts to add students to existing pipelines. A more innovative approach is to create new pathways tied to career paths that are alternatives to graduate school. One occupation that currently needs more graduates than physics departments are supplying is physics teaching. About 3 years ago, MTSU began implementing a strategy to prepare physics majors for careers in high school teaching. These efforts included developing coursework specifically related to physics teaching, creating relationships with the college of education, moving to pedagogies that reflect physics education research (PER)-validated best practices, hiring a tenure-track PER expert, implementing new ways to reach potential majors, and seeking external funding. The cumulative result has not only added a number of physics teaching majors to our roles, but has affected our existing programs in a manner that has yielded further growth. Support provided by the APS/AAPT PhysTEC project.

Commonalities and differences in plants deficient in autophagy and alternative pathways of respiration on response to extended darkness.

PubMed

Barros, Jessica A S; Cavalcanti, João Henrique F; Medeiros, David B; Nunes-Nesi, Adriano; Avin-Wittenberg, Tamar; Fernie, Alisdair R; Araújo, Wagner L

2017-11-02

Autophagy is a highly conserved cellular mechanism in eukaryotes allowing the degradation of cell constituents. It is of crucial significance in both cellular homeostasis and nutrient recycling. During energy limited conditions plant cells can metabolize alternative respiratory substrates, such as amino acids, providing electrons to the mitochondrial metabolism via the tricarboxylic acid (TCA) cycle or electron transfer flavoprotein/ electron transfer flavoprotein ubiquinone oxidoreductase (ETF/ETFQO) system. Our recent study reveals the importance of autophagy in the supply of amino acids to provide energy through alternative pathways of respiration during carbon starvation. This fact apart, autophagy seems to have more generalized effects related not only to amino acid catabolism but also to metabolism in general. By further comparing the metabolic data obtained with atg mutants with those of mutants involved in the alternative pathways of respiration, we observed clear differences between these mutants, pointing out additional effects of the autophagy deficiency on metabolism of Arabidopsis leaves. Collectively, our data point to an interdependence between mitochondrial metabolism and autophagy and suggest an exquisite regulation of primary metabolism under low energetic conditions.

Reverse Engineering a Signaling Network Using Alternative Inputs

PubMed Central

Tanaka, Hiromasa; Yi, Tau-Mu

2009-01-01

One of the goals of systems biology is to reverse engineer in a comprehensive fashion the arrow diagrams of signal transduction systems. An important tool for ordering pathway components is genetic epistasis analysis, and here we present a strategy termed Alternative Inputs (AIs) to perform systematic epistasis analysis. An alternative input is defined as any genetic manipulation that can activate the signaling pathway instead of the natural input. We introduced the concept of an “AIs-Deletions matrix” that summarizes the outputs of all combinations of alternative inputs and deletions. We developed the theory and algorithms to construct a pairwise relationship graph from the AIs-Deletions matrix capturing both functional ordering (upstream, downstream) and logical relationships (AND, OR), and then interpreting these relationships into a standard arrow diagram. As a proof-of-principle, we applied this methodology to a subset of genes involved in yeast mating signaling. This experimental pilot study highlights the robustness of the approach and important technical challenges. In summary, this research formalizes and extends classical epistasis analysis from linear pathways to more complex networks, facilitating computational analysis and reconstruction of signaling arrow diagrams. PMID:19898612

Molecular basis of the evolution of alternative tyrosine biosynthetic routes in plants

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schenck, Craig A.; Holland, Cynthia K.; Schneider, Matthew R.

L-Tyrosine (Tyr) is essential for protein synthesis and is a precursor of numerous specialized metabolites crucial for plant and human health. Tyr can be synthesized via two alternative routes by different key regulatory TyrA family enzymes, prephenate dehydrogenase (PDH, also known as TyrAp) or arogenate dehydrogenase (ADH, also known as TyrAa), representing a unique divergence of primary metabolic pathways. The molecular foundation underlying the evolution of these alternative Tyr pathways is currently unknown. Here we characterized recently diverged plant PDH and ADH enzymes, obtained the X-ray crystal structure of soybean PDH, and identified a single amino acid residue that definesmore » TyrA substrate specificity and regulation. Structures of mutated PDHs co-crystallized with Tyr indicate that substitutions of Asn222 confer ADH activity and Tyr sensitivity. Reciprocal mutagenesis of the corresponding residue in divergent plant ADHs further introduced PDH activity and relaxed Tyr sensitivity, highlighting the critical role of this residue in TyrA substrate specificity that underlies the evolution of alternative Tyr biosynthetic pathways in plants.« less

The Role of Wnt Signal in Glioblastoma Development and Progression: A Possible New Pharmacological Target for the Therapy of This Tumor

PubMed Central

Zuccarini, Mariachiara; Giuliani, Patricia; Ziberi, Sihana; Carluccio, Marzia; Di Iorio, Patrizia; Caciagli, Francesco

2018-01-01

Wnt is a complex signaling pathway involved in the regulation of crucial biological functions such as development, proliferation, differentiation and migration of cells, mainly stem cells, which are virtually present in all embryonic and adult tissues. Conversely, dysregulation of Wnt signal is implicated in development/progression/invasiveness of different kinds of tumors, wherein a certain number of multipotent cells, namely “cancer stem cells”, are characterized by high self-renewal and aggressiveness. Hence, the pharmacological modulation of Wnt pathway could be of particular interest, especially in tumors for which the current standard therapy results to be unsuccessful. This might be the case of glioblastoma multiforme (GBM), one of the most lethal, aggressive and recurrent brain cancers, probably due to the presence of highly malignant GBM stem cells (GSCs) as well as to a dysregulation of Wnt system. By examining the most recent literature, here we point out several factors in the Wnt pathway that are altered in human GBM and derived GSCs, as well as new molecular strategies or experimental drugs able to modulate/inhibit aberrant Wnt signal. Altogether, these aspects serve to emphasize the existence of alternative pharmacological targets that may be useful to develop novel therapies for GBM. PMID:29462960

Regulations and roles for alternative pathways of hexose metabolism in plants

Treesearch

Clanton C. Black; Laszlo Mustardy; S.S. Sung; P.P. Kormanik; D.-P. Xu; Nachman Paz

1987-01-01

Plants have two cytoplasmic pathways of glycolysis and gluconeogenesis for the reversible interconversion of fructose 6-phosphate (F-6-P) and fructose 1,6-bisphosphate (F-1,6,-P2). One pathway is described as a maintenance pathway that is catalyzed by a nucleotide triphosphate-dependent phosphofructokinase (EC 2.7.1.11; ATP-PFK) glycolytically and a F-1,6...

Imaging pathways in fractured rock using three-dimensional electrical resistivity tomography

USGS Publications Warehouse

Robinson, Judith; Slater, Lee; Johnson, Timothy B.; Shapiro, Allen M.; Tiedeman, Claire; Ntlargiannis, Dimitrios; Johnson, Carole D.; Day-Lewis, Frederick D.; Lacombe, Pierre; Imbrigiotta, Thomas; Lane, John W.

2016-01-01

Major challenges exist in delineating bedrock fracture zones because these cause abrupt changes in geological and hydrogeological properties over small distances. Borehole observations cannot sufficiently capture heterogeneity in these systems. Geophysical techniques offer the potential to image properties and processes in between boreholes. We used three-dimensional cross borehole electrical resistivity tomography (ERT) in a 9 m (diameter) × 15 m well field to capture high-resolution flow and transport processes in a fractured mudstone contaminated by chlorinated solvents, primarily trichloroethylene. Conductive (sodium bromide) and resistive (deionized water) injections were monitored in seven boreholes. Electrode arrays with isolation packers and fluid sampling ports were designed to enable acquisition of ERT measurements during pulsed tracer injections. Fracture zone locations and hydraulic pathways inferred from hydraulic head drawdown data were compared with electrical conductivity distributions from ERT measurements. Static ERT imaging has limited resolution to decipher individual fractures; however, these images showed alternating conductive and resistive zones, consistent with alternating laminated and massive mudstone units at the site. Tracer evolution and migration was clearly revealed in time-lapse ERT images and supported by in situ borehole vertical apparent conductivity profiles collected during the pulsed tracer test. While water samples provided important local information at the extraction borehole, ERT delineated tracer migration over spatial scales capturing the primary hydrogeological heterogeneity controlling flow and transport. The fate of these tracer injections at this scale could not have been quantified using borehole logging and/or borehole sampling methods alone.

The Alternative NF-κB Pathway in Regulatory T Cell Homeostasis and Suppressive Function.

PubMed

Grinberg-Bleyer, Yenkel; Caron, Rachel; Seeley, John J; De Silva, Nilushi S; Schindler, Christian W; Hayden, Matthew S; Klein, Ulf; Ghosh, Sankar

2018-04-01

CD4 + Foxp3 + regulatory T cells (Tregs) are essential regulators of immune responses. Perturbation of Treg homeostasis or function can lead to uncontrolled inflammation and autoimmunity. Therefore, understanding the molecular mechanisms involved in Treg biology remains an active area of investigation. It has been shown previously that the NF-κB family of transcription factors, in particular, the canonical pathway subunits, c-Rel and p65, are crucial for the development, maintenance, and function of Tregs. However, the role of the alternative NF-κB pathway components, p100 and RelB, in Treg biology remains unclear. In this article, we show that conditional deletion of the p100 gene, nfkb2 , in Tregs, resulted in massive inflammation because of impaired suppressive function of nfkb2 -deficient Tregs. Surprisingly, mice lacking RelB in Tregs did not exhibit the same phenotype. Instead, deletion of both relb and nfkb2 rescued the inflammatory phenotype, demonstrating an essential role for p100 as an inhibitor of RelB in Tregs. Our data therefore illustrate a new role for the alternative NF-κB signaling pathway in Tregs that has implications for the understanding of molecular pathways driving tolerance and immunity. Copyright © 2018 by The American Association of Immunologists, Inc.

Relational Identities of Students, Families, and Educators: Shaping Educational Pathways

ERIC Educational Resources Information Center

March, Evangelia; Gaffney, Janet S.

2010-01-01

This retrospective study sketched the educational pathways of two seniors attending an alternative high school in an attempt to discern how relational identities of students, families, and educators are defining forces of such pathways. Cumulative school records and special education files were triangulated with interviews of the students, their…

Characterization of vanadium ion uptake in sulfonated diels alder poly(phenylene) membranes

DOE PAGES

Lawton, Jamie; Jones, Amanda; Tang, Zhijiang; ...

2015-11-28

Sulfonated diels alder poly(phenylene) (SDAPP), alternative aromatic hydrocarbon membranes for vanadium redox flow batteries (VRFBs) are characterized using electron paramagnetic resonance (EPR). Membranes soaked in sulfuric acid and vanadyl sulfate are analyzed to determine the membrane environment in which the vanadyl ion (VO 2+) diffuses in the membranes. These results are compared to Nafion 117 membranes. In contrast to Nafion, the VO 2+ in SDAPP membranes exists in two different environments. The results of analysis of rotational diffusion determined from fits the EPR spectral lineshapes in comparison with previously reported permeation studies and measurements of partitioning functions reported here suggestmore » that the diffusion pathways in SDAPP are very different than in Nafion.« less

Interaction between Saccharomyces cerevisiae Mitochondrial DNA-Binding Protein Abf2p and Cce1p Resolvase.

PubMed

Samoilova, E O; Krasheninnikov, I A; Levitskii, S A

2016-10-01

Mitochondrial DNA is susceptible to the action of reactive oxygen species generated by the reactions of oxidative phosphorylation. Homologous recombination is one of the mechanisms providing integrity of the mitochondrial genome. Some proteins that take part in this process in budding yeast mitochondria have been identified. These include Abf2p, the major protein of the mt-nucleoid that specifically binds cruciform DNA, and Cce1p - Holliday junction resolvase. Here we show that Abf2p does not significantly affect either binding of Cce1p to branched DNA or rate and specificity of Holliday junction resolution. These data suggest the existence of an alternative homologous recombination pathway in yeast mitochondria.

Diatoms: a fossil fuel of the future.

PubMed

Levitan, Orly; Dinamarca, Jorge; Hochman, Gal; Falkowski, Paul G

2014-03-01

Long-term global climate change, caused by burning petroleum and other fossil fuels, has motivated an urgent need to develop renewable, carbon-neutral, economically viable alternatives to displace petroleum using existing infrastructure. Algal feedstocks are promising candidate replacements as a 'drop-in' fuel. Here, we focus on a specific algal taxon, diatoms, to become the fossil fuel of the future. We summarize past attempts to obtain suitable diatom strains, propose future directions for their genetic manipulation, and offer biotechnological pathways to improve yield. We calculate that the yields obtained by using diatoms as a production platform are theoretically sufficient to satisfy the total oil consumption of the US, using between 3 and 5% of its land area. Copyright © 2014 Elsevier Ltd. All rights reserved.

Assessment of Nanobiotechnology-Targeted siRNA Designed to inhibit NF-kappaB Classical and Alternative Signaling in Breast Tumor Macrophages

DTIC Science & Technology

2013-07-01

expression of key proteins within each pathway to examine their individual and combined roles with respect to potential breast cancer immunotherapy. We...selected as our initial targets the IKKβ activator (canonical) or p52 (alternative) proteins . In order to harness inhibition of these pathways to...intended to knockdown protein expression of NF-κB modulators with exceptional specificity for TAMs. TAM-specific nanoparticle targeting offers an

Identification of Novel Androgen-Regulated Pathways and mRNA Isoforms through Genome-Wide Exon-Specific Profiling of the LNCaP Transcriptome

PubMed Central

Carling, Phillippa J.; Buist, Thomas; Zhang, Chaolin; Grellscheid, Sushma N.; Armstrong, Kelly; Stockley, Jacqueline; Simillion, Cedric; Gaughan, Luke; Kalna, Gabriela; Zhang, Michael Q.; Robson, Craig N.; Leung, Hing Y.; Elliott, David J.

2011-01-01

Androgens drive the onset and progression of prostate cancer (PCa) by modulating androgen receptor (AR) transcriptional activity. Although several microarray-based studies have identified androgen-regulated genes, here we identify in-parallel global androgen-dependent changes in both gene and alternative mRNA isoform expression by exon-level analyses of the LNCaP transcriptome. While genome-wide gene expression changes correlated well with previously-published studies, we additionally uncovered a subset of 226 novel androgen-regulated genes. Gene expression pathway analysis of this subset revealed gene clusters associated with, and including the tyrosine kinase LYN, as well as components of the mTOR (mammalian target of rapamycin) pathway, which is commonly dysregulated in cancer. We also identified 1279 putative androgen-regulated alternative events, of which 325 (∼25%) mapped to known alternative splicing events or alternative first/last exons. We selected 30 androgen-dependent alternative events for RT-PCR validation, including mRNAs derived from genes encoding tumour suppressors and cell cycle regulators. Of seven positively-validating events (∼23%), five events involved transcripts derived from alternative promoters of known AR gene targets. In particular, we found a novel androgen-dependent mRNA isoform derived from an alternative internal promoter within the TSC2 tumour suppressor gene, which is predicted to encode a protein lacking an interaction domain required for mTOR inhibition. We confirmed that expression of this alternative TSC2 mRNA isoform was directly regulated by androgens, and chromatin immunoprecipitation indicated recruitment of AR to the alternative promoter region at early timepoints following androgen stimulation, which correlated with expression of alternative transcripts. Together, our data suggest that alternative mRNA isoform expression might mediate the cellular response to androgens, and may have roles in clinical PCa. PMID:22194994

Gateway Effects: Why the Cited Evidence Does Not Support Their Existence for Low-Risk Tobacco Products (and What Evidence Would).

PubMed

Phillips, Carl V

2015-05-21

It is often claimed that low-risk drugs still create harm because of "gateway effects", in which they cause the use of a high-risk alternative. Such claims are popular among opponents of tobacco harm reduction, claiming that low-risk tobacco products (e.g., e-cigarettes, smokeless tobacco) cause people to start smoking, sometimes backed by empirical studies that ostensibly support the claim. However, these studies consistently ignore the obvious alternative causal pathways, particularly that observed associations might represent causation in the opposite direction (smoking causes people to seek low-risk alternatives) or confounding (the same individual characteristics increase the chance of using any tobacco product). Due to these complications, any useful analysis must deal with simultaneity and confounding by common cause. In practice, existing analyses seem almost as if they were designed to provide teaching examples about drawing simplistic and unsupported causal conclusions from observed associations. The present analysis examines what evidence and research strategies would be needed to empirically detect such a gateway effect, if there were one, explaining key methodological concepts including causation and confounding, examining the logic of the claim, identifying potentially useful data, and debunking common fallacies on both sides of the argument, as well as presenting an extended example of proper empirical testing. The analysis demonstrates that none of the empirical studies to date that are purported to show a gateway effect from tobacco harm reduction products actually does so. The observations and approaches can be generalized to other cases where observed association of individual characteristics in cross-sectional data could result from any of several causal relationships.

Gateway Effects: Why the Cited Evidence Does Not Support Their Existence for Low-Risk Tobacco Products (and What Evidence Would)

PubMed Central

Phillips, Carl V.

2015-01-01

It is often claimed that low-risk drugs still create harm because of “gateway effects”, in which they cause the use of a high-risk alternative. Such claims are popular among opponents of tobacco harm reduction, claiming that low-risk tobacco products (e.g., e-cigarettes, smokeless tobacco) cause people to start smoking, sometimes backed by empirical studies that ostensibly support the claim. However, these studies consistently ignore the obvious alternative causal pathways, particularly that observed associations might represent causation in the opposite direction (smoking causes people to seek low-risk alternatives) or confounding (the same individual characteristics increase the chance of using any tobacco product). Due to these complications, any useful analysis must deal with simultaneity and confounding by common cause. In practice, existing analyses seem almost as if they were designed to provide teaching examples about drawing simplistic and unsupported causal conclusions from observed associations. The present analysis examines what evidence and research strategies would be needed to empirically detect such a gateway effect, if there were one, explaining key methodological concepts including causation and confounding, examining the logic of the claim, identifying potentially useful data, and debunking common fallacies on both sides of the argument, as well as presenting an extended example of proper empirical testing. The analysis demonstrates that none of the empirical studies to date that are purported to show a gateway effect from tobacco harm reduction products actually does so. The observations and approaches can be generalized to other cases where observed association of individual characteristics in cross-sectional data could result from any of several causal relationships. PMID:26006122

Targeting kinase signaling pathways with constrained peptide scaffolds

PubMed Central

Hanold, Laura E.; Fulton, Melody D.; Kennedy, Eileen J.

2017-01-01

Kinases are amongst the largest families in the human proteome and serve as critical mediators of a myriad of cell signaling pathways. Since altered kinase activity is implicated in a variety of pathological diseases, kinases have become a prominent class of proteins for targeted inhibition. Although numerous small molecule and antibody-based inhibitors have already received clinical approval, several challenges may still exist with these strategies including resistance, target selection, inhibitor potency and in vivo activity profiles. Constrained peptide inhibitors have emerged as an alternative strategy for kinase inhibition. Distinct from small molecule inhibitors, peptides can provide a large binding surface area that allows them to bind shallow protein surfaces rather than defined pockets within the target protein structure. By including chemical constraints within the peptide sequence, additional benefits can be bestowed onto the peptide scaffold such as improved target affinity and target selectivity, cell permeability and proteolytic resistance. In this review, we highlight examples of diverse chemistries that are being employed to constrain kinase-targeting peptide scaffolds and highlight their application to modulate kinase signaling as well as their potential clinical implications. PMID:28185915

Pigs in Toxicology: Breed Differences in Metabolism and Background Findings.

PubMed

Helke, Kristi L; Nelson, Keith N; Sargeant, Aaron M; Jacob, Binod; McKeag, Sean; Haruna, Julius; Vemireddi, Vimala; Greeley, Melanie; Brocksmith, Derek; Navratil, Nicole; Stricker-Krongrad, Alain; Hollinger, Charlotte

2016-06-01

Both a rodent and a nonrodent species are required for evaluation in nonclinical safety studies conducted to support human clinical trials. Historically, dogs and nonhuman primates have been the nonrodent species of choice. Swine, especially the miniature swine or minipigs, are increasingly being used in preclinical safety as an alternate nonrodent species. The pig is an appropriate option for these toxicology studies based on metabolic pathways utilized in xenobiotic biotransformation. Both similarities and differences exist in phase I and phase II biotransformation pathways between humans and pigs. There are numerous breeds of pigs, yet only a few of these breeds are characterized with regard to both xenobiotic-metabolizing enzymes and background pathology findings. Some specific differences in these enzymes based on breed and sex are known. Although swine have been used extensively in biomedical research, there is also a paucity of information in the current literature detailing the incidence of background lesions and differences between commonly used breeds. Here, the xenobiotic-metabolizing enzymes are compared between humans and pigs, and minipig background pathology changes are reviewed with emphasis on breed differences. © The Author(s) 2016.

Regulation of macrophage migration by products of the complement system.

PubMed Central

Bianco, C; Götze, O; Cohn, Z A

1979-01-01

Agents formerly shown to induce rapid macrophage spreading were examined for their ability to modify the migration of macrophages in the capillary tube assay. Products of the activation of the contact phase of blood coagulation as well as the purified component Bb, the large cleavage fragment of factor B of the alternative complement pathway produced a dose-dependent inhibition of migration. In addition, inflammatory macrophages elicited with either a lipopolysaccharide endotoxin or thioglycollate medium exhibited rapid spreading and inhibited migration, whereas resident cells did not. A close correlation existed, therefore, between enhanced spreading and inhibited migration under both in vitro induced and in vivo situations. Cleavage products of component C5 of the classical complement pathway enhanced macrophage migration and did not alter spreading. In mixtures of C5 cleavage products and Bb, the predominant peptide determined the outcome of the reaction. Factor B, a normal secretory product of macrophages, may represent a common substrate for several of the proteases that induce spreading, inhibit migration, and lead to the generation of the enzymatically active fragment Bb. PMID:284412

Why Do Health Economists Promote Technology Adoption Rather Than the Search for Efficiency? A Proposal for a Change in Our Approach to Economic Evaluation in Health Care.

PubMed

Scotland, Graham; Bryan, Stirling

2017-02-01

At a time of intense pressure on health care budgets, the technology management challenge is for disinvestment in low-value technologies and reinvestment in higher value alternatives. The aim of this article is to explore ways in which health economists might begin to redress the observed imbalance between the evaluation of new and existing in-use technologies. The argument is not against evaluating new technologies but in favor of the "search for efficiency," where the ultimate objective is to identify reallocations that improve population health in the face of resource scarcity. We explore why in-use technologies may be of low value and consider how economic evaluation analysts might embrace a broader efficiency lens, first through "technology management" (a process of analysis and evidence-informed decision making throughout a technology's life cycle) and progressing through "pathway management" (the search for efficiency gains across entire clinical care pathways). A number of model-based examples are used to illustrate the approaches.

Identifying and Evaluating Options for Improving Sediment Management and Fish Passage at Hydropower Dams in the Lower Mekong River Basin

NASA Astrophysics Data System (ADS)

Wild, T. B.; Reed, P. M.; Loucks, D. P.

2015-12-01

The Mekong River basin in Southeast Asia is undergoing intensive and pervasive hydropower development to satisfy demand for increased energy and income to support its growing population of 60 million people. Just 20 years ago this river flowed freely. Today some 30 large dams exist in the basin, and over 100 more are being planned for construction. These dams will alter the river's natural water, sediment and nutrient flows, thereby impacting river morphology and ecosystems, and will fragment fish migration pathways. In doing so, they will degrade one of the world's most valuable and productive freshwater fish habitats. For those dams that have not yet been constructed, there still exist opportunities to modify their siting, design and operation (SDO) to potentially achieve a more balanced set of tradeoffs among hydropower production, sediment/nutrient passage and fish passage. We introduce examples of such alternative SDO opportunities for Sambor Dam in Cambodia, planned to be constructed on the main stem of the Mekong River. To evaluate the performance of such alternatives, we developed a Python-based simulation tool called PySedSim. PySedSim is a daily time step mass balance model that identifies the relative tradeoffs among hydropower production, and flow and sediment regime alteration, associated with reservoir sediment management techniques such as flushing, sluicing, bypassing, density current venting and dredging. To date, there has been a very limited acknowledgement or evaluation of the significant uncertainties that impact the evaluation of SDO alternatives. This research is formalizing a model diagnostic assessment of the key assumptions and parametric uncertainties that strongly influence PySedSim SDO evaluations. Using stochastic hydrology and sediment load data, our diagnostic assessment evaluates and compares several Sambor Dam alternatives using several performance measures related to energy production, sediment trapping and regime alteration, and fish passage. We show that performance of the alternatives can be highly variable, and conduct a simultaneous multi-parameter factor screening sensitivity analysis to identify the subset of PySedSim model parameters that contribute most significantly to performance uncertainties in attempts to identify the more robust options.

Grand Coulee - Bell 500-kV Transmission Line Project, Draft Environmental Impact Statement

DOE Office of Scientific and Technical Information (OSTI.GOV)

N /A

2002-08-09

BPA is proposing to construct a 500-kilovolt (kV) transmission line that would extend approximately 84 miles between the Grand Coulee 500-kV Switchyard, near Grand Coulee Dam, and the Bell Substation, in Mead just north of Spokane. The new line would cross portions of Douglas, Grant, Lincoln, and Spokane counties. In addition to the transmission line, new equipment would be installed at the substations at each end of the new line and at other facilities. The proposed action would remove an existing 115-kV transmission line and replace it with the new 500-kV line on existing right-of-way for most of its length.more » Additional right-of-way would be needed in the first 3.5 miles out of the Grand Coulee Switchyard to connect to the existing 115-kV right-of-way. Since the mid-1990s, the transmission path west of Spokane, called the West of Hatwai transmission pathway, has grown increasingly constrained. To date, BPA has been able to manage operation of the path through available operating practices, and customer needed have been met while maintaining the reliability of the path. however, in early 2001, operations showed that the amount of electricity that needs to flow from east to west along this path creates severe transmission congestion. Under these conditions, the system is at risk of overloads and violation of industry safety and reliability standards. The problem is particularly acute in the spring and summer months because of the large amount of power generated by dams east of the path. Large amounts of water cannot be spilled during that time in order for BPA to fulfill its obligation to protect threatened and endangered fish. The amount of power that needs to move through this area during these months at times could exceed the carrying capacity of the existing transmission lines. In additional capacity is not added, BPA will run a significant risk that it will not be able to continue to meet its contractual obligations to deliver power and maintain reliability standards that minimize risks to public safety and to equipment. BPA is considering two construction alternatives, the Agency Proposed Action and the Alternative Action. The Alternative Action would include all the components of the Preferred Action except a double-circuit line would be constructed in the Spokane area between a point about 2 miles west of the Spokane River and Bell Substation, a distance of about 9 miles. BPA is also considering the No Action Alternative.« less

The role of complement system in septic shock.

PubMed

Charchaflieh, Jean; Wei, Jiandong; Labaze, Georges; Hou, Yunfang Joan; Babarsh, Benjamin; Stutz, Helen; Lee, Haekyung; Worah, Samrat; Zhang, Ming

2012-01-01

Septic shock is a critical clinical condition with a high mortality rate. A better understanding of the underlying mechanisms is important to develop effective therapies. Basic and clinical studies suggest that activation of complements in the common cascade, for example, complement component 3 (C3) and C5, is involved in the development of septic shock. The involvement of three upstream complement pathways in septic shock is more complicated. Both the classical and alternative pathways appear to be activated in septic shock, but the alternative pathway may be activated earlier than the classical pathway. Activation of these two pathways is essential to clear endotoxin. Recent investigations have shed light on the role of lectin complement pathway in septic shock. Published reports suggest a protective role of mannose-binding lectin (MBL) against sepsis. Our preliminary study of MBL-associated serine protease-2 (MASP-2) in septic shock patients indicated that acute decrease of MASP-2 in the early phase of septic shock might correlate with in-hospital mortality. It is unknown whether excessive activation of these three upstream complement pathways may contribute to the detrimental effects in septic shock. This paper also discusses additional complement-related pathogenic mechanisms and intervention strategies for septic shock.

Clathrin-independent pathways do not contribute significantly to endocytic flux

PubMed Central

Bitsikas, Vassilis; Corrêa, Ivan R; Nichols, Benjamin J

2014-01-01

Several different endocytic pathways have been proposed to function in mammalian cells. Clathrin-coated pits are well defined, but the identity, mechanism and function of alternative pathways have been controversial. Here we apply universal chemical labelling of plasma membrane proteins to define all primary endocytic vesicles, and labelling of specific proteins with a reducible SNAP-tag substrate. These approaches provide high temporal resolution and stringent discrimination between surface-connected and intracellular membranes. We find that at least 95% of the earliest detectable endocytic vesicles arise from clathrin-coated pits. GPI-anchored proteins, candidate cargoes for alternate pathways, are also found to enter the cell predominantly via coated pits. Experiments employing a mutated clathrin adaptor reveal distinct mechanisms for sorting into coated pits, and thereby explain differential effects on the uptake of transferrin and GPI-anchored proteins. These data call for a revision of models for the activity and diversity of endocytic pathways in mammalian cells. DOI: http://dx.doi.org/10.7554/eLife.03970.001 PMID:25232658

Genetic and Epigenetic Events Generate Multiple Pathways in Colorectal Cancer Progression

PubMed Central

Pancione, Massimo; Remo, Andrea; Colantuoni, Vittorio

2012-01-01

Colorectal cancer (CRC) is one of the most common causes of death, despite decades of research. Initially considered as a disease due to genetic mutations, it is now viewed as a complex malignancy because of the involvement of epigenetic abnormalities. A functional equivalence between genetic and epigenetic mechanisms has been suggested in CRC initiation and progression. A hallmark of CRC is its pathogenetic heterogeneity attained through at least three distinct pathways: a traditional (adenoma-carcinoma sequence), an alternative, and more recently the so-called serrated pathway. While the alternative pathway is more heterogeneous and less characterized, the traditional and serrated pathways appear to be more homogeneous and clearly distinct. One unsolved question in colon cancer biology concerns the cells of origin and from which crypt compartment the different pathways originate. Based on molecular and pathological evidences, we propose that the traditional and serrated pathways originate from different crypt compartments explaining their genetic/epigenetic and clinicopathological differences. In this paper, we will discuss the current knowledge of CRC pathogenesis and, specifically, summarize the role of genetic/epigenetic changes in the origin and progression of the multiple CRC pathways. Elucidation of the link between the molecular and clinico-pathological aspects of CRC would improve our understanding of its etiology and impact both prevention and treatment. PMID:22888469

CORRRECTIVE ACTION DECISION DOCUMENT FOR CORRECTIVE ACTION UNIT 427: AREA 3 SEPTIC WASTE SYSTEMS 2 AND 6, TONOPAH TEST RANGE, NEVADA, REVISION 0, JUNE 1998

DOE Office of Scientific and Technical Information (OSTI.GOV)

ITLV.

1998-06-01

This Corrective Action Decision Document has been prepared for the Area 3 Septic Waste Systems 2 and 6 (Corrective Action Unit 427) in accordance with the Federal Facility Agreement and Consent Order of 1996 (FFACO, 1996). Corrective Action Unit 427 is located at the Tonopah Test Range, Nevada, and is comprised of the following Corrective Action Sites, each an individual septic waste system (DOE/NV, 1996a): Septic Waste System 2 is Corrective Action Site Number 03-05-002-SW02. Septic Waste System 6 is Corrective Action Site Number 03-05-002-SW06. The purpose of this Corrective Action Decision Document is to identify and provide a rationalemore » for the selection of a recommended corrective action alternative for each Corrective Action Site. The scope of this Correction Action Decision Document consists of the following tasks: Develop corrective action objectives. Identify corrective action alternative screening criteria. Develop corrective action alternatives. Perform detailed and comparative evaluations of the corrective action alternatives in relation to the corrective action objectives and screening criteria. Recommend and justify a preferred corrective action alternative for each CAS. From November 1997 through January 1998, a corrective action investigation was performed as set forth in the Corrective Action Investigation Plan for Corrective Action Unit No. 427: Area 3 Septic Waste System Numbers 2 and 6, Tonopah Test Range, Nevada (DOE/NV, 1997b). Details can be found in Appendix A of this document. The results indicated that contamination is present in some portions of the CAU and not in others as described in Table ES-1 and shown in Figure A.2-2 of Appendix A. Based on the potential exposure pathways, the following corrective action objectives have been identified for Corrective Action Unit 427: Prevent or mitigate human exposure to subsurface soils containing TPH at concentrations greater than 100 milligrams per kilogram (NAC, 1996b). Close Septic Tank 33-5 in accordance with Nevada Administrative Code 459 (NAC, 1996c). Prevent adverse impacts to groundwater quality. Based on the review of existing data, future land use, and current operations at the Tonopah Test Range, the following alternatives were developed for consideration at the Area 3 Septic Waste Systems 2 and 6: Alternative 1 - No Further Action Alternative 2 - Closure of Septic Tank 33-5 and Administrative Controls Alternative 3 - Closure of Septic Tank 33-5, Excavation, and Disposal The corrective action alternatives were evaluated based on four general corrective action standards and five remedy selection decision factors. Based on the results of this evaluation, the preferred alternative for Corrective Action Unit 427 is Alternative 2, Closure of Septic Tank 33-5 and Administrative Controls. The preferred corrective action alternative was evaluated on technical merit, focusing on performance, reliability, feasibility, and safety. The alternative was judged to meet all requirements for the technical components evaluated. The alternative meets all applicable state and federal regulations for closure of the site and will reduce potential future exposure pathways to the contaminated soils. During corrective action implementation, this alternative will present minimal potential threat to site workers who come in contact with the waste. However, procedures will be developed and implemented to ensure worker health and safety.« less

Allelic Variants of Complement Genes Associated with Dense Deposit Disease

PubMed Central

Abrera-Abeleda, Maria Asuncion; Nishimura, Carla; Frees, Kathy; Jones, Michael; Maga, Tara; Katz, Louis M.; Zhang, Yuzhou

2011-01-01

The alternative pathway of the complement cascade plays a role in the pathogenesis of dense deposit disease (DDD). Deficiency of complement factor H and mutations in CFH associate with the development of DDD, but it is unknown whether allelic variants in other complement genes also associate with this disease. We studied patients with DDD and identified previously unreported sequence alterations in several genes in addition to allelic variants and haplotypes common to patients with DDD. We found that the likelihood of developing DDD increases with the presence of two or more risk alleles in CFH and C3. To determine the functional consequence of this finding, we measured the activity of the alternative pathway in serum samples from phenotypically normal controls genotyped for variants in CFH and C3. Alternative pathway activity was higher in the presence of variants associated with DDD. Taken together, these data confirm that DDD is a complex genetic disease and may provide targets for the development of disease-specific therapies. PMID:21784901

Genetic modification of alternative respiration in Nicotiana benthamiana affects basal and salicylic acid-induced resistance to potato virus X

PubMed Central

2011-01-01

Background Salicylic acid (SA) regulates multiple anti-viral mechanisms, including mechanism(s) that may be negatively regulated by the mitochondrial enzyme, alternative oxidase (AOX), the sole component of the alternative respiratory pathway. However, studies of this mechanism can be confounded by SA-mediated induction of RNA-dependent RNA polymerase 1, a component of the antiviral RNA silencing pathway. We made transgenic Nicotiana benthamiana plants in which alternative respiratory pathway capacity was either increased by constitutive expression of AOX, or decreased by expression of a dominant-negative mutant protein (AOX-E). N. benthamiana was used because it is a natural mutant that does not express a functional RNA-dependent RNA polymerase 1. Results Antimycin A (an alternative respiratory pathway inducer and also an inducer of resistance to viruses) and SA triggered resistance to tobacco mosaic virus (TMV). Resistance to TMV induced by antimycin A, but not by SA, was inhibited in Aox transgenic plants while SA-induced resistance to this virus appeared to be stronger in Aox-E transgenic plants. These effects, which were limited to directly inoculated leaves, were not affected by the presence or absence of a transgene constitutively expressing a functional RNA-dependent RNA polymerase (MtRDR1). Unexpectedly, Aox-transgenic plants infected with potato virus X (PVX) showed markedly increased susceptibility to systemic disease induction and virus accumulation in inoculated and systemically infected leaves. SA-induced resistance to PVX was compromised in Aox-transgenic plants but plants expressing AOX-E exhibited enhanced SA-induced resistance to this virus. Conclusions We conclude that AOX-regulated mechanisms not only play a role in SA-induced resistance but also make an important contribution to basal resistance against certain viruses such as PVX. PMID:21356081

Integration of C₁ and C₂ Metabolism in Trees.

PubMed

Jardine, Kolby J; Fernandes de Souza, Vinicius; Oikawa, Patty; Higuchi, Niro; Bill, Markus; Porras, Rachel; Niinemets, Ülo; Chambers, Jeffrey Q

2017-09-23

C₁ metabolism in plants is known to be involved in photorespiration, nitrogen and amino acid metabolism, as well as methylation and biosynthesis of metabolites and biopolymers. Although the flux of carbon through the C₁ pathway is thought to be large, its intermediates are difficult to measure and relatively little is known about this potentially ubiquitous pathway. In this study, we evaluated the C₁ pathway and its integration with the central metabolism using aqueous solutions of 13 C-labeled C₁ and C₂ intermediates delivered to branches of the tropical species Inga edulis via the transpiration stream. Delivery of [ 13 C]methanol and [ 13 C]formaldehyde rapidly stimulated leaf emissions of [ 13 C]methanol, [ 13 C]formaldehyde, [ 13 C]formic acid, and 13 CO₂, confirming the existence of the C1 pathway and rapid interconversion between methanol and formaldehyde. However, while [ 13 C]formate solutions stimulated emissions of 13 CO₂, emissions of [ 13 C]methanol or [ 13 C]formaldehyde were not detected, suggesting that once oxidation to formate occurs it is rapidly oxidized to CO₂ within chloroplasts. 13 C-labeling of isoprene, a known photosynthetic product, was linearly related to 13 CO₂ across C₁ and C₂ ([ 13 C₂]acetate and [2- 13 C]glycine) substrates, consistent with reassimilation of C₁, respiratory, and photorespiratory CO₂. Moreover, [ 13 C]methanol and [ 13 C]formaldehyde induced a quantitative labeling of both carbon atoms of acetic acid emissions, possibly through the rapid turnover of the chloroplastic acetyl-CoA pool via glycolate oxidation. The results support a role of the C₁ pathway to provide an alternative carbon source for glycine methylation in photorespiration, enhance CO₂ concentrations within chloroplasts, and produce key C₂ intermediates (e.g., acetyl-CoA) central to anabolic and catabolic metabolism.

Endocytosis via caveolae: alternative pathway with distinct cellular compartments to avoid lysosomal degradation?

PubMed Central

Kiss, Anna L; Botos, Erzsébet

2009-01-01

Endocytosis – the uptake of extracellular ligands, soluble molecules, protein and lipids from the extracellular surface – is a vital process, comprising multiple mechanisms, including phagocytosis, macropinocytosis, clathrin-dependent and clathrin-independent uptake such as caveolae-mediated and non-caveolar raft-dependent endocytosis. The best-studied endocytotic pathway for internalizing both bulk membrane and specific proteins is the clathrin-mediated endocytosis. Although many papers were published about the caveolar endocytosis, it is still not known whether it represents an alternative pathway with distinct cellular compartments to avoid lysosomal degradation or ligands taken up by caveolae can also be targeted to late endosomes/lysosomes. In this paper, we summarize data available about caveolar endocytosis. We are especially focussing on the intracellular route of caveolae and providing data supporting that caveolar endocytosis can join to the classical endocytotic pathway. PMID:19382909

Pancreatic Cancer Sensitive to Selective p38 Pathway Inhibition | Center for Cancer Research

Cancer.gov

Pancreatic ductal adenocarcinoma (PDAC), the most-common cancer of the pancreas, is an aggressive disease that is estimated by the American Cancer Society to be the fourth leading cause of cancer death in men and women in 2015. Like most solid tumors, PDAC is surrounded by an inflammatory microenvironment containing numerous infiltrating immune cells. These cells are unable to eliminate the tumor and instead create a hospitable environment by providing tumor growth-promoting cytokines, the production of which lies downstream of the kinase p38. Unlike most immune cells, which use the classical pathway to activate p38, T cells employ an alternative p38 pathway that involves phosphorylation of tyrosine 323 (pY323) by the T cell receptor. Jonathan Ashwell, M.D., of CCR’s Laboratory of Immune Cell Biology and his colleagues decided to assess the role of the alternative p38 pathway in pancreatic cancer.

Serrated pathway: Alternative route to colorectal cancer

PubMed Central

Patai, Árpád V; Molnár, Béla; Tulassay, Zsolt; Sipos, Ferenc

2013-01-01

Serrated polyps have been an area of intense focus for gastroenterologists over the past several years. Contrary to what was thought before, a growing body of literature indicates that these polyps can be precursors of colorectal cancer (CRC). Most of these lesions, particularly those in the proximal colon, have so far been under-recognized and missed during colonoscopy, qualifying these lesions to be the main cause of interval cancers. It is estimated that 10%-20% of CRCs evolve through this alternative, serrated pathway, with a distinct genetic and epigenetic profile. Aberrant DNA methylation plays a central role in the development of this CRC subtype. This characteristic molecular background is reflected in a unique pathological and clinical manifestation different from cancers arising via the traditional pathway. In this review we would like to highlight morphological, molecular and clinical features of this emerging pathway that are essential for gastroenterologists and may influence their everyday practice. PMID:23431044

Contribution of the Alternative Respiratory Pathway to PSII Photoprotection in C3 and C4 Plants.

PubMed

Zhang, Zi-Shan; Liu, Mei-Jun; Scheibe, Renate; Selinski, Jennifer; Zhang, Li-Tao; Yang, Cheng; Meng, Xiang-Long; Gao, Hui-Yuan

2017-01-09

The mechanism by which the mitochondrial alternative oxidase (AOX) pathway contributes to photosystem II (PSII) photoprotection is in dispute. It was generally thought that the AOX pathway protects photosystems by dissipating excess reducing equivalents exported from chloroplasts through the malate/oxaloacetate (Mal/OAA) shuttle and thus preventing the over-reduction of chloroplasts. In this study, using the aox1a Arabidopsis mutant and nine other C3 and C4 plant species, we revealed an additional action model of the AOX pathway in PSII photoprotection. Although the AOX pathway contributes to PSII photoprotection in C3 leaves treated with high light, this contribution was observed to disappear when photorespiration was suppressed. Disruption or inhibition of the AOX pathway significantly decreased the photorespiration in C3 leaves. Moreover, the AOX pathway did not respond to high light and contributed little to PSII photoprotection in C4 leaves possessing a highly active Mal/OAA shuttle but with little photorespiration. These results demonstrate that the AOX pathway contributes to PSII photoprotection in C3 plants by maintaining photorespiration to detoxify glycolate and via the indirect export of excess reducing equivalents from chloroplasts by the Mal/OAA shuttle. This new action model explains why the AOX pathway does not contribute to PSII photoprotection in C4 plants. Copyright © 2017 The Author. Published by Elsevier Inc. All rights reserved.

Synergy between the classical and alternative pathways of complement is essential for conferring effective protection against the pandemic influenza A(H1N1) 2009 virus infection

PubMed Central

Rattan, Ajitanuj; Pawar, Shailesh D.; Nawadkar, Renuka; Kulkarni, Neeraja

2017-01-01

The pandemic influenza A(H1N1) 2009 virus caused significant morbidity and mortality worldwide thus necessitating the need to understand the host factors that influence its control. Previously, the complement system has been shown to provide protection during the seasonal influenza virus infection, however, the role of individual complement pathways is not yet clear. Here, we have dissected the role of intact complement as well as of its individual activation pathways during the pandemic influenza virus infection using mouse strains deficient in various complement components. We show that the virus infection in C3-/- mice results in increased viral load and 100% mortality, which can be reversed by adoptive transfer of naïve wild-type (WT) splenocytes, purified splenic B cells, or passive transfer of immune sera from WT, but not C3-/- mice. Blocking of C3a and/or C5a receptor signaling in WT mice using receptor antagonists and use of C3aR-/- and C5aR-/- mice showed significant mortality after blocking/ablation of C3aR, with little or no effect after blocking/ablation of C5aR. Intriguingly, deficiency of C4 and FB in mice resulted in only partial mortality (24%-32%) suggesting a necessary cross-talk between the classical/lectin and alternative pathways for providing effective protection. In vitro virus neutralization experiments performed to probe the cross-talk between the various pathways indicated that activation of the classical and alternative pathways in concert, owing to coating of viral surface by antibodies, is needed for its efficient neutralization. Examination of the virus-specific complement-binding antibodies in virus positive subjects showed that their levels vary among individuals. Together these results indicate that cooperation between the classical and alternative pathways not only result in efficient direct neutralization of the pandemic influenza virus, but also lead to the optimum generation of C3a, which when sensed by the immune cells along with the antigen culminates in generation of effective protective immune responses. PMID:28301559

Carnegie Math Pathways 2015-2016 Impact Report: A Five-Year Review. Carnegie Math Pathways Technical Report

ERIC Educational Resources Information Center

Hoang, Hai; Huang, Melrose; Sulcer, Brian; Yesilyurt, Suleyman

2017-01-01

College math is a gateway course that has become a constraining gatekeeper for tens of thousands of students annually. Every year, over 500,000 students fail developmental mathematics, preventing them from achieving their college and career goals. The Carnegie Math Pathways initiative offers students an alternative. It comprises two Pathways…

A Systematic Review on the Existing Screening Pathways for Lynch Syndrome Identification.

PubMed

Tognetto, Alessia; Michelazzo, Maria Benedetta; Calabró, Giovanna Elisa; Unim, Brigid; Di Marco, Marco; Ricciardi, Walter; Pastorino, Roberta; Boccia, Stefania

2017-01-01

Lynch syndrome (LS) is the most common hereditary colon cancer syndrome, accounting for 3-5% of colorectal cancer (CRC) cases, and it is associated with the development of other cancers. Early detection of individuals with LS is relevant, since they can take advantage of life-saving intensive care surveillance. The debate regarding the best screening policy, however, is far from being concluded. This prompted us to conduct a systematic review of the existing screening pathways for LS. We performed a systematic search of MEDLINE, ISI Web of Science, and SCOPUS online databases for the existing screening pathways for LS. The eligibility criteria for inclusion in this review required that the studies evaluated a structured and permanent screening pathway for the identification of LS carriers. The effectiveness of the pathways was analyzed in terms of LS detection rate. We identified five eligible studies. All the LS screening pathways started from CRC cases, of which three followed a universal screening approach. Concerning the laboratory procedures, the pathways used immunohistochemistry and/or microsatellite instability testing. If the responses of the tests indicated a risk for LS, the genetic counseling, performed by a geneticist or a genetic counselor, was mandatory to undergo DNA genetic testing. The overall LS detection rate ranged from 0 to 5.2%. This systematic review reported different existing pathways for the identification of LS patients. Although current clinical guidelines suggest to test all the CRC cases to identify LS cases, the actual implementation of pathways for LS identification has not been realized. Large-scale screening programs for LS have the potential to reduce morbidity and mortality for CRC, but coordinated efforts in educating all key stakeholders and addressing public needs are still required.

Alternative Routes to Teaching: Mapping the New Landscape of Teacher Education

ERIC Educational Resources Information Center

Grossman, Pam, Ed.; Loeb, Susanna, Ed.

2008-01-01

Over the past 20 years, alternative certification for teachers has emerged as a major avenue of teacher preparation. The proliferation of new pathways has spurred heated debate over how best to recruit, prepare, and support qualified teachers. "Alternative Routes to Teaching" provides a thorough and dispassionate review of the research evidence on…

Student Adjustment to Higher Education: The Role of Alternative Educational Pathways in Coping with the Demands of Student Life

ERIC Educational Resources Information Center

Shankland, Rebecca; Genolini, Christophe; Franca, Lionel Riou; Guelfi, Julien-Daniel; Ionescu, Serban

2010-01-01

The present longitudinal study measured student adjustment to higher education, comparing 50 participants from alternative schools (Steiner, Montessori, New Schools) with 80 students from the traditional school system. We hypothesized that students from alternative schools adapt better, because of greater perceived social support, academic…

Cucumber possesses a single terminal alternative oxidase gene that is upregulated by cold stress and in the mosaic (MSC) mitochondrial mutants

USDA-ARS?s Scientific Manuscript database

In plants alternative oxidase (AOX) is an important nuclear-encoded enzyme active in the mitochondrial electron-transport chain, transferring electrons from ubiquinol to alternative oxidase instead of the cytochrome pathway to yield ubiquinone and water. AOX protects against unexpected inhibition of...

Connecting the dots: chromatin and alternative splicing in EMT.

PubMed

Warns, Jessica A; Davie, James R; Dhasarathy, Archana

2016-02-01

Nature has devised sophisticated cellular machinery to process mRNA transcripts produced by RNA Polymerase II, removing intronic regions and connecting exons together, to produce mature RNAs. This process, known as splicing, is very closely linked to transcription. Alternative splicing, or the ability to produce different combinations of exons that are spliced together from the same genomic template, is a fundamental means of regulating protein complexity. Similar to transcription, both constitutive and alternative splicing can be regulated by chromatin and its associated factors in response to various signal transduction pathways activated by external stimuli. This regulation can vary between different cell types, and interference with these pathways can lead to changes in splicing, often resulting in aberrant cellular states and disease. The epithelial to mesenchymal transition (EMT), which leads to cancer metastasis, is influenced by alternative splicing events of chromatin remodelers and epigenetic factors such as DNA methylation and non-coding RNAs. In this review, we will discuss the role of epigenetic factors including chromatin, chromatin remodelers, DNA methyltransferases, and microRNAs in the context of alternative splicing, and discuss their potential involvement in alternative splicing during the EMT process.

77 FR 4834 - Proposed Extension of Existing Information Collection; Refuge Alternatives for Underground Coal...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-01-31

... Extension of Existing Information Collection; Refuge Alternatives for Underground Coal Mines AGENCY: Mine... Underground Coal Mines DATES: Submit comments on or before April 2, 2012. ADDRESSES: Comments must be.... Title: Refuge Alternatives for Underground Coal Mines. OMB Number: 1219-0146. Affected Public: Business...

30 CFR 585.1005 - How do I request an Alternate Use RUE?

Code of Federal Regulations, 2014 CFR

2014-07-01

... Section 585.1005 Mineral Resources BUREAU OF OCEAN ENERGY MANAGEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE RENEWABLE ENERGY AND ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS Facilities Requesting An Alternate...

30 CFR 585.1013 - Is an Alternate Use RUE assignable?

Code of Federal Regulations, 2014 CFR

2014-07-01

... Section 585.1013 Mineral Resources BUREAU OF OCEAN ENERGY MANAGEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE RENEWABLE ENERGY AND ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS Facilities Alternate Use Rue...

30 CFR 285.1016 - When will an Alternate Use RUE be cancelled?

Code of Federal Regulations, 2010 CFR

2010-07-01

... OFFSHORE RENEWABLE ENERGY ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS Facilities Alternate Use... marine, coastal, or human environment; or sites, structures, or objects of historical or archaeological...

30 CFR 285.1014 - When will MMS suspend an Alternate Use RUE?

Code of Federal Regulations, 2010 CFR

2010-07-01

... OFFSHORE RENEWABLE ENERGY ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS Facilities Alternate Use... resources; life (including human and wildlife); property; the marine, coastal, or human environment; or...

30 CFR 585.1015 - How do I relinquish an Alternate Use RUE?

Code of Federal Regulations, 2012 CFR

2012-07-01

....1015 Section 585.1015 Mineral Resources BUREAU OF OCEAN ENERGY MANAGEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE RENEWABLE ENERGY AND ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS Facilities Alternate...

30 CFR 585.1013 - Is an Alternate Use RUE assignable?

Code of Federal Regulations, 2012 CFR

2012-07-01

... Section 585.1013 Mineral Resources BUREAU OF OCEAN ENERGY MANAGEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE RENEWABLE ENERGY AND ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS Facilities Alternate Use Rue...

30 CFR 585.1015 - How do I relinquish an Alternate Use RUE?

Code of Federal Regulations, 2014 CFR

2014-07-01

....1015 Section 585.1015 Mineral Resources BUREAU OF OCEAN ENERGY MANAGEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE RENEWABLE ENERGY AND ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS Facilities Alternate...

30 CFR 585.1005 - How do I request an Alternate Use RUE?

Code of Federal Regulations, 2013 CFR

2013-07-01

... Section 585.1005 Mineral Resources BUREAU OF OCEAN ENERGY MANAGEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE RENEWABLE ENERGY AND ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS Facilities Requesting An Alternate...

30 CFR 585.1013 - Is an Alternate Use RUE assignable?

Code of Federal Regulations, 2013 CFR

2013-07-01

... Section 585.1013 Mineral Resources BUREAU OF OCEAN ENERGY MANAGEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE RENEWABLE ENERGY AND ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS Facilities Alternate Use Rue...

30 CFR 585.1005 - How do I request an Alternate Use RUE?

Code of Federal Regulations, 2012 CFR

2012-07-01

... Section 585.1005 Mineral Resources BUREAU OF OCEAN ENERGY MANAGEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE RENEWABLE ENERGY AND ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS Facilities Requesting An Alternate...

30 CFR 585.1015 - How do I relinquish an Alternate Use RUE?

Code of Federal Regulations, 2013 CFR

2013-07-01

....1015 Section 585.1015 Mineral Resources BUREAU OF OCEAN ENERGY MANAGEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE RENEWABLE ENERGY AND ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS Facilities Alternate...

EarthConnections: Integrating Community Science and Geoscience Education Pathways for More Resilient Communities.

NASA Astrophysics Data System (ADS)

Manduca, C. A.

2017-12-01

To develop a diverse geoscience workforce, the EarthConnections collective impact alliance is developing regionally focused, Earth education pathways. These pathways support and guide students from engagement in relevant, Earth-related science at an early age through the many steps and transitions to geoscience-related careers. Rooted in existing regional activities, pathways are developed using a process that engages regional stakeholders and community members with EarthConnections partners. Together they connect, sequence, and create multiple learning opportunities that link geoscience education and community service to address one or more local geoscience issues. Three initial pilots are demonstrating different starting points and strategies for creating pathways that serve community needs while supporting geoscience education. The San Bernardino pilot is leveraging existing academic relationships and programs; the Atlanta pilot is building into existing community activities; and the Oklahoma Tribal Nations pilot is co-constructing a pathway focus and approach. The project is using pathway mapping and a collective impact framework to support and monitor progress. The goal is to develop processes and activities that can help other communities develop similar community-based geoscience pathways. By intertwining Earth education with local community service we aspire to increase the resilience of communities in the face of environmental hazards and limited Earth resources.

Catabolite-mediated mutations in alternate toluene degradative pathways in Pseudomonas putida.

PubMed Central

Leddy, M B; Phipps, D W; Ridgway, H F

1995-01-01

Pseudomonas putida 54g grew on mineral salts with toluene and exhibited catechol-2,3-dioxygenase (C23O) activity, indicating a meta pathway. After 10 to 15 days on toluene, nondegrading (Tol-) variants approached nearly 10% of total CFU. Auxotrophs were not detected among variants, suggesting selective loss of catabolic function(s). Variant formation was substrate dependent, since Tol- cells were observed on neither ethylbenzene, glucose, nor peptone-based media nor when toluene catabolism was suppressed by glucose. Unlike wild-type cells, variants did not grow on gasoline, toluene, benzene, ethylbenzene, benzoate, or catechol, suggesting loss of meta pathway function. Catabolic and C23O activities were restored to variants via transfer of a 78-mDa TOL-like plasmid from a wild-type Tol+ donor. Tests for reversion of variants to Tol+ were uniformly negative, suggesting possible delection or excision of catabolic genes. Deletions were confirmed in some variants by failure to hybridize with a DNA probe specific for the xylE gene encoding C23O. Cells grown on benzoate remained Tol+ but were C23O- and contained a plasmid of reduced size or were plasmid free, suggesting an alternate chromosomal catabolic pathway, also defective in variants. Cells exposed to benzyl alcohol, the initial oxidation product of toluene, accumulated > 13% variants in 5 days, even when cell division was repressed by nitrogen deprivation to abrogate selection processes. No variants formed in identical ethylbenzene-exposed controls. The results suggest that benzyl alcohol mediates irreversible defects in both a plasmid-associated meta pathway and an alternate chromosomal pathway. PMID:7642499

Accessory pathway ablation in a 6-year-old girl using remote magnetic navigation as an alternative to cryoablation.

PubMed

Mantziari, Lilian; Rigby, Michael; Till, Janice; Ernst, Sabine

2013-03-01

A 6-year-old girl with evidence of a parahisian accessory pathway on a baseline electrocardiogram underwent successful catheter ablation using magnetic navigation. Magnetic remote controlled ablation eliminated the parahisian pathway with the first radiofrequency application. A second anterolaterally located concealed pathway was successfully ablated in the same session, resulting in exclusively atrioventricular nodal conduction bidirectionally (total fluoroscopy, 4 min; 25 μGy).

Cloning and Analysis of the Alternative Oxidase Gene of Neurospora Crassa

PubMed Central

Li, Q.; Ritzel, R. G.; McLean, LLT.; McIntosh, L.; Ko, T.; Bertrand, H.; Nargang, F. E.

1996-01-01

Mitochondria of Neurospora crassa contain a cyanide-resistant alternative respiratory pathway in addition to the cytochrome pathway. The alternative oxidase is present only when electron flow through the cytochrome chain is restricted. Both genomic and cDNA copies for the alternative oxidase gene have been isolated and analyzed. The sequence of the predicted protein is homologous to that of other species. The mRNA for the alternative oxidase is scarce in wild-type cultures grown under normal conditions, but it is abundant in cultures grown in the presence of chloramphenicol, an inhibitor of mitochondrial protein synthesis, or in mutants deficient in mitochondrial cytochromes. Thus, induction of alternative oxidase appears to be at the transcriptional level. Restriction fragment length polymorphism mapping of the isolated gene demonstrated that it is located in a position corresponding to the aod-1 locus. Sequence analysis of mutant aod-1 alleles reveals mutations affecting the coding sequence of the alternative oxidase. The level of aod-1 mRNA in an aod-2 mutant strain that had been grown in the presence of chloramphenicol was reduced several fold relative to wild-type, supporting the hypothesis that the product of aod-2 is required for optimal expression of aod-1. PMID:8770590

A Web Tool for Generating High Quality Machine-readable Biological Pathways.

PubMed

Ramirez-Gaona, Miguel; Marcu, Ana; Pon, Allison; Grant, Jason; Wu, Anthony; Wishart, David S

2017-02-08

PathWhiz is a web server built to facilitate the creation of colorful, interactive, visually pleasing pathway diagrams that are rich in biological information. The pathways generated by this online application are machine-readable and fully compatible with essentially all web-browsers and computer operating systems. It uses a specially developed, web-enabled pathway drawing interface that permits the selection and placement of different combinations of pre-drawn biological or biochemical entities to depict reactions, interactions, transport processes and binding events. This palette of entities consists of chemical compounds, proteins, nucleic acids, cellular membranes, subcellular structures, tissues, and organs. All of the visual elements in it can be interactively adjusted and customized. Furthermore, because this tool is a web server, all pathways and pathway elements are publicly accessible. This kind of pathway "crowd sourcing" means that PathWhiz already contains a large and rapidly growing collection of previously drawn pathways and pathway elements. Here we describe a protocol for the quick and easy creation of new pathways and the alteration of existing pathways. To further facilitate pathway editing and creation, the tool contains replication and propagation functions. The replication function allows existing pathways to be used as templates to create or edit new pathways. The propagation function allows one to take an existing pathway and automatically propagate it across different species. Pathways created with this tool can be "re-styled" into different formats (KEGG-like or text-book like), colored with different backgrounds, exported to BioPAX, SBGN-ML, SBML, or PWML data exchange formats, and downloaded as PNG or SVG images. The pathways can easily be incorporated into online databases, integrated into presentations, posters or publications, or used exclusively for online visualization and exploration. This protocol has been successfully applied to generate over 2,000 pathway diagrams, which are now found in many online databases including HMDB, DrugBank, SMPDB, and ECMDB.

Plasmid-borne Tn5 insertion mutation resulting in accumulation of gentisate from salicylate.

PubMed Central

Monticello, D J; Bakker, D; Schell, M; Finnerty, W R

1985-01-01

Plasmid-borne Tn5 insertion mutants of a Pseudomonas species which accumulated 2,5-dihydroxybenzoate (gentisate) following growth on 2-hydroxybenzoate (salicylate) were obtained from a pool of mutants that were unable to grow on naphthalene. One such mutant was characterized further. The ability of this mutant to oxidize gentisate was 100-fold less than the ability of a Nah+ Sal+ strain harboring the unmutagenized plasmid, although both strains oxidized and grew on salicylate. These bacteria were presumably able to metabolize salicylate via catechol, since they possessed an inducible, plasmid-encoded catechol 2,3-dioxygenase. Our results suggest that there is an alternate, plasmid-encoded route of salicylate degradation via gentisate and that some plasmid-associated relationship between this pathway and naphthalene oxidation exists. PMID:2988437

Reverse engineering of logic-based differential equation models using a mixed-integer dynamic optimization approach

PubMed Central

Henriques, David; Rocha, Miguel; Saez-Rodriguez, Julio; Banga, Julio R.

2015-01-01

Motivation: Systems biology models can be used to test new hypotheses formulated on the basis of previous knowledge or new experimental data, contradictory with a previously existing model. New hypotheses often come in the shape of a set of possible regulatory mechanisms. This search is usually not limited to finding a single regulation link, but rather a combination of links subject to great uncertainty or no information about the kinetic parameters. Results: In this work, we combine a logic-based formalism, to describe all the possible regulatory structures for a given dynamic model of a pathway, with mixed-integer dynamic optimization (MIDO). This framework aims to simultaneously identify the regulatory structure (represented by binary parameters) and the real-valued parameters that are consistent with the available experimental data, resulting in a logic-based differential equation model. The alternative to this would be to perform real-valued parameter estimation for each possible model structure, which is not tractable for models of the size presented in this work. The performance of the method presented here is illustrated with several case studies: a synthetic pathway problem of signaling regulation, a two-component signal transduction pathway in bacterial homeostasis, and a signaling network in liver cancer cells. Supplementary information: Supplementary data are available at Bioinformatics online. Contact: julio@iim.csic.es or saezrodriguez@ebi.ac.uk PMID:26002881

Reverse engineering of logic-based differential equation models using a mixed-integer dynamic optimization approach.

PubMed

Henriques, David; Rocha, Miguel; Saez-Rodriguez, Julio; Banga, Julio R

2015-09-15

Systems biology models can be used to test new hypotheses formulated on the basis of previous knowledge or new experimental data, contradictory with a previously existing model. New hypotheses often come in the shape of a set of possible regulatory mechanisms. This search is usually not limited to finding a single regulation link, but rather a combination of links subject to great uncertainty or no information about the kinetic parameters. In this work, we combine a logic-based formalism, to describe all the possible regulatory structures for a given dynamic model of a pathway, with mixed-integer dynamic optimization (MIDO). This framework aims to simultaneously identify the regulatory structure (represented by binary parameters) and the real-valued parameters that are consistent with the available experimental data, resulting in a logic-based differential equation model. The alternative to this would be to perform real-valued parameter estimation for each possible model structure, which is not tractable for models of the size presented in this work. The performance of the method presented here is illustrated with several case studies: a synthetic pathway problem of signaling regulation, a two-component signal transduction pathway in bacterial homeostasis, and a signaling network in liver cancer cells. Supplementary data are available at Bioinformatics online. julio@iim.csic.es or saezrodriguez@ebi.ac.uk. © The Author 2015. Published by Oxford University Press.

Imaging Pathways in Fractured Rock Using Three-Dimensional Electrical Resistivity Tomography.

PubMed

Robinson, Judith; Slater, Lee; Johnson, Timothy; Shapiro, Allen; Tiedeman, Claire; Ntarlagiannis, Dimitrios; Johnson, Carole; Day-Lewis, Frederick; Lacombe, Pierre; Imbrigiotta, Thomas; Lane, John

2016-03-01

Major challenges exist in delineating bedrock fracture zones because these cause abrupt changes in geological and hydrogeological properties over small distances. Borehole observations cannot sufficiently capture heterogeneity in these systems. Geophysical techniques offer the potential to image properties and processes in between boreholes. We used three-dimensional cross borehole electrical resistivity tomography (ERT) in a 9 m (diameter) × 15 m well field to capture high-resolution flow and transport processes in a fractured mudstone contaminated by chlorinated solvents, primarily trichloroethylene. Conductive (sodium bromide) and resistive (deionized water) injections were monitored in seven boreholes. Electrode arrays with isolation packers and fluid sampling ports were designed to enable acquisition of ERT measurements during pulsed tracer injections. Fracture zone locations and hydraulic pathways inferred from hydraulic head drawdown data were compared with electrical conductivity distributions from ERT measurements. Static ERT imaging has limited resolution to decipher individual fractures; however, these images showed alternating conductive and resistive zones, consistent with alternating laminated and massive mudstone units at the site. Tracer evolution and migration was clearly revealed in time-lapse ERT images and supported by in situ borehole vertical apparent conductivity profiles collected during the pulsed tracer test. While water samples provided important local information at the extraction borehole, ERT delineated tracer migration over spatial scales capturing the primary hydrogeological heterogeneity controlling flow and transport. The fate of these tracer injections at this scale could not have been quantified using borehole logging and/or borehole sampling methods alone. © 2015, National Ground Water Association.

Associations between colorectal cancer molecular markers and pathways with clinicopathologic features in older women.

PubMed

Samadder, N Jewel; Vierkant, Robert A; Tillmans, Lori S; Wang, Alice H; Weisenberger, Daniel J; Laird, Peter W; Lynch, Charles F; Anderson, Kristin E; French, Amy J; Haile, Robert W; Potter, John D; Slager, Susan L; Smyrk, Thomas C; Thibodeau, Stephen N; Cerhan, James R; Limburg, Paul J

2013-08-01

Colorectal tumors have a large degree of molecular heterogeneity. Three integrated pathways of carcinogenesis (ie, traditional, alternate, and serrated) have been proposed, based on specific combinations of microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and mutations in BRAF and KRAS. We used resources from the population-based Iowa Women's Health Study (n = 41,836) to associate markers of colorectal tumors, integrated pathways, and clinical and pathology characteristics, including survival times. We assessed archived specimens from 732 incident colorectal tumors and characterized them as microsatellite stable (MSS), MSI high or MSI low, CIMP high or CIMP low, CIMP negative, and positive or negative for BRAF and/or KRAS mutations. Informative marker data were collected from 563 tumors (77%), which were assigned to the following integrated pathways: traditional (MSS, CIMP negative, BRAF mutation negative, and KRAS mutation negative; n = 170), alternate (MSS, CIMP low, BRAF mutation negative, and KRAS mutation positive; n = 58), serrated (any MSI, CIMP high, BRAF mutation positive, and KRAS mutation negative; n = 142), or unassigned (n = 193). Multivariable-adjusted Cox proportional hazards regression models were used to assess the associations of interest. Patients' mean age (P = .03) and tumors' anatomic subsite (P = .0001) and grade (P = .0001) were significantly associated with integrated pathway assignment. Colorectal cancer (CRC) mortality was not associated with the traditional, alternate, or serrated pathways, but was associated with a subset of pathway-unassigned tumors (MSS or MSI low, CIMP negative, BRAF mutation negative, and KRAS mutation positive) (n = 96 cases; relative risk = 1.76; 95% confidence interval, 1.07-2.89, compared with the traditional pathway). We identified clinical and pathology features associated with molecularly defined CRC subtypes. However, additional studies are needed to determine how these features might influence prognosis. Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

30 CFR 585.1012 - What financial assurance is required for an Alternate Use RUE?

Code of Federal Regulations, 2014 CFR

2014-07-01

... Alternate Use RUE? 585.1012 Section 585.1012 Mineral Resources BUREAU OF OCEAN ENERGY MANAGEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE RENEWABLE ENERGY AND ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS...

30 CFR 585.1010 - How long may I conduct activities under an Alternate Use RUE?

Code of Federal Regulations, 2013 CFR

2013-07-01

... Alternate Use RUE? 585.1010 Section 585.1010 Mineral Resources BUREAU OF OCEAN ENERGY MANAGEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE RENEWABLE ENERGY AND ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS...

30 CFR 585.1006 - How will BOEM decide whether to issue an Alternate Use RUE?

Code of Federal Regulations, 2013 CFR

2013-07-01

... Alternate Use RUE? 585.1006 Section 585.1006 Mineral Resources BUREAU OF OCEAN ENERGY MANAGEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE RENEWABLE ENERGY AND ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS...

30 CFR 585.1012 - What financial assurance is required for an Alternate Use RUE?

Code of Federal Regulations, 2012 CFR

2012-07-01

... Alternate Use RUE? 585.1012 Section 585.1012 Mineral Resources BUREAU OF OCEAN ENERGY MANAGEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE RENEWABLE ENERGY AND ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS...

30 CFR 285.1018 - Who is responsible for decommissioning an OCS facility subject to an Alternate Use RUE?

Code of Federal Regulations, 2011 CFR

2011-07-01

... ENERGY MANAGEMENT, REGULATION, AND ENFORCEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE RENEWABLE ENERGY ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS Facilities Decommissioning An Alternate Use Rue § 285...

30 CFR 585.1006 - How will BOEM decide whether to issue an Alternate Use RUE?

Code of Federal Regulations, 2012 CFR

2012-07-01

... Alternate Use RUE? 585.1006 Section 585.1006 Mineral Resources BUREAU OF OCEAN ENERGY MANAGEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE RENEWABLE ENERGY AND ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS...

30 CFR 585.1019 - What are the decommissioning requirements for an Alternate Use RUE?

Code of Federal Regulations, 2012 CFR

2012-07-01

... an Alternate Use RUE? 585.1019 Section 585.1019 Mineral Resources BUREAU OF OCEAN ENERGY MANAGEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE RENEWABLE ENERGY AND ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS...

30 CFR 585.1012 - What financial assurance is required for an Alternate Use RUE?

Code of Federal Regulations, 2013 CFR

2013-07-01

... Alternate Use RUE? 585.1012 Section 585.1012 Mineral Resources BUREAU OF OCEAN ENERGY MANAGEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE RENEWABLE ENERGY AND ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS...

30 CFR 585.1010 - How long may I conduct activities under an Alternate Use RUE?

Code of Federal Regulations, 2014 CFR

2014-07-01

... Alternate Use RUE? 585.1010 Section 585.1010 Mineral Resources BUREAU OF OCEAN ENERGY MANAGEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE RENEWABLE ENERGY AND ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS...

30 CFR 585.1019 - What are the decommissioning requirements for an Alternate Use RUE?

Code of Federal Regulations, 2013 CFR

2013-07-01

... an Alternate Use RUE? 585.1019 Section 585.1019 Mineral Resources BUREAU OF OCEAN ENERGY MANAGEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE RENEWABLE ENERGY AND ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS...

30 CFR 585.1019 - What are the decommissioning requirements for an Alternate Use RUE?

Code of Federal Regulations, 2014 CFR

2014-07-01

... an Alternate Use RUE? 585.1019 Section 585.1019 Mineral Resources BUREAU OF OCEAN ENERGY MANAGEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE RENEWABLE ENERGY AND ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS...

30 CFR 585.1006 - How will BOEM decide whether to issue an Alternate Use RUE?

Code of Federal Regulations, 2014 CFR

2014-07-01

... Alternate Use RUE? 585.1006 Section 585.1006 Mineral Resources BUREAU OF OCEAN ENERGY MANAGEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE RENEWABLE ENERGY AND ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS...

30 CFR 585.1010 - How long may I conduct activities under an Alternate Use RUE?

Code of Federal Regulations, 2012 CFR

2012-07-01

... Alternate Use RUE? 585.1010 Section 585.1010 Mineral Resources BUREAU OF OCEAN ENERGY MANAGEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE RENEWABLE ENERGY AND ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS...

75 FR 49536 - Petitions for Modification of Existing Mandatory Safety Standards

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-13

... alternative method of achieving the result of such standard exists which will at all times guarantee no less... for inspection; (8) the proposed alternative method will not be implemented until miners who have been... training plans will apply. The petitioner asserts that the proposed alternative method will at all times...

30 CFR 285.1008-285.1009 - [Reserved

Code of Federal Regulations, 2010 CFR

2010-07-01

... ENERGY ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS Facilities Requesting An Alternate Use...

75 FR 13 - Alternate Fracture Toughness Requirements for Protection Against Pressurized Thermal Shock Events

Federal Register 2010, 2011, 2012, 2013, 2014

2010-01-04

...The Nuclear Regulatory Commission (NRC) is amending its regulations to provide alternate fracture toughness requirements for protection against pressurized thermal shock (PTS) events for pressurized water reactor (PWR) pressure vessels. This final rule provides alternate PTS requirements based on updated analysis methods. This action is desirable because the existing requirements are based on unnecessarily conservative probabilistic fracture mechanics analyses. This action reduces regulatory burden for those PWR licensees who expect to exceed the existing requirements before the expiration of their licenses, while maintaining adequate safety, and may choose to comply with the final rule as an alternative to complying with the existing requirements.

[Role of mitochondrial alternative oxidase (AOX) pathway in photoprotection in Rumex K-1 leaves].

PubMed

Meng, Xiang-Long; Zhang, Li-Tao; Zhang, Zi-Shan; Gao, Hui-Yuan; Meng, Qing-Wei

2012-07-01

Taking Rumex K-1 leaves as test materials, this paper studied the role of mitochondrial alternative oxidase (AOX) pathway in photoprotection under different light intensities. Under low light intensity (200 micromol x m(-2) x s(-1)), and after treated with salicylhydroxamic acid to inhibit the AOX pathway, the leaf actual photochemical efficiency of PS II, linear electron transport rate of photosynthesis, and photosynthetic O2 evolution rate all decreased significantly while the non-Q(B) reducing reaction center had a significant increase, indicating that under low light, the photoinhibition was aggravated while the scavenging enzymes of reactive oxygen species (ROS) increased, which avoided the over-accumulation of ROS and partially alleviated the photoinhibition of Rumex K-1 leaves. Under high light intensity (800 micromol x m(-2) x s(-1)), the inhibition of AOX pathway caused more severe photoinhibition, and the increased activities of ROS scavenging enzymes were insufficient to prevent the over-accumulation of ROS. This study demonstrated that AOX pathway played an important role in the photoprotection in Rumex K-1 leaves under both high and low light intensities, and the role of AOX pathway in photoprotection under high light could be irreplaceable by the other photoprotection pathways in chloroplast.

CAMPways: constrained alignment framework for the comparative analysis of a pair of metabolic pathways.

PubMed

Abaka, Gamze; Bıyıkoğlu, Türker; Erten, Cesim

2013-07-01

Given a pair of metabolic pathways, an alignment of the pathways corresponds to a mapping between similar substructures of the pair. Successful alignments may provide useful applications in phylogenetic tree reconstruction, drug design and overall may enhance our understanding of cellular metabolism. We consider the problem of providing one-to-many alignments of reactions in a pair of metabolic pathways. We first provide a constrained alignment framework applicable to the problem. We show that the constrained alignment problem even in a primitive setting is computationally intractable, which justifies efforts for designing efficient heuristics. We present our Constrained Alignment of Metabolic Pathways (CAMPways) algorithm designed for this purpose. Through extensive experiments involving a large pathway database, we demonstrate that when compared with a state-of-the-art alternative, the CAMPways algorithm provides better alignment results on metabolic networks as far as measures based on same-pathway inclusion and biochemical significance are concerned. The execution speed of our algorithm constitutes yet another important improvement over alternative algorithms. Open source codes, executable binary, useful scripts, all the experimental data and the results are freely available as part of the Supplementary Material at http://code.google.com/p/campways/. Supplementary data are available at Bioinformatics online.

Evaluation of Yersinia pestis Transmission Pathways for Sylvatic Plague in Prairie Dog Populations in the Western U.S.

PubMed

Richgels, Katherine L D; Russell, Robin E; Bron, Gebbiena M; Rocke, Tonie E

2016-06-01

Sylvatic plague, caused by the bacterium Yersinia pestis, is periodically responsible for large die-offs in rodent populations that can spillover and cause human mortalities. In the western US, prairie dog populations experience nearly 100% mortality during plague outbreaks, suggesting that multiple transmission pathways combine to amplify plague dynamics. Several alternate pathways in addition to flea vectors have been proposed, such as transmission via direct contact with bodily fluids or inhalation of infectious droplets, consumption of carcasses, and environmental sources of plague bacteria, such as contaminated soil. However, evidence supporting the ability of these proposed alternate pathways to trigger large-scale epizootics remains elusive. Here we present a short review of potential plague transmission pathways and use an ordinary differential equation model to assess the contribution of each pathway to resulting plague dynamics in black-tailed prairie dogs (Cynomys ludovicianus) and their fleas (Oropsylla hirsuta). Using our model, we found little evidence to suggest that soil contamination was capable of producing plague epizootics in prairie dogs. However, in the absence of flea transmission, direct transmission, i.e., contact with bodily fluids or inhalation of infectious droplets, could produce enzootic dynamics, and transmission via contact with or consumption of carcasses could produce epizootics. This suggests that these pathways warrant further investigation.

SALO, a novel classical pathway complement inhibitor from saliva of the sand fly Lutzomyia longipalpis

PubMed Central

Ferreira, Viviana P.; Fazito Vale, Vladimir; Pangburn, Michael K.; Abdeladhim, Maha; Ferreira Mendes-Sousa, Antonio; Coutinho-Abreu, Iliano V.; Rasouli, Manoochehr; Brandt, Elizabeth A.; Meneses, Claudio; Lima, Kolyvan Ferreira; Nascimento Araújo, Ricardo; Horácio Pereira, Marcos; Kotsyfakis, Michalis; Oliveira, Fabiano; Kamhawi, Shaden; Ribeiro, Jose M. C.; Gontijo, Nelder F.; Collin, Nicolas; Valenzuela, Jesus G.

2016-01-01

Blood-feeding insects inject potent salivary components including complement inhibitors into their host’s skin to acquire a blood meal. Sand fly saliva was shown to inhibit the classical pathway of complement; however, the molecular identity of the inhibitor remains unknown. Here, we identified SALO as the classical pathway complement inhibitor. SALO, an 11 kDa protein, has no homology to proteins of any other organism apart from New World sand flies. rSALO anti-complement activity has the same chromatographic properties as the Lu. longipalpis salivary gland homogenate (SGH)counterparts and anti-rSALO antibodies blocked the classical pathway complement activity of rSALO and SGH. Both rSALO and SGH inhibited C4b deposition and cleavage of C4. rSALO, however, did not inhibit the protease activity of C1s nor the enzymatic activity of factor Xa, uPA, thrombin, kallikrein, trypsin and plasmin. Importantly, rSALO did not inhibit the alternative or the lectin pathway of complement. In conclusion our data shows that SALO is a specific classical pathway complement inhibitor present in the saliva of Lu. longipalpis. Importantly, due to its small size and specificity, SALO may offer a therapeutic alternative for complement classical pathway-mediated pathogenic effects in human diseases. PMID:26758086

Evaluation of Yersinia pestis transmission pathways for sylvatic plague in prairie dog populations in the western U.S.

USGS Publications Warehouse

Richgels, Katherine L. D.; Russell, Robin E.; Bron, Gebbiena; Rocke, Tonie E.

2016-01-01

Sylvatic plague, caused by the bacterium Yersinia pestis, is periodically responsible for large die-offs in rodent populations that can spillover and cause human mortalities. In the western US, prairie dog populations experience nearly 100% mortality during plague outbreaks, suggesting that multiple transmission pathways combine to amplify plague dynamics. Several alternate pathways in addition to flea vectors have been proposed, such as transmission via direct contact with bodily fluids or inhalation of infectious droplets, consumption of carcasses, and environmental sources of plague bacteria, such as contaminated soil. However, evidence supporting the ability of these proposed alternate pathways to trigger large-scale epizootics remains elusive. Here we present a short review of potential plague transmission pathways and use an ordinary differential equation model to assess the contribution of each pathway to resulting plague dynamics in black-tailed prairie dogs (Cynomys ludovicianus) and their fleas (Oropsylla hirsuta). Using our model, we found little evidence to suggest that soil contamination was capable of producing plague epizootics in prairie dogs. However, in the absence of flea transmission, direct transmission, i.e., contact with bodily fluids or inhalation of infectious droplets, could produce enzootic dynamics, and transmission via contact with or consumption of carcasses could produce epizootics. This suggests that these pathways warrant further investigation.

Costs Associated With Access Site and Same-Day Discharge Among Medicare Beneficiaries Undergoing Percutaneous Coronary Intervention: An Evaluation of the Current Percutaneous Coronary Intervention Care Pathways in the United States.

PubMed

Amin, Amit P; Patterson, Mark; House, John A; Giersiefen, Helmut; Spertus, John A; Baklanov, Dmitri V; Chhatriwalla, Adnan K; Safley, David M; Cohen, David J; Rao, Sunil V; Marso, Steven P

2017-02-27

The aim of this study was to examine the independent impact of various care pathways, including those involving transradial intervention (TRI) and same-day discharge (SDD) after elective percutaneous coronary intervention (PCI), on hospital costs. PCI is associated with costs of $10 billion annually. Alternative payment models for PCI are being implemented, but few data exist on strategies to reduce costs. Various PCI care pathways, including TRI and SDD, exist, but their association with costs and outcomes is unknown. In total, 279,987 PCI patients eligible for SDD in the National Cardiovascular Data Registry CathPCI Registry linked to Medicare claims files were analyzed. Hospital costs in 2014 U.S. dollars were estimated using cost-to-charge ratios. Propensity scores for TRI and SDD, with propensity adjustment via inverse probability weighting, was performed. Of the 279,987 PCI procedures, TRI was used in 9.0% (13.5% of which were SDD), and SDD was used in 5.3% of cases (23.1% of which were TRI). TRI (vs. transfemoral intervention) was associated with lower adjusted costs of $916 (95% confidence interval [CI]: $778 to $1,035), as was SDD ($3,502; 95% CI: $3,486 to $3,902). The adjusted cost associated with TRI and SDD was $13,389 (95% CI: $13,161 to $13,607), while the cost associated with transfemoral intervention and non-same-day discharge was $17,076 (95% CI: $16,999 to $17,147), a difference of $3,689 (95% CI: $3,486 to $3,902; p < 0.0001). Shifting current practice from transfemoral intervention non-same-day discharge to TRI SDD by 30% could potentially save a hospital performing 1,000 PCIs each year $1 million and the country $300 million annually. Among Medicare beneficiaries, TRI with SDD was independently associated with fewer complications and lower in-hospital costs. These findings have important implications for changing the current PCI care pathways to improve outcomes and reduce costs. Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Bayesian parameter estimation for the Wnt pathway: an infinite mixture models approach.

PubMed

Koutroumpas, Konstantinos; Ballarini, Paolo; Votsi, Irene; Cournède, Paul-Henry

2016-09-01

Likelihood-free methods, like Approximate Bayesian Computation (ABC), have been extensively used in model-based statistical inference with intractable likelihood functions. When combined with Sequential Monte Carlo (SMC) algorithms they constitute a powerful approach for parameter estimation and model selection of mathematical models of complex biological systems. A crucial step in the ABC-SMC algorithms, significantly affecting their performance, is the propagation of a set of parameter vectors through a sequence of intermediate distributions using Markov kernels. In this article, we employ Dirichlet process mixtures (DPMs) to design optimal transition kernels and we present an ABC-SMC algorithm with DPM kernels. We illustrate the use of the proposed methodology using real data for the canonical Wnt signaling pathway. A multi-compartment model of the pathway is developed and it is compared to an existing model. The results indicate that DPMs are more efficient in the exploration of the parameter space and can significantly improve ABC-SMC performance. In comparison to alternative sampling schemes that are commonly used, the proposed approach can bring potential benefits in the estimation of complex multimodal distributions. The method is used to estimate the parameters and the initial state of two models of the Wnt pathway and it is shown that the multi-compartment model fits better the experimental data. Python scripts for the Dirichlet Process Gaussian Mixture model and the Gibbs sampler are available at https://sites.google.com/site/kkoutroumpas/software konstantinos.koutroumpas@ecp.fr. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

MicroRNA: Biogenesis, Function and Role in Cancer

PubMed Central

MacFarlane, Leigh-Ann; Murphy, Paul R.

2010-01-01

MicroRNAs are small, highly conserved non-coding RNA molecules involved in the regulation of gene expression. MicroRNAs are transcribed by RNA polymerases II and III, generating precursors that undergo a series of cleavage events to form mature microRNA. The conventional biogenesis pathway consists of two cleavage events, one nuclear and one cytoplasmic. However, alternative biogenesis pathways exist that differ in the number of cleavage events and enzymes responsible. How microRNA precursors are sorted to the different pathways is unclear but appears to be determined by the site of origin of the microRNA, its sequence and thermodynamic stability. The regulatory functions of microRNAs are accomplished through the RNA-induced silencing complex (RISC). MicroRNA assembles into RISC, activating the complex to target messenger RNA (mRNA) specified by the microRNA. Various RISC assembly models have been proposed and research continues to explore the mechanism(s) of RISC loading and activation. The degree and nature of the complementarity between the microRNA and target determine the gene silencing mechanism, slicer-dependent mRNA degradation or slicer-independent translation inhibition. Recent evidence indicates that P-bodies are essential for microRNA-mediated gene silencing and that RISC assembly and silencing occurs primarily within P-bodies. The P-body model outlines microRNA sorting and shuttling between specialized P-body compartments that house enzymes required for slicer –dependent and –independent silencing, addressing the reversibility of these silencing mechanisms. Detailed knowledge of the microRNA pathways is essential for understanding their physiological role and the implications associated with dysfunction and dysregulation. PMID:21532838

Elicitors aboveground: an alternative for control of a belowground pest

USDA-ARS?s Scientific Manuscript database

Plant defense pathways mediate multitrophic interactions above and belowground. Understanding the effects of these pathways on pests and natural enemies above and belowground holds great potential for designing effective control strategies. Here we investigate the effects of aboveground stimulation ...

The Group B Streptococcus–Secreted Protein CIP Interacts with C4, Preventing C3b Deposition via the Lectin and Classical Complement Pathways

PubMed Central

Pietrocola, Giampiero; Rindi, Simonetta; Rosini, Roberto; Buccato, Scilla

2016-01-01

The group B Streptococcus (GBS) is a leading cause of neonatal invasive disease. GBS bacteria are surrounded by a thick capsular polysaccharide that is a potent inhibitor of complement deposition via the alternative pathway. Several of its surface molecules can however activate the classical and lectin complement pathways, rendering this species still vulnerable to phagocytic killing. In this study we have identified a novel secreted protein named complement interfering protein (CIP) that downregulates complement activation via the classical and lectin pathways, but not the alternative pathway. The CIP protein showed high affinity toward C4b and inhibited its interaction with C2, presumably preventing the formation of the C4bC2a convertase. Addition of recombinant CIP to GBS cip-negative bacteria resulted in decreased deposition of C3b on their surface and in diminished phagocytic killing in a whole-blood assay. Our data reveal a novel strategy exploited by GBS to counteract innate immunity and could be valuable for the development of anti-infective agents against this important pathogen. PMID:26608922

The IMD innate immunity pathway of Drosophila influences somatic sex determination via regulation of the Doa locus.

PubMed

Zhao, Yunpo; Cocco, Claudia; Domenichini, Severine; Samson, Marie-Laure; Rabinow, Leonard

2015-11-15

The IMD pathway induces the innate immune response to infection by gram-negative bacteria. We demonstrate strong female-to-male sex transformations in double mutants of the IMD pathway in combination with Doa alleles. Doa encodes a protein kinase playing a central role in somatic sex determination through its regulation of alternative splicing of dsx transcripts. Transcripts encoding two specific Doa isoforms are reduced in Rel null mutant females, supporting our genetic observations. A role for the IMD pathway in somatic sex determination is further supported by the induction of female-to-male sex transformations by Dredd mutations in sensitized genetic backgrounds. In contrast, mutations in either dorsal or Dif, the two other NF-κB paralogues of Drosophila, display no effects on sex determination, demonstrating the specificity of IMD signaling. Our results reveal a novel role for the innate immune IMD signaling pathway in the regulation of somatic sex determination in addition to its role in response to microbial infection, demonstrating its effects on alternative splicing through induction of a crucial protein kinase. Copyright © 2015 Elsevier Inc. All rights reserved.

Corrective Action Decision Document for Corrective Action Unit 428: Area 3 Septic Waste Systems 1 and 5, Tonopah Test Range, Nevada

DOE Office of Scientific and Technical Information (OSTI.GOV)

U.S. Department of Energy, Nevada Operations Office

2000-02-08

This Corrective Action Decision Document identifies and rationalizes the US Department of Energy, Nevada Operations Office's selection of a recommended corrective action alternative (CAA) appropriate to facilitate the closure of Corrective Action Unit (CAU) 428, Septic Waste Systems 1 and 5, under the Federal Facility Agreement and Consent Order. Located in Area 3 at the Tonopah Test Range (TTR) in Nevada, CAU 428 is comprised of two Corrective Action Sites (CASs): (1) CAS 03-05-002-SW01, Septic Waste System 1 and (2) CAS 03-05-002- SW05, Septic Waste System 5. A corrective action investigation performed in 1999 detected analyte concentrations that exceeded preliminarymore » action levels; specifically, contaminants of concern (COCs) included benzo(a) pyrene in a septic tank integrity sample associated with Septic Tank 33-1A of Septic Waste System 1, and arsenic in a soil sample associated with Septic Waste System 5. During this investigation, three Corrective Action Objectives (CAOs) were identified to prevent or mitigate exposure to contents of the septic tanks and distribution box, to subsurface soil containing COCs, and the spread of COCs beyond the CAU. Based on these CAOs, a review of existing data, future use, and current operations in Area 3 of the TTR, three CAAs were developed for consideration: Alternative 1 - No Further Action; Alternative 2 - Closure in Place with Administrative Controls; and Alternative 3 - Clean Closure by Excavation and Disposal. These alternatives were evaluated based on four general corrective action standards and five remedy selection decision factors. Based on the results of the evaluation, the preferred CAA was Alternative 3. This alternative meets all applicable state and federal regulations for closure of the site and will eliminate potential future exposure pathways to the contaminated soils at the Area 3 Septic Waste Systems 1 and 5.« less

Alternative energy production pathways in Taenia crassiceps cysticerci in vitro exposed to a benzimidazole derivative (RCB20).

PubMed

Fraga, Carolina Miguel; Da Costa, Tatiane Luiza; De Castro, Ana Maria; Reynoso-Ducoing, Olivia; Ambrosio, Javier; Hernández-Campos, Alicia; Castillo, Rafael; Vinaud, Marina Clare

2016-04-01

Biochemical studies of benzimidazole derivatives are important to determine their mode of action and activity against parasites. The lack of antihelminthic alternatives to treat parasitic infections and albendazole resistance cases make the search for new antiparasitary drugs of utmost importance. The 6-chloro-5-(1-naphthyloxy)-2-(trifluoromethyl)-1H-benzimidazole (RCB20) is a benzimidazole derivative with promising effect. This study evaluated the effect of different concentrations of RCB20 in the alternative energetic pathway of in vitro Taenia crassiceps cysticerci. The parasites were in vitro exposed to 6.5 and 13 µM of RCB20 and albendazole sulfoxide (ABZSO). The quantification of acetate, acetoacetate, β-hydroxybutyrate, fumarate and propionate was performed by high-performance liquid chromatography. The quantification of urea, creatinine and total proteins was performed by spectrophotometry. The increase in β-hydroxybutyrate reflects the enhancement of the fatty acid oxidation in the treated groups. Volatile fatty acids secretion, acetate and propionate, was increased in the treated groups. The secretion mechanisms of the treated parasites were impaired due to organic acids increased concentrations in the cysticerci. It is possible to conclude that the metabolic effect on alternative energetic pathways is slightly increased in the parasites treated with RCB20 than the ones treated with ABZSO.

[Shunt and short circuit].

PubMed

Rangel-Abundis, Alberto

2006-01-01

Shunt and short circuit are antonyms. In French, the term shunt has been adopted to denote the alternative pathway of blood flow. However, in French, as well as in Spanish, the word short circuit (court-circuit and cortocircuito) is synonymous with shunt, giving rise to a linguistic and scientific inconsistency. Scientific because shunt and short circuit made reference to a phenomenon that occurs in the field of the physics. Because shunt and short circuit are antonyms, it is necessary to clarify that shunt is an alternative pathway of flow from a net of high resistance to a net of low resistance, maintaining the stream. Short circuit is the interruption of the flow, because a high resistance impeaches the flood. This concept is applied to electrical and cardiovascular physiology, as well as to the metabolic pathways.

COX-2 – A Novel Target for Reducing Tumor Angiogenesis and Metastasis | Center for Cancer Research

Cancer.gov

Angiogenesis is essential for tumor growth and metastasis, by supplying a steady stream of nutrients, removing waste, and providing tumor cells access to other sites in the body. The vascular endothelial growth factor (VEGF) and its receptors (VEGFRs) play a key role in tumor-mediated angiogenesis, and this pathway is the target of monoclonal antibodies and tyrosine kinase inhibitors (TKIs) that have been approved to treat patients with cancer. Unfortunately, tumors can use alternative angiogenesis mechanisms to escape VEGF pathway blockade, but these alternate pathways are not well understood. Brad St. Croix, Ph.D., of CCR’s Mouse Cancer Genetics Program, along with Lihong Xu, Ph.D., a Postdoctoral Fellow in the St. Croix laboratory, and colleagues set out to identify VEGF-independent mediators of tumor angiogenesis.

The air quality and health co-benefits of alternative post-2020 pathways for achieving peak carbon targets in Jiangsu, China

NASA Astrophysics Data System (ADS)

Liu, M.; Bi, J.; Huang, Y.; Kinney, P. L.

2016-12-01

Jiangsu, which has three national low-carbon pilot cities, is set to be a model province in China for achieving peak carbon targets before 2030. However, according to local planning of responding to climate change, carbon emissions are projected to keep going up before 2020 even the strictest measures are implemented. In other words, innovative measures must be in action after 2020. This work aimed at assessing the air quality and health co-benefits of alternative post-2020 measures to help remove barriers of policy implementation through tying it to local incentives for air quality improvement. To achieve the aim, we select 2010 as baseline year and develop Bussiness As Usual (BAU) and Traditional Carbon Reduction (TCR) scenarios before 2020. Under BAU, only existing climate and air pollution control policies are considered; under TCR, potential climate policies in local planning and existing air pollution control policies are considered. After 2020, integrated gasification combined cycle (IGCC) plant with carbon capture and storage (CCS) technology and large-scale substitution of renewable energy seem to be two promising pathways for achieving peak carbon targets. Therefore, two additional scenarios (TCR-IGCC and TCR-SRE) are set after 2020. Based on the projections of future energy balances and industrial productions, we estimate the pollutant emissions and simulate PM2.5 and ozone concentrations by 2017, 2020, 2030 and 2050 using CMAQ. Then using health impact assessment approach, the premature deaths are estimated and monetized. Results show that the carbon peak in Jiangsu will be achieved before 2030 only under TCR-IGCC and TCR-SRE scenarios. Under three policy scenarios, Jiangsu's carbon emission control targets would have substantial effects on primary air pollutant emissions far beyond those we estimate would be needed to meet the PM2.5 concentration targets in 2017. Compared with IGCC with CCS, large-scale substitutions of renewable energy bring comparable pollutant emission reductions but more health benefits because it reduces more emissions from traffic sources which are more harmful to health. However, large-scale substitution of renewable energy posed challenges on energy supply capacity, which need to be seriously considered in future policy decision.

Neuronal pathway finding: from neurons to initial neural networks.

PubMed

Roscigno, Cecelia I

2004-10-01

Neuronal pathway finding is crucial for structured cellular organization and development of neural circuits within the nervous system. Neuronal pathway finding within the visual system has been extensively studied and therefore is used as a model to review existing knowledge regarding concepts of this developmental process. General principles of neuron pathway finding throughout the nervous system exist. Comprehension of these concepts guides neuroscience nurses in gaining an understanding of the developmental course of action, the implications of different anomalies, as well as the theoretical basis and nursing implications of some provocative new therapies being proposed to treat neurodegenerative diseases and neurologic injuries. These therapies have limitations in light of current ethical, developmental, and delivery modes and what is known about the development of neuronal pathways.

Solvent-free and catalyst-free chemistry: A benign pathway to sustainability

EPA Science Inventory

In the past decade, alternative benign organic methodologies have become an imperative part of organic syntheses and novel chemical reactions. The various new and innovative sustainable organic reactions and methodologies using no solvents or catalysts and employing alternative ...

The Alternative Epac/cAMP Pathway and the MAPK Pathway Mediate hCG Induction of Leptin in Placental Cells

PubMed Central

Maymó, Julieta Lorena; Pérez Pérez, Antonio; Maskin, Bernardo; Dueñas, José Luis; Calvo, Juan Carlos; Sánchez Margalet, Víctor; Varone, Cecilia Laura

2012-01-01

Pleiotropic effects of leptin have been identified in reproduction and pregnancy, particularly in the placenta, where it works as an autocrine hormone. In this work, we demonstrated that human chorionic gonadotropin (hCG) added to JEG-3 cell line or to placental explants induces endogenous leptin expression. We also found that hCG increased cAMP intracellular levels in BeWo cells in a dose-dependent manner, stimulated cAMP response element (CRE) activity and the cotransfection with an expression plasmid of a dominant negative mutant of CREB caused a significant inhibition of hCG stimulation of leptin promoter activity. These results demonstrate that hCG indeed activates cAMP/PKA pathway, and that this pathway is involved in leptin expression. Nevertheless, we found leptin induction by hCG is dependent on cAMP levels. Treatment with (Bu)2cAMP in combination with low and non stimulatory hCG concentrations led to an increase in leptin expression, whereas stimulatory concentrations showed the opposite effect. We found that specific PKA inhibition by H89 caused a significant increase of hCG leptin induction, suggesting that probably high cAMP levels might inhibit hCG effect. It was found that hCG enhancement of leptin mRNA expression involved the MAPK pathway. In this work, we demonstrated that hCG leptin induction through the MAPK signaling pathway is inhibited by PKA. We observed that ERK1/2 phosphorylation increased when hCG treatment was combined with H89. In view of these results, the involvement of the alternative cAMP/Epac signaling pathway was studied. We observed that a cAMP analogue that specifically activates Epac (CPT-OMe) stimulated leptin expression by hCG. In addition, the overexpression of Epac and Rap1 proteins increased leptin promoter activity and enhanced hCG. In conclusion, we provide evidence suggesting that hCG induction of leptin gene expression in placenta is mediated not only by activation of the MAPK signaling pathway but also by the alternative cAMP/Epac signaling pathway. PMID:23056265

Glomeruli of Dense Deposit Disease contain components of the alternative and terminal complement pathway

PubMed Central

Sethi, Sanjeev; Gamez, Jeffrey D.; Vrana, Julie A.; Theis, Jason D.; Bergen, H. Robert; Zipfel, Peter F.; Dogan, Ahmet; Smith, Richard J. H.

2009-01-01

Dense Deposit Disease (DDD), or membranoproliferative glomerulonephritis type II, is a rare renal disease characterized by dense deposits in the mesangium and along the glomerular basement membranes that can be seen by electron microscopy. Although these deposits contain complement factor C3, as determined by immunofluorescence microscopy, their precise composition remains unknown. To address this question, we used mass spectrometry to identify the proteins in laser microdissected glomeruli isolated from paraffin-embedded tissue of eight confirmed cases of DDD. Compared to glomeruli from five control patients, we found that all of the glomeruli from patients with DDD contain components of the alternative pathway and terminal complement complex. Factor C9 was uniformly present as well as the two fluid-phase regulators of terminal complement complex clusterin and vitronectin. In contrast, in nine patients with immune complex–mediated membranoproliferative glomerulonephritis, glomerular samples contained mainly immunoglobulins and complement factors C3 and C4. Our study shows that in addition to fluid-phase dysregulation of the alternative pathway, soluble components of the terminal complement complex contribute to glomerular lesions found in DDD. PMID:19177158

PKC-Theta is a Novel SC35 Splicing Factor Regulator in Response to T Cell Activation.

PubMed

McCuaig, Robert Duncan; Dunn, Jennifer; Li, Jasmine; Masch, Antonia; Knaute, Tobias; Schutkowski, Mike; Zerweck, Johannes; Rao, Sudha

2015-01-01

Alternative splicing of nuclear pre-mRNA is essential for generating protein diversity and regulating gene expression. While many immunologically relevant genes undergo alternative splicing, the role of regulated splicing in T cell immune responses is largely unexplored, and the signaling pathways and splicing factors that regulate alternative splicing in T cells are poorly defined. Here, we show using a combination of Jurkat T cells, human primary T cells, and ex vivo naïve and effector virus-specific T cells isolated after influenza A virus infection that SC35 phosphorylation is induced in response to stimulatory signals. We show that SC35 colocalizes with RNA polymerase II in activated T cells and spatially overlaps with H3K27ac and H3K4me3, which mark transcriptionally active genes. Interestingly, SC35 remains coupled to the active histone marks in the absence of continuing stimulatory signals. We show for the first time that nuclear PKC-θ co-exists with SC35 in the context of the chromatin template and is a key regulator of SC35 in T cells, directly phosphorylating SC35 peptide residues at RNA recognition motif and RS domains. Collectively, our findings suggest that nuclear PKC-θ is a novel regulator of the key splicing factor SC35 in T cells.

Alternative transitions between existing representations in multi-scale maps

NASA Astrophysics Data System (ADS)

Dumont, Marion; Touya, Guillaume; Duchêne, Cécile

2018-05-01

Map users may have issues to achieve multi-scale navigation tasks, as cartographic objects may have various representations across scales. We assume that adding intermediate representations could be one way to reduce the differences between existing representations, and to ease the transitions across scales. We consider an existing multiscale map on the scale range from 1 : 25k to 1 : 100k scales. Based on hypotheses about intermediate representations design, we build custom multi-scale maps with alternative transitions. We will conduct in a next future a user evaluation to compare the efficiency of these alternative maps for multi-scale navigation. This paper discusses the hypotheses and production process of these alternative maps.

Modular Approach to Launch Vehicle Design Based on a Common Core Element

NASA Technical Reports Server (NTRS)

Creech, Dennis M.; Threet, Grady E., Jr.; Philips, Alan D.; Waters, Eric D.; Baysinger, Mike

2010-01-01

With a heavy lift launch vehicle as the centerpiece of our nation's next exploration architecture's infrastructure, the Advanced Concepts Office at NASA's Marshall Space Flight Center initiated a study to examine the utilization of elements derived from a heavy lift launch vehicle for other potential launch vehicle applications. The premise of this study is to take a vehicle concept, which has been optimized for Lunar Exploration, and utilize the core stage with other existing or near existing stages and boosters to determine lift capabilities for alternative missions. This approach not only yields a vehicle matrix with a wide array of capabilities, but also produces an evolutionary pathway to a vehicle family based on a minimum development and production cost approach to a launch vehicle system architecture, instead of a purely performance driven approach. The upper stages and solid rocket booster selected for this study were chosen to reflect a cross-section of: modified existing assets in the form of a modified Delta IV upper stage and Castor-type boosters; potential near term launch vehicle component designs including an Ares I upper stage and 5-segment boosters; and longer lead vehicle components such as a Shuttle External Tank diameter upper stage. The results of this approach to a modular launch system are given in this paper.

Connecting the dots: chromatin and alternative splicing in EMT

PubMed Central

Warns, Jessica A.; Davie, James R.; Dhasarathy, Archana

2015-01-01

Nature has devised sophisticated cellular machinery to process mRNA transcripts produced by RNA Polymerase II, removing intronic regions and connecting exons together, to produce mature RNAs. This process, known as splicing, is very closely linked to transcription. Alternative splicing, or the ability to produce different combinations of exons that are spliced together from the same genomic template, is a fundamental means of regulating protein complexity. Similar to transcription, both constitutive and alternative splicing can be regulated by chromatin and its associated factors in response to various signal transduction pathways activated by external stimuli. This regulation can vary between different cell types, and interference with these pathways can lead to changes in splicing, often resulting in aberrant cellular states and disease. The epithelial to mesenchymal transition (EMT), which leads to cancer metastasis, is influenced by alternative splicing events of chromatin remodelers and epigenetic factors such as DNA methylation and non-coding RNAs. In this review, we will discuss the role of epigenetic factors including chromatin, chromatin remodelers, DNA methyltransferases and microRNAs in the context of alternative splicing, and discuss their potential involvement in alternative splicing during the EMT process. PMID:26291837

30 CFR 285.1011 - What payments are required for an Alternate Use RUE?

Code of Federal Regulations, 2010 CFR

2010-07-01

... INTERIOR OFFSHORE RENEWABLE ENERGY ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS Facilities...

A computational platform to maintain and migrate manual functional annotations for BioCyc databases.

PubMed

Walsh, Jesse R; Sen, Taner Z; Dickerson, Julie A

2014-10-12

BioCyc databases are an important resource for information on biological pathways and genomic data. Such databases represent the accumulation of biological data, some of which has been manually curated from literature. An essential feature of these databases is the continuing data integration as new knowledge is discovered. As functional annotations are improved, scalable methods are needed for curators to manage annotations without detailed knowledge of the specific design of the BioCyc database. We have developed CycTools, a software tool which allows curators to maintain functional annotations in a model organism database. This tool builds on existing software to improve and simplify annotation data imports of user provided data into BioCyc databases. Additionally, CycTools automatically resolves synonyms and alternate identifiers contained within the database into the appropriate internal identifiers. Automating steps in the manual data entry process can improve curation efforts for major biological databases. The functionality of CycTools is demonstrated by transferring GO term annotations from MaizeCyc to matching proteins in CornCyc, both maize metabolic pathway databases available at MaizeGDB, and by creating strain specific databases for metabolic engineering.

Below the radar innovations and emerging property right approaches in Tibetan medicine.

PubMed

Madhavan, Harilal

2017-11-01

Outside the established legal framework of intellectual property rights, countries have pursued multiple pathways to protect and promote traditional medicine. As Tibetan medicine is a late entrant into commercialization, the proposals to propertize generally fall within the rationale of existing sui-generis paradigms of Intellectual property. In this context, the article enquires the state of innovations in this sector viz-a-viz the property right approaches in place especially in India and China. It argues that beyond the usual complex medical science and technology led-innovations, the pathways of cumulative processes and creative additions through informal experiential learning platforms, where the transfers of knowledge become part of livelihood and social benefits (we call them "below the radar innovations") is ubiquitous in Tibetan medicine. The trends and politics in two recent strategies of protection, that is, Tibetan medicine as economic property (emphasizing patents here among many others) and as a cultural property (intangible cultural heritage) are juxtaposed with these informal innovative attempts. The paper underlines that the productivity-based economic rationale of these protection mechanisms should not obscure sustainability alternatives of "below the radar" (BtR) innovations in Tibetan medicine.

Below the radar innovations and emerging property right approaches in Tibetan medicine

PubMed Central

2017-01-01

Outside the established legal framework of intellectual property rights, countries have pursued multiple pathways to protect and promote traditional medicine. As Tibetan medicine is a late entrant into commercialization, the proposals to propertize generally fall within the rationale of existing sui‐generis paradigms of Intellectual property. In this context, the article enquires the state of innovations in this sector viz‐a‐viz the property right approaches in place especially in India and China. It argues that beyond the usual complex medical science and technology led—innovations, the pathways of cumulative processes and creative additions through informal experiential learning platforms, where the transfers of knowledge become part of livelihood and social benefits (we call them “below the radar innovations”) is ubiquitous in Tibetan medicine. The trends and politics in two recent strategies of protection, that is, Tibetan medicine as economic property (emphasizing patents here among many others) and as a cultural property (intangible cultural heritage) are juxtaposed with these informal innovative attempts. The paper underlines that the productivity‐based economic rationale of these protection mechanisms should not obscure sustainability alternatives of “below the radar” (BtR) innovations in Tibetan medicine. PMID:29398953

Effect of the SH3-SH2 domain linker sequence on the structure of Hck kinase.

PubMed

Meiselbach, Heike; Sticht, Heinrich

2011-08-01

The coordination of activity in biological systems requires the existence of different signal transduction pathways that interact with one another and must be precisely regulated. The Src-family tyrosine kinases, which are found in many signaling pathways, differ in their physiological function despite their high overall structural similarity. In this context, the differences in the SH3-SH2 domain linkers might play a role for differential regulation, but the structural consequences of linker sequence remain poorly understood. We have therefore performed comparative molecular dynamics simulations of wildtype Hck and of a mutant Hck in which the SH3-SH2 domain linker is replaced by the corresponding sequence from the homologous kinase Lck. These simulations reveal that linker replacement not only affects the orientation of the SH3 domain itself, but also leads to an alternative conformation of the activation segment in the Hck kinase domain. The sequence of the SH3-SH2 domain linker thus exerts a remote effect on the active site geometry and might therefore play a role in modulating the structure of the inactive kinase or in fine-tuning the activation process itself.

Human Monocytes Engage an Alternative Inflammasome Pathway.

PubMed

Gaidt, Moritz M; Ebert, Thomas S; Chauhan, Dhruv; Schmidt, Tobias; Schmid-Burgk, Jonathan L; Rapino, Francesca; Robertson, Avril A B; Cooper, Matthew A; Graf, Thomas; Hornung, Veit

2016-04-19

Interleukin-1β (IL-1β) is a cytokine whose bioactivity is controlled by activation of the inflammasome. However, in response to lipopolysaccharide, human monocytes secrete IL-1β independently of classical inflammasome stimuli. Here, we report that this constituted a species-specific response that is not observed in the murine system. Indeed, in human monocytes, lipopolysaccharide triggered an "alternative inflammasome" that relied on NLRP3-ASC-caspase-1 signaling, yet was devoid of any classical inflammasome characteristics including pyroptosome formation, pyroptosis induction, and K(+) efflux dependency. Genetic dissection of the underlying signaling pathway in a monocyte transdifferentiation system revealed that alternative inflammasome activation was propagated by TLR4-TRIF-RIPK1-FADD-CASP8 signaling upstream of NLRP3. Importantly, involvement of this signaling cascade was limited to alternative inflammasome activation and did not extend to classical NLRP3 activation. Because alternative inflammasome activation embraces both sensitivity and promiscuity of TLR4, we propose a pivotal role for this signaling cascade in TLR4-driven, IL-1β-mediated immune responses and immunopathology in humans. Copyright © 2016 Elsevier Inc. All rights reserved.

Cloning and functional expression of the mitochondrial alternative oxidase gene (aox1) of Aspergillus niger in Lactococcus lactis and its induction by oxidizing conditions.

PubMed

Papagianni, Maria; Avramidis, Nicholaos

2012-01-05

Lactococcus lactis is a widely used food bacterium mainly known for its fermentation metabolism. An important, and for long time overlooked, trait of this species is its ability to perform respiratory metabolism in the presence of heme and under aerobic conditions. There is no evidence however for the presence of an alternative respiration pathway and AOX activity. In this study, a cDNA fragment encoding the mitochondrial alternative oxidase, the enzyme responsible for alternative respiration, from a citric acid producing Aspergillus niger strain was cloned and expressed in L. lactis as a host strain. Expression of aox1 conferred on this organism cyanide-resistant and salicylhydroxamate-sensitive growth. Bioreactor cultures under fully aerobic conditions of the transformed L. lactis showed that the alternative respiratory pathway operates and improves significantly the microorganism's response to oxidizing stress conditions as it enhances biomass production, suppresses lactate formation, and leads to accumulation of large amounts of nisin. Copyright © 2011 Elsevier Inc. All rights reserved.

FMDP reactor alternative summary report. Volume 1 - existing LWR alternative

DOE Office of Scientific and Technical Information (OSTI.GOV)

Greene, S.R.; Bevard, B.B.

1996-10-07

Significant quantities of weapons-usable fissile materials [primarily plutonium and highly enriched uranium (HEU)] are becoming surplus to national defense needs in both the United States and Russia. These stocks of fissile materials pose significant dangers to national and international security. The dangers exist not only in the potential proliferation of nuclear weapons but also in the potential for environmental, safety, and health (ES&H) consequences if surplus fissile materials are not properly managed. This document summarizes the results of analysis concerned with existing light water reactor plutonium disposition alternatives.

Alternative complement pathway activation during invasive coronary procedures in acute myocardial infarction and stable angina pectoris.

PubMed

Horváth, Zsófia; Csuka, Dorottya; Vargova, Katarina; Kovács, Andrea; Leé, Sarolta; Varga, Lilian; Préda, István; Tóth Zsámboki, Emese; Prohászka, Zoltán; Kiss, Róbert Gábor

2016-12-01

The effect of invasive percutaneous coronary procedures on complement activation has not been elucidated. We enrolled stable angina patients with elective percutaneous coronary intervention (SA-PCI, n=24), diagnostic coronary angiography (CA, n=52) and 23 patients with ST segment elevation myocardial infarction and primary PCI (STEMI-PCI). Complement activation products (C1rC1sC1inh, C3bBbP and SC5b-9) were measured on admission, 6 and 24h after coronary procedures. The alternative pathway product, C3bBbP significantly and reversibly increased 6h after elective PCI (baseline: 7.81AU/ml, 6h: 16.09AU/ml, 24h: 4.27AU/ml, p<0.01, n=23) and diagnostic angiography (baseline: 6.13AU/ml, 6h: 12.08AU/ml, 24h: 5.4AU/ml, p<0.01, n=52). Six hour C3bBbP values correlated with post-procedural CK, creatinine level and the applied contrast material volume (r=0.41, r=0.4, r=0.3, p<0.05, respectively). In STEMI-PCI, baseline C3bBbP level was higher, compared to SA-PCI or CA patients (11.33AU/ml vs. 7.81AU/ml or 6.13AU/ml, p<0.001). Similarly, the terminal complex (SC5b-9) level was already elevated at baseline compared to SA-PCI group (3.49AU/ml vs. 1.87AU/ml, p=0.011). Complement pathway products did not increase further after primary PCI. Elective coronary procedures induced transient alternative complement pathway activation, influenced by the applied contrast volume. In STEMI, the alternative complement pathway is promptly activated during the atherothrombotic event and PCI itself had no further detectable effect. Copyright © 2016 Elsevier B.V. All rights reserved.

30 CFR 285.1012 - What financial assurance is required for an Alternate Use RUE?

Code of Federal Regulations, 2010 CFR

2010-07-01

... THE INTERIOR OFFSHORE RENEWABLE ENERGY ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS Facilities...

30 CFR 285.1004 - What must I do before I request an Alternate Use RUE?

Code of Federal Regulations, 2010 CFR

2010-07-01

... INTERIOR OFFSHORE RENEWABLE ENERGY ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS Facilities...

30 CFR 285.1019 - What are the decommissioning requirements for an Alternate Use RUE?

Code of Federal Regulations, 2010 CFR

2010-07-01

..., DEPARTMENT OF THE INTERIOR OFFSHORE RENEWABLE ENERGY ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS...

30 CFR 285.1010 - How long may I conduct activities under an Alternate Use RUE?

Code of Federal Regulations, 2010 CFR

2010-07-01

... THE INTERIOR OFFSHORE RENEWABLE ENERGY ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS Facilities...

Signal transduction profile of chemical sensitisers in dendritic cells: An endpoint to be included in a cell-based in vitro alternative approach to hazard identification?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Neves, Bruno Miguel; Centro de Neurociencias e Biologia Celular, Universidade de Coimbra, Coimbra 3004-517; Goncalo, Margarida

2011-01-15

The development of non-animal testing methods for the assessment of skin sensitisation potential is an urgent challenge within the framework of existing and forthcoming legislation. Efforts have been made to replace current animal tests, but so far no alternative methods have been developed. It is widely recognised that alternatives to animal testing cannot be accomplished with a single approach, but rather will require the integration of results obtained from different in vitro and in silico assays. The argument subjacent to the development of in vitro dendritic cell (DC)-based assays is that sensitiser-induced changes in the DC phenotype can be differentiatedmore » from those induced by irritants. This assumption is derived from the unique capacity of DC to convert environmental signals encountered at the skin into a receptor expression pattern (MHC class II molecules, co-stimulatory molecules, chemokine receptors) and a soluble mediator release profile that will stimulate T lymphocytes. Since signal transduction cascades precede changes in surface marker expression and cytokine/chemokine secretion, these phenotypic modifications are a consequence of a signal transduction profile that is specifically triggered by sensitisers and not by irritants. A limited number of studies have addressed this subject and the present review attempts to summarise and highlight all of the signalling pathways modulated by skin sensitisers and irritants. Furthermore, we conclude this review by focusing on the most promising strategies suitable for inclusion into a cell-based in vitro alternative approach to hazard identification.« less

Spatially explicit global population scenarios consistent with the Shared Socioeconomic Pathways

DOE PAGES

Jones, B.; O’Neill, B. C.

2016-07-29

Here we report that the projected size and spatial distribution of the future population are important drivers of global change and key determinants of exposure and vulnerability to hazards. Spatial demographic projections are widely used as inputs to spatial projections of land use, energy use, and emissions, as well as to assessments of the impacts of extreme events, sea level rise, and other climate-related outcomes. To date, however, there are very few global-scale, spatially explicit population projections, and those that do exist are often based on simple scaling or trend extrapolation. Here we present a new set of global, spatiallymore » explicit population scenarios that are consistent with the new Shared Socioeconomic Pathways (SSPs) developed to facilitate global change research. We use a parameterized gravity-based downscaling model to produce projections of spatial population change that are quantitatively consistent with national population and urbanization projections for the SSPs and qualitatively consistent with assumptions in the SSP narratives regarding spatial development patterns. We show that the five SSPs lead to substantially different spatial population outcomes at the continental, national, and sub-national scale. In general, grid cell-level outcomes are most influenced by national-level population change, second by urbanization rate, and third by assumptions about the spatial style of development. However, the relative importance of these factors is a function of the magnitude of the projected change in total population and urbanization for each country and across SSPs. We also demonstrate variation in outcomes considering the example of population existing in a low-elevation coastal zone under alternative scenarios.« less

Spatially explicit global population scenarios consistent with the Shared Socioeconomic Pathways

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jones, B.; O’Neill, B. C.

Here we report that the projected size and spatial distribution of the future population are important drivers of global change and key determinants of exposure and vulnerability to hazards. Spatial demographic projections are widely used as inputs to spatial projections of land use, energy use, and emissions, as well as to assessments of the impacts of extreme events, sea level rise, and other climate-related outcomes. To date, however, there are very few global-scale, spatially explicit population projections, and those that do exist are often based on simple scaling or trend extrapolation. Here we present a new set of global, spatiallymore » explicit population scenarios that are consistent with the new Shared Socioeconomic Pathways (SSPs) developed to facilitate global change research. We use a parameterized gravity-based downscaling model to produce projections of spatial population change that are quantitatively consistent with national population and urbanization projections for the SSPs and qualitatively consistent with assumptions in the SSP narratives regarding spatial development patterns. We show that the five SSPs lead to substantially different spatial population outcomes at the continental, national, and sub-national scale. In general, grid cell-level outcomes are most influenced by national-level population change, second by urbanization rate, and third by assumptions about the spatial style of development. However, the relative importance of these factors is a function of the magnitude of the projected change in total population and urbanization for each country and across SSPs. We also demonstrate variation in outcomes considering the example of population existing in a low-elevation coastal zone under alternative scenarios.« less

Alternative RNA splicing and cancer

PubMed Central

Liu, Sali; Cheng, Chonghui

2015-01-01

Alternative splicing of pre-messenger RNA (mRNA) is a fundamental mechanism by which a gene can give rise to multiple distinct mRNA transcripts, yielding protein isoforms with different, even opposing, functions. With the recognition that alternative splicing occurs in nearly all human genes, its relationship with cancer-associated pathways has emerged as a rapidly growing field. In this review, we summarize recent findings that have implicated the critical role of alternative splicing in cancer and discuss current understandings of the mechanisms underlying dysregulated alternative splicing in cancer cells. PMID:23765697

Erythrocytic adenosine monophosphate as an alternative purine source in Plasmodium falciparum.

PubMed

Cassera, María B; Hazleton, Keith Z; Riegelhaupt, Paul M; Merino, Emilio F; Luo, Minkui; Akabas, Myles H; Schramm, Vern L

2008-11-21

Plasmodium falciparum is a purine auxotroph, salvaging purines from erythrocytes for synthesis of RNA and DNA. Hypoxanthine is the key precursor for purine metabolism in Plasmodium. Inhibition of hypoxanthine-forming reactions in both erythrocytes and parasites is lethal to cultured P. falciparum. We observed that high concentrations of adenosine can rescue cultured parasites from purine nucleoside phosphorylase and adenosine deaminase blockade but not when erythrocyte adenosine kinase is also inhibited. P. falciparum lacks adenosine kinase but can salvage AMP synthesized in the erythrocyte cytoplasm to provide purines when both human and Plasmodium purine nucleoside phosphorylases and adenosine deaminases are inhibited. Transport studies in Xenopus laevis oocytes expressing the P. falciparum nucleoside transporter PfNT1 established that this transporter does not transport AMP. These metabolic patterns establish the existence of a novel nucleoside monophosphate transport pathway in P. falciparum.

Formation of buckminsterfullerene (C60) in interstellar space.

PubMed

Berné, Olivier; Tielens, A G G M

2012-01-10

Buckminsterfullerene (C(60)) was recently confirmed as the largest molecule identified in space. However, it remains unclear how and where this molecule is formed. It is generally believed that C(60) is formed from the buildup of small carbonaceous compounds in the hot and dense envelopes of evolved stars. Analyzing infrared observations, obtained by Spitzer and Herschel, we found that C(60) is efficiently formed in the tenuous and cold environment of an interstellar cloud illuminated by strong ultraviolet (UV) radiation fields. This implies that another formation pathway, efficient at low densities, must exist. Based on recent laboratory and theoretical studies, we argue that polycyclic aromatic hydrocarbons are converted into graphene, and subsequently C(60), under UV irradiation from massive stars. This shows that alternative--top-down--routes are key to understanding the organic inventory in space.

Formation of buckminsterfullerene (C60) in interstellar space

NASA Astrophysics Data System (ADS)

Berné, Olivier; Tielens, Alexander G. G. M.

2012-01-01

Buckminsterfullerene (C60) was recently confirmed to be the largest molecule identified in space. However, it remains unclear how, and where this molecule is formed. It is generally believed that C60 is formed from the build up of small carbonaceous compounds, in the hot and dense envelopes of evolved stars. Analyzing infrared observations, obtained by Spitzer and Herschel, we found that C60 is efficiently formed in the tenuous and cold environment of an interstellar cloud illuminated by strong ultraviolet (UV) radiation fields. This implies that another formation pathway, efficient at low densities, must exist. Based on recent laboratory and theoretical studies, we argue that Polycyclic Aromatic Hydrocarbons are converted into graphene, and subsequently C60, under UV irradiation from massive stars. This shows that alternative - top-down - routes are key to understanding the organic inventory in space.

Engineering cytosolic acetyl-coenzyme A supply in Saccharomyces cerevisiae: Pathway stoichiometry, free-energy conservation and redox-cofactor balancing.

PubMed

van Rossum, Harmen M; Kozak, Barbara U; Pronk, Jack T; van Maris, Antonius J A

2016-07-01

Saccharomyces cerevisiae is an important industrial cell factory and an attractive experimental model for evaluating novel metabolic engineering strategies. Many current and potential products of this yeast require acetyl coenzyme A (acetyl-CoA) as a precursor and pathways towards these products are generally expressed in its cytosol. The native S. cerevisiae pathway for production of cytosolic acetyl-CoA consumes 2 ATP equivalents in the acetyl-CoA synthetase reaction. Catabolism of additional sugar substrate, which may be required to generate this ATP, negatively affects product yields. Here, we review alternative pathways that can be engineered into yeast to optimize supply of cytosolic acetyl-CoA as a precursor for product formation. Particular attention is paid to reaction stoichiometry, free-energy conservation and redox-cofactor balancing of alternative pathways for acetyl-CoA synthesis from glucose. A theoretical analysis of maximally attainable yields on glucose of four compounds (n-butanol, citric acid, palmitic acid and farnesene) showed a strong product dependency of the optimal pathway configuration for acetyl-CoA synthesis. Moreover, this analysis showed that combination of different acetyl-CoA production pathways may be required to achieve optimal product yields. This review underlines that an integral analysis of energy coupling and redox-cofactor balancing in precursor-supply and product-formation pathways is crucial for the design of efficient cell factories. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Goal-Directed Visual Processing Differentially Impacts Human Ventral and Dorsal Visual Representations

PubMed Central

2017-01-01

Recent studies have challenged the ventral/“what” and dorsal/“where” two-visual-processing-pathway view by showing the existence of “what” and “where” information in both pathways. Is the two-pathway distinction still valid? Here, we examined how goal-directed visual information processing may differentially impact visual representations in these two pathways. Using fMRI and multivariate pattern analysis, in three experiments on human participants (57% females), by manipulating whether color or shape was task-relevant and how they were conjoined, we examined shape-based object category decoding in occipitotemporal and parietal regions. We found that object category representations in all the regions examined were influenced by whether or not object shape was task-relevant. This task effect, however, tended to decrease as task-relevant and irrelevant features were more integrated, reflecting the well-known object-based feature encoding. Interestingly, task relevance played a relatively minor role in driving the representational structures of early visual and ventral object regions. They were driven predominantly by variations in object shapes. In contrast, the effect of task was much greater in dorsal than ventral regions, with object category and task relevance both contributing significantly to the representational structures of the dorsal regions. These results showed that, whereas visual representations in the ventral pathway are more invariant and reflect “what an object is,” those in the dorsal pathway are more adaptive and reflect “what we do with it.” Thus, despite the existence of “what” and “where” information in both visual processing pathways, the two pathways may still differ fundamentally in their roles in visual information representation. SIGNIFICANCE STATEMENT Visual information is thought to be processed in two distinctive pathways: the ventral pathway that processes “what” an object is and the dorsal pathway that processes “where” it is located. This view has been challenged by recent studies revealing the existence of “what” and “where” information in both pathways. Here, we found that goal-directed visual information processing differentially modulates shape-based object category representations in the two pathways. Whereas ventral representations are more invariant to the demand of the task, reflecting what an object is, dorsal representations are more adaptive, reflecting what we do with the object. Thus, despite the existence of “what” and “where” information in both pathways, visual representations may still differ fundamentally in the two pathways. PMID:28821655

Role of different pathways of the complement cascade in experimental bullous pemphigoid

PubMed Central

Nelson, Kelly C.; Zhao, Minglang; Schroeder, Pamela R.; Li, Ning; Wetsel, Rick A.; Diaz, Luis A.; Liu, Zhi

2006-01-01

Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease associated with autoantibodies directed against the hemidesmosomal proteins BP180 and BP230 and inflammation. Passive transfer of antibodies to the murine BP180 (mBP180) induces a skin disease that closely resembles human BP. In the present study, we defined the roles of the different complement activation pathways in this model system. Mice deficient in the alternative pathway component factor B (Fb) and injected with pathogenic anti-mBP180 IgG developed delayed and less intense subepidermal blisters. Mice deficient in the classical pathway component complement component 4 (C4) and WT mice pretreated with neutralizing antibody against the first component of the classical pathway, C1q, were resistant to experimental BP. These mice exhibited a significantly reduced level of mast cell degranulation and polymorphonuclear neutrophil (PMN) infiltration in the skin. Intradermal administration of compound 48/80, a mast cell degranulating agent, restored BP disease in C4–/– mice. Furthermore, C4–/– mice became susceptible to experimental BP after local injection of PMN chemoattractant IL-8 or local reconstitution with PMNs. These findings provide the first direct evidence to our knowledge that complement activation via the classical and alternative pathways is crucial in subepidermal blister formation in experimental BP. PMID:17024247

Parallelizing alternating direction implicit solver on GPUs

USDA-ARS?s Scientific Manuscript database

We present a parallel Alternating Direction Implicit (ADI) solver on GPUs. Our implementation significantly improves existing implementations in two aspects. First, we address the scalability issue of existing Parallel Cyclic Reduction (PCR) implementations by eliminating their hardware resource con...

FLIM reveals alternative EV-mediated cellular up-take pathways of paclitaxel.

PubMed

Saari, H; Lisitsyna, E; Rautaniemi, K; Rojalin, T; Niemi, L; Nivaro, O; Laaksonen, T; Yliperttula, M; Vuorimaa-Laukkanen, E

2018-06-15

In response to physiological and artificial stimuli, cells generate nano-scale extracellular vesicles (EVs) by encapsulating biomolecules in plasma membrane-derived phospholipid envelopes. These vesicles are released to bodily fluids, hence acting as powerful endogenous mediators in intercellular signaling. EVs provide a compelling alternative for biomarker discovery and targeted drug delivery, but their kinetics and dynamics while interacting with living cells are poorly understood. Here we introduce a novel method, fluorescence lifetime imaging microscopy (FLIM) to investigate these interaction attributes. By FLIM, we show distinct cellular uptake mechanisms of different EV subtypes, exosomes and microvesicles, loaded with anti-cancer agent, paclitaxel. We demonstrate differences in intracellular behavior and drug release profiles of paclitaxel-containing EVs. Exosomes seem to deliver the drug mostly by endocytosis while microvesicles enter the cells by both endocytosis and fusion with cell membrane. This research offers a new real-time method to investigate EV kinetics with living cells, and it is a potential advancement to complement the existing techniques. The findings of this study improve the current knowledge in exploiting EVs as next-generation targeted drug delivery systems. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Integrating genome-wide association studies and gene expression data highlights dysregulated multiple sclerosis risk pathways.

PubMed

Liu, Guiyou; Zhang, Fang; Jiang, Yongshuai; Hu, Yang; Gong, Zhongying; Liu, Shoufeng; Chen, Xiuju; Jiang, Qinghua; Hao, Junwei

2017-02-01

Much effort has been expended on identifying the genetic determinants of multiple sclerosis (MS). Existing large-scale genome-wide association study (GWAS) datasets provide strong support for using pathway and network-based analysis methods to investigate the mechanisms underlying MS. However, no shared genetic pathways have been identified to date. We hypothesize that shared genetic pathways may indeed exist in different MS-GWAS datasets. Here, we report results from a three-stage analysis of GWAS and expression datasets. In stage 1, we conducted multiple pathway analyses of two MS-GWAS datasets. In stage 2, we performed a candidate pathway analysis of the large-scale MS-GWAS dataset. In stage 3, we performed a pathway analysis using the dysregulated MS gene list from seven human MS case-control expression datasets. In stage 1, we identified 15 shared pathways. In stage 2, we successfully replicated 14 of these 15 significant pathways. In stage 3, we found that dysregulated MS genes were significantly enriched in 10 of 15 MS risk pathways identified in stages 1 and 2. We report shared genetic pathways in different MS-GWAS datasets and highlight some new MS risk pathways. Our findings provide new insights on the genetic determinants of MS.

Molecular Mechanisms Underlying β-Adrenergic Receptor-Mediated Cross-Talk between Sympathetic Neurons and Immune Cells

PubMed Central

Lorton, Dianne; Bellinger, Denise L.

2015-01-01

Cross-talk between the sympathetic nervous system (SNS) and immune system is vital for health and well-being. Infection, tissue injury and inflammation raise firing rates of sympathetic nerves, increasing their release of norepinephrine (NE) in lymphoid organs and tissues. NE stimulation of β2-adrenergic receptors (ARs) in immune cells activates the cAMP-protein kinase A (PKA) intracellular signaling pathway, a pathway that interfaces with other signaling pathways that regulate proliferation, differentiation, maturation and effector functions in immune cells. Immune–SNS cross-talk is required to maintain homeostasis under normal conditions, to develop an immune response of appropriate magnitude after injury or immune challenge, and subsequently restore homeostasis. Typically, β2-AR-induced cAMP is immunosuppressive. However, many studies report actions of β2-AR stimulation in immune cells that are inconsistent with typical cAMP–PKA signal transduction. Research during the last decade in non-immune organs, has unveiled novel alternative signaling mechanisms induced by β2-AR activation, such as a signaling switch from cAMP–PKA to mitogen-activated protein kinase (MAPK) pathways. If alternative signaling occurs in immune cells, it may explain inconsistent findings of sympathetic regulation of immune function. Here, we review β2-AR signaling, assess the available evidence for alternative signaling in immune cells, and provide insight into the circumstances necessary for “signal switching” in immune cells. PMID:25768345

Nitric oxide induces the alternative oxidase pathway in Arabidopsis seedlings deprived of inorganic phosphate.

PubMed

Royo, Beatriz; Moran, Jose F; Ratcliffe, R George; Gupta, Kapuganti J

2015-10-01

Phosphate starvation compromises electron flow through the cytochrome pathway of the mitochondrial electron transport chain, and plants commonly respond to phosphate deprivation by increasing flow through the alternative oxidase (AOX). To test whether this response is linked to the increase in nitric oxide (NO) production that also increases under phosphate starvation, Arabidopsis thaliana seedlings were grown for 15 d on media containing either 0 or 1mM inorganic phosphate. The effects of the phosphate supply on growth, the production of NO, respiration, the AOX level and the production of superoxide were compared for wild-type (WT) seedlings and the nitrate reductase double mutant nia. Phosphate deprivation increased NO production in WT roots, and the AOX level and the capacity of the alternative pathway to consume electrons in WT seedlings; whereas the same treatment failed to stimulate NO production and AOX expression in the nia mutant, and the plants had an altered growth phenotype. The NO donor S-nitrosoglutathione rescued the growth phenotype of the nia mutants under phosphate deprivation to some extent, and it also increased the respiratory capacity of AOX. It is concluded that NO is required for the induction of the AOX pathway when seedlings are grown under phosphate-limiting conditions. © The Author 2015. Published by Oxford University Press on behalf of the Society for Experimental Biology.

Pathway analysis with next-generation sequencing data.

PubMed

Zhao, Jinying; Zhu, Yun; Boerwinkle, Eric; Xiong, Momiao

2015-04-01

Although pathway analysis methods have been developed and successfully applied to association studies of common variants, the statistical methods for pathway-based association analysis of rare variants have not been well developed. Many investigators observed highly inflated false-positive rates and low power in pathway-based tests of association of rare variants. The inflated false-positive rates and low true-positive rates of the current methods are mainly due to their lack of ability to account for gametic phase disequilibrium. To overcome these serious limitations, we develop a novel statistic that is based on the smoothed functional principal component analysis (SFPCA) for pathway association tests with next-generation sequencing data. The developed statistic has the ability to capture position-level variant information and account for gametic phase disequilibrium. By intensive simulations, we demonstrate that the SFPCA-based statistic for testing pathway association with either rare or common or both rare and common variants has the correct type 1 error rates. Also the power of the SFPCA-based statistic and 22 additional existing statistics are evaluated. We found that the SFPCA-based statistic has a much higher power than other existing statistics in all the scenarios considered. To further evaluate its performance, the SFPCA-based statistic is applied to pathway analysis of exome sequencing data in the early-onset myocardial infarction (EOMI) project. We identify three pathways significantly associated with EOMI after the Bonferroni correction. In addition, our preliminary results show that the SFPCA-based statistic has much smaller P-values to identify pathway association than other existing methods.

Impaired anterior swim bladder inflation following exposure to the thyroid peroxidase inhibitor 2-Mercaptobenzothiazole Part I: Fathead minnow

EPA Science Inventory

Development of adverse outcome pathways linking specific chemical-induced pathway perturbations to adverse outcomes relevant to regulatory decision-making has potential to support the development of alternatives to traditional whole organism toxicity tests, such as the fish early...

Use of 2D chemical structure and bioactivity profiles to generate chemical categories within an Adverse Outcome Pathway network

EPA Science Inventory

The Adverse Outcome Pathway (AOP) framework has emerged to capitalise on the vast quantity of mechanistic data generated by alternative techniques, as well as advances in systems biology, cheminformatics, and bioinformatics. AOPs provide a scaffold onto which mechanistic data can...

Divergent pathways in the reaction of Fischer carbenes and palladium.

PubMed

López-Alberca, María P; Mancheño, María J; Fernandez, Israel; Gómez-Gallego, Mar; Sierra, Miguel A; Torres, Rosario

2007-04-26

[reaction: see text] The Pd-catalyzed reaction of beta-arylaminochromium(0) carbene complexes produces by transmetalation the first isolated and X-ray structurally characterized bis-Pd(II) carbene complex, as well as other alternative reaction pathways, such as the oxidative addition-transmetalation sequence, not seen before in this chemistry.

Inhalation toxicity of indoor air pollutants in Drosophila melanogaster using integrated transcriptomics and computational behavior analyses

NASA Astrophysics Data System (ADS)

Eom, Hyun-Jeong; Liu, Yuedan; Kwak, Gyu-Suk; Heo, Muyoung; Song, Kyung Seuk; Chung, Yun Doo; Chon, Tae-Soo; Choi, Jinhee

2017-06-01

We conducted an inhalation toxicity test on the alternative animal model, Drosophila melanogaster, to investigate potential hazards of indoor air pollution. The inhalation toxicity of toluene and formaldehyde was investigated using comprehensive transcriptomics and computational behavior analyses. The ingenuity pathway analysis (IPA) based on microarray data suggests the involvement of pathways related to immune response, stress response, and metabolism in formaldehyde and toluene exposure based on hub molecules. We conducted a toxicity test using mutants of the representative genes in these pathways to explore the toxicological consequences of alterations of these pathways. Furthermore, extensive computational behavior analysis showed that exposure to either toluene or formaldehyde reduced most of the behavioral parameters of both wild-type and mutants. Interestingly, behavioral alteration caused by toluene or formaldehyde exposure was most severe in the p38b mutant, suggesting that the defects in the p38 pathway underlie behavioral alteration. Overall, the results indicate that exposure to toluene and formaldehyde via inhalation causes severe toxicity in Drosophila, by inducing significant alterations in gene expression and behavior, suggesting that Drosophila can be used as a potential alternative model in inhalation toxicity screening.

The Group B Streptococcus-Secreted Protein CIP Interacts with C4, Preventing C3b Deposition via the Lectin and Classical Complement Pathways.

PubMed

Pietrocola, Giampiero; Rindi, Simonetta; Rosini, Roberto; Buccato, Scilla; Speziale, Pietro; Margarit, Immaculada

2016-01-01

The group B Streptococcus (GBS) is a leading cause of neonatal invasive disease. GBS bacteria are surrounded by a thick capsular polysaccharide that is a potent inhibitor of complement deposition via the alternative pathway. Several of its surface molecules can however activate the classical and lectin complement pathways, rendering this species still vulnerable to phagocytic killing. In this study we have identified a novel secreted protein named complement interfering protein (CIP) that downregulates complement activation via the classical and lectin pathways, but not the alternative pathway. The CIP protein showed high affinity toward C4b and inhibited its interaction with C2, presumably preventing the formation of the C4bC2a convertase. Addition of recombinant CIP to GBS cip-negative bacteria resulted in decreased deposition of C3b on their surface and in diminished phagocytic killing in a whole-blood assay. Our data reveal a novel strategy exploited by GBS to counteract innate immunity and could be valuable for the development of anti-infective agents against this important pathogen. Copyright © 2015 by The American Association of Immunologists, Inc.

The Significance of Different Diacylgycerol Synthesis Pathways on Plant Oil Composition and Bioengineering

PubMed Central

Bates, Philip D.; Browse, John

2012-01-01

The unique properties of vegetable oils from different plants utilized for food, industrial feedstocks, and fuel is dependent on the fatty acid (FA) composition of triacylglycerol (TAG). Plants can use two main pathways to produce diacylglycerol (DAG), the immediate precursor molecule to TAG synthesis: (1) De novo DAG synthesis, and (2) conversion of the membrane lipid phosphatidylcholine (PC) to DAG. The FA esterified to PC are also the substrate for FA modification (e.g., desaturation, hydroxylation, etc.), such that the FA composition of PC-derived DAG can be substantially different than that of de novo DAG. Since DAG provides two of the three FA in TAG, the relative flux of TAG synthesis from de novo DAG or PC-derived DAG can greatly affect the final oil FA composition. Here we review how the fluxes through these two alternate pathways of DAG/TAG synthesis are determined and present evidence that suggests which pathway is utilized in different plants. Additionally, we present examples of how the endogenous DAG synthesis pathway in a transgenic host plant can produce bottlenecks for engineering of plant oil FA composition, and discuss alternative strategies to overcome these bottlenecks to produce crop plants with designer vegetable oil compositions. PMID:22783267

Inhalation toxicity of indoor air pollutants in Drosophila melanogaster using integrated transcriptomics and computational behavior analyses

PubMed Central

Eom, Hyun-Jeong; Liu, Yuedan; Kwak, Gyu-Suk; Heo, Muyoung; Song, Kyung Seuk; Chung, Yun Doo; Chon, Tae-Soo; Choi, Jinhee

2017-01-01

We conducted an inhalation toxicity test on the alternative animal model, Drosophila melanogaster, to investigate potential hazards of indoor air pollution. The inhalation toxicity of toluene and formaldehyde was investigated using comprehensive transcriptomics and computational behavior analyses. The ingenuity pathway analysis (IPA) based on microarray data suggests the involvement of pathways related to immune response, stress response, and metabolism in formaldehyde and toluene exposure based on hub molecules. We conducted a toxicity test using mutants of the representative genes in these pathways to explore the toxicological consequences of alterations of these pathways. Furthermore, extensive computational behavior analysis showed that exposure to either toluene or formaldehyde reduced most of the behavioral parameters of both wild-type and mutants. Interestingly, behavioral alteration caused by toluene or formaldehyde exposure was most severe in the p38b mutant, suggesting that the defects in the p38 pathway underlie behavioral alteration. Overall, the results indicate that exposure to toluene and formaldehyde via inhalation causes severe toxicity in Drosophila, by inducing significant alterations in gene expression and behavior, suggesting that Drosophila can be used as a potential alternative model in inhalation toxicity screening. PMID:28621308

Elderly patients’ participation in emergency medical services when offered an alternative care pathway

PubMed Central

Vicente, Veronica; Castren, Maaret; Sjöstrand, Fredrik; Sundström, Birgitta Wireklint

2013-01-01

As organizational changes in the healthcare system are in progress, to enhance care quality and reduce costs, it is important to investigate how these changes affect elderly patients’ experiences and their rights to participate in the choice of healthcare. The aim of this study is to describe elderly patients’ lived experience of participating in the choice of healthcare when being offered an alternative care pathway by the emergency medical services, when the individual patient's medical needs made this choice possible. This study was carried out from the perspective of caring science, and a phenomenological approach was applied, where data were analysed for meaning. Data consist of 11 semi-structured interviews with elderly patients who chose a healthcare pathway to a community-based hospital when they were offered an alternative level of healthcare. The findings show that the essence of the phenomenon is described as “There was a ray of hope about a caring encounter and about being treated like a unique human being”. Five meaningful constituents emerged in the descriptions: endurable waiting, speedy transference, a concerned encounter, trust in competence, and a choice based on memories of suffering from care. The conclusion is that patient participation in the choice of a healthcare alternative instead of the emergency department is an opportunity of avoiding suffering from care and being objectified. PMID:23445898

30 CFR 285.1017 - [Reserved

Code of Federal Regulations, 2010 CFR

2010-07-01

... Resources MINERALS MANAGEMENT SERVICE, DEPARTMENT OF THE INTERIOR OFFSHORE RENEWABLE ENERGY ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS Facilities Alternate Use Rue Administration § 285.1017...

30 CFR 285.1017 - [Reserved

Code of Federal Regulations, 2011 CFR

2011-07-01

... Resources BUREAU OF OCEAN ENERGY MANAGEMENT, REGULATION, AND ENFORCEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE RENEWABLE ENERGY ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS Facilities Alternate Use...

A Unified Model for Left-Right Asymmetry? Comparison and Synthesis of Molecular Models of Embryonic Laterality

PubMed Central

Vandenberg, Laura N.; Levin, Michael

2013-01-01

Understanding how and when the left-right (LR) axis is first established is a fundamental question in developmental biology. A popular model is that the LR axis is established relatively late in embryogenesis, due to the movement of motile cilia and the resultant directed fluid flow during late gastrulation/early neurulation. Yet, a large body of evidence suggests that biophysical, molecular, and bioelectrical asymmetries exist much earlier in development, some as early as the first cell cleavage after fertilization. Alternative models of LR asymmetry have been proposed that accommodate these data, postulating that asymmetry is established due to a chiral cytoskeleton and/or the asymmetric segregation of chromatids. There are some similarities, and many differences, in how these various models postulate the origin and timing of symmetry breaking and amplification, and these events’ linkage to the well-conserved subsequent asymmetric transcriptional cascades. This review examines experimental data that lend strong support to an early origin of LR asymmetry, yet are also consistent with later roles for cilia in the amplification of LR pathways. In this way, we propose that the various models of asymmetry can be unified: early events are needed to initiate LR asymmetry, and later events could be utilized by some species to maintain LR-biases. We also present an alternative hypothesis, which proposes that individual embryos stochastically choose one of several possible pathways with which to establish their LR axis. These two hypotheses are both tractable in appropriate model species; testing them to resolve open questions in the field of LR patterning will reveal interesting new biology of wide relevance to developmental, cell, and evolutionary biology. PMID:23583583

A unified model for left-right asymmetry? Comparison and synthesis of molecular models of embryonic laterality.

PubMed

Vandenberg, Laura N; Levin, Michael

2013-07-01

Understanding how and when the left-right (LR) axis is first established is a fundamental question in developmental biology. A popular model is that the LR axis is established relatively late in embryogenesis, due to the movement of motile cilia and the resultant directed fluid flow during late gastrulation/early neurulation. Yet, a large body of evidence suggests that biophysical, molecular, and bioelectrical asymmetries exist much earlier in development, some as early as the first cell cleavage after fertilization. Alternative models of LR asymmetry have been proposed that accommodate these data, postulating that asymmetry is established due to a chiral cytoskeleton and/or the asymmetric segregation of chromatids. There are some similarities, and many differences, in how these various models postulate the origin and timing of symmetry breaking and amplification, and these events' linkage to the well-conserved subsequent asymmetric transcriptional cascades. This review examines experimental data that lend strong support to an early origin of LR asymmetry, yet are also consistent with later roles for cilia in the amplification of LR pathways. In this way, we propose that the various models of asymmetry can be unified: early events are needed to initiate LR asymmetry, and later events could be utilized by some species to maintain LR-biases. We also present an alternative hypothesis, which proposes that individual embryos stochastically choose one of several possible pathways with which to establish their LR axis. These two hypotheses are both tractable in appropriate model species; testing them to resolve open questions in the field of LR patterning will reveal interesting new biology of wide relevance to developmental, cell, and evolutionary biology. Copyright © 2013 Elsevier Inc. All rights reserved.

Two enzymatic reaction pathways in the formation of pyropheophorbide a.

PubMed

Suzuki, Yasuyo; Doi, Michio; Shioi, Yuzo

2002-01-01

The demethoxycarbonyl reaction of pheophorbide a in plants and algae was investigated. Two types of enzyme that catalyze alternative reactions in the formation of pyropheophorbide a were found. One enzyme, designated 'pheophorbidase (Phedase)', was purified nearly to homogeneity from cotyledons of radish (Raphanus sativus). This enzyme catalyzes the conversion of pheophorbide a to a precursor of pyropheophorbide a, C-13(2)-carboxylpyropheophorbide a, by demethylation, and then the precursor is decarboxylated non-enzymatically to yield pyropheophorbide a. The activity of Phedase was inhibited by the reaction product, methanol. The other enzyme, termed 'pheophorbide demethoxycarbonylase (PDC)', was highly purified from the Chl b-less mutant NL-105 of Chlamydomonas reinhardtii. This enzyme had produced no intermediate as shown in the Phedase reaction, indicating that it converts pheophorbide a directly into pyropheophorbide a, probably by nucleophilic reaction. Phedase and PDC consisted of both senescence-induced and constitutive enzymes. The molecular weight of both Phedases was 113 000 and of senescence-induced PDC was 170 000. The K (m) values against pheophorbide a for both Phedases were 14-15 muM and 283 muM for senescence-induced PDC. The activity of both Phedases was inhibited by the reaction product, methanol, whereas methanol had no specific effect on senescence-induced PDC. Phenylmethylsulfonic fluoride and N-ethylmaleimide inhibited the senescence-induced Phedase and PDC, respectively. Among the 23 species from 15 different families tested, Phedase activity was found in 10 species from three families. PDC activity was not detected in plants lacking Phedase activity, except for Chlamydomonas. Based on these findings, a likely conclusion is that at least two alternative pathways that are catalyzed by two different enzymes, Phedase and PDC, exist for the formation of pyropheophorbide a.

Economic Impact of Alvimopan Considering Varying Definitions of Postoperative Ileus.

PubMed

Earnshaw, Stephanie R; Kauf, Teresa L; McDade, Cheryl; Potashman, Michele H; Pauyo, Cassandra; Reese, Emily S; Senagore, Anthony

2015-11-01

Prolonged postoperative ileus (POI) is the predominant cause of extended hospitalization after bowel resection surgery. Alvimopan accelerates gastrointestinal recovery, potentially reducing health care costs. We examined the value of alvimopan in reducing prolonged POI and length of stay for patients undergoing abdominal surgery using different definitions of POI. We developed a decision analytic model to examine costs and outcomes associated with postoperative treatment with either an accelerated care pathway (ACP) only or alvimopan+ACP. To represent an overall perspective for alvimopan, data from four phase 3 bowel resection trials and one phase 4 radical cystectomy trial were used to populate the model with 3 different definitions of POI. The period analyzed included start of surgery to 7 days post discharge. Costs were obtained from standard US costing sources and are reported in 2015 US dollars. Due to variations in published definitions of POI, alternative definitions based on adverse event reports, NG tube insertion, and time to food toleration were examined. The combined clinical trial data included 1,003 ACP and 1,013 alvimopan+ACP patients. When POI was reported as an adverse event, the incidence of POI was significantly lower with alvimopan+ACP (n = 70 [7%]) vs ACP alone (n = 148 [15%]; p < 0.0001). Time to discharge order written was shorter for patients with POI who were treated with alvimopan+ACP than with ACP (202 ± 115 hours vs 266 ± 138 hours; p < 0.0001). As a result, costs were $731 lower with alvimopan+ACP ($17,835) vs ACP ($18,566). Alternative definitions of POI produced similar results. The addition of alvimopan to existing treatment pathways for patients undergoing abdominal surgery can reduce overall hospital costs. Copyright © 2015 American College of Surgeons. Published by Elsevier Inc. All rights reserved.

Trends and Issues in California's Low Carbon Fuel Standard - Learning from Response to Existing Climate Policy

NASA Astrophysics Data System (ADS)

Witcover, J.

2015-12-01

Debate over lower greenhouse gas (GHG) emissions from transportation has included heated discussion about appropriate policies and their cost and feasibility. One prominent policy mechanism, a carbon intensity standard, rates transport fuels based on analysis of lifecycle GHG emissions, and targets lower fuel pool carbon intensity through a market mechanism that uses a system of tradable, bankable credits and deficits. California instituted such a policy -- the Low Carbon Fuel Standard (LCFS) - in 2010, which targets a 10% carbon intensity (CI) reduction by 2020. The program rolled out amid concerns over slow development of new fuels expected to be very low carbon (such as cellulosic) and has faced court challenges that added considerable policy uncertainty. Since the program's start, state transport energy mix has shifted modestly but noticeably. Looking ahead, emerging issues for the program include amendments and re-adoption in response to a court ruling, potential interaction with California's multi-sector cap on carbon emissions (which started covering transport fuels in 2015), and impacts from similar CI standards in other jurisdictions. This study provides an analysis of fuel mix changes since the LCFS was implemented in 2011, and a discussion of emerging issues focusing on policy interaction. Descriptive statistics on alternative fuel use, available fuel pathways, and CI ratings are presented based on data from the California Air Resources Board (which runs the program). They document a shift towards more alternative fuels in a more diverse mix, with lower average CI ratings for most alternative fuel types. Financial incentives for various fuels are compared under the LCFS and the US federal Renewable Fuel Standard; disincentives from conceptually different carbon pricing schemes under the LCFS and the Cap-and-Trade are also outlined. The results provide important information on response to an existing market-based policy mechanism for addressing GHG emissions in transportation, as other jurisdictions weigh similar climate policies and debate mechanisms and costs and California announced an ambitious target of halving petroleum use by 2030.

SYNTHESIS OF PARTIAL-OXYGENATED HYDROCARBONS USING PHOTOCATALYSIS IN A LAMINAR FALLING FILM SLURRY REACTOR

EPA Science Inventory

The search for "Green" alternative processes for the oxidation of hydrocarbons selectively to partial oxygenates has been the subject of intense chemical research for many years. The USEPA is currently investigating an alternative synthesis pathway for the production of alcoho...

SYNTHESIS OF PARTIALLY-OXYGENATED HYDROCARBONS USING PHOTOCATALYSIS IN A LAMINAR FALLING FILM SLURRY REACTOR

EPA Science Inventory

The search for "Green" alternative processes for the oxidation of hydrocarbons selectively to partial oxygenates has been the subject of intense chemical research for many years. The USEPA is currently investigating an alternative synthesis pathway for the production of alcoho...

Quiescent Fibroblasts Exhibit High Metabolic Activity

PubMed Central

Lemons, Johanna M. S.; Feng, Xiao-Jiang; Bennett, Bryson D.; Legesse-Miller, Aster; Johnson, Elizabeth L.; Raitman, Irene; Pollina, Elizabeth A.; Rabitz, Herschel A.; Rabinowitz, Joshua D.; Coller, Hilary A.

2010-01-01

Many cells in mammals exist in the state of quiescence, which is characterized by reversible exit from the cell cycle. Quiescent cells are widely reported to exhibit reduced size, nucleotide synthesis, and metabolic activity. Much lower glycolytic rates have been reported in quiescent compared with proliferating lymphocytes. In contrast, we show here that primary human fibroblasts continue to exhibit high metabolic rates when induced into quiescence via contact inhibition. By monitoring isotope labeling through metabolic pathways and quantitatively identifying fluxes from the data, we show that contact-inhibited fibroblasts utilize glucose in all branches of central carbon metabolism at rates similar to those of proliferating cells, with greater overflow flux from the pentose phosphate pathway back to glycolysis. Inhibition of the pentose phosphate pathway resulted in apoptosis preferentially in quiescent fibroblasts. By feeding the cells labeled glutamine, we also detected a “backwards” flux in the tricarboxylic acid cycle from α-ketoglutarate to citrate that was enhanced in contact-inhibited fibroblasts; this flux likely contributes to shuttling of NADPH from the mitochondrion to cytosol for redox defense or fatty acid synthesis. The high metabolic activity of the fibroblasts was directed in part toward breakdown and resynthesis of protein and lipid, and in part toward excretion of extracellular matrix proteins. Thus, reduced metabolic activity is not a hallmark of the quiescent state. Quiescent fibroblasts, relieved of the biosynthetic requirements associated with generating progeny, direct their metabolic activity to preservation of self integrity and alternative functions beneficial to the organism as a whole. PMID:21049082

2 °C and SDGs: united they stand, divided they fall?

NASA Astrophysics Data System (ADS)

von Stechow, Christoph; Minx, Jan C.; Riahi, Keywan; Jewell, Jessica; McCollum, David L.; Callaghan, Max W.; Bertram, Christoph; Luderer, Gunnar; Baiocchi, Giovanni

2016-03-01

The adoption of the Sustainable Development Goals (SDGs) and the new international climate treaty could put 2015 into the history books as a defining year for setting human development on a more sustainable pathway. The global climate policy and SDG agendas are highly interconnected: the way that the climate problem is addressed strongly affects the prospects of meeting numerous other SDGs and vice versa. Drawing on existing scenario results from a recent energy-economy-climate model inter-comparison project, this letter analyses these synergies and (risk) trade-offs of alternative 2 °C pathways across indicators relevant for energy-related SDGs and sustainable energy objectives. We find that limiting the availability of key mitigation technologies yields some co-benefits and decreases risks specific to these technologies but greatly increases many others. Fewer synergies and substantial trade-offs across SDGs are locked into the system for weak short-term climate policies that are broadly in line with current Intended Nationally Determined Contributions (INDCs), particularly when combined with constraints on technologies. Lowering energy demand growth is key to managing these trade-offs and creating synergies across multiple energy-related SD dimensions. We argue that SD considerations are central for choosing socially acceptable 2 °C pathways: the prospects of meeting other SDGs need not dwindle and can even be enhanced for some goals if appropriate climate policy choices are made. Progress on the climate policy and SDG agendas should therefore be tracked within a unified framework.

Isoleucine Biosynthesis in Leptospira interrogans Serotype lai Strain 56601 Proceeds via a Threonine-Independent Pathway† ‡

PubMed Central

Xu, Hai; Zhang, Yuzhen; Guo, Xiaokui; Ren, Shuangxi; Staempfli, Andreas A.; Chiao, Juishen; Jiang, Weihong; Zhao, Guoping

2004-01-01

Three leuA-like protein-coding sequences were identified in Leptospira interrogans. One of these, the cimA gene, was shown to encode citramalate synthase (EC 4.1.3.-). The other two encoded α-isopropylmalate synthase (EC 4.1.3.12). Expressed in Escherichia coli, the citramalate synthase was purified and characterized. Although its activity was relatively low, it was strictly specific for pyruvate as the keto acid substrate. Unlike the citramalate synthase of the thermophile Methanococcus jannaschii, the L. interrogans enzyme is temperature sensitive but exhibits a much lower Km (0.04 mM) for pyruvate. The reaction product was characterized as (R)-citramalate, and the proposed β-methyl-d-malate pathway was further confirmed by demonstrating that citraconate was the substrate for the following reaction. This alternative pathway for isoleucine biosynthesis from pyruvate was analyzed both in vitro by assays of leptospiral isopropylmalate isomerase (EC 4.2.1.33) and β-isopropylmalate dehydrogenase (EC 1.1.1.85) in E. coli extracts bearing the corresponding clones and in vivo by complementation of E. coli ilvA, leuC/D, and leuB mutants. Thus, the existence of a leucine-like pathway for isoleucine biosynthesis in L. interrogans under physiological conditions was unequivocally proven. Significant variations in either the enzymatic activities or mRNA levels of the cimA and leuA genes were detected in L. interrogans grown on minimal medium supplemented with different levels of the corresponding amino acids or in cells grown on serum-containing rich medium. The similarity of this metabolic pathway in leptospires and archaea is consistent with the evolutionarily primitive status of the eubacterial spirochetes. PMID:15292141

Nitrogen-responsive Regulation of GATA Protein Family Activators Gln3 and Gat1 Occurs by Two Distinct Pathways, One Inhibited by Rapamycin and the Other by Methionine Sulfoximine*

PubMed Central

Georis, Isabelle; Tate, Jennifer J.; Cooper, Terrance G.; Dubois, Evelyne

2011-01-01

Nitrogen availability regulates the transcription of genes required to degrade non-preferentially utilized nitrogen sources by governing the localization and function of transcription activators, Gln3 and Gat1. TorC1 inhibitor, rapamycin (Rap), and glutamine synthetase inhibitor, methionine sulfoximine (Msx), elicit responses grossly similar to those of limiting nitrogen, implicating both glutamine synthesis and TorC1 in the regulation of Gln3 and Gat1. To better understand this regulation, we compared Msx- versus Rap-elicited Gln3 and Gat1 localization, their DNA binding, nitrogen catabolite repression-sensitive gene expression, and the TorC1 pathway phosphatase requirements for these responses. Using this information we queried whether Rap and Msx inhibit sequential steps in a single, linear cascade connecting glutamine availability to Gln3 and Gat1 control as currently accepted or alternatively inhibit steps in two distinct parallel pathways. We find that Rap most strongly elicits nuclear Gat1 localization and expression of genes whose transcription is most Gat1-dependent. Msx, on the other hand, elicits nuclear Gln3 but not Gat1 localization and expression of genes that are most Gln3-dependent. Importantly, Rap-elicited nuclear Gln3 localization is absolutely Sit4-dependent, but that elicited by Msx is not. PP2A, although not always required for nuclear GATA factor localization, is highly required for GATA factor binding to nitrogen-responsive promoters and subsequent transcription irrespective of the gene GATA factor specificities. Collectively, our data support the existence of two different nitrogen-responsive regulatory pathways, one inhibited by Msx and the other by rapamycin. PMID:22039046

Nitrogen-responsive regulation of GATA protein family activators Gln3 and Gat1 occurs by two distinct pathways, one inhibited by rapamycin and the other by methionine sulfoximine.

PubMed

Georis, Isabelle; Tate, Jennifer J; Cooper, Terrance G; Dubois, Evelyne

2011-12-30

Nitrogen availability regulates the transcription of genes required to degrade non-preferentially utilized nitrogen sources by governing the localization and function of transcription activators, Gln3 and Gat1. TorC1 inhibitor, rapamycin (Rap), and glutamine synthetase inhibitor, methionine sulfoximine (Msx), elicit responses grossly similar to those of limiting nitrogen, implicating both glutamine synthesis and TorC1 in the regulation of Gln3 and Gat1. To better understand this regulation, we compared Msx- versus Rap-elicited Gln3 and Gat1 localization, their DNA binding, nitrogen catabolite repression-sensitive gene expression, and the TorC1 pathway phosphatase requirements for these responses. Using this information we queried whether Rap and Msx inhibit sequential steps in a single, linear cascade connecting glutamine availability to Gln3 and Gat1 control as currently accepted or alternatively inhibit steps in two distinct parallel pathways. We find that Rap most strongly elicits nuclear Gat1 localization and expression of genes whose transcription is most Gat1-dependent. Msx, on the other hand, elicits nuclear Gln3 but not Gat1 localization and expression of genes that are most Gln3-dependent. Importantly, Rap-elicited nuclear Gln3 localization is absolutely Sit4-dependent, but that elicited by Msx is not. PP2A, although not always required for nuclear GATA factor localization, is highly required for GATA factor binding to nitrogen-responsive promoters and subsequent transcription irrespective of the gene GATA factor specificities. Collectively, our data support the existence of two different nitrogen-responsive regulatory pathways, one inhibited by Msx and the other by rapamycin.

Characterization of immune genes from the schistosome host snail Biomphalaria glabrata that encode peptidoglycan recognition proteins and gram-negative bacteria binding protein

PubMed Central

Zeng, Yong; Loker, Eric S.

2013-01-01

Peptidoglycan (PGN) recognition proteins (PGRPs) and gram-negative bacteria binding proteins (GNBPs) play an essential role in Toll/Imd signaling pathways in arthropods. The existence of homologous pathways involving PGRPs and GNBPs in other major invertebrate phyla such as the Mollusca remains unclear. In this paper, we report four full-length PGRP cDNAs and one full-length GNBP cDNA cloned from the snail Biomphalaria glabrata, the intermediate host of the human blood fluke Schistosoma mansoni, designated as BgPGRPs and BgGNBP, respectively. Three transcripts are generated from a long form PGRP gene (BgPGRP-LA) by alternative splicing and one from a short form PGRP gene (BgPGRP-SA). BgGNBP encodes a putative secreted protein. Northern blots demonstrated that expression of BgPGRP-SA and BgGNBP was down-regulated in B. glabrata at 6 h after exposure to three types of microbes. No significant changes in expression were observed in snails at 2 days post-exposure (dpe) to the trematodes Echinostoma paraensei or S. mansoni. However, up-regulation of BgPGRP-SA in M line snails at later time points of infection with E. paraensei (i.e., 12 and 17 dpe) was observed. Our study revealed that exposure to either microbes or trematodes did not alter the expression levels of BgPGRP-LAs, which were consistently low. This study provides new insights into the potential pathogen recognition capabilities of molluscs, indicates that further studies of the Toll/Imd pathways in this phylum are in order, and provides additional ways to judge the importance of this pathway in the evolution of internal defense across the animal phyla. PMID:17805526

Blastobotrys (Arxula) adeninivorans: a promising alternative yeast for biotechnology and basic research.

PubMed

Malak, Anna; Baronian, Kim; Kunze, Gotthard

2016-10-01

Blastobotrys adeninivorans (syn. Arxula adeninivorans) is a non-conventional, non-pathogenic, imperfect, haploid yeast, belonging to the subphylum Saccharomycotina, which has to date received comparatively little attention from researchers. It possesses unusual properties such as thermo- and osmotolerance, and a broad substrate spectrum. Depending on the cultivation temperature B. (A.) adeninivorans exhibits different morphological forms and various post-translational modifications and protein expression properties that are strongly correlated with the morphology. The genome has been completely sequenced and, in addition, there is a well-developed transformation/expression platform, which makes rapid, simple gene manipulations possible. This yeast species is a very good host for homologous and heterologous gene expression and is also a useful gene donor. Blastobotrys (A.) adeninivorans is able to use a very wide range of substrates as carbon and/or nitrogen sources and is an interesting organism owing to the presence of many metabolic pathways, for example degradation of n-butanol, purines and tannin. In addition, its unusual properties and robustness make it a useful bio-component for whole cell biosensors. There are currently a number of products on the market produced by B. (A.) adeninivorans and further investigation may contribute further innovative solutions for current challenges that exist in the biotechnology industry. Additionally it may become a useful alternative to existing commercial yeast strains and as a model organism in research. In this review we present information relevant to the exploitation of B. (A.) adeninivorans in research and industrial settings. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

The synthesis of monomers with pendent ethynyl groups for modified high performance thermoplastics

NASA Technical Reports Server (NTRS)

Nwokogu, Godson C.; Antoine, Miquel D.; Ansong, Omari

1994-01-01

Synthetic schemes were developed and optimized for twelve new monomers possessing unique structural features and one aspartimide. Two synthetic pathways were compared for preparation of the triarylethane monomers with pendent ethynyl groups. The results show that one of these pathways can be generally applied. The alternative pathway was applicable to the preparation of only one of the twelve compounds, the problem being secondary reactions of the initially formed desired product.

Clinging to the Past: The Air Force’s War on Dual-Career Families

DTIC Science & Technology

2014-06-01

combines existing research on stress and work-family conflict with new primary research on current USAF dual-career families in the form of a case...incompatibilities between the Air Force family schema (conceptions of, and practices relating to, USAF families). The study combines existing research on stress ... Stress Pathways ..................................................... 74 Figure 5, Civilian Dual-Career Stress Pathways

30 CFR 585.1017 - [Reserved

Code of Federal Regulations, 2012 CFR

2012-07-01

... Resources BUREAU OF OCEAN ENERGY MANAGEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE RENEWABLE ENERGY AND ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS Facilities Alternate Use Rue Administration § 585...

30 CFR 585.1017 - [Reserved

Code of Federal Regulations, 2014 CFR

2014-07-01

... Resources BUREAU OF OCEAN ENERGY MANAGEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE RENEWABLE ENERGY AND ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS Facilities Alternate Use Rue Administration § 585...

30 CFR 585.1017 - [Reserved

Code of Federal Regulations, 2013 CFR

2013-07-01

... Resources BUREAU OF OCEAN ENERGY MANAGEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE RENEWABLE ENERGY AND ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS Facilities Alternate Use Rue Administration § 585...

Salicylic Acid Regulation of Respiration in Higher Plants: Alternative Oxidase Expression.

PubMed Central

Rhoads, DM; McIntosh, L

1992-01-01

Alternative respiratory pathway capacity increases during the development of the thermogenic appendix of a voodoo lily inflorescence. The levels of the alternative oxidase proteins increased dramatically between D-4 (4 days prior to the day of anthesis) and D-3 and continued to increase until the day of anthesis (D-day). The level of salicylic acid (SA) in the appendix is very low early on D-1, but increases to a high level in the evening of D-1. Thermogenesis occurs after a few hours of light on D-day. Therefore, the initial accumulation of the alternative oxidase proteins precedes the increase in SA by 3 days, indicating that other regulators may be involved. A 1.6-kb transcript encoding the alternative oxidase precursor protein accumulated to a high level in the appendix tissue by D-1. Application of SA to immature appendix tissue caused an increase in alternative pathway capacity and a dramatic accumulation of the alternative oxidase proteins and the 1.6-kb transcript. Time course experiments showed that the increase in capacity, protein levels, and transcript level corresponded precisely. The response to SA was blocked by cycloheximide or actinomycin D, indicating that de novo transcription and translation are required. However, nuclear, in vitro transcription assays indicated that the accumulation of the 1.6-kb transcript did not result from a simple increase in the rate of transcription of aox1. PMID:12297672

Alternative splicing disabled by Nova2.

PubMed

Park, Tae-Ju; Curran, Tom

2010-06-24

Disabled-1 is a key signaling molecule in the Reelin pathway that plays a critical role in neuronal migration and positioning during brain development. In this issue of Neuron, Yano et al. demonstrate that the neuron-specific RNA binding protein Nova2 contributes to neuronal migration by regulating alternative splicing of disabled-1.

Second Chances Academy: Alternative School or Pathway to Prison?

ERIC Educational Resources Information Center

Horsford, Sonya Douglass; Powell, Keyona L.

2016-01-01

This case considers the leadership challenge facing district officials in a mid-sized urban-suburban school district receiving negative media coverage for the overrepresentation of poor, Black, and Latino males in its alternative high school, Second Chances Academy. Many of its students also qualify for special education and English learner…

Theoretical study of the decomposition pathways and products of C5- perfluorinated ketone (C5 PFK)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fu, Yuwei; Wang, Xiaohua, E-mail: xhw@mail.xjtu.edu.cn, E-mail: mzrong@mail.xjtu.edu.cn; Li, Xi

Due to the high global warming potential (GWP) and increasing environmental concerns, efforts on searching the alternative gases to SF{sub 6}, which is predominantly used as insulating and interrupting medium in high-voltage equipment, have become a hot topic in recent decades. Overcoming the drawbacks of the existing candidate gases, C5- perfluorinated ketone (C5 PFK) was reported as a promising gas with remarkable insulation capacity and the low GWP of approximately 1. Experimental measurements of the dielectric strength of this novel gas and its mixtures have been carried out, but the chemical decomposition pathways and products of C5 PFK during breakdownmore » are still unknown, which are the essential factors in evaluating the electric strength of this gas in high-voltage equipment. Therefore, this paper is devoted to exploring all the possible decomposition pathways and species of C5 PFK by density functional theory (DFT). The structural optimizations, vibrational frequency calculations and energy calculations of the species involved in a considered pathway were carried out with DFT-(U)B3LYP/6-311G(d,p) method. Detailed potential energy surface was then investigated thoroughly by the same method. Lastly, six decomposition pathways of C5 PFK decomposition involving fission reactions and the reactions with a transition states were obtained. Important intermediate products were also determined. Among all the pathways studied, the favorable decomposition reactions of C5 PFK were found, involving C-C bond ruptures producing Ia and Ib in pathway I, followed by subsequent C-C bond ruptures and internal F atom transfers in the decomposition of Ia and Ib presented in pathways II + III and IV + V, respectively. Possible routes were pointed out in pathway III and lead to the decomposition of IIa, which is the main intermediate product found in pathway II of Ia decomposition. We also investigated the decomposition of Ib, which can undergo unimolecular reactions to give the formation of IV a, IV b and products of CF{sub 3} + CF-CF{sub 3} in pathway IV. Although IV a is dominant to a lesser extent due to its relative high energy barrier, its complicated decomposition pathway V was also studied and CF{sub 3}, C = CF{sub 2} as well as C-CF{sub 3} species were found as the ultimate products. To complete the decomposition of C5 PFK, pathway V I of Ic decomposition was fully explored and the final products were obtained. Therefore, the integrate decomposition scheme of C5 PFK was proposed, which contains six pathways and forty-eight species (including all the reactants, products and transition states). This work is hopeful to lay a theoretical basis for the insulating properties of C5 PFK.« less

Cellular and molecular engineering of yeast Saccharomyces cerevisiae for advanced biobutanol production.

PubMed

Kuroda, Kouichi; Ueda, Mitsuyoshi

2016-02-01

Butanol is an attractive alternative energy fuel owing to several advantages over ethanol. Among the microbial hosts for biobutanol production, yeast Saccharomyces cerevisiae has a great potential as a microbial host due to its powerful genetic tools, a history of successful industrial use, and its inherent tolerance to higher alcohols. Butanol production by S. cerevisiae was first attempted by transferring the 1-butanol-producing metabolic pathway from native microorganisms or using the endogenous Ehrlich pathway for isobutanol synthesis. Utilizing alternative enzymes with higher activity, eliminating competitive pathways, and maintaining cofactor balance achieved significant improvements in butanol production. Meeting future challenges, such as enhancing butanol tolerance and implementing a comprehensive strategy by high-throughput screening, would further elevate the biobutanol-producing ability of S. cerevisiae toward an ideal microbial cell factory exhibiting high productivity of biobutanol. © FEMS 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Pathway analysis from lists of microRNAs: common pitfalls and alternative strategy

PubMed Central

Godard, Patrice; van Eyll, Jonathan

2015-01-01

MicroRNAs (miRNAs) are involved in the regulation of gene expression at a post-transcriptional level. As such, monitoring miRNA expression has been increasingly used to assess their role in regulatory mechanisms of biological processes. In large scale studies, once miRNAs of interest have been identified, the target genes they regulate are often inferred using algorithms or databases. A pathway analysis is then often performed in order to generate hypotheses about the relevant biological functions controlled by the miRNA signature. Here we show that the method widely used in scientific literature to identify these pathways is biased and leads to inaccurate results. In addition to describing the bias and its origin we present an alternative strategy to identify potential biological functions specifically impacted by a miRNA signature. More generally, our study exemplifies the crucial need of relevant negative controls when developing, and using, bioinformatics methods. PMID:25800743

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hiser, C.; McIntosh, L.

The rise in alternative respiratory capacity upon aging of potato (Solanum tuberosum) tuber slices is correlated with changes in mitochondrial membrane protein composition and a requirement for cytoplasmic protein synthesis. However, the lack of an antibody specific to the alternative oxidase has, until recently, prevented examination of the alternative oxidase protein(s) itself. We have employed a monoclonal antibody raised against the Sauromatum guttatum alternative oxidase to investigate developmental changes in the alternative pathway of aging potato slice mitochondria and to characterize the potato alternative oxidase by one- and two-dimensional gel electrophoresis. The relative levels of a 36 kilodalton protein parallelmore » the rise in alternative path capacity. A plausible interpretation is that this alternative oxidase protein is synthesized de novo during aging of potato slices.« less

Effect of temperature on rates of alternative and cytochrome pathway respiration and their relationship with the redox poise of the quinone pool.

PubMed

Atkin, Owen K; Zhang, Qisen; Wiskich, Joe T

2002-01-01

We investigated the effect of short-term changes in temperature on alternative (Alt) and cytochrome (Cyt) pathway respiration, both in intact tissues and isolated mitochondria of 14-d-old cotyledons of soybean (Glycine max L. cv Stevens). We also established the extent to which temperature alters the interaction between the oxidizing pathways and the level of ubiquinone (UQ) reduction (UQ(r)/UQ(t)). No difference was found between the temperature coefficient of respiration (Q(10); proportional change per 10 degrees C) of Alt and Cyt pathway respiration in cotyledon slices (Q(10) = 1.92 and 1.86, respectively). In isolated mitochondria, the Q(10) of the fully activated Alt pathway (Q(10) = 2.24-2.61) was always equal to, or higher than, that of Cyt c oxidase (COX) alone (Q(10) = 2.08) and the complete Cyt pathway (Q(10) = 2.40-2.55). This was true regardless of substrate or whether ADP was present. There was little difference in the Q(10) of the Cyt pathway with or without ADP; however, the Q(10) of COX was substantially lower in the presence of an uncoupler (Q(10) = 1.61) than its absence (Q(10) = 2.08). The kinetics of Alt and Cyt pathway activity in relation to UQ(r)/UQ(t) were not affected by temperature. For a given UQ(r)/UQ(t) value, the proportion of maximum flux taking place was similar at all temperatures for both pathways (+/-ADP). However, the Q(10) of the Alt and the Cyt pathways (+ADP) increased with increasing UQ(r)/UQ(t). We conclude that the Alt pathway is not less temperature sensitive than the Cyt pathway or COX per se and that changes in the degree of control exerted by individual steps in the respiratory apparatus could result in changes in the Q(10) of mitochondrial O(2) uptake.

The role of propriospinal neuronal network in transmitting the alternating muscular activities of flexor and extensor in parkinsonian tremor.

PubMed

Hao, M; He, X; Lan, N

2012-01-01

It has been shown that normal cyclic movement of human arm and resting limb tremor in Parkinson's disease (PD) are associated with the oscillatory neuronal activities in different cerebral networks, which are transmitted to the antagonistic muscles via the same spinal pathway. There are mono-synaptic and multi-synaptic corticospinal pathways for conveying motor commands. This study investigates the plausible role of propriospinal neuronal (PN) network in the C3-C4 levels in multi-synaptic transmission of cortical commands for oscillatory movements. A PN network model is constructed based on known neurophysiological connections, and is hypothesized to achieve the conversion of cortical oscillations into alternating antagonistic muscle bursts. Simulations performed with a virtual arm (VA) model indicate that without the PN network, the alternating bursts of antagonistic muscle EMG could not be reliably generated, whereas with the PN network, the alternating pattern of bursts were naturally displayed in the three pairs of antagonist muscles. Thus, it is suggested that oscillations in the primary motor cortex (M1) of single and double tremor frequencies are processed at the PN network to compute the alternating burst pattern in the flexor and extensor muscles.

30 CFR 585.1008-585.1009 - [Reserved

Code of Federal Regulations, 2014 CFR

2014-07-01

...-585.1009 Mineral Resources BUREAU OF OCEAN ENERGY MANAGEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE RENEWABLE ENERGY AND ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS Facilities Requesting An Alternate...

30 CFR 585.1008-585.1009 - [Reserved

Code of Federal Regulations, 2013 CFR

2013-07-01

...-585.1009 Mineral Resources BUREAU OF OCEAN ENERGY MANAGEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE RENEWABLE ENERGY AND ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS Facilities Requesting An Alternate...

30 CFR 585.1008-585.1009 - [Reserved

Code of Federal Regulations, 2012 CFR

2012-07-01

...-585.1009 Mineral Resources BUREAU OF OCEAN ENERGY MANAGEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE RENEWABLE ENERGY AND ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS Facilities Requesting An Alternate...

Analysis of Alternative Extensions of the Existing Production Tax Credit for Wind Generators

EIA Publications

2007-01-01

Requestor: Ms. Janice Mays, Chief Counsel, Committee on Ways & Means, U.S. House of Representatives This is a letter response requesting analysis of alternative extensions of the existing production tax credit (PTC) that would apply to wind generators only.

PathNER: a tool for systematic identification of biological pathway mentions in the literature

PubMed Central

2013-01-01

Background Biological pathways are central to many biomedical studies and are frequently discussed in the literature. Several curated databases have been established to collate the knowledge of molecular processes constituting pathways. Yet, there has been little focus on enabling systematic detection of pathway mentions in the literature. Results We developed a tool, named PathNER (Pathway Named Entity Recognition), for the systematic identification of pathway mentions in the literature. PathNER is based on soft dictionary matching and rules, with the dictionary generated from public pathway databases. The rules utilise general pathway-specific keywords, syntactic information and gene/protein mentions. Detection results from both components are merged. On a gold-standard corpus, PathNER achieved an F1-score of 84%. To illustrate its potential, we applied PathNER on a collection of articles related to Alzheimer's disease to identify associated pathways, highlighting cases that can complement an existing manually curated knowledgebase. Conclusions In contrast to existing text-mining efforts that target the automatic reconstruction of pathway details from molecular interactions mentioned in the literature, PathNER focuses on identifying specific named pathway mentions. These mentions can be used to support large-scale curation and pathway-related systems biology applications, as demonstrated in the example of Alzheimer's disease. PathNER is implemented in Java and made freely available online at http://sourceforge.net/projects/pathner/. PMID:24555844

A taxonomy of visualization tasks for the analysis of biological pathway data.

PubMed

Murray, Paul; McGee, Fintan; Forbes, Angus G

2017-02-15

Understanding complicated networks of interactions and chemical components is essential to solving contemporary problems in modern biology, especially in domains such as cancer and systems research. In these domains, biological pathway data is used to represent chains of interactions that occur within a given biological process. Visual representations can help researchers understand, interact with, and reason about these complex pathways in a number of ways. At the same time, these datasets offer unique challenges for visualization, due to their complexity and heterogeneity. Here, we present taxonomy of tasks that are regularly performed by researchers who work with biological pathway data. The generation of these tasks was done in conjunction with interviews with several domain experts in biology. These tasks require further classification than is provided by existing taxonomies. We also examine existing visualization techniques that support each task, and we discuss gaps in the existing visualization space revealed by our taxonomy. Our taxonomy is designed to support the development and design of future biological pathway visualization applications. We conclude by suggesting future research directions based on our taxonomy and motivated by the comments received by our domain experts.

Integration of C1 and C2 Metabolism in Trees

PubMed Central

Jardine, Kolby J.; Higuchi, Niro; Bill, Markus; Porras, Rachel; Chambers, Jeffrey Q.

2017-01-01

C1 metabolism in plants is known to be involved in photorespiration, nitrogen and amino acid metabolism, as well as methylation and biosynthesis of metabolites and biopolymers. Although the flux of carbon through the C1 pathway is thought to be large, its intermediates are difficult to measure and relatively little is known about this potentially ubiquitous pathway. In this study, we evaluated the C1 pathway and its integration with the central metabolism using aqueous solutions of 13C-labeled C1 and C2 intermediates delivered to branches of the tropical species Inga edulis via the transpiration stream. Delivery of [13C]methanol and [13C]formaldehyde rapidly stimulated leaf emissions of [13C]methanol, [13C]formaldehyde, [13C]formic acid, and 13CO2, confirming the existence of the C1 pathway and rapid interconversion between methanol and formaldehyde. However, while [13C]formate solutions stimulated emissions of 13CO2, emissions of [13C]methanol or [13C]formaldehyde were not detected, suggesting that once oxidation to formate occurs it is rapidly oxidized to CO2 within chloroplasts. 13C-labeling of isoprene, a known photosynthetic product, was linearly related to 13CO2 across C1 and C2 ([13C2]acetate and [2-13C]glycine) substrates, consistent with reassimilation of C1, respiratory, and photorespiratory CO2. Moreover, [13C]methanol and [13C]formaldehyde induced a quantitative labeling of both carbon atoms of acetic acid emissions, possibly through the rapid turnover of the chloroplastic acetyl-CoA pool via glycolate oxidation. The results support a role of the C1 pathway to provide an alternative carbon source for glycine methylation in photorespiration, enhance CO2 concentrations within chloroplasts, and produce key C2 intermediates (e.g., acetyl-CoA) central to anabolic and catabolic metabolism. PMID:28946627

Integration of C 1 and C 2 Metabolism in Trees

DOE PAGES

Jardine, Kolby J.; Fernandes de Souza, Vinicius; Oikawa, Patty; ...

2017-09-23

C 1 metabolism in plants is known to be involved in photorespiration, nitrogen and amino acid metabolism, as well as methylation and biosynthesis of metabolites and biopolymers. Although the flux of carbon through the C 1 pathway is thought to be large, its intermediates are difficult to measure and relatively little is known about this potentially ubiquitous pathway. In this study, we evaluated the C 1 pathway and its integration with the central metabolism using aqueous solutions of 13C-labeled C 1 and C 2 intermediates delivered to branches of the tropical species Inga edulis via the transpiration stream. Delivery ofmore » [ 13C]methanol and [ 13C]formaldehyde rapidly stimulated leaf emissions of [ 13C]methanol, [ 13C]formaldehyde, [ 13C]formic acid, and 13CO 2, confirming the existence of the C 1 pathway and rapid interconversion between methanol and formaldehyde. However, while [ 13C]formate solutions stimulated emissions of 13CO 2, emissions of [ 13C]methanol or [ 13C]formaldehyde were not detected, suggesting that once oxidation to formate occurs it is rapidly oxidized to CO 2 within chloroplasts. 13C-labeling of isoprene, a known photosynthetic product, was linearly related to 13CO 2 across C 1 and C 2 ([ 13C 2]acetate and [2- 13C]glycine) substrates, consistent with reassimilation of C 1, respiratory, and photorespiratory CO 2. Moreover, [ 13C]methanol and [ 13C]formaldehyde induced a quantitative labeling of both carbon atoms of acetic acid emissions, possibly through the rapid turnover of the chloroplastic acetyl-CoA pool via glycolate oxidation. The results support a role of the C 1 pathway to provide an alternative carbon source for glycine methylation in photorespiration, enhance CO 2 concentrations within chloroplasts, and produce key C 2 intermediates (e.g., acetyl-CoA) central to anabolic and catabolic metabolism.« less

Integration of C 1 and C 2 Metabolism in Trees

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jardine, Kolby J.; Fernandes de Souza, Vinicius; Oikawa, Patty

C 1 metabolism in plants is known to be involved in photorespiration, nitrogen and amino acid metabolism, as well as methylation and biosynthesis of metabolites and biopolymers. Although the flux of carbon through the C 1 pathway is thought to be large, its intermediates are difficult to measure and relatively little is known about this potentially ubiquitous pathway. In this study, we evaluated the C 1 pathway and its integration with the central metabolism using aqueous solutions of 13C-labeled C 1 and C 2 intermediates delivered to branches of the tropical species Inga edulis via the transpiration stream. Delivery ofmore » [ 13C]methanol and [ 13C]formaldehyde rapidly stimulated leaf emissions of [ 13C]methanol, [ 13C]formaldehyde, [ 13C]formic acid, and 13CO 2, confirming the existence of the C 1 pathway and rapid interconversion between methanol and formaldehyde. However, while [ 13C]formate solutions stimulated emissions of 13CO 2, emissions of [ 13C]methanol or [ 13C]formaldehyde were not detected, suggesting that once oxidation to formate occurs it is rapidly oxidized to CO 2 within chloroplasts. 13C-labeling of isoprene, a known photosynthetic product, was linearly related to 13CO 2 across C 1 and C 2 ([ 13C 2]acetate and [2- 13C]glycine) substrates, consistent with reassimilation of C 1, respiratory, and photorespiratory CO 2. Moreover, [ 13C]methanol and [ 13C]formaldehyde induced a quantitative labeling of both carbon atoms of acetic acid emissions, possibly through the rapid turnover of the chloroplastic acetyl-CoA pool via glycolate oxidation. The results support a role of the C 1 pathway to provide an alternative carbon source for glycine methylation in photorespiration, enhance CO 2 concentrations within chloroplasts, and produce key C 2 intermediates (e.g., acetyl-CoA) central to anabolic and catabolic metabolism.« less

Identification of DEAD-Box RNA Helicase DDX41 as a Trafficking Protein That Involves in Multiple Innate Immune Signaling Pathways in a Zebrafish Model.

PubMed

Ma, Jun-Xia; Li, Jiang-Yuan; Fan, Dong-Dong; Feng, Wei; Lin, Ai-Fu; Xiang, Li-Xin; Shao, Jian-Zhong

2018-01-01

DDX41 is an important sensor for host recognition of DNA viruses and initiation of nuclear factor-κB (NF-κB) and IFN signaling pathways in mammals. However, its occurrence and functions in other vertebrates remain poorly defined. Here, a DDX41 ortholog [ Danio rerio DDX41 ( Dr DDX41)] with various conserved structural features to its mammalian counterparts was identified from a zebrafish model. This Dr DDX41 was found to be a trafficking protein distributed in the nucleus of resting cells but transported into the cytoplasm under DNA stimulation. Two nuclear localization signal motifs were localized beside the coiled-coil domain, whereas one nuclear export signal motif existed in the DEADc domain. Dr DDX41 acts as an initiator for the activation of NF-κB and IFN signaling pathways in a Danio rerio STING ( Dr STING)-dependent manner through its DEADc domain, which is a typical performance of mammalian DDX41. These observations suggested the conservation of DDX41 proteins throughout the vertebrate evolution, making zebrafish an alternative model in understanding DDX41-mediated immunology. With this model system, we found that Dr DDX41 contributes to Dr STING- Danio rerio STAT6 ( Dr STAT6)-mediated chemokine ( Danio rerio CCL20) production through its DEADc domain. To the best of our knowledge, this work is the first report showing that DDX41 is an upstream initiator in this newly identified signaling pathway. The Dr DDX41-mediated signaling pathways play important roles in innate antibacterial immunity because knockdown of either Dr DDX41 or Dr STING/ Dr STAT6 significantly reduced the survival of zebrafish under Aeromonas hydrophilia or Edwardsiella tarda infection. Our findings would enrich the current knowledge of DDX41-mediated immunology and the evolutionary history of the DDX41 family.

Using decision pathway surveys to inform climate engineering policy choices

PubMed Central

Gregory, Robin; Satterfield, Terre; Hasell, Ariel

2016-01-01

Over the coming decades citizens living in North America and Europe will be asked about a variety of new technological and behavioral initiatives intended to mitigate the worst impacts of climate change. A common approach to public input has been surveys whereby respondents’ attitudes about climate change are explained by individuals’ demographic background, values, and beliefs. In parallel, recent deliberative research seeks to more fully address the complex value tradeoffs linked to novel technologies and difficult ethical questions that characterize leading climate mitigation alternatives. New methods such as decision pathway surveys may offer important insights for policy makers by capturing much of the depth and reasoning of small-group deliberations while meeting standard survey goals including large-sample stakeholder engagement. Pathway surveys also can help participants to deepen their factual knowledge base and arrive at a more complete understanding of their own values as they apply to proposed policy alternatives. The pathway results indicate more fully the conditional and context-specific nature of support for several “upstream” climate interventions, including solar radiation management techniques and carbon dioxide removal technologies. PMID:26729883

Alternative end-joining pathway(s): bricolage at DNA breaks.

PubMed

Frit, Philippe; Barboule, Nadia; Yuan, Ying; Gomez, Dennis; Calsou, Patrick

2014-05-01

To cope with DNA double strand break (DSB) genotoxicity, cells have evolved two main repair pathways: homologous recombination which uses homologous DNA sequences as repair templates, and non-homologous Ku-dependent end-joining involving direct sealing of DSB ends by DNA ligase IV (Lig4). During the last two decades a third player most commonly named alternative end-joining (A-EJ) has emerged, which is defined as any Ku- or Lig4-independent end-joining process. A-EJ increasingly appears as a highly error-prone bricolage on DSBs and despite expanding exploration, it still escapes full characterization. In the present review, we discuss the mechanism and regulation of A-EJ as well as its biological relevance under physiological and pathological situations, with a particular emphasis on chromosomal instability and cancer. Whether or not it is a genuine DSB repair pathway, A-EJ is emerging as an important cellular process and understanding A-EJ will certainly be a major challenge for the coming years. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.

Constitutive activation of alternative nuclear factor kappa B pathway in canine diffuse large B-cell lymphoma contributes to tumor cell survival and is a target of new adjuvant therapies.

PubMed

Seelig, Davis M; Ito, Daisuke; Forster, Colleen L; Yoon, Una A; Breen, Matthew; Burns, Linda J; Bachanova, Veronika; Lindblad-Toh, Kerstin; O'Brien, Timothy D; Schmechel, Stephen C; Rizzardi, Anthony E; Modiano, Jaime F; Linden, Michael A

2017-07-01

Activation of the classical nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) pathway is a common molecular event observed in both human and canine diffuse large B-cell lymphoma (DLBCL). Although the oncogenic potential of the alternative NFκB pathway (ANFκBP) has also been recently identified in DLBCL, its precise role in tumor pathogenesis and potential as a treatment target is understudied. We hypothesized that up-regulation of the ANFκBP plays an important role in the proliferation and survival of canine DLBCL cells, and we demonstrate that the ANFκBP is constitutively active in primary canine DLBCL samples and a cell line (CLBL1). We further demonstrate that a small interfering RNA inhibits the activation of the NFκB pathway and induces apoptosis in canine DLBCL cells. In conclusion, the ANFκBP facilitates survival of canine DLBCL cells, and thus, dogs with spontaneous DLBCL can provide a useful large animal model to study therapies targeting the ANFκBP.

Using decision pathway surveys to inform climate engineering policy choices.

PubMed

Gregory, Robin; Satterfield, Terre; Hasell, Ariel

2016-01-19

Over the coming decades citizens living in North America and Europe will be asked about a variety of new technological and behavioral initiatives intended to mitigate the worst impacts of climate change. A common approach to public input has been surveys whereby respondents' attitudes about climate change are explained by individuals' demographic background, values, and beliefs. In parallel, recent deliberative research seeks to more fully address the complex value tradeoffs linked to novel technologies and difficult ethical questions that characterize leading climate mitigation alternatives. New methods such as decision pathway surveys may offer important insights for policy makers by capturing much of the depth and reasoning of small-group deliberations while meeting standard survey goals including large-sample stakeholder engagement. Pathway surveys also can help participants to deepen their factual knowledge base and arrive at a more complete understanding of their own values as they apply to proposed policy alternatives. The pathway results indicate more fully the conditional and context-specific nature of support for several "upstream" climate interventions, including solar radiation management techniques and carbon dioxide removal technologies.

KRE5 Suppression Induces Cell Wall Stress and Alternative ER Stress Response Required for Maintaining Cell Wall Integrity in Candida glabrata

PubMed Central

Sasaki, Masato; Ito, Fumie; Aoyama, Toshio; Sato-Okamoto, Michiyo; Takahashi-Nakaguchi, Azusa; Chibana, Hiroji; Shibata, Nobuyuki

2016-01-01

The maintenance of cell wall integrity in fungi is required for normal cell growth, division, hyphae formation, and antifungal tolerance. We observed that endoplasmic reticulum stress regulated cell wall integrity in Candida glabrata, which possesses uniquely evolved mechanisms for unfolded protein response mechanisms. Tetracycline-mediated suppression of KRE5, which encodes a predicted UDP-glucose:glycoprotein glucosyltransferase localized in the endoplasmic reticulum, significantly increased cell wall chitin content and decreased cell wall β-1,6-glucan content. KRE5 repression induced endoplasmic reticulum stress-related gene expression and MAP kinase pathway activation, including Slt2p and Hog1p phosphorylation, through the cell wall integrity signaling pathway. Moreover, the calcineurin pathway negatively regulated cell wall integrity, but not the reduction of β-1,6-glucan content. These results indicate that KRE5 is required for maintaining both endoplasmic reticulum homeostasis and cell wall integrity, and that the calcineurin pathway acts as a regulator of chitin-glucan balance in the cell wall and as an alternative mediator of endoplasmic reticulum stress in C. glabrata. PMID:27548283

Automatically visualise and analyse data on pathways using PathVisioRPC from any programming environment.

PubMed

Bohler, Anwesha; Eijssen, Lars M T; van Iersel, Martijn P; Leemans, Christ; Willighagen, Egon L; Kutmon, Martina; Jaillard, Magali; Evelo, Chris T

2015-08-23

Biological pathways are descriptive diagrams of biological processes widely used for functional analysis of differentially expressed genes or proteins. Primary data analysis, such as quality control, normalisation, and statistical analysis, is often performed in scripting languages like R, Perl, and Python. Subsequent pathway analysis is usually performed using dedicated external applications. Workflows involving manual use of multiple environments are time consuming and error prone. Therefore, tools are needed that enable pathway analysis directly within the same scripting languages used for primary data analyses. Existing tools have limited capability in terms of available pathway content, pathway editing and visualisation options, and export file formats. Consequently, making the full-fledged pathway analysis tool PathVisio available from various scripting languages will benefit researchers. We developed PathVisioRPC, an XMLRPC interface for the pathway analysis software PathVisio. PathVisioRPC enables creating and editing biological pathways, visualising data on pathways, performing pathway statistics, and exporting results in several image formats in multiple programming environments. We demonstrate PathVisioRPC functionalities using examples in Python. Subsequently, we analyse a publicly available NCBI GEO gene expression dataset studying tumour bearing mice treated with cyclophosphamide in R. The R scripts demonstrate how calls to existing R packages for data processing and calls to PathVisioRPC can directly work together. To further support R users, we have created RPathVisio simplifying the use of PathVisioRPC in this environment. We have also created a pathway module for the microarray data analysis portal ArrayAnalysis.org that calls the PathVisioRPC interface to perform pathway analysis. This module allows users to use PathVisio functionality online without having to download and install the software and exemplifies how the PathVisioRPC interface can be used by data analysis pipelines for functional analysis of processed genomics data. PathVisioRPC enables data visualisation and pathway analysis directly from within various analytical environments used for preliminary analyses. It supports the use of existing pathways from WikiPathways or pathways created using the RPC itself. It also enables automation of tasks performed using PathVisio, making it useful to PathVisio users performing repeated visualisation and analysis tasks. PathVisioRPC is freely available for academic and commercial use at http://projects.bigcat.unimaas.nl/pathvisiorpc.

Conceptual Regional Sediment Budget for USACE North Atlantic Division

DTIC Science & Technology

2015-03-01

sediment budget is the first phase in development of the working budget and is intended to provide a general framework based on existing transport ...existing literature and databases were reviewed and analyzed to characterize sediment transport pathways and magnitudes, and morphologic zones of...net sediment transport pathways for Region 1 (includes NACCS planning regions VA1 through VA6 and MD2 through MD5

A roadmap for nuclear energy technology

NASA Astrophysics Data System (ADS)

Sofu, Tanju

2018-01-01

The prospects for the future use of nuclear energy worldwide can best be understood within the context of global population growth, urbanization, rising energy need and associated pollution concerns. As the world continues to urbanize, sustainable development challenges are expected to be concentrated in cities of the lower-middle-income countries where the pace of urbanization is fastest. As these countries continue their trajectory of economic development, their energy need will also outpace their population growth adding to the increased demand for electricity. OECD IEA's energy system deployment pathway foresees doubling of the current global nuclear capacity by 2050 to reduce the impact of rapid urbanization. The pending "retirement cliff" of the existing U.S. nuclear fleet, representing over 60 percent of the nation's emission-free electricity, also poses a large economic and environmental challenge. To meet the challenge, the U.S. DOE has developed the vision and strategy for development and deployment of advanced reactors. As part of that vision, the U.S. government pursues programs that aim to expand the use of nuclear power by supporting sustainability of the existing nuclear fleet, deploying new water-cooled large and small modular reactors to enable nuclear energy to help meet the energy security and climate change goals, conducting R&D for advanced reactor technologies with alternative coolants, and developing sustainable nuclear fuel cycle strategies. Since the current path relying heavily on water-cooled reactors and "once-through" fuel cycle is not sustainable, next generation nuclear energy systems under consideration aim for significant advances over existing and evolutionary water-cooled reactors. Among the spectrum of advanced reactor options, closed-fuel-cycle systems using reactors with fast-neutron spectrum to meet the sustainability goals offer the most attractive alternatives. However, unless the new public-private partnership models emerge to tackle the licensing and demonstration challenges for these advanced reactor concepts, realization of their enormous potential is not likely, at least in the U.S.

The endoplasmic reticulum is a hub to sort proteins toward unconventional traffic pathways and endosymbiotic organelles.

PubMed

Bellucci, Michele; De Marchis, Francesca; Pompa, Andrea

2017-12-18

The discovery that much of the extracellular proteome in eukaryotic cells consists of proteins lacking a signal peptide, which cannot therefore enter the secretory pathway, has led to the identification of alternative protein secretion routes bypassing the Golgi apparatus. However, proteins harboring a signal peptide for translocation into the endoplasmic reticulum can also be transported along these alternative routes, which are still far from being well elucidated in terms of the molecular machineries and subcellular/intermediate compartments involved. In this review, we first try to provide a definition of all the unconventional protein secretion pathways in eukaryotic cells, as those pathways followed by proteins directed to an 'external space' bypassing the Golgi, where 'external space' refers to the extracellular space plus the lumen of the secretory route compartments and the inner space of mitochondria and plastids. Then, we discuss the role of the endoplasmic reticulum in sorting proteins toward unconventional traffic pathways in plants. In this regard, various unconventional pathways exporting proteins from the endoplasmic reticulum to the vacuole, plasma membrane, apoplast, mitochondria, and plastids are described, including the short routes followed by the proteins resident in the endoplasmic reticulum. © The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Balancing Energy, Food Security, and Critical Ecosystems: Dam Siting, Design and Operations in the Mekong River Basin

NASA Astrophysics Data System (ADS)

Wild, T. B.; Reed, P. M.; Loucks, D.

2016-12-01

The Mekong River basin in Southeast Asia is one of several river basins with exceptionally high biodiversity value where intensive hydropower dam development is anticipated. In the Mekong basin, over 100 dams are planned to be constructed in the next 20-30 years. As planned, these dams will alter the river's natural water, sediment and nutrient flows, and will fragment fish migration pathways. In doing so, they will degrade one of the world's most productive freshwater fish habitats, upon which some 60 million people depend for food and income security. For those dams that have not yet been constructed, there still exist opportunities to modify their siting, design and operation (SDO) to achieve a more balanced set of tradeoffs among hydropower production, sediment/nutrient passage and adult fish/larvae passage. We present a successful case study wherein we explored such alternative SDO opportunities in partnership with the Government of Cambodia for Sambor Dam, planned to be built on the main stem of the Mekong. Sambor would be one of the world's longest dams, spanning 18 km across the river just upstream of (1) Tonle Sap Lake, which supplies 70% of Cambodians' protein, and (2) the Mekong Delta in Vietnam, responsible for 50% of Vietnam's rice production. We will describe key dam siting and design modifications required to mitigate ecological impacts. We will then focus on the most promising alternative dam siting/design concept, exploring the reservoir operations space to demonstrate that a complex set of tradeoffs exist among a diverse set of energy and ecosystem objectives. Results indicate that even for a hydrologically small reservoir, a wide array of potential reservoir operating policies exist that have vastly different food-energy implications. While some policies would significantly mitigate ecological impacts, many policies exist that would pose a severe threat to the sustainability of the fishery. Failure to sample the reservoir operations space at appropriate resolution could result in failure to accurately identify tradeoffs and vulnerabilities. We explore energy-ecosystem tradeoffs while demonstrating to stakeholders the impacts of transitioning from their initial deterministic analysis that largely focused on energy revenue to broader many-objective stochastic problem formulations.

30 CFR 285.1013 - Is an Alternate Use RUE assignable?

Code of Federal Regulations, 2011 CFR

2011-07-01

... Section 285.1013 Mineral Resources BUREAU OF OCEAN ENERGY MANAGEMENT, REGULATION, AND ENFORCEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE RENEWABLE ENERGY ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS...

In their own words: Content analysis of pathways to recovery among individuals with the lived experience of homelessness and alcohol use disorders.

PubMed

Collins, Susan E; Jones, Connor B; Hoffmann, Gail; Nelson, Lonnie A; Hawes, Starlyn M; Grazioli, Véronique S; Mackelprang, Jessica L; Holttum, Jessica; Kaese, Greta; Lenert, James; Herndon, Patrick; Clifasefi, Seema L

2016-01-01

Alcohol use disorders (AUDs) are more prevalent among homeless individuals than in the general population, and homeless individuals are disproportionately affected by alcohol-related morbidity and mortality. Unfortunately, abstinence-based approaches are neither desirable to nor highly effective for most members of this population. Recent research has indicated that homeless people aspire to clinically significant recovery goals beyond alcohol abstinence, including alcohol harm reduction and quality-of-life improvement. However, no research has documented this population's preferred pathways toward self-defined recovery. Considering principles of patient-centred care, a richer understanding of this population's desired pathways to recovery may help providers better engage and support them. Participants (N=50) had lived experience of homelessness and AUDs and participated in semi-structured interviews regarding histories of homelessness, alcohol use, and abstinence-based treatment as well as suggestions for improving alcohol treatment. Conventional content analysis was used to ascertain participants' perceptions of abstinence-based treatment and mutual-help modalities, while it additionally revealed alternative pathways to recovery. Most participants reported involvement in abstinence-based modalities for reasons other than the goal of achieving long-term abstinence from alcohol (e.g., having shelter in winter months, "taking a break" from alcohol use, being among "like-minded people"). In contrast, most participants preferred alternative pathways to recovery, including fulfilling basic needs (e.g., obtaining housing), using harm reduction approaches (e.g., switching from higher to lower alcohol content beverages), engaging in meaningful activities (e.g., art, outings, spiritual/cultural activities), and making positive social connections. Most people with the lived experience of homelessness and AUDs we interviewed were uninterested in abstinence-based modalities as a means of attaining long-term alcohol abstinence. These individuals do, however, have creative ideas about alternative pathways to recovery that treatment providers may support to reduce alcohol-related harm and enhance quality of life. Copyright © 2015 Elsevier B.V. All rights reserved.

In their own words: Content analysis of pathways to recovery among individuals with the lived experience of homelessness and alcohol use disorders

PubMed Central

Collins, Susan E.; Jones, Connor B.; Hoffmann, Gail; Nelson, Lonnie A.; Hawes, Starlyn M.; Grazioli, Véronique S.; Mackelprang, Jessica L.; Holttum, Jessica; Kaese, Greta; Lenert, James; Herndon, Patrick; Clifasefi, Seema L.

2015-01-01

Background Alcohol use disorders (AUDs) are more prevalent among homeless individuals than in the general population, and homeless individuals are disproportionately affected by alcohol-related morbidity and mortality. Unfortunately, abstinence-based approaches are neither desirable to nor highly effective for most members of this population. Recent research has indicated that homeless people aspire to clinically significant recovery goals beyond alcohol abstinence, including alcohol harm reduction and quality-of-life improvement. However, no research has documented this population’s preferred pathways toward self-defined recovery. Considering principles of patient-centred care, a richer understanding of this population’s desired pathways to recovery may help providers better engage and support them. Methods Participants (N = 50) had lived experience of homelessness and AUDs and participated in semi-structured interviews regarding histories of homelessness, alcohol use, and abstinence-based treatment as well as suggestions for improving alcohol treatment. Conventional content analysis was used to ascertain participants’ perceptions of abstinence-based treatment and mutual-help modalities, while it additionally revealed alternative pathways to recovery. Results Most participants reported involvement in abstinence-based modalities for reasons other than the goal of achieving long-term abstinence from alcohol (e.g., having shelter in winter months, “taking a break” from alcohol use, being among “like-minded people”). In contrast, most participants preferred alternative pathways to recovery, including fulfilling basic needs (e.g., obtaining housing), using harm reduction approaches (e.g., switching from higher to lower alcohol content beverages), engaging in meaningful activities (e.g., art, outings, spiritual/cultural activities), and making positive social connections. Conclusions Most people with the lived experience of homelessness and AUDs we interviewed were uninterested in abstinence-based modalities as a means of attaining long-term alcohol abstinence. These individuals do, however, have creative ideas about alternative pathways to recovery that treatment providers may support to reduce alcohol-related harm and enhance quality of life. PMID:26364078

Biochemical evidence for Ku-independent backup pathways of NHEJ.

PubMed

Wang, Huichen; Perrault, Ange Ronel; Takeda, Yoshihiko; Qin, Wei; Wang, Hongyan; Iliakis, George

2003-09-15

Cells of higher eukaryotes process within minutes double strand breaks (DSBs) in their genome using a non-homologous end joining (NHEJ) apparatus that engages DNA-PKcs, Ku, DNA ligase IV, XRCC4 and other as of yet unidentified factors. Although chemical inhibition, or mutation, in any of these factors delays processing, cells ultimately remove the majority of DNA DSBs using an alternative pathway operating with an order of magnitude slower kinetics. This alternative pathway is active in mutants deficient in genes of the RAD52 epistasis group and frequently joins incorrect ends. We proposed, therefore, that it reflects an alternative form of NHEJ that operates as a backup (B-NHEJ) to the DNA-PK-dependent (D-NHEJ) pathway, rather than homology directed repair of DSBs. The present study investigates the role of Ku in the coordination of these pathways using as a model end joining of restriction endonuclease linearized plasmid DNA in whole cell extracts. Efficient, error-free, end joining observed in such in vitro reactions is strongly inhibited by anti-Ku antibodies. The inhibition requires DNA-PKcs, despite the fact that Ku efficiently binds DNA ends in the presence of antibodies, or in the absence of DNA-PKcs. Strong inhibition of DNA end joining is also mediated by wortmannin, an inhibitor of DNA-PKcs, in the presence but not in the absence of Ku, and this inhibition can be rescued by pre-incubating the reaction with double stranded oligonucleotides. The results are compatible with a role of Ku in directing end joining to a DNA-PK dependent pathway, mediated by efficient end binding and productive interactions with DNA-PKcs. On the other hand, efficient end joining is observed in extracts of cells lacking DNA-PKcs, as well as in Ku-depleted extracts in line with the operation of alternative pathways. Extracts depleted of Ku and DNA-PKcs rejoin blunt ends, as well as homologous ends with 3' or 5' protruding single strands with similar efficiency, but addition of Ku suppresses joining of blunt ends and homologous ends with 3' overhangs. We propose that the affinity of Ku for DNA ends, particularly when cooperating with DNA-PKcs, suppresses B-NHEJ by quickly and efficiently binding DNA ends and directing them to D-NHEJ for rapid joining. A chromatin-based model of DNA DSB rejoining accommodating biochemical and genetic results is presented and deviations between in vitro and in vivo results discussed.

Biochemical evidence for Ku-independent backup pathways of NHEJ

PubMed Central

Wang, Huichen; Perrault, Ange Ronel; Takeda, Yoshihiko; Qin, Wei; Wang, Hongyan; Iliakis, George

2003-01-01

Cells of higher eukaryotes process within minutes double strand breaks (DSBs) in their genome using a non-homologous end joining (NHEJ) apparatus that engages DNA-PKcs, Ku, DNA ligase IV, XRCC4 and other as of yet unidentified factors. Although chemical inhibition, or mutation, in any of these factors delays processing, cells ultimately remove the majority of DNA DSBs using an alternative pathway operating with an order of magnitude slower kinetics. This alternative pathway is active in mutants deficient in genes of the RAD52 epistasis group and frequently joins incorrect ends. We proposed, therefore, that it reflects an alternative form of NHEJ that operates as a backup (B-NHEJ) to the DNA-PK-dependent (D-NHEJ) pathway, rather than homology directed repair of DSBs. The present study investigates the role of Ku in the coordination of these pathways using as a model end joining of restriction endonuclease linearized plasmid DNA in whole cell extracts. Efficient, error-free, end joining observed in such in vitro reactions is strongly inhibited by anti-Ku antibodies. The inhibition requires DNA-PKcs, despite the fact that Ku efficiently binds DNA ends in the presence of antibodies, or in the absence of DNA-PKcs. Strong inhibition of DNA end joining is also mediated by wortmannin, an inhibitor of DNA-PKcs, in the presence but not in the absence of Ku, and this inhibition can be rescued by pre-incubating the reaction with double stranded oligonucleotides. The results are compatible with a role of Ku in directing end joining to a DNA-PK dependent pathway, mediated by efficient end binding and productive interactions with DNA-PKcs. On the other hand, efficient end joining is observed in extracts of cells lacking DNA-PKcs, as well as in Ku-depleted extracts in line with the operation of alternative pathways. Extracts depleted of Ku and DNA-PKcs rejoin blunt ends, as well as homologous ends with 3′ or 5′ protruding single strands with similar efficiency, but addition of Ku suppresses joining of blunt ends and homologous ends with 3′ overhangs. We propose that the affinity of Ku for DNA ends, particularly when cooperating with DNA-PKcs, suppresses B-NHEJ by quickly and efficiently binding DNA ends and directing them to D-NHEJ for rapid joining. A chromatin-based model of DNA DSB rejoining accommodating biochemical and genetic results is presented and deviations between in vitro and in vivo results discussed. PMID:12954774

Landscape genomic insights into the historic migration of mountain hemlock in response to Holocene climate change.

PubMed

Johnson, Jeremy S; Gaddis, Keith D; Cairns, David M; Konganti, Kranti; Krutovsky, Konstantin V

2017-03-01

Untangling alternative historic dispersal pathways in long-lived tree species is critical to better understand how temperate tree species may respond to climatic change. However, disentangling these alternative pathways is often difficult. Emerging genomic technologies and landscape genetics techniques improve our ability to assess these pathways in natural systems. We address the question to what degree have microrefugial patches and long-distance dispersal been responsible for the colonization of mountain hemlock ( Tsuga mertensiana ) on the Alaskan Kenai Peninsula. We used double-digest restriction-associated DNA sequencing (ddRADseq) to identify genetic variants across eight mountain hemlock sample sites on the Kenai Peninsula, Alaska. We assessed genetic diversity and linkage disequilibrium using landscape and population genetics approaches. Alternative historic dispersal pathways were assessed using discriminant analysis of principle components and electrical circuit theory. A combination of decreasing diversity, high gene flow, and landscape connectivity indicates that mountain hemlock colonization on the Kenai Peninsula is the result of long-distance dispersal. We found that contemporary climate best explained gene flow patterns and that isolation by resistance was a better model explaining genetic variation than isolation by distance. Our findings support the conclusion that mountain hemlock colonization is the result of several long-distance dispersal events following Pleistocene glaciation. The high dispersal capability suggests that mountain hemlock may be able to respond to future climate change and expand its range as new habitat opens along its northern distribution. © 2017 Botanical Society of America.

Challenges and Alternatives to Sustainable Management of Agriculture and Pastoral Ecosystems in Asian Drylands

NASA Astrophysics Data System (ADS)

Qi, J.

2015-12-01

There is no question that human must produce additional 70% food to feed the new 2.2 billion of people on the planet by 2050, but the question is where to grow the additional food. The demand for the additional food lies not only in producing the basic resources needed to sustain a healthy lifestyle, but also from a changing diet, especially in rapidly developing countries in the dryland regions around the world. It is forecast that this demand for meat will require an additional 0.2 billion tons per year by 2050, which is almost a doubling of present meat consumption. These new demands create mounting pressures on agriculture and pastoral ecosystems and the reported trajectory of warmer and drier climate in the future increases uncertainties in food security, adding further stresses to the already stressed nations in the Asian dryland belt. Different approaches are being either proposed or practiced in the region but the question is whether or not the current practices are sustainable or optimal in addressing the emerging issues. Given the complexity and interplay among the food, water and energy, what are alternatives to ensure a sustainable trajectory of regional development to meet the new food demand? This presentation reviews existing practices and proposes alternative solutions, by specifically examining the trade-offs between different ecosystem services that drylands in Asian may provide. Preliminary analysis suggested that the current trajectory of meat and milk production is likely not on a sustainable pathway.

Trading-off emission reduction, carbon capture and geoengineering to reach the Paris agreement

NASA Astrophysics Data System (ADS)

Gasser, T.; Boucher, O.; Lecocq, F.; Obersteiner, M.

2017-12-01

We explore virtually all possible future pathways that respect the Paris agreement, with an innovative modeling framework. We show that immediate and extreme mitigation of CO2 and non-CO2 species alike, carbon dioxide removal (CDR) and/or solar radiation management (SRM) technologies are required. We analyze the tradeoffs between these solutions. We generate thousands of temperature change pathways that extend historical records, stay below 2°C, and aim at 1.5°C in the long run. Non-CO2 forcings are generated likewise. With a simple model of the Earth system, we then back-calculate anthropogenic CO2 emissions compatible with these pathways. Other key global variables such as ocean acidity, sea level and permafrost thaw are also simulated. From this large ensemble of fully consistent scenarios, we analyze subsets that meet certain criteria: physical targets, emission levels, technology use, or any combination thereof. We show that staying below 1.5°C is feasible if CO2 emissions peak before 2025 and non-CO2 forcings are also reduced to zero. In case of a positive long-term non-CO2 forcing (a mitigation floor), CDR is necessary. Alternatively, emissions can peak later and/or higher if SRM is allowed. For pathways overshooting 1.5°C, results depend on the overshoot's size and length. Because of thawing permafrost, virtually all overshoot pathways require CDR, unless non-CO2 species (possibly SRM) are cooling the system at the time of peak temperature. When considering additional physical targets, which can be relevant for preserving ecosystems, the space of allowable pathways is systematically reduced. Especially: limiting ocean acidification rules out SRM. The nationally determined contributions (NDCs) indicate that reaching even the strictest interpretation of the agreement is feasible. However, if SRM is ruled out and only a reasonable amount of CDR is allowed, NDCs are compatible with very few of our pathways (≈5%). If a mitigation floor is added on top of that, virtually no pathways remain (<1%). We conclude that, in its strictest interpretation, the Paris agreement relies heavily on currently non-existent (and potentially harmful) technologies. In a looser interpretation, these technologies may not be needed, although the window of opportunity is closing extremely fast.

Advanced Post-Irradiation Examination Capabilities Alternatives Analysis Report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jeff Bryan; Bill Landman; Porter Hill

2012-12-01

An alternatives analysis was performed for the Advanced Post-Irradiation Capabilities (APIEC) project in accordance with the U.S. Department of Energy (DOE) Order DOE O 413.3B, “Program and Project Management for the Acquisition of Capital Assets”. The Alternatives Analysis considered six major alternatives: ? No Action ? Modify Existing DOE Facilities – capabilities distributed among multiple locations ? Modify Existing DOE Facilities – capabilities consolidated at a few locations ? Construct New Facility ? Commercial Partnership ? International Partnerships Based on the alternatives analysis documented herein, it is recommended to DOE that the advanced post-irradiation examination capabilities be provided by amore » new facility constructed at the Materials and Fuels Complex at the Idaho National Laboratory.« less

Unemployment and ill health: understanding the relationship.

PubMed Central

Bartley, M

1994-01-01

OBJECTIVE--To review research relevant to understanding the psychological, social, and biological pathways by which unemployment may affect health risk; to consider the importance of four specific mechanisms; and to indicate some directions for future research. CRITERIA FOR INCLUSION AND EXCLUSION OF PUBLISHED STUDIES--Studies were chosen to illustrate the development of four major hypotheses regarding the relationship between unemployment and ill health, as well as the present state of knowledge. The review therefore includes some much-cited "classics" drawn from a long time span. Where recent reviews already exist relevant to individual mechanisms, these are referred to. Recent (since 1987) reports were sought by searching the BIDS data base. Particular effort was made to locate studies which enabled alternative hypotheses to be evaluated, and to point out where existing evidence is inconsistent or incomplete, indicating the need for further research. CONCLUSIONS--To understand the relationship between unemployment and ill health and mortality, four mechanisms need to be considered: the role of relative poverty; social isolation and loss of self esteem; health related behaviour (including that associated with membership of certain types of "subculture"); and the effect that a spell of unemployment has on subsequent employment patterns. PMID:7964329

Robustness of atomistic Gō models in predicting native-like folding intermediates

NASA Astrophysics Data System (ADS)

Estácio, S. G.; Fernandes, C. S.; Krobath, H.; Faísca, P. F. N.; Shakhnovich, E. I.

2012-08-01

Gō models are exceedingly popular tools in computer simulations of protein folding. These models are native-centric, i.e., they are directly constructed from the protein's native structure. Therefore, it is important to understand up to which extent the atomistic details of the native structure dictate the folding behavior exhibited by Gō models. Here we address this challenge by performing exhaustive discrete molecular dynamics simulations of a Gō potential combined with a full atomistic protein representation. In particular, we investigate the robustness of this particular type of Gō models in predicting the existence of intermediate states in protein folding. We focus on the N47G mutational form of the Spc-SH3 folding domain (x-ray structure) and compare its folding pathway with that of alternative native structures produced in silico. Our methodological strategy comprises equilibrium folding simulations, structural clustering, and principal component analysis.

Erythrocytic Adenosine Monophosphate as an Alternative Purine Source in Plasmodium falciparum*

PubMed Central

Cassera, María B.; Hazleton, Keith Z.; Riegelhaupt, Paul M.; Merino, Emilio F.; Luo, Minkui; Akabas, Myles H.; Schramm, Vern L.

2008-01-01

Plasmodium falciparum is a purine auxotroph, salvaging purines from erythrocytes for synthesis of RNA and DNA. Hypoxanthine is the key precursor for purine metabolism in Plasmodium. Inhibition of hypoxanthine-forming reactions in both erythrocytes and parasites is lethal to cultured P. falciparum. We observed that high concentrations of adenosine can rescue cultured parasites from purine nucleoside phosphorylase and adenosine deaminase blockade but not when erythrocyte adenosine kinase is also inhibited. P. falciparum lacks adenosine kinase but can salvage AMP synthesized in the erythrocyte cytoplasm to provide purines when both human and Plasmodium purine nucleoside phosphorylases and adenosine deaminases are inhibited. Transport studies in Xenopus laevis oocytes expressing the P. falciparum nucleoside transporter PfNT1 established that this transporter does not transport AMP. These metabolic patterns establish the existence of a novel nucleoside monophosphate transport pathway in P. falciparum. PMID:18799466

A multi-scale, multi-disciplinary approach for assessing the technological, economic and environmental performance of bio-based chemicals.

PubMed

Herrgård, Markus; Sukumara, Sumesh; Campodonico, Miguel; Zhuang, Kai

2015-12-01

In recent years, bio-based chemicals have gained interest as a renewable alternative to petrochemicals. However, there is a significant need to assess the technological, biological, economic and environmental feasibility of bio-based chemicals, particularly during the early research phase. Recently, the Multi-scale framework for Sustainable Industrial Chemicals (MuSIC) was introduced to address this issue by integrating modelling approaches at different scales ranging from cellular to ecological scales. This framework can be further extended by incorporating modelling of the petrochemical value chain and the de novo prediction of metabolic pathways connecting existing host metabolism to desirable chemical products. This multi-scale, multi-disciplinary framework for quantitative assessment of bio-based chemicals will play a vital role in supporting engineering, strategy and policy decisions as we progress towards a sustainable chemical industry. © 2015 Authors; published by Portland Press Limited.

Benzimidazoles: an ideal privileged drug scaffold for the design of multitargeted anti-inflammatory ligands.

PubMed

Kaur, Gaganpreet; Kaur, Maninder; Silakari, Om

2014-01-01

The recent research area endeavors to discover ultimate multi-target ligands, an increasingly feasible and attractive alternative to existing mono-targeted drugs for treatment of complex, multi-factorial inflammation process which underlays plethora of debilitated health conditions. In order to improvise this option, exploration of relevant chemical core scaffold will be an utmost need. Privileged benzimidazole scaffold being historically versatile structural motif could offer a viable starting point in the search for novel multi-target ligands against multi-factorial inflammation process since, when appropriately substituted, it can selectively modulate diverse receptors, pathways and enzymes associated with the pathogenesis of inflammation. Despite this remarkable capability, the multi-target capacity of the benzimidazole scaffold remains largely unexploited. With this in focus, the present review article attempts to provide synopsis of published research to exemplify the valuable use of benzimidazole nucleus and focus on their suitability as starting scaffold to develop multi-targeted anti-inflammatory ligands.

A Novel Framework for the Comparative Analysis of Biological Networks

PubMed Central

Pache, Roland A.; Aloy, Patrick

2012-01-01

Genome sequencing projects provide nearly complete lists of the individual components present in an organism, but reveal little about how they work together. Follow-up initiatives have deciphered thousands of dynamic and context-dependent interrelationships between gene products that need to be analyzed with novel bioinformatics approaches able to capture their complex emerging properties. Here, we present a novel framework for the alignment and comparative analysis of biological networks of arbitrary topology. Our strategy includes the prediction of likely conserved interactions, based on evolutionary distances, to counter the high number of missing interactions in the current interactome networks, and a fast assessment of the statistical significance of individual alignment solutions, which vastly increases its performance with respect to existing tools. Finally, we illustrate the biological significance of the results through the identification of novel complex components and potential cases of cross-talk between pathways and alternative signaling routes. PMID:22363585

Perception as a Route for Motor Skill Learning: Perspectives from Neuroscience.

PubMed

Ossmy, Ori; Mukamel, Roy

2018-04-22

Learning a motor skill requires physical practice that engages neural networks involved in movement. These networks have also been found to be engaged during perception of sensory signals associated with actions. Nonetheless, despite extensive evidence for the existence of such sensory-evoked neural activity in motor pathways, much less is known about their contribution to learning and actual changes in behavior. Primate studies usually involve an overlearned task while studies in humans have largely focused on characterizing activity of the action observation network (AON) in the context of action understanding, theory of mind, and social interactions. Relatively few studies examined neural plasticity induced by perception and its role in transfer of motor knowledge. Here, we review this body of literature and point to future directions for the development of alternative, physiologically grounded ways in which sensory signals could be harnessed to improve motor skills. Copyright © 2018. Published by Elsevier Ltd.

The sustainability solutions agenda.

PubMed

Sarewitz, Daniel; Clapp, Richard; Crumbley, Cathy; Kriebel, David; Tickner, Joel

2012-01-01

Progress toward a more sustainable society is usually described in a "knowledge-first" framework, where science characterizes a problem in terms of its causes and mechanisms as a basis for subsequent action. Here we present a different approach-A Sustainability Solutions Agenda (SSA)-which seeks from the outset to identify the possible pathways to solutions. SSA focuses on uncovering paths to sustainability by improving current technological practice, and applying existing knowledge to identify and evaluate technological alternatives. SSA allows people and organizations to transition toward greater sustainability without sacrificing essential technological functions, and therefore does not threaten the interests that depend on those functions. Whereas knowledge-first approaches view scientific information as sufficient to convince people to take the right actions, even if those actions are perceived as against their immediate interests, SSA allows values to evolve toward greater attention to sustainability as a result of the positive experience of solving a problem.

The Anterior Insular Cortex→Central Amygdala Glutamatergic Pathway Is Critical to Relapse after Contingency Management.

PubMed

Venniro, Marco; Caprioli, Daniele; Zhang, Michelle; Whitaker, Leslie R; Zhang, Shiliang; Warren, Brandon L; Cifani, Carlo; Marchant, Nathan J; Yizhar, Ofer; Bossert, Jennifer M; Chiamulera, Cristiano; Morales, Marisela; Shaham, Yavin

2017-10-11

Despite decades of research on neurobiological mechanisms of psychostimulant addiction, the only effective treatment for many addicts is contingency management, a behavioral treatment that uses alternative non-drug reward to maintain abstinence. However, when contingency management is discontinued, most addicts relapse to drug use. The brain mechanisms underlying relapse after cessation of contingency management are largely unknown, and, until recently, an animal model of this human condition did not exist. Here we used a novel rat model, in which the availability of a mutually exclusive palatable food maintains prolonged voluntary abstinence from intravenous methamphetamine self-administration, to demonstrate that the activation of monosynaptic glutamatergic projections from anterior insular cortex to central amygdala is critical to relapse after the cessation of contingency management. We identified the anterior insular cortex-to-central amygdala projection as a new addiction- and motivation-related projection and a potential target for relapse prevention. Published by Elsevier Inc.

Deciphering Transcriptome and Complex Alternative Splicing Transcripts in Mammary Gland Tissues from Cows Naturally Infected with Staphylococcus aureus Mastitis

PubMed Central

Jiang, Qiang; Yang, Chun Hong; Zhang, Yan; Sun, Yan; Li, Rong Ling; Wang, Chang Fa; Zhong, Ji Feng; Huang, Jin Ming

2016-01-01

Alternative splicing (AS) contributes to the complexity of the mammalian proteome and plays an important role in diseases, including infectious diseases. The differential AS patterns of these transcript sequences between the healthy (HS3A) and mastitic (HS8A) cows naturally infected by Staphylococcus aureus were compared to understand the molecular mechanisms underlying mastitis resistance and susceptibility. In this study, using the Illumina paired-end RNA sequencing method, 1352 differentially expressed genes (DEGs) with higher than twofold changes were found in the HS3A and HS8A mammary gland tissues. Gene ontology and KEGG pathway analyses revealed that the cytokine–cytokine receptor interaction pathway is the most significantly enriched pathway. Approximately 16k annotated unigenes were respectively identified in two libraries, based on the bovine Bos taurus UMD3.1 sequence assembly and search. A total of 52.62% and 51.24% annotated unigenes were alternatively spliced in term of exon skipping, intron retention, alternative 5′ splicing and alternative 3ʹ splicing. Additionally, 1,317 AS unigenes were HS3A-specific, whereas 1,093 AS unigenes were HS8A-specific. Some immune-related genes, such as ITGB6, MYD88, ADA, ACKR1, and TNFRSF1B, and their potential relationships with mastitis were highlighted. From Chromosome 2, 4, 6, 7, 10, 13, 14, 17, and 20, 3.66% (HS3A) and 5.4% (HS8A) novel transcripts, which harbor known quantitative trait locus associated with clinical mastitis, were identified. Many DEGs in the healthy and mastitic mammary glands are involved in immune, defense, and inflammation responses. These DEGs, which exhibit diverse and specific splicing patterns and events, can endow dairy cattle with the potential complex genetic resistance against mastitis. PMID:27459697

30 CFR 585.1016 - When will an Alternate Use RUE be cancelled?

Code of Federal Regulations, 2013 CFR

2013-07-01

...? 585.1016 Section 585.1016 Mineral Resources BUREAU OF OCEAN ENERGY MANAGEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE RENEWABLE ENERGY AND ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS Facilities...

30 CFR 585.1016 - When will an Alternate Use RUE be cancelled?

Code of Federal Regulations, 2012 CFR

2012-07-01

...? 585.1016 Section 585.1016 Mineral Resources BUREAU OF OCEAN ENERGY MANAGEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE RENEWABLE ENERGY AND ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS Facilities...

30 CFR 585.1011 - What payments are required for an Alternate Use RUE?

Code of Federal Regulations, 2012 CFR

2012-07-01

... RUE? 585.1011 Section 585.1011 Mineral Resources BUREAU OF OCEAN ENERGY MANAGEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE RENEWABLE ENERGY AND ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS Facilities...

30 CFR 585.1011 - What payments are required for an Alternate Use RUE?

Code of Federal Regulations, 2014 CFR

2014-07-01

... RUE? 585.1011 Section 585.1011 Mineral Resources BUREAU OF OCEAN ENERGY MANAGEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE RENEWABLE ENERGY AND ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS Facilities...

30 CFR 285.1015 - How do I relinquish an Alternate Use RUE?

Code of Federal Regulations, 2011 CFR

2011-07-01

....1015 Section 285.1015 Mineral Resources BUREAU OF OCEAN ENERGY MANAGEMENT, REGULATION, AND ENFORCEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE RENEWABLE ENERGY ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS...

30 CFR 585.1011 - What payments are required for an Alternate Use RUE?

Code of Federal Regulations, 2013 CFR

2013-07-01

... RUE? 585.1011 Section 585.1011 Mineral Resources BUREAU OF OCEAN ENERGY MANAGEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE RENEWABLE ENERGY AND ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS Facilities...

30 CFR 285.1014 - When will MMS suspend an Alternate Use RUE?

Code of Federal Regulations, 2011 CFR

2011-07-01

....1014 Section 285.1014 Mineral Resources BUREAU OF OCEAN ENERGY MANAGEMENT, REGULATION, AND ENFORCEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE RENEWABLE ENERGY ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS...

30 CFR 585.1016 - When will an Alternate Use RUE be cancelled?

Code of Federal Regulations, 2014 CFR

2014-07-01

...? 585.1016 Section 585.1016 Mineral Resources BUREAU OF OCEAN ENERGY MANAGEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE RENEWABLE ENERGY AND ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS Facilities...

30 CFR 285.1005 - How do I request an Alternate Use RUE?

Code of Federal Regulations, 2011 CFR

2011-07-01

... Section 285.1005 Mineral Resources BUREAU OF OCEAN ENERGY MANAGEMENT, REGULATION, AND ENFORCEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE RENEWABLE ENERGY ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS...

30 CFR 585.1014 - When will BOEM suspend an Alternate Use RUE?

Code of Federal Regulations, 2014 CFR

2014-07-01

...? 585.1014 Section 585.1014 Mineral Resources BUREAU OF OCEAN ENERGY MANAGEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE RENEWABLE ENERGY AND ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS Facilities...

30 CFR 585.1014 - When will BOEM suspend an Alternate Use RUE?

Code of Federal Regulations, 2012 CFR

2012-07-01

...? 585.1014 Section 585.1014 Mineral Resources BUREAU OF OCEAN ENERGY MANAGEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE RENEWABLE ENERGY AND ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS Facilities...

30 CFR 585.1014 - When will BOEM suspend an Alternate Use RUE?

Code of Federal Regulations, 2013 CFR

2013-07-01

...? 585.1014 Section 585.1014 Mineral Resources BUREAU OF OCEAN ENERGY MANAGEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE RENEWABLE ENERGY AND ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS Facilities...

Dynamics and control of the ERK signaling pathway: Sensitivity, bistability, and oscillations.

PubMed

Arkun, Yaman; Yasemi, Mohammadreza

2018-01-01

Cell signaling is the process by which extracellular information is transmitted into the cell to perform useful biological functions. The ERK (extracellular-signal-regulated kinase) signaling controls several cellular processes such as cell growth, proliferation, differentiation and apoptosis. The ERK signaling pathway considered in this work starts with an extracellular stimulus and ends with activated (double phosphorylated) ERK which gets translocated into the nucleus. We model and analyze this complex pathway by decomposing it into three functional subsystems. The first subsystem spans the initial part of the pathway from the extracellular growth factor to the formation of the SOS complex, ShC-Grb2-SOS. The second subsystem includes the activation of Ras which is mediated by the SOS complex. This is followed by the MAPK subsystem (or the Raf-MEK-ERK pathway) which produces the double phosphorylated ERK upon being activated by Ras. Although separate models exist in the literature at the subsystems level, a comprehensive model for the complete system including the important regulatory feedback loops is missing. Our dynamic model combines the existing subsystem models and studies their steady-state and dynamic interactions under feedback. We establish conditions under which bistability and oscillations exist for this important pathway. In particular, we show how the negative and positive feedback loops affect the dynamic characteristics that determine the cellular outcome.

Alternative ground states enable pathway switching in biological electron transfer

DOE PAGES

Abriata, Luciano A.; Alvarez-Paggi, Damian; Ledesma, Gabirela N.; ...

2012-10-10

Electron transfer is the simplest chemical reaction and constitutes the basis of a large variety of biological processes, such as photosynthesis and cellular respiration. Nature has evolved specific proteins and cofactors for these functions. The mechanisms optimizing biological electron transfer have been matter of intense debate, such as the role of the protein milieu between donor and acceptor sites. Here we propose a mechanism regulating long-range electron transfer in proteins. Specifically, we report a spectroscopic, electrochemical, and theoretical study on WT and single-mutant CuA redox centers from Thermus thermophilus, which shows that thermal fluctuations may populate two alternative ground-state electronicmore » wave functions optimized for electron entry and exit, respectively, through two different and nearly perpendicular pathways. In conclusion, these findings suggest a unique role for alternative or “invisible” electronic ground states in directional electron transfer. Moreover, it is shown that this energy gap and, therefore, the equilibrium between ground states can be fine-tuned by minor perturbations, suggesting alternative ways through which protein–protein interactions and membrane potential may optimize and regulate electron–proton energy transduction.« less

The alternative complement component factor B regulates UV-induced oedema, systemic suppression of contact and delayed hypersensitivity, and mast cell infiltration into the skin.

PubMed

Byrne, Scott N; Hammond, Kirsten J L; Chan, Carling Y-Y; Rogers, Linda J; Beaugie, Clare; Rana, Sabita; Marsh-Wakefield, Felix; Thurman, Joshua M; Halliday, Gary M

2015-04-01

Ultraviolet (UV) wavelengths in sunlight are the prime cause of skin cancer in humans with both the UVA and UVB wavebands making a contribution to photocarcinogenesis. UV has many different biological effects on the skin that contribute to carcinogenesis, including suppression of adaptive immunity, sunburn and altering the migration of mast cells into and away from irradiated skin. Many molecular mechanisms have been identified as contributing to skin responses to UV. Recently, using gene set enrichment analysis of microarray data, we identified the alternative complement pathway with a central role for factor B (fB) in UVA-induced immunosuppression. In the current study we used mice genetically deficient in fB (fB-/- mice) to study the functional role of the alternative complement pathway in skin responses to UV. We found that fB is required for not only UVA but also UVB-induced immunosuppression and solar-simulated UV induction of the oedemal component of sunburn. Factor B-/- mice had a larger number of resident skin mast cells than control mice, but unlike the controls did not respond to UV by increasing mast cell infiltration into the skin. This study provides evidence for a function role for fB in skin responses to UV radiation. Factor B regulates UVA and UVB induced immunosuppression, UV induced oedema and mast cell infiltration into the skin. The alternative complement pathway is therefore an important regulator of skin responses to UV.

The response difference of mitochondria in recalcitrant Antiaris toxicaria axes and orthodox Zea mays embryos to dehydration injury.

PubMed

Song, Song-Quan; Tian, Mei-Hua; Kan, Jing; Cheng, Hong-Yan

2009-07-01

Long-term preservation of recalcitrant seeds is very difficult because the physiological basis on their desiccation sensitivity is poorly understood. Survival of Antiaris toxicaria axes rapidly decreased and that of immature maize embryos very slowly decreased with dehydration. To understand their different responses to dehydration, we examined the changes in mitochondria activity during dehydration. Although activities of cytochrome (Cyt) c oxidase and malate dehydrogenase of the A. toxicaria axis and maize embryo mitochondria decreased with dehydration, the parameters of maize embryo mitochondria were much higher than those of A. toxicaria, showing that the damage was more severe for the A. toxicaria axis mitochondria than for those of maize embryo. The state I and III respiration of the A. toxicaria axis mitochondria were higher than those of maize embryo, the former rapidly decreased, and the latter slowly decreased with dehydration. The proportion of Cyt c pathway to state III respiration for the A. toxicaria axis mitochondria was low and rapidly decreased with dehydration, and the proportion of alternative oxidase pathway was high and slightly increased with dehydration. In contrast, the proportion of Cyt c pathway for maize embryo mitochondria was high, and that of alternative oxidase pathway was low. Both pathways decreased slowly with dehydration.

Collaboration pathway(s) using new tools for optimizing `operational' climate monitoring from space

NASA Astrophysics Data System (ADS)

Helmuth, Douglas B.; Selva, Daniel; Dwyer, Morgan M.

2015-09-01

Consistently collecting the earth's climate signatures remains a priority for world governments and international scientific organizations. Architecting a long term solution requires transforming scientific missions into an optimized robust `operational' constellation that addresses the collective needs of policy makers, scientific communities and global academic users for trusted data. The application of new tools offers pathways for global architecture collaboration. Recent rule-based expert system (RBES) optimization modeling of the intended NPOESS architecture becomes a surrogate for global operational climate monitoring architecture(s). These rulebased systems tools provide valuable insight for global climate architectures, by comparison/evaluation of alternatives and the sheer range of trade space explored. Optimization of climate monitoring architecture(s) for a partial list of ECV (essential climate variables) is explored and described in detail with dialogue on appropriate rule-based valuations. These optimization tool(s) suggest global collaboration advantages and elicit responses from the audience and climate science community. This paper will focus on recent research exploring joint requirement implications of the high profile NPOESS architecture and extends the research and tools to optimization for a climate centric case study. This reflects work from SPIE RS Conferences 2013 and 2014, abridged for simplification30, 32. First, the heavily securitized NPOESS architecture; inspired the recent research question - was Complexity (as a cost/risk factor) overlooked when considering the benefits of aggregating different missions into a single platform. Now years later a complete reversal; should agencies considering Disaggregation as the answer. We'll discuss what some academic research suggests. Second, using the GCOS requirements of earth climate observations via ECV (essential climate variables) many collected from space-based sensors; and accepting their definitions of global coverages intended to ensure the needs of major global and international organizations (UNFCCC and IPCC) are met as a core objective. Consider how new optimization tools like rule-based engines (RBES) offer alternative methods of evaluating collaborative architectures and constellations? What would the trade space of optimized operational climate monitoring architectures of ECV look like? Third, using the RBES tool kit (2014) demonstrate with application to a climate centric rule-based decision engine - optimizing architectural trades of earth observation satellite systems, allowing comparison(s) to existing architectures and gaining insights for global collaborative architectures. How difficult is it to pull together an optimized climate case study - utilizing for example 12 climate based instruments on multiple existing platforms and nominal handful of orbits; for best cost and performance benefits against the collection requirements of representative set of ECV. How much effort and resources would an organization expect to invest to realize these analysis and utility benefits?

Dynamics Sampling in Transition Pathway Space.

PubMed

Zhou, Hongyu; Tao, Peng

2018-01-09

The minimum energy pathway contains important information describing the transition between two states on a potential energy surface (PES). Chain-of-states methods were developed to efficiently calculate minimum energy pathways connecting two stable states. In the chain-of-states framework, a series of structures are generated and optimized to represent the minimum energy pathway connecting two states. However, multiple pathways may exist connecting two existing states and should be identified to obtain a full view of the transitions. Therefore, we developed an enhanced sampling method, named as the direct pathway dynamics sampling (DPDS) method, to facilitate exploration of a PES for multiple pathways connecting two stable states as well as addition minima and their associated transition pathways. In the DPDS method, molecular dynamics simulations are carried out on the targeting PES within a chain-of-states framework to directly sample the transition pathway space. The simulations of DPDS could be regulated by two parameters controlling distance among states along the pathway and smoothness of the pathway. One advantage of the chain-of-states framework is that no specific reaction coordinates are necessary to generate the reaction pathway, because such information is implicitly represented by the structures along the pathway. The chain-of-states setup in a DPDS method greatly enhances the sufficient sampling in high-energy space between two end states, such as transition states. By removing the constraint on the end states of the pathway, DPDS will also sample pathways connecting minima on a PES in addition to the end points of the starting pathway. This feature makes DPDS an ideal method to directly explore transition pathway space. Three examples demonstrate the efficiency of DPDS methods in sampling the high-energy area important for reactions on the PES.

Origin of fatty acid synthesis - Thermodynamics and kinetics of reaction pathways

NASA Technical Reports Server (NTRS)

Weber, Arthur L.

1991-01-01

The primitiveness of contemporary fatty acid biosynthesis was evaluated by using the thermodynamics and kinetics of its component reactions to estimate the extent of its dependence on powerful and selective catalysis by enzymes. Since this analysis indicated that the modern pathway is not primitive because it requires sophisticated enzymatic catalysis, an alternative pathway of primitive fatty acid synthesis is proposed that uses glycolaldehyde as a substrate. In contrast to the modern pathway, this primitive pathway is not dependent on an exogenous source of phosphoanhydride energy. Furthermore, the chemical spontaneity of its reactions suggests that it could have been readily catalyzed by the rudimentary biocatalysts available at an early stage in the origin of life.

Core discrete event simulation model for the evaluation of health care technologies in major depressive disorder.

PubMed

Vataire, Anne-Lise; Aballéa, Samuel; Antonanzas, Fernando; Roijen, Leona Hakkaart-van; Lam, Raymond W; McCrone, Paul; Persson, Ulf; Toumi, Mondher

2014-03-01

A review of existing economic models in major depressive disorder (MDD) highlighted the need for models with longer time horizons that also account for heterogeneity in treatment pathways between patients. A core discrete event simulation model was developed to estimate health and cost outcomes associated with alternative treatment strategies. This model simulated short- and long-term clinical events (partial response, remission, relapse, recovery, and recurrence), adverse events, and treatment changes (titration, switch, addition, and discontinuation) over up to 5 years. Several treatment pathways were defined on the basis of fictitious antidepressants with three levels of efficacy, tolerability, and price (low, medium, and high) from first line to third line. The model was populated with input data from the literature for the UK setting. Model outputs include time in different health states, quality-adjusted life-years (QALYs), and costs from National Health Service and societal perspectives. The codes are open source. Predicted costs and QALYs from this model are within the range of results from previous economic evaluations. The largest cost components from the payer perspective were physician visits and hospitalizations. Key parameters driving the predicted costs and QALYs were utility values, effectiveness, and frequency of physician visits. Differences in QALYs and costs between two strategies with different effectiveness increased approximately twofold when the time horizon increased from 1 to 5 years. The discrete event simulation model can provide a more comprehensive evaluation of different therapeutic options in MDD, compared with existing Markov models, and can be used to compare a wide range of health care technologies in various groups of patients with MDD. Copyright © 2014 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

High hydrostatic pressure increases amino acid requirements in the piezo-hyperthermophilic archaeon Thermococcus barophilus.

PubMed

Cario, Anaïs; Lormières, Florence; Xiang, Xiao; Oger, Philippe

2015-11-01

We have established a defined growth medium for the piezophilic hyperthermophilic archaeon Thermococcus barophilus, which allows growth yields of ca. 10(8) cells/ml under both atmospheric and high hydrostatic pressure. Our results demonstrate a major impact of hydrostatic pressure on amino acid metabolism, with increases from 3 amino acids required at atmospheric pressure to 17 at 40 MPa. We observe in T. barophilus and other Thermococcales a similar discrepancy between the presence/absence of amino acid synthesis pathways and amino acid requirements, which supports the existence of alternate, but yet unknown, amino acid synthesis pathways, and may explain the low number of essential amino acids observed in T. barophilus and other Thermococcales. T. barophilus displays a strong metabolic preference for organic polymers such as polypeptides and chitin, which may constitute a more readily available resource of carbon and energy in situ in deep-sea hydrothermal vents. We hypothesize that the low energy yields of fermentation of organic polymers, together with energetic constraints imposed by high hydrostatic pressure, may render de novo synthesis of amino acids ecologically unfavorable. Induction of this metabolic switch to amino acid recycling can explain the requirement for non-essential amino acids by Thermococcales for efficient growth in defined medium. Copyright © 2015 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

Analysis of Chemical Bioactivity through In Vitro Profiling ...

EPA Pesticide Factsheets

Safety assessment of drugs and environmental chemicals relies extensively on animal testing. However, the quantity of chemicals needing assessment and challenges of species extrapolation drive the development of alternative approaches. The EPA’s ToxCast and the multiagency Tox21 programs address this through use of an extensive in vitro screening program to generate data on a large library of important environmental chemicals. These in vitro assays encompass both cell-free, biochemical assays targeting proteins that may be potential molecular initiating events and cellular assays that provide coverage of critical signaling pathways and toxicity phenotypes. Effects on model organisms such as the developing zebrafish, are also part of the testing strategy. A variety of computational approaches are used to analyze the resulting complex data sets to gain insight in to inherent biological activity of chemicals and possible mechanisms of toxicity. Several case studies including identification of modulators of estrogen receptor and aromatic hydrocarbon receptor pathways with effects in primary human cell systems will be described. In addition, existing in vivo data from a subset of the chemicals was used to anchor predictive models using in vitro data for a number of adverse endpoints including reproductive and developmental toxicities. The strengths and weaknesses of this approach will be described. This work does not necessarily reflect official Agency policy. Pres

UK: the current state of regulation of complementary and alternative medicine.

PubMed

Walker, L A; Budd, S

2002-03-01

There is no legislation that restricts the practice of CAM in the UK apart from the practice of chiropractic and osteopathy and limits on advertising the treatments of certain conditions such as cancer and tuberculosis. The UK government has increasingly recognised the need for comprehensive regulation of CAM, though it abandoned its original plan for a single overarching regulatory body. Initiatives to examine and hasten the process of regulation have included setting up a central, well-recognised charitable body to facilitate progress for individual professions, and an authoritative survey of the existing professional organisations. One pathway open to individual professions is statutory self-regulation, which requires a single governing body, a systematic corpus of knowledge, recognised training courses and demonstrated efficacy. The other pathway is voluntary self-regulation. Chiropractic and osteopathy have adopted statutory self-regulation, though this has proved expensive for individual members of these professions. A recent House of Lords report on CAM has recommended that the herbal medicine and acupuncture professions should also develop a system of statutory regulation. Other professions, such as aromatherapy, are in the process of establishing single professional bodies as a first step towards self-regulation. Among the issues that remain to be resolved is the relationship between the CAM professions and statutory registered practitioners who also practise CAM.

The role of nNOS and PGC-1α in skeletal muscle cells.

PubMed

Baldelli, Sara; Lettieri Barbato, Daniele; Tatulli, Giuseppe; Aquilano, Katia; Ciriolo, Maria Rosa

2014-11-15

Neuronal nitric oxide synthase (nNOS) and peroxisome proliferator activated receptor γ co-activator 1α (PGC-1α) are two fundamental factors involved in the regulation of skeletal muscle cell metabolism. nNOS exists as several alternatively spliced variants, each having a specific pattern of subcellular localisation. Nitric oxide (NO) functions as a second messenger in signal transduction pathways that lead to the expression of metabolic genes involved in oxidative metabolism, vasodilatation and skeletal muscle contraction. PGC-1α is a transcriptional coactivator and represents a master regulator of mitochondrial biogenesis by promoting the transcription of mitochondrial genes. PGC-1α can be induced during physical exercise, and it plays a key role in coordinating the oxidation of intracellular fatty acids with mitochondrial remodelling. Several lines of evidence demonstrate that NO could act as a key regulator of PGC-1α expression; however, the link between nNOS and PGC-1α in skeletal muscle remains only poorly understood. In this Commentary, we review important metabolic pathways that are governed by nNOS and PGC-1α, and aim to highlight how they might intersect and cooperatively regulate skeletal muscle mitochondrial and lipid energetic metabolism and contraction. © 2014. Published by The Company of Biologists Ltd.

Calcineurin inhibition enhances motor neuron survival following injury

PubMed Central

Hui, Kelvin KW; Liadis, Nicole; Robertson, Jennifer; Kanungo, Anish; Henderson, Jeffrey T

2010-01-01

Abstract The immunosuppressive agents cyclosporin A (CsA) and FK-506 have previously been shown to exhibit neurotrophic and neuroprotective properties in vivo. Given that significant clinical expertise exists for both drugs, they represent an attractive starting point for treatment of acute neural injuries. One putative mechanism for neuroprotection by these drugs relates to inhibition of calcineurin activity. However each drug–immunophilin complex can potentially influence additional signal transduction pathways. Furthermore, several non-immunosuppressive immunophilin ligands have been described as possessing neuroprotective properties, suggesting that neuroprotection may be separable from calcineurin inhibition. In the present study, we examined the mechanism of this neuroprotection in facial motor neurons following axotomy-induced injury. Similar to previous studies in rats, CsA and FK-506 enhanced motor neuron survival in mice following acute injury. To examine the mechanism responsible for neuroprotection by these agents, pharmacologic inhibitors of several potential alternate signalling pathways (17-(allylamino)-17-demethoxygeldanamycin, rapamycin, cypermethrin) were evaluated with respect to neuroprotection. Of these, only cypermethrin, a direct calcineurin inhibitor not previously associated with neuronal survival properties, was observed to significantly enhance motor neuron survival following injury. The results demonstrate for the first time that direct inhibition of calcineurin is neuroprotective in vivo. These data support a model in which calcineurin inhibition promotes neuronal survival, distinct from effects upon neurite outgrowth. PMID:19243469

Cytogenomic profiling of breast cancer brain metastases reveals potential for repurposing targeted therapeutics

PubMed Central

Bollig-Fischer, Aliccia; Michelhaugh, Sharon K.; Wijesinghe, Priyanga; Dyson, Greg; Kruger, Adele; Palanisamy, Nallasivam; Choi, Lydia; Alosh, Baraa; Ali-Fehmi, Rouba; Mittal, Sandeep

2015-01-01

Breast cancer brain metastases remain a significant clinical problem. Chemotherapy is ineffective and a lack of treatment options result in poor patient outcomes. Targeted therapeutics have proven to be highly effective in primary breast cancer, but lack of molecular genomic characterization of metastatic brain tumors is hindering the development of new treatment regimens. Here we contribute to fill this void by reporting on gene copy number variation (CNV) in 10 breast cancer metastatic brain tumors, assayed by array comparative genomic hybridization (aCGH). Results were compared to a list of cancer genes verified by others to influence cancer. Cancer gene aberrations were identified in all specimens and pathway-level analysis was applied to aggregate data, which identified stem cell pluripotency pathway enrichment and highlighted recurring, significant amplification of SOX2, PIK3CA, NTRK1, GNAS, CTNNB1, and FGFR1. For a subset of the metastatic brain tumor samples (n=4) we compared patient-matched primary breast cancer specimens. The results of our CGH analysis and validation by alternative methods indicate that oncogenic signals driving growth of metastatic tumors exist in the original cancer. This report contributes support for more rapid development of new treatments of metastatic brain tumors, the use of genomic-based diagnostic tools and repurposed drug treatments. PMID:25970776

Cytogenomic profiling of breast cancer brain metastases reveals potential for repurposing targeted therapeutics.

PubMed

Bollig-Fischer, Aliccia; Michelhaugh, Sharon K; Wijesinghe, Priyanga; Dyson, Greg; Kruger, Adele; Palanisamy, Nallasivam; Choi, Lydia; Alosh, Baraa; Ali-Fehmi, Rouba; Mittal, Sandeep

2015-06-10

Breast cancer brain metastases remain a significant clinical problem. Chemotherapy is ineffective and a lack of treatment options result in poor patient outcomes. Targeted therapeutics have proven to be highly effective in primary breast cancer, but lack of molecular genomic characterization of metastatic brain tumors is hindering the development of new treatment regimens. Here we contribute to fill this void by reporting on gene copy number variation (CNV) in 10 breast cancer metastatic brain tumors, assayed by array comparative genomic hybridization (aCGH). Results were compared to a list of cancer genes verified by others to influence cancer. Cancer gene aberrations were identified in all specimens and pathway-level analysis was applied to aggregate data, which identified stem cell pluripotency pathway enrichment and highlighted recurring, significant amplification of SOX2, PIK3CA, NTRK1, GNAS, CTNNB1, and FGFR1. For a subset of the metastatic brain tumor samples (n = 4) we compared patient-matched primary breast cancer specimens. The results of our CGH analysis and validation by alternative methods indicate that oncogenic signals driving growth of metastatic tumors exist in the original cancer. This report contributes support for more rapid development of new treatments of metastatic brain tumors, the use of genomic-based diagnostic tools and repurposed drug treatments.

EuPathDB: the eukaryotic pathogen genomics database resource

PubMed Central

Aurrecoechea, Cristina; Barreto, Ana; Basenko, Evelina Y.; Brestelli, John; Brunk, Brian P.; Cade, Shon; Crouch, Kathryn; Doherty, Ryan; Falke, Dave; Fischer, Steve; Gajria, Bindu; Harb, Omar S.; Heiges, Mark; Hertz-Fowler, Christiane; Hu, Sufen; Iodice, John; Kissinger, Jessica C.; Lawrence, Cris; Li, Wei; Pinney, Deborah F.; Pulman, Jane A.; Roos, David S.; Shanmugasundram, Achchuthan; Silva-Franco, Fatima; Steinbiss, Sascha; Stoeckert, Christian J.; Spruill, Drew; Wang, Haiming; Warrenfeltz, Susanne; Zheng, Jie

2017-01-01

The Eukaryotic Pathogen Genomics Database Resource (EuPathDB, http://eupathdb.org) is a collection of databases covering 170+ eukaryotic pathogens (protists & fungi), along with relevant free-living and non-pathogenic species, and select pathogen hosts. To facilitate the discovery of meaningful biological relationships, the databases couple preconfigured searches with visualization and analysis tools for comprehensive data mining via intuitive graphical interfaces and APIs. All data are analyzed with the same workflows, including creation of gene orthology profiles, so data are easily compared across data sets, data types and organisms. EuPathDB is updated with numerous new analysis tools, features, data sets and data types. New tools include GO, metabolic pathway and word enrichment analyses plus an online workspace for analysis of personal, non-public, large-scale data. Expanded data content is mostly genomic and functional genomic data while new data types include protein microarray, metabolic pathways, compounds, quantitative proteomics, copy number variation, and polysomal transcriptomics. New features include consistent categorization of searches, data sets and genome browser tracks; redesigned gene pages; effective integration of alternative transcripts; and a EuPathDB Galaxy instance for private analyses of a user's data. Forthcoming upgrades include user workspaces for private integration of data with existing EuPathDB data and improved integration and presentation of host–pathogen interactions. PMID:27903906

Hsp90 prevents phenotypic variation by suppressing the mutagenic activity of transposons.

PubMed

Specchia, Valeria; Piacentini, Lucia; Tritto, Patrizia; Fanti, Laura; D'Alessandro, Rosalba; Palumbo, Gioacchino; Pimpinelli, Sergio; Bozzetti, Maria P

2010-02-04

The canalization concept describes the resistance of a developmental process to phenotypic variation, regardless of genetic and environmental perturbations, owing to the existence of buffering mechanisms. Severe perturbations, which overcome such buffering mechanisms, produce altered phenotypes that can be heritable and can themselves be canalized by a genetic assimilation process. An important implication of this concept is that the buffering mechanism could be genetically controlled. Recent studies on Hsp90, a protein involved in several cellular processes and development pathways, indicate that it is a possible molecular mechanism for canalization and genetic assimilation. In both flies and plants, mutations in the Hsp90-encoding gene induce a wide range of phenotypic abnormalities, which have been interpreted as an increased sensitivity of different developmental pathways to hidden genetic variability. Thus, Hsp90 chaperone machinery may be an evolutionarily conserved buffering mechanism of phenotypic variance, which provides the genetic material for natural selection. Here we offer an additional, perhaps alternative, explanation for proposals of a concrete mechanism underlying canalization. We show that, in Drosophila, functional alterations of Hsp90 affect the Piwi-interacting RNA (piRNA; a class of germ-line-specific small RNAs) silencing mechanism leading to transposon activation and the induction of morphological mutants. This indicates that Hsp90 mutations can generate new variation by transposon-mediated 'canonical' mutagenesis.

Necroptosis inhibitors as therapeutic targets in inflammation mediated disorders - a review of the current literature and patents.

PubMed

Kopalli, Spandana Rajendra; Kang, Tae-Bong; Koppula, Sushruta

2016-11-01

Recent studies have shown substantial interplay between the apoptosis and necroptosis pathways. Necroptosis, a form of programmed cell death, has been found to stimulate the immune system contributing to the pathophysiology of several inflammation-mediated disorders. Determining the contribution of necroptotic signaling pathways to inflammation may lead to the development of selective and specific molecular target implicated necroptosis inhibitors. Areas covered: This review summarizes the recently published and patented necroptosis inhibitors as therapeutic targets in inflammation-mediated disorders. The role of several necroptosis inhibitors, focusing on specific signaling molecules, was discussed with particular attention to inflammation-mediated disorders. Data was obtained from Espacenet®, WIPO®, USPTO® patent websites, and other relevant sources (2006-2016). Expert opinion: Necroptosis inhibitors hold promise for treatment of inflammation-mediated clinical conditions in which necroptotic cell death plays a major role. Although necroptosis inhibitors reviewed in this survey showed inhibitory effects against several inflammation-mediated disorders, only a few have passed to the stage of clinical testing and need extensive research for therapeutic practice. Revisiting the existing drugs and developing novel necroptosis inhibiting agents as well as understanding their mechanism are essential. A detailed study of necroptosis function in animal models of inflammation may provide us an alternative strategy for the development of drug-like necroptosis inhibitors.

Drosophila Ionotropic Receptor 25a mediates circadian clock resetting by temperature.

PubMed

Chen, Chenghao; Buhl, Edgar; Xu, Min; Croset, Vincent; Rees, Johanna S; Lilley, Kathryn S; Benton, Richard; Hodge, James J L; Stanewsky, Ralf

2015-11-26

Circadian clocks are endogenous timers adjusting behaviour and physiology with the solar day. Synchronized circadian clocks improve fitness and are crucial for our physical and mental well-being. Visual and non-visual photoreceptors are responsible for synchronizing circadian clocks to light, but clock-resetting is also achieved by alternating day and night temperatures with only 2-4 °C difference. This temperature sensitivity is remarkable considering that the circadian clock period (~24 h) is largely independent of surrounding ambient temperatures. Here we show that Drosophila Ionotropic Receptor 25a (IR25a) is required for behavioural synchronization to low-amplitude temperature cycles. This channel is expressed in sensory neurons of internal stretch receptors previously implicated in temperature synchronization of the circadian clock. IR25a is required for temperature-synchronized clock protein oscillations in subsets of central clock neurons. Extracellular leg nerve recordings reveal temperature- and IR25a-dependent sensory responses, and IR25a misexpression confers temperature-dependent firing of heterologous neurons. We propose that IR25a is part of an input pathway to the circadian clock that detects small temperature differences. This pathway operates in the absence of known 'hot' and 'cold' sensors in the Drosophila antenna, revealing the existence of novel periphery-to-brain temperature signalling channels.

A structure- and chemical genomics-based approach for repositioning of drugs against VCP/p97 ATPase.

PubMed

Segura-Cabrera, Aldo; Tripathi, Reshmi; Zhang, Xiaoyi; Gui, Lin; Chou, Tsui-Fen; Komurov, Kakajan

2017-03-21

Valosin-containing protein (VCP/p97) ATPase (a.k.a. Cdc48) is a key member of the ER-associated protein degradation (ERAD) pathway. ERAD and VCP/p97 have been implicated in a multitude of human diseases, such as neurodegenerative diseases and cancer. Inhibition of VCP/p97 induces proteotoxic ER stress and cell death in cancer cells, making it an attractive target for cancer treatment. However, no drugs exist against this protein in the market. Repositioning of drugs towards new indications is an attractive alternative to the de novo drug development due to the potential for significantly shorter time to clinical translation. Here, we employed an integrative strategy for the repositioning of drugs as novel inhibitors of the VCP/p97 ATPase. We integrated structure-based virtual screening with the chemical genomics analysis of drug molecular signatures, and identified several candidate inhibitors of VCP/p97 ATPase. Importantly, experimental validation with cell-based and in vitro ATPase assays confirmed three (ebastine, astemizole and clotrimazole) out of seven tested candidates (~40% true hit rate) as direct inhibitors of VCP/p97 and ERAD. This study introduces an effective integrative strategy for drug repositioning, and identified new drugs against the VCP/p97/ERAD pathway in human diseases.

Pathways to Teacher Certification: Does It Really Matter when It Comes to Efficacy and Effectiveness?

ERIC Educational Resources Information Center

Tournaki, Nelly; Lyublinskaya, Irina; Carolan, Brian V.

2009-01-01

The pressure to provide qualified teachers for all students has resulted in reform efforts, including the upgrading of credential and course requirements, as well as the proliferation of so-called alternative routes to teacher certification, which seek to create differentiated pathways into the classroom. In the present study, we compared teacher…

Long-Term Management Strategy for Dredged Material Disposal for Naval Facilities at Pearl Harbor, Hawaii. Phase II - Evaulation of Alternatives

DTIC Science & Technology

2000-03-01

26 Leachate Pathway.................................... 31 Plant Uptake Pathway.................................. 35 Volatization and Odor...Bi13 Appendix C - Surface Runoff Testing............................Cl Appendix D - Leachate Evaluation..............................D1 Appendix E...Oxidized Dredged Material..........................29 Table 7. Mixing Zone Requirement for Runoff Discharges............ 30 Table 8. Leachate Quality

Pathways of Youth Development in a Rural Trailer Park

ERIC Educational Resources Information Center

MacTavish, Katherine A.; Salamon, Sonya

2006-01-01

Limited empirical documentation exists for the developmental pathways available to "rural" youth growing up in low-resource community settings. Drawing on ethnographic data, this article examines the developmental pathways experienced by youth in a rural trailer park. Findings reveal how various factors, some inherent to working poor class status…

Frameworks for organizing exposure and toxicity data - the Aggregate Exposure Pathway (AEP) and the Adverse Outcome Pathway (AOP)

EPA Science Inventory

The Adverse Outcome Pathway (AOP) framework organizes existing knowledge regarding a series of biological events, starting with a molecular initiating event (MIE) and ending at an adverse outcome. The AOP framework provides a biological context to interpret in vitro toxicity dat...

The canonical Wnt signaling pathway in autism.

PubMed

Zhang, Yinghua; Yuan, Xiangshan; Wang, Zhongping; Li, Ruixi

2014-01-01

Mounting attention is being focused on the canonical Wnt signaling pathway which has been implicated in the pathogenesis of autism in some our and other recent studies. The canonical Wnt pathway is involved in cell proliferation, differentiation and migration, especially during nervous system development. Given its various functions, dysfunction of the canonical Wnt pathway may exert adverse effects on neurodevelopment and therefore leads to the pathogenesis of autism. Here, we review human and animal studies that implicate the canonical Wnt signal transduction pathway in the pathogenesis of autism. We also describe the crosstalk between the canonical Wnt pathway and the Notch signaling pathway in several types of autism spectrum disorders, including Asperger syndrome and Fragile X. Further research on the crosstalk between the canonical Wnt signaling pathway and other signaling cascades in autism may be an efficient avenue to understand the etiology of autism and ultimately lead to alternative medications for autism-like phenotypes.

Cultural pathways through universal development.

PubMed

Greenfield, Patricia M; Keller, Heidi; Fuligni, Andrew; Maynard, Ashley

2003-01-01

We focus our review on three universal tasks of human development: relationship formation, knowledge acquisition, and the balance between autonomy and relatedness at adolescence. We present evidence that each task can be addressed through two deeply different cultural pathways through development: the pathways of independence and interdependence. Whereas core theories in developmental psychology are universalistic in their intentions, they in fact presuppose the independent pathway of development. Because the independent pathway is therefore well-known in psychology, we focus a large part of our review on empirically documenting the alternative, interdependent pathway for each developmental task. We also present three theoretical approaches to culture and development: the ecocultural, the sociohistorical, and the cultural values approach. We argue that an understanding of cultural pathways through human development requires all three approaches. We review evidence linking values (cultural values approach), ecological conditions (ecocultural approach), and socialization practices (sociohistorical approach) to cultural pathways through universal developmental tasks.

Comparison of the new Japanese legislation for expedited approval of regenerative medicine products with the existing systems in the USA and European Union

PubMed Central

Jokura, Yoji; Yano, Kazuo

2017-01-01

Abstract Legislation for expedited‐approval pathways and programmes for drugs, biologics or medical devices has been enacted for rapid commercialization of innovative products in the United States of America (USA) and the European Union (EU). However, less innovative products are increasingly benefitting from these expedited‐approval pathways, and obligations to collect and report post‐marketing data on approved products are being bypassed frequently. The Japanese government recently enacted legislation for a new conditional and time‐limited approval pathway dedicated to regenerative medicine products. The current study examines this new legislation and compares it with existing US and EU regulatory frameworks, with a particular focus on how it addresses the limitations of existing systems. Regulations, guidance documents and approval information were gathered from the websites of the respective authorities in the USA, the EU and Japan, and the systems were categorized through qualitative analysis. The pathways and programmes from each region were categorized into four groups, based on the requirement of pre‐ or post‐marketing clinical data. Expedited‐approval pathways in the USA and the EU provide similar qualification criteria, such as severity of target disease; however, such criteria are not specified for the new pathway in Japan. Only the Japanese pathway stipulates a time limitation on exceptional approval, requiring post‐marketing study for conditional and time‐limited products. Continuous improvement is necessary to solve previously addressed issues within the expedited‐approval pathways and programmes and to ensure that innovative medical products are rigourously screened, but also readily available to patients in need. The time limitation of conditional approval could be a potential solution to some of these problems. Copyright © 2017 The Authors. Tissue Engineering Regenerative Medicine published by John Wiley & Sons, Ltd. PMID:28211195

Lineage-specific splicing of a brain-enriched alternative exon promotes glioblastoma progression

PubMed Central

Ferrarese, Roberto; Harsh, Griffith R.; Yadav, Ajay K.; Bug, Eva; Maticzka, Daniel; Reichardt, Wilfried; Dombrowski, Stephen M.; Miller, Tyler E.; Masilamani, Anie P.; Dai, Fangping; Kim, Hyunsoo; Hadler, Michael; Scholtens, Denise M.; Yu, Irene L.Y.; Beck, Jürgen; Srinivasasainagendra, Vinodh; Costa, Fabrizio; Baxan, Nicoleta; Pfeifer, Dietmar; von Elverfeldt, Dominik; Backofen, Rolf; Weyerbrock, Astrid; Duarte, Christine W.; He, Xiaolin; Prinz, Marco; Chandler, James P.; Vogel, Hannes; Chakravarti, Arnab; Rich, Jeremy N.; Carro, Maria S.; Bredel, Markus

2014-01-01

Tissue-specific alternative splicing is critical for the emergence of tissue identity during development, yet the role of this process in malignant transformation is undefined. Tissue-specific splicing involves evolutionarily conserved, alternative exons that represent only a minority of the total alternative exons identified. Many of these conserved exons have functional features that influence signaling pathways to profound biological effect. Here, we determined that lineage-specific splicing of a brain-enriched cassette exon in the membrane-binding tumor suppressor annexin A7 (ANXA7) diminishes endosomal targeting of the EGFR oncoprotein, consequently enhancing EGFR signaling during brain tumor progression. ANXA7 exon splicing was mediated by the ribonucleoprotein PTBP1, which is normally repressed during neuronal development. PTBP1 was highly expressed in glioblastomas due to loss of a brain-enriched microRNA (miR-124) and to PTBP1 amplification. The alternative ANXA7 splicing trait was present in precursor cells, suggesting that glioblastoma cells inherit the trait from a potential tumor-initiating ancestor and that these cells exploit this trait through accumulation of mutations that enhance EGFR signaling. Our data illustrate that lineage-specific splicing of a tissue-regulated alternative exon in a constituent of an oncogenic pathway eliminates tumor suppressor functions and promotes glioblastoma progression. This paradigm may offer a general model as to how tissue-specific regulatory mechanisms can reprogram normal developmental processes into oncogenic ones. PMID:24865424

Computational identification and validation of alternative splicing in ZSF1 rat RNA-seq data, a preclinical model for type 2 diabetic nephropathy.

PubMed

Zhang, Chi; Dower, Ken; Zhang, Baohong; Martinez, Robert V; Lin, Lih-Ling; Zhao, Shanrong

2018-05-16

Obese ZSF1 rats exhibit spontaneous time-dependent diabetic nephropathy and are considered to be a highly relevant animal model of progressive human diabetic kidney disease. We previously identified gene expression changes between disease and control animals across six time points from 12 to 41 weeks. In this study, the same data were analysed at the isoform and exon levels to reveal additional disease mechanisms that may be governed by alternative splicing. Our analyses identified alternative splicing patterns in genes that may be implicated in disease pathogenesis (such as Shc1, Serpinc1, Epb4.1l5, and Il-33), which would have been overlooked in standard gene-level analysis. The alternatively spliced genes were enriched in pathways related to cell adhesion, cell-cell interactions/junctions, and cytoskeleton signalling, whereas the differentially expressed genes were enriched in pathways related to immune response, G protein-coupled receptor, and cAMP signalling. Our findings indicate that additional mechanistic insights can be gained from exon- and isoform-level data analyses over standard gene-level analysis. Considering alternative splicing is poorly conserved between rodents and humans, it is noted that this work is not translational, but the point holds true that additional insights can be gained from alternative splicing analysis of RNA-seq data.

40 CFR 300.420 - Remedial site evaluation.

Code of Federal Regulations, 2010 CFR

2010-07-01

... existing information about a release such as information on the pathways of exposure, exposure targets, and... known contaminants; (iii) A description of pathways of migration of contaminants; (iv) An identification...

40 CFR 300.420 - Remedial site evaluation.

Code of Federal Regulations, 2011 CFR

2011-07-01

... existing information about a release such as information on the pathways of exposure, exposure targets, and... known contaminants; (iii) A description of pathways of migration of contaminants; (iv) An identification...

40 CFR 300.420 - Remedial site evaluation.

Code of Federal Regulations, 2012 CFR

2012-07-01

... existing information about a release such as information on the pathways of exposure, exposure targets, and... known contaminants; (iii) A description of pathways of migration of contaminants; (iv) An identification...

Assateague Island National Seashore alternative transportation systems planning study and business plan for alternative transportation

DOT National Transportation Integrated Search

2012-08-31

The purpose of this study was to (1) study the potential expansion of existing alternative transportation systems (bicycle facilities) and development of new alternative transportation systems in and around the Maryland District of Assateague Island ...

Third Space Strategists: International Students Negotiating the Transition from Pathway Program to Postgraduate Coursework Degree

ERIC Educational Resources Information Center

Benzie, Helen

2015-01-01

Pathway programs exist to prepare students for progression into university degrees but the transition experience for many students may not be as smooth as is suggested by the notion of the pathway. While attending a pathway program and at the beginning of their university degree, students may be in a third space, a liminal space where they engage…

Modelling and performance analysis of clinical pathways using the stochastic process algebra PEPA.

PubMed

Yang, Xian; Han, Rui; Guo, Yike; Bradley, Jeremy; Cox, Benita; Dickinson, Robert; Kitney, Richard

2012-01-01

Hospitals nowadays have to serve numerous patients with limited medical staff and equipment while maintaining healthcare quality. Clinical pathway informatics is regarded as an efficient way to solve a series of hospital challenges. To date, conventional research lacks a mathematical model to describe clinical pathways. Existing vague descriptions cannot fully capture the complexities accurately in clinical pathways and hinders the effective management and further optimization of clinical pathways. Given this motivation, this paper presents a clinical pathway management platform, the Imperial Clinical Pathway Analyzer (ICPA). By extending the stochastic model performance evaluation process algebra (PEPA), ICPA introduces a clinical-pathway-specific model: clinical pathway PEPA (CPP). ICPA can simulate stochastic behaviours of a clinical pathway by extracting information from public clinical databases and other related documents using CPP. Thus, the performance of this clinical pathway, including its throughput, resource utilisation and passage time can be quantitatively analysed. A typical clinical pathway on stroke extracted from a UK hospital is used to illustrate the effectiveness of ICPA. Three application scenarios are tested using ICPA: 1) redundant resources are identified and removed, thus the number of patients being served is maintained with less cost; 2) the patient passage time is estimated, providing the likelihood that patients can leave hospital within a specific period; 3) the maximum number of input patients are found, helping hospitals to decide whether they can serve more patients with the existing resource allocation. ICPA is an effective platform for clinical pathway management: 1) ICPA can describe a variety of components (state, activity, resource and constraints) in a clinical pathway, thus facilitating the proper understanding of complexities involved in it; 2) ICPA supports the performance analysis of clinical pathway, thereby assisting hospitals to effectively manage time and resources in clinical pathway.

PathFinder: reconstruction and dynamic visualization of metabolic pathways.

PubMed

Goesmann, Alexander; Haubrock, Martin; Meyer, Folker; Kalinowski, Jörn; Giegerich, Robert

2002-01-01

Beyond methods for a gene-wise annotation and analysis of sequenced genomes new automated methods for functional analysis on a higher level are needed. The identification of realized metabolic pathways provides valuable information on gene expression and regulation. Detection of incomplete pathways helps to improve a constantly evolving genome annotation or discover alternative biochemical pathways. To utilize automated genome analysis on the level of metabolic pathways new methods for the dynamic representation and visualization of pathways are needed. PathFinder is a tool for the dynamic visualization of metabolic pathways based on annotation data. Pathways are represented as directed acyclic graphs, graph layout algorithms accomplish the dynamic drawing and visualization of the metabolic maps. A more detailed analysis of the input data on the level of biochemical pathways helps to identify genes and detect improper parts of annotations. As an Relational Database Management System (RDBMS) based internet application PathFinder reads a list of EC-numbers or a given annotation in EMBL- or Genbank-format and dynamically generates pathway graphs.

Prokaryotic Heme Biosynthesis: Multiple Pathways to a Common Essential Product

PubMed Central

Dailey, Tamara A.; Gerdes, Svetlana; Jahn, Dieter; O'Brian, Mark R.; Warren, Martin J.

2017-01-01

SUMMARY The advent of heme during evolution allowed organisms possessing this compound to safely and efficiently carry out a variety of chemical reactions that otherwise were difficult or impossible. While it was long assumed that a single heme biosynthetic pathway existed in nature, over the past decade, it has become clear that there are three distinct pathways among prokaryotes, although all three pathways utilize a common initial core of three enzymes to produce the intermediate uroporphyrinogen III. The most ancient pathway and the only one found in the Archaea converts siroheme to protoheme via an oxygen-independent four-enzyme-step process. Bacteria utilize the initial core pathway but then add one additional common step to produce coproporphyrinogen III. Following this step, Gram-positive organisms oxidize coproporphyrinogen III to coproporphyrin III, insert iron to make coproheme, and finally decarboxylate coproheme to protoheme, whereas Gram-negative bacteria first decarboxylate coproporphyrinogen III to protoporphyrinogen IX and then oxidize this to protoporphyrin IX prior to metal insertion to make protoheme. In order to adapt to oxygen-deficient conditions, two steps in the bacterial pathways have multiple forms to accommodate oxidative reactions in an anaerobic environment. The regulation of these pathways reflects the diversity of bacterial metabolism. This diversity, along with the late recognition that three pathways exist, has significantly slowed advances in this field such that no single organism's heme synthesis pathway regulation is currently completely characterized. PMID:28123057

77 FR 1019 - Renewable Energy Alternate Uses of Existing Facilities on the Outer Continental Shelf-Acquire a...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-01-09

...-0045] RIN 1010-AD79 Renewable Energy Alternate Uses of Existing Facilities on the Outer Continental... rule related to acquiring a lease non-competitively for offshore renewable energy projects. DATES... or Timothy Redding, Renewable Energy, BOEM, at (703) 787-1219 or email [email protected

76 FR 4244 - Regulation and Enforcement; Renewable Energy Alternate Uses of Existing Facilities on the Outer...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-01-25

... DEPARTMENT OF THE INTERIOR Bureau of Ocean Energy Management 30 CFR Part 285 [Docket ID: BOEM-2010-0045] RIN 1010-AD71 Regulation and Enforcement; Renewable Energy Alternate Uses of Existing Facilities...: BOEMRE is withdrawing the direct final rule to amend BOEMRE's renewable energy regulatory provisions that...

30 CFR 585.1004 - What must I do before I request an Alternate Use RUE?

Code of Federal Regulations, 2013 CFR

2013-07-01

... Use RUE? 585.1004 Section 585.1004 Mineral Resources BUREAU OF OCEAN ENERGY MANAGEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE RENEWABLE ENERGY AND ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS...

30 CFR 585.1004 - What must I do before I request an Alternate Use RUE?

Code of Federal Regulations, 2014 CFR

2014-07-01

... Use RUE? 585.1004 Section 585.1004 Mineral Resources BUREAU OF OCEAN ENERGY MANAGEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE RENEWABLE ENERGY AND ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS...

30 CFR 585.1004 - What must I do before I request an Alternate Use RUE?

Code of Federal Regulations, 2012 CFR

2012-07-01

... Use RUE? 585.1004 Section 585.1004 Mineral Resources BUREAU OF OCEAN ENERGY MANAGEMENT, DEPARTMENT OF THE INTERIOR OFFSHORE RENEWABLE ENERGY AND ALTERNATE USES OF EXISTING FACILITIES ON THE OUTER CONTINENTAL SHELF Rights of Use and Easement for Energy- and Marine-Related Activities Using Existing OCS...

Molecular analysis of alternative transcripts of equine AXL receptor tyrosine kinase gene.

PubMed

Park, Jeong-Woong; Song, Ki-Duk; Kim, Nam Young; Choi, Jae-Young; Hong, Seul A; Oh, Jin Hyeog; Kim, Si Won; Lee, Jeong Hyo; Park, Tae Sub; Kim, Jin-Kyoo; Kim, Jong Geun; Cho, Byung-Wook

2017-10-01

Since athletic performance is a most importance trait in horses, most research focused on physiological and physical studies of horse athletic abilities. In contrast, the molecular analysis as well as the regulatory pathway studies remain insufficient for evaluation and prediction of horse athletic abilities. In our previous study, we identified AXL receptor tyrosine kinase ( AXL ) gene which was expressed as alternative spliced isoforms in skeletal muscle during exercise. In the present study, we validated two AXL alternative splicing transcripts (named as AXLa for long form and AXLb for short form) in equine skeletal muscle to gain insight(s) into the role of each alternative transcript during exercise. We validated two isoforms of AXL transcripts in horse tissues by reverse transcriptase polymerase chain reaction (RT-PCR), and then cloned the transcripts to confirm the alternative locus and its sequences. Additionally, we examined the expression patterns of AXLa and AXLb transcripts in horse tissues by quantitative RT-PCR (qRT-PCR). Both of AXLa and AXLb transcripts were expressed in horse skeletal muscle and the expression levels were significantly increased after exercise. The sequencing analysis showed that there was an alternative splicing event at exon 11 between AXLa and AXLb transcripts. 3-dimentional (3D) prediction of the alternative protein structures revealed that the structural distance of the connective region between fibronectin type 3 (FN3) and immunoglobin (Ig) domain was different between two alternative isoforms. It is assumed that the expression patterns of AXLa and AXLb transcripts would be involved in regulation of exercise-induced stress in horse muscle possibly through an NF-κB signaling pathway. Further study is necessary to uncover biological function(s) and significance of the alternative splicing isoforms in race horse skeletal muscle.

Salinity tolerance is related to cyanide-resistant alternative respiration in Medicago truncatula under sudden severe stress.

PubMed

Del-Saz, Néstor Fernández; Florez-Sarasa, Igor; Clemente-Moreno, María José; Mhadhbi, Haytem; Flexas, Jaume; Fernie, Alisdair R; Ribas-Carbó, Miquel

2016-11-01

Salt respiration is defined as the increase of respiration under early salt stress. However, the response of respiration varies depending on the degree of salt tolerance and salt stress. It has been hypothesized that the activity of the alternative pathway may increase preventing over-reduction of the ubiquinone pool in response to salinity, which in turn can increase respiration. Three genotypes of Medicago truncatula are reputed as differently responsive to salinity: TN1.11, A17 and TN6.18. We used the oxygen-isotope fractionation technique to study the in vivo respiratory activities of the cytochrome oxidase pathway (COP) and the alternative oxidase pathway (AOP) in leaves and roots of these genotypes treated with severe salt stress (300 mM) during 1 and 3 days. In parallel, AOX capacity, gas exchange measurements, relative water content and metabolomics were determined in control and treated plants. Our study shows for first time that salt respiration is induced by the triggered AOP in response to salinity. Moreover, this phenomenon coincides with increased levels of metabolites such as amino and organic acids, and is shown to be related with higher photosynthetic rate and water content in TN6.18. © 2016 John Wiley & Sons Ltd.

Modular and selective biosynthesis of gasoline-range alkanes.

PubMed

Sheppard, Micah J; Kunjapur, Aditya M; Prather, Kristala L J

2016-01-01

Typical renewable liquid fuel alternatives to gasoline are not entirely compatible with current infrastructure. We have engineered Escherichia coli to selectively produce alkanes found in gasoline (propane, butane, pentane, heptane, and nonane) from renewable substrates such as glucose or glycerol. Our modular pathway framework achieves carbon-chain extension by two different mechanisms. A fatty acid synthesis route is used to generate longer chains heptane and nonane, while a more energy efficient alternative, reverse-β-oxidation, is used for synthesis of propane, butane, and pentane. We demonstrate that both upstream (thiolase) and intermediate (thioesterase) reactions can act as control points for chain-length specificity. Specific free fatty acids are subsequently converted to alkanes using a broad-specificity carboxylic acid reductase and a cyanobacterial aldehyde decarbonylase (AD). The selectivity obtained by different module pairings provides a foundation for tuning alkane product distribution for desired fuel properties. Alternate ADs that have greater activity on shorter substrates improve observed alkane titer. However, even in an engineered host strain that significantly reduces endogenous conversion of aldehyde intermediates to alcohol byproducts, AD activity is observed to be limiting for all chain lengths. Given these insights, we discuss guiding principles for pathway selection and potential opportunities for pathway improvement. Copyright © 2015 International Metabolic Engineering Society. Published by Elsevier Inc. All rights reserved.

Simple method to distinguish between primary and secondary C3 deficiencies.

PubMed

Pereira de Carvalho Florido, Marlene; Ferreira de Paula, Patrícia; Isaac, Lourdes

2003-03-01

Due to the increasing numbers of reported clinical cases of complement deficiency in medical centers, clinicians are now more aware of the role of the complement system in the protection against infections caused by microorganisms. Therefore, clinical laboratories are now prepared to perform a number of diagnostic tests of the complement system other than the standard 50% hemolytic component assay. Deficiencies of alternative complement pathway proteins are related to severe and recurrent infections; and the application of easy, reliable, and low-cost methods for their detection and distinction are always welcome, notably in developing countries. When activation of the alternative complement pathway is evaluated in hemolytic agarose plates, some but not all human sera cross-react to form a late linear lysis. Since the formation of this linear lysis is dependent on C3 and factor B, it is possible to use late linear lysis to routinely screen for the presence of deficiencies of alternative human complement pathway proteins such as factor B. Furthermore, since linear lysis is observed between normal human serum and primary C3-deficient serum but not between normal human serum and secondary C3-deficient serum caused by the lack of factor H or factor I, this assay may also be used to discriminate between primary and secondary C3 deficiencies.

Amending pine bark with alternative substrates

USDA-ARS?s Scientific Manuscript database

Due to a number of factors, pine bark supplies have significantly decreased over the past few years. While alternative substrates are being evaluated, many growers are asking if these alternative substrates can be used to stretch existing PB supplies. In this study, two alternative substrates, “Cl...

Classical and alternative complement activation on photoreceptor outer segments drives monocyte-dependent retinal atrophy.

PubMed

Katschke, Kenneth J; Xi, Hongkang; Cox, Christian; Truong, Tom; Malato, Yann; Lee, Wyne P; McKenzie, Brent; Arceo, Rommel; Tao, Jianhua; Rangell, Linda; Reichelt, Mike; Diehl, Lauri; Elstrott, Justin; Weimer, Robby M; Campagne, Menno van Lookeren

2018-05-09

Geographic atrophy (GA), the advanced form of dry age-related macular degeneration (AMD), is characterized by progressive loss of retinal pigment epithelium cells and photoreceptors in the setting of characteristic extracellular deposits and remains a serious unmet medical need. While genetic predisposition to AMD is dominated by polymorphisms in complement genes, it remains unclear how complement activation contributes to retinal atrophy. Here we demonstrate that complement is activated on photoreceptor outer segments (POS) in the retina peripheral to atrophic lesions associated with GA. When exposed to human serum following outer blood-retinal barrier breakdown, POS act as potent activators of the classical and alternative complement pathway. In mouse models of retinal degeneration, classical and alternative pathway complement activation on photoreceptors contributed to the loss of photoreceptor function. This was dependent on C5a-mediated recruitment of peripheral blood monocytes but independent of resident microglia. Genetic or pharmacologic inhibition of both classical and alternative complement C3 and C5 convertases was required to reduce progressive degeneration of photoreceptor rods and cones. Our study implicates systemic classical and alternative complement proteins and peripheral blood monocytes as critical effectors of localized retinal degeneration with potential relevance for the contribution of complement activation to GA.

Mathematics Problem Solving, Literacy, and ELL for Alternative Certification Teachers

ERIC Educational Resources Information Center

Evans, Brian R.; Ardito, Gerald; Kim, Soonhyang

2017-01-01

New teachers who entered the profession through alternative pathways often teach in high-need urban environments, which means there may be a significant number of English Language Learner (ELL) students in their classrooms. In order to best support these students, techniques can be employed to best facilitate learning for students who do not have…

Journey on greener pathways: from the use of alternate energy inputs and benign reaction media to sustainable applications of nano-catalysts in synthesis and environmental remediation

EPA Science Inventory

Sustainable synthetic processes developed during the past two decades involving the use of alternate energy inputs and greener reaction media are summarized. These processes include examples of coupling reactions, the synthesis of heterocyclic compounds, and a variety of reactio...

Comparision of Alternatively Certified and Traditionally Certified Missouri High School Science Teachers' Perceptions of Self-Efficacy during the Induction Period

ERIC Educational Resources Information Center

Gaither, Linda

2013-01-01

Sixty percent of America's teachers choose traditional baccalaureate programs while the remaining choose one of several alternative pathways. While certification/training is certainly important to preparing effective teachers, other research indicates that teacher efficacy serves as the foundation of teacher behaviors and classroom practice. The…

Clusterin and COMMD1 Independently Regulate Degradation of the Mammalian Copper ATPases ATP7A and ATP7B*

PubMed Central

Materia, Stephanie; Cater, Michael A.; Klomp, Leo W. J.; Mercer, Julian F. B.; La Fontaine, Sharon

2012-01-01

ATP7A and ATP7B are copper-transporting P1B-type ATPases (Cu-ATPases) that are critical for regulating intracellular copper homeostasis. Mutations in the genes encoding ATP7A and ATP7B lead to copper deficiency and copper toxicity disorders, Menkes and Wilson diseases, respectively. Clusterin and COMMD1 were previously identified as interacting partners of these Cu-ATPases. In this study, we confirmed that clusterin and COMMD1 interact to down-regulate both ATP7A and ATP7B. Overexpression and knockdown of clusterin/COMMD1 decreased and increased, respectively, endogenous levels of ATP7A and ATP7B, consistent with a role in facilitating Cu-ATPase degradation. We demonstrate that whereas the clusterin/ATP7B interaction was enhanced by oxidative stress or mutation of ATP7B, the COMMD1/ATP7B interaction did not change under oxidative stress conditions, and only increased with ATP7B mutations that led to its misfolding. Clusterin and COMMD1 facilitated the degradation of ATP7B containing the same Wilson disease-causing C-terminal mutations via different degradation pathways, clusterin via the lysosomal pathway and COMMD1 via the proteasomal pathway. Furthermore, endogenous ATP7B existed in a complex with clusterin and COMMD1, but these interactions were neither competitive nor cooperative and occurred independently of each other. Together these data indicate that clusterin and COMMD1 represent alternative and independent systems regulating Cu-ATPase quality control, and consequently contributing to the maintenance of copper homeostasis. PMID:22130675

Bad seeds produce bad crops: a single stage-process of prostate tumor invasion

PubMed Central

Man, Yan-gao; Gardner, William A.

2008-01-01

It is a commonly held belief that prostate carcinogenesis is a multi-stage process and that tumor invasion is triggered by the overproduction of proteolytic enzymes. This belief is consistent with data from cell cultures and animal models, whereas is hard to interpret several critical facts, including the presence of cancer in “healthy” young men and cancer DNA phenotype in morphologically normal prostate tissues. These facts argue that alternative pathways may exist for prostate tumor invasion in some cases. Since degradation of the basal cell layer is the most distinct sign of invasion, our recent studies have attempted to identify pre-invasive lesions with focal basal cell layer alterations. Our studies revealed that about 30% of prostate cancer patients harbored normal appearing duct or acinar clusters with a high frequency of focal basal cell layer disruptions. These focally disrupted basal cell layers had significantly reduced cell proliferation and tumor suppressor expression, whereas significantly elevated degeneration, apoptosis, and infiltration of immunoreactive cells. In sharp contrast, associated epithelial cell had significantly elevated proliferation, expression of malignancy-signature markers, and physical continuity with invasive lesions. Based on these and other findings, we have proposed that these normal appearing duct or acinar clusters are derived from monoclonal proliferation of genetically damaged stem cells and could progress directly to invasion through two pathways: 1) clonal in situ transformation (CIST) and 2) multi-potential progenitor mediated “budding” (MPMB). These pathways may contribute to early onset of prostate cancer at young ages, and to clinically more aggressive prostate tumors. PMID:18725981

Spatial and Temporal Eye–Hand Coordination Relies on the Parietal Reach Region

PubMed Central

Hauschild, Markus; Wilke, Melanie; Andersen, Richard A.

2014-01-01

Coordinated eye movements are crucial for precision control of our hands. A commonly believed neural mechanism underlying eye–hand coordination is interaction between the neural networks controlling each effector, exchanging, and matching information, such as movement target location and onset time. Alternatively, eye–hand coordination may result simply from common inputs to independent eye and hand control pathways. Thus far, it remains unknown whether and where either of these two possible mechanisms exists. A candidate location for the former mechanism, interpathway communication, includes the posterior parietal cortex (PPC) where distinct effector-specific areas reside. If the PPC were within the network for eye–hand coordination, perturbing it would affect both eye and hand movements that are concurrently planned. In contrast, if eye–hand coordination arises solely from common inputs, perturbing one effector pathway, e.g., the parietal reach region (PRR), would not affect the other effector. To test these hypotheses, we inactivated part of PRR in the macaque, located in the medial bank of the intraparietal sulcus encompassing the medial intraparietal area and area 5V. When each effector moved alone, PRR inactivation shortened reach but not saccade amplitudes, compatible with the known reach-selective activity of PRR. However, when both effectors moved concurrently, PRR inactivation shortened both reach and saccade amplitudes, and decoupled their reaction times. Therefore, consistent with the interpathway communication hypothesis, we propose that the planning of concurrent eye and hand movements causes the spatial information in PRR to influence the otherwise independent eye control pathways, and that their temporal coupling requires an intact PRR. PMID:25232123

Towards quantitative PET/MRI: a review of MR-based attenuation correction techniques.

PubMed

Hofmann, Matthias; Pichler, Bernd; Schölkopf, Bernhard; Beyer, Thomas

2009-03-01

Positron emission tomography (PET) is a fully quantitative technology for imaging metabolic pathways and dynamic processes in vivo. Attenuation correction of raw PET data is a prerequisite for quantification and is typically based on separate transmission measurements. In PET/CT attenuation correction, however, is performed routinely based on the available CT transmission data. Recently, combined PET/magnetic resonance (MR) has been proposed as a viable alternative to PET/CT. Current concepts of PET/MRI do not include CT-like transmission sources and, therefore, alternative methods of PET attenuation correction must be found. This article reviews existing approaches to MR-based attenuation correction (MR-AC). Most groups have proposed MR-AC algorithms for brain PET studies and more recently also for torso PET/MR imaging. Most MR-AC strategies require the use of complementary MR and transmission images, or morphology templates generated from transmission images. We review and discuss these algorithms and point out challenges for using MR-AC in clinical routine. MR-AC is work-in-progress with potentially promising results from a template-based approach applicable to both brain and torso imaging. While efforts are ongoing in making clinically viable MR-AC fully automatic, further studies are required to realize the potential benefits of MR-based motion compensation and partial volume correction of the PET data.

Structural Basis of Resistance to Anti-Cytochrome bc1 Complex Inhibitors: Implication for Drug Improvement

PubMed Central

Esser, Lothar; Yu, Chang-An; Xia, Di

2016-01-01

The emergence of drug resistance has devastating economic and social consequences, a testimonial of which is the rise and fall of inhibitors against the respiratory component cytochrome bc1 complex, a time tested and highly effective target for disease control. Unfortunately, the mechanism of resistance is a multivariate problem, including primarily mutations in the gene of the cytochrome b subunit but also activation of alternative pathways of ubiquinol oxidation and pharmacokinetic effects. There is a considerable interest in designing new bc1 inhibitors with novel modes of binding and lower propensity to induce the development of resistance. The accumulation of crystallographic data of bc1 complexes with and without inhibitors bound provides the structural basis for rational drug design. In particular, the cytochrome b subunit offers two distinct active sites that can be targeted for inhibition - the quinol oxidation site and the quinone reduction site. This review brings together available structural information of inhibited bc1 by various quinol oxidation- and reduction-site inhibitors, the inhibitor binding modes, conformational changes upon inhibitor binding of side chains in the active site and large scale domain movements of the iron-sulfur protein subunit. Structural data analysis provides a clear understanding of where and why existing inhibitors fail and points towards promising alternatives. PMID:23688079

Rituximab fails where eculizumab restores renal function in C3nef-related DDD.

PubMed

Rousset-Rouvière, Caroline; Cailliez, Mathilde; Garaix, Florentine; Bruno, Daniele; Laurent, Daniel; Tsimaratos, Michel

2014-06-01

Dense deposit disease (DDD), a C3 glomerulopathy (C3G), is a rare disease with unfavorable progression towards end-stage kidney disease. The pathogenesis of DDD is due to cytotoxic effects related to acquired or genetic dysregulation of the complement alternative pathway, which is at times accompanied by the production of C3 nephritic factor (C3NeF), an auto-antibody directed against the alternative C3 convertase. Available treatments include plasma exchange, CD20-targeted antibodies, and a terminal complement blockade via the anti-C5 monoclonal antibody eculizumab. We report here the case of an 8-year-old child with C3NeF and refractory DDD who presented with a nephritic syndrome. She tested positive for C3NeF activity; C3 was undetectable. Genetic analyses of the alternative complement pathway were normal. Methylprednisolone pulses and mycophenolate mofetil treatment resulted in complete recovery of renal function and a reduction in proteinuria. Corticosteroids were tapered and then withdrawn. Four months after corticosteroid discontinuation, hematuria and proteinuria recurred, and a renal biopsy confirmed an active DDD with a majority of extracapillary crescents. Despite an increase in immunosuppressive drugs, including methylprednisolone pulses and rituximab therapy, the patient suffered acute renal failure within 3 weeks, requiring dialysis. Eculizumab treatment resulted in a quick and impressive response. Hematuria very quickly resolved, kidney function improved, and no further dialysis was required. The patient received bimonthly eculizumab injections of 600 mg, allowing for normalization of renal function and reduction of proteinuria to <0.5 g per day. Since then, she continues to receive eculizumab. Complement regulation pathway-targeted therapy may be a specific and useful treatment for rapidly progressing DDD prior to the development of glomerulosclerosis. Our data provide evidence supporting the pivotal role of complement alternative pathway abnormalities in C3G with DDD.

Reconstruction of metabolic pathways by combining probabilistic graphical model-based and knowledge-based methods

PubMed Central

2014-01-01

Automatic reconstruction of metabolic pathways for an organism from genomics and transcriptomics data has been a challenging and important problem in bioinformatics. Traditionally, known reference pathways can be mapped into an organism-specific ones based on its genome annotation and protein homology. However, this simple knowledge-based mapping method might produce incomplete pathways and generally cannot predict unknown new relations and reactions. In contrast, ab initio metabolic network construction methods can predict novel reactions and interactions, but its accuracy tends to be low leading to a lot of false positives. Here we combine existing pathway knowledge and a new ab initio Bayesian probabilistic graphical model together in a novel fashion to improve automatic reconstruction of metabolic networks. Specifically, we built a knowledge database containing known, individual gene / protein interactions and metabolic reactions extracted from existing reference pathways. Known reactions and interactions were then used as constraints for Bayesian network learning methods to predict metabolic pathways. Using individual reactions and interactions extracted from different pathways of many organisms to guide pathway construction is new and improves both the coverage and accuracy of metabolic pathway construction. We applied this probabilistic knowledge-based approach to construct the metabolic networks from yeast gene expression data and compared its results with 62 known metabolic networks in the KEGG database. The experiment showed that the method improved the coverage of metabolic network construction over the traditional reference pathway mapping method and was more accurate than pure ab initio methods. PMID:25374614

A System-Level Pathway-Phenotype Association Analysis Using Synthetic Feature Random Forest

PubMed Central

Pan, Qinxin; Hu, Ting; Malley, James D.; Andrew, Angeline S.; Karagas, Margaret R.; Moore, Jason H.

2015-01-01

As the cost of genome-wide genotyping decreases, the number of genome-wide association studies (GWAS) has increased considerably. However, the transition from GWAS findings to the underlying biology of various phenotypes remains challenging. As a result, due to its system-level interpretability, pathway analysis has become a popular tool for gaining insights on the underlying biology from high-throughput genetic association data. In pathway analyses, gene sets representing particular biological processes are tested for significant associations with a given phenotype. Most existing pathway analysis approaches rely on single-marker statistics and assume that pathways are independent of each other. As biological systems are driven by complex biomolecular interactions, embracing the complex relationships between single-nucleotide polymorphisms (SNPs) and pathways needs to be addressed. To incorporate the complexity of gene-gene interactions and pathway-pathway relationships, we propose a system-level pathway analysis approach, synthetic feature random forest (SF-RF), which is designed to detect pathway-phenotype associations without making assumptions about the relationships among SNPs or pathways. In our approach, the genotypes of SNPs in a particular pathway are aggregated into a synthetic feature representing that pathway via Random Forest (RF). Multiple synthetic features are analyzed using RF simultaneously and the significance of a synthetic feature indicates the significance of the corresponding pathway. We further complement SF-RF with pathway-based Statistical Epistasis Network (SEN) analysis that evaluates interactions among pathways. By investigating the pathway SEN, we hope to gain additional insights into the genetic mechanisms contributing to the pathway-phenotype association. We apply SF-RF to a population-based genetic study of bladder cancer and further investigate the mechanisms that help explain the pathway-phenotype associations using SEN. The bladder cancer associated pathways we found are both consistent with existing biological knowledge and reveal novel and plausible hypotheses for future biological validations. PMID:24535726

Do Reciprocal Associations Exist between Social and Language Pathways in Preschoolers with Autism Spectrum Disorders?

ERIC Educational Resources Information Center

Bennett, Teresa A.; Szatmari, Peter; Georgiades, Katholiki; Hanna, Steven; Janus, Magdelena; Georgiades, Stelios; Duku, Eric; Bryson, Susan; Fombonne, Eric; Smith, Isabel M.; Mirenda, Pat; Volden, Joanne; Waddell, Charlotte; Roberts, Wendy; Vaillancourt, Tracy; Zwaigenbaum, Lonnie; Elsabbagh, Mayada; Thompson, Ann

2015-01-01

Background: Differences in how developmental pathways interact dynamically in children with autism spectrum disorder (ASD) likely contribute in important ways to phenotypic heterogeneity. This study aimed to model longitudinal reciprocal associations between social competence (SOC) and language (LANG) pathways in young children with ASD. Methods:…

Application of adverse outcome pathways (AOPs) in human health and ecotoxicology capturing divergent consequences of conserved molecular initiating events via AOP networks

EPA Science Inventory

The adverse outcome pathway (AOP) framework was developed to help organize and disseminate existing knowledge concerning the means through which specific perturbations of biological pathways can lead to adverse outcomes considered relevant to risk-based regulatory decision-making...

Application of Adverse Outcome Pathways (AOPs) in Human Health and Ecotoxicology Capturing Divergent Consequences of Conserved Molecular Initiating Events via AOP Networks (Presentation)

EPA Science Inventory

The adverse outcome pathway (AOP) framework was developed to help organize and disseminate existing knowledge concerning the means through which specific perturbations of biological pathways can lead to adverse outcomes considered relevant to risk-based regulatory decision-making...

10 CFR 60.134 - Design of seals for shafts and boreholes.

Code of Federal Regulations, 2014 CFR

2014-01-01

... boreholes shall be designed so that following permanent closure they do not become pathways that compromise... pathway for groundwater to contact the waste packages or (2) For radionuclide migration through existing pathways. [48 FR 28222, June 21, 1983, as amended at 50 FR 29648, July 22, 1985] Design Criteria for the...

10 CFR 60.134 - Design of seals for shafts and boreholes.

Code of Federal Regulations, 2012 CFR

2012-01-01

... boreholes shall be designed so that following permanent closure they do not become pathways that compromise... pathway for groundwater to contact the waste packages or (2) For radionuclide migration through existing pathways. [48 FR 28222, June 21, 1983, as amended at 50 FR 29648, July 22, 1985] Design Criteria for the...

10 CFR 60.134 - Design of seals for shafts and boreholes.

Code of Federal Regulations, 2013 CFR

2013-01-01

... boreholes shall be designed so that following permanent closure they do not become pathways that compromise... pathway for groundwater to contact the waste packages or (2) For radionuclide migration through existing pathways. [48 FR 28222, June 21, 1983, as amended at 50 FR 29648, July 22, 1985] Design Criteria for the...

Pathways through Secondary School in a Comprehensive System: Does Parental Education and School Attended Affect Students' Choice?

ERIC Educational Resources Information Center

Chesters, Jenny

2015-01-01

As the Australian labour market restructured during the 1980s and 1990s, Year 12 retention rates more than doubled between 1983 and 1993 secondary schools diversified to include vocational education and training programs as alternative pathways through school. From a human capital perspective, the completion of vocational qualifications in school…

Endogenous boldenone-formation in cattle: alternative invertebrate organisms to elucidate the enzymatic pathway and the potential role of edible fungi on cattle's feed.

PubMed

Verheyden, K; Noppe, H; Zorn, H; Van Immerseel, F; Vanden Bussche, J; Wille, K; Bekaert, K; Janssen, C R; De Brabander, H F; Vanhaecke, L

2010-04-01

Although beta-boldenone (bBol) used to be a marker of illegal steroid administration in calves, its endogenous formation has recently been demonstrated in these vertebrates. However, research on the pathway leading to bBol remains scarce. This study shows the usefulness of in vivo invertebrate models as alternatives to vertebrate animal experiments, using Neomysis integer and Lucilia sericata. In accordance with vertebrates, androstenedione (AED) was the main metabolite of beta-testosterone (bT) produced by these invertebrates, and bBol was also frequently detected. Moreover, in vitro experiments using feed-borne fungi and microsomes were useful to perform the pathway from bT to bBol. Even the conversion of phytosterols into steroids was shown in vitro. Both in vivo and in vitro, the conversion of bT into bBol could be demonstrated in this study. Metabolism of phytosterols by feed-borne fungi may be of particular importance to explain the endogenous bBol-formation by cattle. To the best of our knowledge, it is the first time the latter pathway is described in literature. 2010 Elsevier Ltd. All rights reserved.

Organization of biogeochemical nitrogen pathways with switch-like adjustment in fluctuating soil redox conditions

PubMed Central

Lamba, Sanjay; Bera, Soumen; Rashid, Mubasher; Medvinsky, Alexander B.; Acquisti, Claudia; Li, Bai-Lian

2017-01-01

Nitrogen is cycled throughout ecosystems by a suite of biogeochemical processes. The high complexity of the nitrogen cycle resides in an intricate interplay between reversible biochemical pathways alternatively and specifically activated in response to diverse environmental cues. Despite aggressive research, how the fundamental nitrogen biochemical processes are assembled and maintained in fluctuating soil redox conditions remains elusive. Here, we address this question using a kinetic modelling approach coupled with dynamical systems theory and microbial genomics. We show that alternative biochemical pathways play a key role in keeping nitrogen conversion and conservation properties invariant in fluctuating environments. Our results indicate that the biochemical network holds inherent adaptive capacity to stabilize ammonium and nitrate availability, and that the bistability in the formation of ammonium is linked to the transient upregulation of the amo-hao mediated nitrification pathway. The bistability is maintained by a pair of complementary subsystems acting as either source or sink type systems in response to soil redox fluctuations. It is further shown how elevated anthropogenic pressure has the potential to break down the stability of the system, altering substantially ammonium and nitrate availability in the soil, with dramatic effects on biodiversity. PMID:28280580

Social Identities as Pathways into and out of Addiction.

PubMed

Dingle, Genevieve A; Cruwys, Tegan; Frings, Daniel

2015-01-01

There exists a predominant identity loss and "redemption" narrative in the addiction literature describing how individuals move from a "substance user" identity to a "recovery" identity. However, other identity related pathways influencing onset, treatment seeking and recovery may exist, and the process through which social identities unrelated to substance use change over time is not well understood. This study was designed to provide a richer understanding of such social identities processes. Semi-structured interviews were conducted with 21 adults residing in a drug and alcohol therapeutic community (TC) and thematic analysis revealed two distinct identity-related pathways leading into and out of addiction. Some individuals experienced a loss of valued identities during addiction onset that were later renewed during recovery (consistent with the existing redemption narrative). However, a distinct identity gain pathway emerged for socially isolated individuals, who described the onset of their addiction in terms of a new valued social identity. Almost all participants described their TC experience in terms of belonging to a recovery community. Participants on the identity loss pathway aimed to renew their pre-addiction identities after treatment while those on the identity gain pathway aimed to build aspirational new identities involving study, work, or family roles. These findings help to explain how social factors are implicated in the course of addiction, and may act as either motivations for or barriers to recovery. The qualitative analysis yielded a testable model for future research in other samples and settings.

Social Identities as Pathways into and out of Addiction

PubMed Central

Dingle, Genevieve A.; Cruwys, Tegan; Frings, Daniel

2015-01-01

There exists a predominant identity loss and “redemption” narrative in the addiction literature describing how individuals move from a “substance user” identity to a “recovery” identity. However, other identity related pathways influencing onset, treatment seeking and recovery may exist, and the process through which social identities unrelated to substance use change over time is not well understood. This study was designed to provide a richer understanding of such social identities processes. Semi-structured interviews were conducted with 21 adults residing in a drug and alcohol therapeutic community (TC) and thematic analysis revealed two distinct identity-related pathways leading into and out of addiction. Some individuals experienced a loss of valued identities during addiction onset that were later renewed during recovery (consistent with the existing redemption narrative). However, a distinct identity gain pathway emerged for socially isolated individuals, who described the onset of their addiction in terms of a new valued social identity. Almost all participants described their TC experience in terms of belonging to a recovery community. Participants on the identity loss pathway aimed to renew their pre-addiction identities after treatment while those on the identity gain pathway aimed to build aspirational new identities involving study, work, or family roles. These findings help to explain how social factors are implicated in the course of addiction, and may act as either motivations for or barriers to recovery. The qualitative analysis yielded a testable model for future research in other samples and settings. PMID:26648882

Financing the FAA : comparisons of existing and alternative systems to provide funding for the development and operations of the National Airspace System

DOT National Transportation Integrated Search

2000-03-30

This paper examines selected alternative methods of financing the National : Airspace System (NAS), and presents information on the consequences to major : system users of alternative financing mechanisms. The paper examines : alternatives that have ...

26 CFR 20.2032-1 - Alternate valuation.

Code of Federal Regulations, 2010 CFR

2010-04-01

... alternate valuation method under section 2032, the property included in the decedent's gross estate on the..., the alternate valuation method applies to all property included in the gross estate and cannot be... elects the alternate valuation method under section 2432, all property interests existing at the date of...

An alternative approach to depigmentation by soybean extracts via inhibition of the PAR-2 pathway.

PubMed

Paine, C; Sharlow, E; Liebel, F; Eisinger, M; Shapiro, S; Seiberg, M

2001-04-01

The protease-activated receptor 2, expressed on keratinocytes but not on melanocytes, has been ascribed functional importance in the regulation of pigmentation by phagocytosis of melanosomes. Inhibition of protease-activated receptor 2 activation by synthetic serine protease inhibitors requires keratinocyte-melanocyte contact and results in depigmentation of the dark skinned Yucatan swine, suggesting a new class of depigmenting mechanism and agents. We therefore examined natural agents that could exert their effect via the protease-activated receptor 2 pathway. Here we show that soymilk and the soybean-derived serine protease inhibitors soybean trypsin inhibitor and Bowman-Birk inhibitor inhibit protease-activated receptor 2 cleavage, affect cytoskeletal and cell surface organization, and reduce keratinocyte phagocytosis. The depigmenting activity of these agents and their capability to prevent ultraviolet-induced pigmentation are demonstrated both in vitro and in vivo. These results imply that inhibition of the protease-activated receptor 2 pathway by soymilk may be used as a natural alternative to skin lightening.

How quantitative measures unravel design principles in multi-stage phosphorylation cascades.

PubMed

Frey, Simone; Millat, Thomas; Hohmann, Stefan; Wolkenhauer, Olaf

2008-09-07

We investigate design principles of linear multi-stage phosphorylation cascades by using quantitative measures for signaling time, signal duration and signal amplitude. We compare alternative pathway structures by varying the number of phosphorylations and the length of the cascade. We show that a model for a weakly activated pathway does not reflect the biological context well, unless it is restricted to certain parameter combinations. Focusing therefore on a more general model, we compare alternative structures with respect to a multivariate optimization criterion. We test the hypothesis that the structure of a linear multi-stage phosphorylation cascade is the result of an optimization process aiming for a fast response, defined by the minimum of the product of signaling time and signal duration. It is then shown that certain pathway structures minimize this criterion. Several popular models of MAPK cascades form the basis of our study. These models represent different levels of approximation, which we compare and discuss with respect to the quantitative measures.

Toward a Network Model of MHC Class II-Restricted Antigen Processing

PubMed Central

Miller, Michael A.; Ganesan, Asha Purnima V.; Eisenlohr, Laurence C.

2013-01-01

The standard model of Major Histocompatibility Complex class II (MHCII)-restricted antigen processing depicts a straightforward, linear pathway: internalized antigens are converted into peptides that load in a chaperone dependent manner onto nascent MHCII in the late endosome, the complexes subsequently trafficking to the cell surface for recognition by CD4+ T cells (TCD4+). Several variations on this theme, both moderate and radical, have come to light but these alternatives have remained peripheral, the conventional pathway generally presumed to be the primary driver of TCD4+ responses. Here we continue to press for the conceptual repositioning of these alternatives toward the center while proposing that MHCII processing be thought of less in terms of discrete pathways and more in terms of a network whose major and minor conduits are variable depending upon many factors, including the epitope, the nature of the antigen, the source of the antigen, and the identity of the antigen-presenting cell. PMID:24379819

Suppression of the alternative lengthening of telomere pathway by the chromatin remodelling factor ATRX

PubMed Central

Clynes, David; Jelinska, Clare; Xella, Barbara; Ayyub, Helena; Scott, Caroline; Mitson, Matthew; Taylor, Stephen; Higgs, Douglas R.; Gibbons, Richard J.

2015-01-01

Fifteen per cent of cancers maintain telomere length independently of telomerase by the homologous recombination (HR)-associated alternative lengthening of telomeres (ALT) pathway. A unifying feature of these tumours are mutations in ATRX. Here we show that expression of ectopic ATRX triggers a suppression of the pathway and telomere shortening. Importantly ATRX-mediated ALT suppression is dependent on the histone chaperone DAXX. Re-expression of ATRX is associated with a reduction in replication fork stalling, a known trigger for HR and loss of MRN from telomeres. A G-quadruplex stabilizer partially reverses the effect of ATRX, inferring ATRX may normally facilitate replication through these sequences that, if they persist, promote ALT. We propose that defective telomere chromatinization through loss of ATRX promotes the persistence of aberrant DNA secondary structures, which in turn present a barrier to DNA replication, leading to replication fork stalling, collapse, HR and subsequent recombination-mediated telomere synthesis in ALT cancers. PMID:26143912

5-Hydroxytryptophan, a major product of tryptophan degradation, is essential for optimal replication of human parainfluenza virus.

PubMed

Rabbani, M A G; Barik, Sailen

2017-03-01

Interferon (IFN) exerts its antiviral effect by inducing a large family of cellular genes, named interferon (IFN)-stimulated genes (ISGs). An intriguing member of this family is indoleamine 2,3-dioxygenase (IDO), which catalyzes the first and rate-limiting step of the main branch of tryptophan (Trp) degradation, the kynurenine pathway. We recently showed that IDO strongly inhibits human parainfluenza virus type 3 (PIV3), a significant respiratory pathogen. Here, we show that 5-hydoxytryptophan (5-HTP), the first product of an alternative branch of Trp degradation and a serotonin precursor, is essential to protect virus growth against IDO in cell culture. We also show that the apparent antiviral effect of IDO on PIV3 is not due to the generation of the kynurenine pathway metabolites, but rather due to the depletion of intracellular Trp by IDO, as a result of which this rare amino acid becomes unavailable for the alternative, proviral 5-HTP pathway. Copyright © 2017 Elsevier Inc. All rights reserved.

A spiking neural network based on the basal ganglia functional anatomy.

PubMed

Baladron, Javier; Hamker, Fred H

2015-07-01

We introduce a spiking neural network of the basal ganglia capable of learning stimulus-action associations. We model learning in the three major basal ganglia pathways, direct, indirect and hyperdirect, by spike time dependent learning and considering the amount of dopamine available (reward). Moreover, we allow to learn a cortico-thalamic pathway that bypasses the basal ganglia. As a result the system develops new functionalities for the different basal ganglia pathways: The direct pathway selects actions by disinhibiting the thalamus, the hyperdirect one suppresses alternatives and the indirect pathway learns to inhibit common mistakes. Numerical experiments show that the system is capable of learning sets of either deterministic or stochastic rules. Copyright © 2015 Elsevier Ltd. All rights reserved.