Working group 1B - basis for the standard-liquid pathway

International Nuclear Information System (INIS)

Budnitz, R.

1993-01-01

This paper presents a summary of the progress made by working group 1B (Basis for the Standard-Liquid Pathway) during the Electric Power Research Institute's EPRI Workshop on the technical basis of EPA HLW Disposal Criteria, March 1993. This group discussed the containment requirements of Environmental Protection Agency (EPA) standard 40 CFR Part 191. This is a major issue when considering the liquid pathway of contamination during the disposal of high-level radioactive wastes. Questions that were raised by this group were (1) What were the problems with Table 1 of 40 CFR Part 191?; (2) What would be fixed with the person-rem alternative that is offered?; and (3) What would be fixed if Table 1 were supplemented with additional columns for other pathways? Other topics that were touched on were the definition of the term open-quotes reasonable expectationsclose quotes and 100,000 year criteria

Benchmarking pathway interaction network for colorectal cancer to identify dysregulated pathways

Directory of Open Access Journals (Sweden)

Q. Wang

Full Text Available Different pathways act synergistically to participate in many biological processes. Thus, the purpose of our study was to extract dysregulated pathways to investigate the pathogenesis of colorectal cancer (CRC based on the functional dependency among pathways. Protein-protein interaction (PPI information and pathway data were retrieved from STRING and Reactome databases, respectively. After genes were aligned to the pathways, each pathway activity was calculated using the principal component analysis (PCA method, and the seed pathway was discovered. Subsequently, we constructed the pathway interaction network (PIN, where each node represented a biological pathway based on gene expression profile, PPI data, as well as pathways. Dysregulated pathways were then selected from the PIN according to classification performance and seed pathway. A PIN including 11,960 interactions was constructed to identify dysregulated pathways. Interestingly, the interaction of mRNA splicing and mRNA splicing-major pathway had the highest score of 719.8167. Maximum change of the activity score between CRC and normal samples appeared in the pathway of DNA replication, which was selected as the seed pathway. Starting with this seed pathway, a pathway set containing 30 dysregulated pathways was obtained with an area under the curve score of 0.8598. The pathway of mRNA splicing, mRNA splicing-major pathway, and RNA polymerase I had the maximum genes of 107. Moreover, we found that these 30 pathways had crosstalks with each other. The results suggest that these dysregulated pathways might be used as biomarkers to diagnose CRC.

Women's Work Pathways Across the Life Course.

Science.gov (United States)

Damaske, Sarah; Frech, Adrianne

2016-04-01

Despite numerous changes in women's employment in the latter half of the twentieth century, women's employment continues to be uneven and stalled. Drawing from data on women's weekly work hours in the National Longitudinal Survey of Youth (NLSY79), we identify significant inequality in women's labor force experiences across adulthood. We find two pathways of stable full-time work for women, three pathways of part-time employment, and a pathway of unpaid labor. A majority of women follow one of the two full-time work pathways, while fewer than 10% follow a pathway of unpaid labor. Our findings provide evidence of the lasting influence of work-family conflict and early socioeconomic advantages and disadvantages on women's work pathways. Indeed, race, poverty, educational attainment, and early family characteristics significantly shaped women's work careers. Work-family opportunities and constraints also were related to women's work hours, as were a woman's gendered beliefs and expectations. We conclude that women's employment pathways are a product of both their resources and changing social environment as well as individual agency. Significantly, we point to social stratification, gender ideologies, and work-family constraints, all working in concert, as key explanations for how women are "tracked" onto work pathways from an early age.

Kynurenine pathway metabolites and enzymes involved in redox reactions.

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González Esquivel, D; Ramírez-Ortega, D; Pineda, B; Castro, N; Ríos, C; Pérez de la Cruz, V

2017-01-01

Oxido-reduction reactions are a fundamental part of the life due to support many vital biological processes as cellular respiration and glucose oxidation. In the redox reactions, one substance transfers one or more electrons to another substance. An important electron carrier is the coenzyme NAD + , which is involved in many metabolic pathways. De novo biosynthesis of NAD + is through the kynurenine pathway, the major route of tryptophan catabolism, which is sensitive to redox environment and produces metabolites with redox capacity, able to alter biological functions that are controlled by redox-responsive signaling pathways. Kynurenine pathway metabolites have been implicated in the physiology process and in the physiopathology of many diseases; processes that also share others factors as dysregulation of calcium homeostasis, mitochondrial dysfunction, oxidative stress, inflammation and cell death, which impact the redox environment. This review examines in detail the available evidence in which kynurenine pathway metabolites participate in redox reactions and their effect on cellular redox homeostasis, since the knowledge of the main factors and mechanisms that lead to cell death in many neurodegenative disorders and other pathologies, such as mitochondrial dysfunction, oxidative stress and kynurenines imbalance, will allow to develop therapies using them as targets. This article is part of the Special Issue entitled 'The Kynurenine Pathway in Health and Disease'. Copyright © 2016 Elsevier Ltd. All rights reserved.

Microbial production of natural and non-natural flavonoids: Pathway engineering, directed evolution and systems/synthetic biology.

Science.gov (United States)

Pandey, Ramesh Prasad; Parajuli, Prakash; Koffas, Mattheos A G; Sohng, Jae Kyung

2016-01-01

In this review, we address recent advances made in pathway engineering, directed evolution, and systems/synthetic biology approaches employed in the production and modification of flavonoids from microbial cells. The review is divided into two major parts. In the first, various metabolic engineering and system/synthetic biology approaches used for production of flavonoids and derivatives are discussed broadly. All the manipulations/engineering accomplished on the microorganisms since 2000 are described in detail along with the biosynthetic pathway enzymes, their sources, structures of the compounds, and yield of each product. In the second part of the review, post-modifications of flavonoids by four major reactions, namely glycosylations, methylations, hydroxylations and prenylations using recombinant strains are described. Copyright © 2016 Elsevier Inc. All rights reserved.

Puerarin suppresses proliferation of endometriotic stromal cells partly via the MAPK signaling pathway induced by 17ß-estradiol-BSA.

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Wen Cheng

Full Text Available BACKGROUND: Puerarin is a major isoflavonoid compound extracted from Radix puerariae. It has a weak estrogenic action by binding to estrogen receptors (ERs. In our early clinical practice to treat endometriosis, a better therapeutic effect was achieved if the formula of traditional Chinese medicine included Radix puerariae. The genomic and non-genomic effects of puerarin were studied in our Lab. This study aims to investigate the ability of puerarin to bind competitively to ERs in human endometriotic stromal cells (ESCs, determine whether and how puerarin may influence phosphorylation of the non-genomic signaling pathway induced by 17ß-estradiol conjugated to BSA (E(2-BSA. METHODOLOGY: ESCs were successfully established. Binding of puerarin to ERs was assessed by a radioactive competitive binding assay in ESCs. Activation of the signaling pathway was screened by human phospho-kinase array, and was further confirmed by western blot. Cell proliferation was analyzed according to the protocol of CCK-8. The mRNA and protein levels of cyclin D1, Cox-2 and Cyp19 were determined by real-time PCR and western blotting. Inhibitor of MEK1/2 or ER antagonist was used to confirm the involved signal pathway. PRINCIPAL FINDINGS: Our data demonstrated that the total binding ability of puerarin to ERs on viable cells is around 1/3 that of 17ß-estradiol (E(2. E(2-BSA was able to trigger a rapid, non-genomic, membrane-mediated activation of ERK1/2 in ESCs and this phenomenon was associated with an increased proliferation of ESCs. Treating ESCs with puerarin abrogated the phosphorylation of ERK and significantly decreased cell proliferation, as well as related gene expression levels enhanced by E(2-BSA. CONCLUSIONS/SIGNIFICANCE: Puerarin suppresses proliferation of ESCs induced by E(2-BSA partly via impeding a rapid, non-genomic, membrane-initiated ERK pathway, and down-regulation of Cyclin D1, Cox-2 and Cyp19 are involved in the process. Our data further show

EGF stimulates the activation of EGF receptors and the selective activation of major signaling pathways during mitosis.

Science.gov (United States)

Wee, Ping; Shi, Huaiping; Jiang, Jennifer; Wang, Yuluan; Wang, Zhixiang

2015-03-01

Mitosis and epidermal growth factor (EGF) receptor (EGFR) are both targets for cancer therapy. The role of EGFR signaling in mitosis has been rarely studied and poorly understood. The limited studies indicate that the activation of EGFR and downstream signaling pathways is mostly inhibited during mitosis. However, we recently showed that EGFR is phosphorylated in response to EGF stimulation in mitosis. Here we studied EGF-induced EGFR activation and the activation of major signaling pathways downstream of EGFR during mitosis. We showed that EGFR was strongly activated by EGF during mitosis as all the five major tyrosine residues including Y992, Y1045, Y1068, Y1086, and Y1173 were phosphorylated to a level similar to that in the interphase. We further showed that the activated EGFR is able to selectively activate some downstream signaling pathways while avoiding others. Activated EGFR is able to activate PI3K and AKT2, but not AKT1, which may be responsible for the observed effects of EGF against nocodazole-induced cell death. Activated EGFR is also able to activate c-Src, c-Cbl and PLC-γ1 during mitosis. However, activated EGFR is unable to activate ERK1/2 and their downstream substrates RSK and Elk-1. While it activated Ras, EGFR failed to fully activate Raf-1 in mitosis due to the lack of phosphorylation at Y341 and the lack of dephosphorylation at pS259. We conclude that contrary to the dogma, EGFR is activated by EGF during mitosis. Moreover, EGFR-mediated cell signaling is regulated differently from the interphase to specifically serve the needs of the cell in mitosis. Copyright © 2015 Elsevier Inc. All rights reserved.

Green tea polyphenol (−)-epigallocatechin-3-gallate triggered hepatotoxicity in mice: Responses of major antioxidant enzymes and the Nrf2 rescue pathway

International Nuclear Information System (INIS)

Wang, Dongxu; Wang, Yijun; Wan, Xiaochun; Yang, Chung S.; Zhang, Jinsong

2015-01-01

(−)-Epigallocatechin-3-gallate (EGCG), a constituent of green tea, has been suggested to have numerous health-promoting effects. On the other hand, high-dose EGCG is able to evoke hepatotoxicity. In the present study, we elucidated the responses of hepatic major antioxidant enzymes and nuclear factor erythroid 2-related factor 2 (Nrf2) rescue pathway to high-dose levels of EGCG in Kunming mice. At a non-lethal toxic dose (75 mg/kg, i.p.), repeated EGCG treatments markedly decreased the levels of superoxide dismutase, catalase, and glutathione peroxidase. As a rescue response, the nuclear distribution of Nrf2 was significantly increased; a battery of Nrf2-target genes, including heme oxygenase 1 (HO1), NAD(P)H:quinone oxidoreductase 1 (NQO1), glutathione S-transferase (GST), and those involved in glutathione and thioredoxin systems, were all up-regulated. At the maximum tolerated dose (45 mg/kg, i.p.), repeated EGCG treatments did not disturb the major antioxidant defense. Among the above-mentioned genes, only HO1, NQO1, and GST genes were significantly but modestly up-regulated, suggesting a comprehensive and extensive activation of Nrf2-target genes principally occurs at toxic levels of EGCG. At a lethal dose (200 mg/kg, i.p.), a single EGCG treatment dramatically decreased not only the major antioxidant defense but also the Nrf2-target genes, demonstrating that toxic levels of EGCG are able to cause a biphasic response of Nrf2. Overall, the mechanism of EGCG-triggered hepatotoxicity involves suppression of major antioxidant enzymes, and the Nrf2 rescue pathway plays a vital role for counteracting EGCG toxicity. - Highlights: • EGCG at maximum tolerated dose does not disturb hepatic major antioxidant defense. • EGCG at maximum tolerated dose modestly upregulates hepatic Nrf2 target genes. • EGCG at toxic dose suppresses hepatic major antioxidant enzymes. • EGCG at non-lethal toxic dose pronouncedly activates hepatic Nrf2 rescue response. • EGCG at

Green tea polyphenol (−)-epigallocatechin-3-gallate triggered hepatotoxicity in mice: Responses of major antioxidant enzymes and the Nrf2 rescue pathway

Energy Technology Data Exchange (ETDEWEB)

Wang, Dongxu; Wang, Yijun; Wan, Xiaochun [Key Laboratory of Tea Biochemistry & Biotechnology, School of Tea & Food Science, Anhui Agricultural University, Hefei, Anhui 230036 (China); Yang, Chung S. [Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854 (United States); Zhang, Jinsong, E-mail: zjs@ahau.edu.cn [Key Laboratory of Tea Biochemistry & Biotechnology, School of Tea & Food Science, Anhui Agricultural University, Hefei, Anhui 230036 (China)

2015-02-15

(−)-Epigallocatechin-3-gallate (EGCG), a constituent of green tea, has been suggested to have numerous health-promoting effects. On the other hand, high-dose EGCG is able to evoke hepatotoxicity. In the present study, we elucidated the responses of hepatic major antioxidant enzymes and nuclear factor erythroid 2-related factor 2 (Nrf2) rescue pathway to high-dose levels of EGCG in Kunming mice. At a non-lethal toxic dose (75 mg/kg, i.p.), repeated EGCG treatments markedly decreased the levels of superoxide dismutase, catalase, and glutathione peroxidase. As a rescue response, the nuclear distribution of Nrf2 was significantly increased; a battery of Nrf2-target genes, including heme oxygenase 1 (HO1), NAD(P)H:quinone oxidoreductase 1 (NQO1), glutathione S-transferase (GST), and those involved in glutathione and thioredoxin systems, were all up-regulated. At the maximum tolerated dose (45 mg/kg, i.p.), repeated EGCG treatments did not disturb the major antioxidant defense. Among the above-mentioned genes, only HO1, NQO1, and GST genes were significantly but modestly up-regulated, suggesting a comprehensive and extensive activation of Nrf2-target genes principally occurs at toxic levels of EGCG. At a lethal dose (200 mg/kg, i.p.), a single EGCG treatment dramatically decreased not only the major antioxidant defense but also the Nrf2-target genes, demonstrating that toxic levels of EGCG are able to cause a biphasic response of Nrf2. Overall, the mechanism of EGCG-triggered hepatotoxicity involves suppression of major antioxidant enzymes, and the Nrf2 rescue pathway plays a vital role for counteracting EGCG toxicity. - Highlights: • EGCG at maximum tolerated dose does not disturb hepatic major antioxidant defense. • EGCG at maximum tolerated dose modestly upregulates hepatic Nrf2 target genes. • EGCG at toxic dose suppresses hepatic major antioxidant enzymes. • EGCG at non-lethal toxic dose pronouncedly activates hepatic Nrf2 rescue response. • EGCG at

Major Differences in Neurooxidative and Neuronitrosative Stress Pathways Between Major Depressive Disorder and Types I and II Bipolar Disorder.

Science.gov (United States)

Maes, Michael; Landucci Bonifacio, Kamila; Morelli, Nayara Rampazzo; Vargas, Heber Odebrecht; Barbosa, Décio Sabbatini; Carvalho, André F; Nunes, Sandra Odebrecht Vargas

2018-04-21

Accumulating evidence indicates that oxidative and nitrosative stress (O&NS) pathways play a key role in the pathophysiology of bipolar disorder (BD) and major depressive disorder (MDD). However, only a handful of studies have directly compared alterations in O&NS pathways among patients with MDD and BD types I (BPI) and BPII. Thus, the current study compared superoxide dismutase (SOD1), lipid hydroperoxides (LOOH), catalase, nitric oxide metabolites (NOx), malondialdehyde (MDA), and advanced oxidation protein products (AOPP) between mood disorder patients in a clinically remitted state. To this end 45, 23, and 37 participants with BPI, BPII, and MDD, respectively, as well as 54 healthy controls (HCs) were recruited. Z-unit weighted composite scores were computed as indices of reactive oxygen species (ROS) production and nitro-oxidative stress driving lipid or protein oxidation. SOD1, NOx, and MDA were significantly higher in MDD than in the other three groups. AOPP was significantly higher in BPI than in HCs and BPII patients. BPII patients showed lower SOD1 compared to all other groups. Furthermore, MDD was characterized by increased indices of ROS and lipid hydroperoxide production compared to BPI and BPII groups. Indices of nitro-oxidative stress coupled with aldehyde production or protein oxidation were significantly different among the three patient groups (BDII > BDI > MDD). Finally, depressive symptom scores were significantly associated with higher LOOH and AOPP levels. In conclusion, depression is accompanied by increased ROS production, which is insufficiently dampened by catalase activity, thereby increasing nitro-oxidative damage to lipids and aldehyde production. Increased protein oxidation with formation of AOPP appeared to be hallmark of MDD and BPI. In addition, patients with BPII may have protection against the damaging effects of ROS including lipid peroxidation and aldehyde formation. This study suggests that biomarkers related to O&NS could aid

IKK connects autophagy to major stress pathways.

Science.gov (United States)

Criollo, Alfredo; Senovilla, Laura; Authier, Hélène; Maiuri, Maria Chiara; Morselli, Eugenia; Vitale, Ilio; Kepp, Oliver; Tasdemir, Ezgi; Galluzzi, Lorenzo; Shen, Shensi; Tailler, Maximilien; Delahaye, Nicolas; Tesniere, Antoine; De Stefano, Daniela; Younes, Aména Ben; Harper, Francis; Pierron, Gérard; Lavandero, Sergio; Zitvogel, Laurence; Israel, Alain; Baud, Véronique; Kroemer, Guido

2010-01-01

Cells respond to stress by activating cytoplasmic mechanisms as well as transcriptional programs that can lead to adaptation or death. Autophagy represents an important cytoprotective response that is regulated by both transcriptional and transcription-independent pathways. NFkappaB is perhaps the transcription factor most frequently activated by stress and has been ascribed with either pro- or anti-autophagic functions, depending on the cellular context. Our results demonstrate that activation of the IKK (IkappaB kinase) complex, which is critical for the stress-elicited activation of NFkappaB, is sufficient to promote autophagy independent of NFkappaB, and that IKK is required for the optimal induction of autophagy by both physiological and pharmacological autophagic triggers.

Axillary lymph nodes and arm lymphatic drainage pathways are spared during routine complete axillary clearance in majority of women undergoing breast cancer surgery.

Science.gov (United States)

Szuba, A; Chachaj, Z; Koba-Wszedybylb, M; Hawro, R; Jasinski, R; Tarkowski, R; Szewczyk, K; Bebenek, M; Forgacz, J; Jodkowska, A; Jedrzejuk, D; Janczak, D; Mrozinska, M; Pilch, U; Wozniewski, M

2011-09-01

Alterations in axillary lymph nodes (ALNs) after complete axillary lymph node dissection (ALND) in comparison to the preoperative status were evaluated using lymphoscintigraphy performed preoperatively and 1-6 weeks after surgery in 30 women with a new diagnosis of unilateral, invasive breast carcinoma. Analysis of lymphoscintigrams revealed that ALNs after surgery were present in 26 of 30 examined women. In comparison to preoperative status, they were visualized in the same location (12 women), in the same and additionally in different locations (9 women), or only in different locations (4 women). No lymph nodes were visualized in one woman and lymphocoele were in 4 women. Thus, after ALND, a variable number of axillary lymph nodes remain and were visualized on lymphoscintigraphy in the majority of women. The classical ALND, therefore, does not allow complete dissection and removal of axillary nodes with total disruption of axillary lymphatic pathways, accounting in part for the variable incidence and severity of lymphedema after the procedure.

The mevalonate pathway in C. Elegans

Directory of Open Access Journals (Sweden)

Rauthan Manish

2011-12-01

Full Text Available Abstract The mevalonate pathway in human is responsible for the synthesis of cholesterol and other important biomolecules such as coenzyme Q, dolichols and isoprenoids. These molecules are required in the cell for functions ranging from signaling to membrane integrity, protein prenylation and glycosylation, and energy homeostasis. The pathway consists of a main trunk followed by sub-branches that synthesize the different biomolecules. The majority of our knowledge about the mevalonate pathway is currently focused on the cholesterol synthesis branch, which is the target of the cholesterol-lowering statins; less is known about the function and regulation of the non-cholesterol-related branches. To study them, we need a biological system where it is possible to specifically modulate these metabolic branches individually or in groups. The nematode Caenorhabditis elegans (C. elegans is a promising model to study these non-cholesterol branches since its mevalonate pathway seems very well conserved with that in human except that it has no cholesterol synthesis branch. The simple genetic makeup and tractability of C. elegans makes it relatively easy to identify and manipulate key genetic components of the mevalonate pathway, and to evaluate the consequences of tampering with their activity. This general experimental approach should lead to new insights into the physiological roles of the non-cholesterol part of the mevalonate pathway. This review will focus on the current knowledge related to the mevalonate pathway in C. elegans and its possible applications as a model organism to study the non-cholesterol functions of this pathway.

Non Linear Programming (NLP) formulation for quantitative modeling of protein signal transduction pathways.

Science.gov (United States)

Mitsos, Alexander; Melas, Ioannis N; Morris, Melody K; Saez-Rodriguez, Julio; Lauffenburger, Douglas A; Alexopoulos, Leonidas G

2012-01-01

Modeling of signal transduction pathways plays a major role in understanding cells' function and predicting cellular response. Mathematical formalisms based on a logic formalism are relatively simple but can describe how signals propagate from one protein to the next and have led to the construction of models that simulate the cells response to environmental or other perturbations. Constrained fuzzy logic was recently introduced to train models to cell specific data to result in quantitative pathway models of the specific cellular behavior. There are two major issues in this pathway optimization: i) excessive CPU time requirements and ii) loosely constrained optimization problem due to lack of data with respect to large signaling pathways. Herein, we address both issues: the former by reformulating the pathway optimization as a regular nonlinear optimization problem; and the latter by enhanced algorithms to pre/post-process the signaling network to remove parts that cannot be identified given the experimental conditions. As a case study, we tackle the construction of cell type specific pathways in normal and transformed hepatocytes using medium and large-scale functional phosphoproteomic datasets. The proposed Non Linear Programming (NLP) formulation allows for fast optimization of signaling topologies by combining the versatile nature of logic modeling with state of the art optimization algorithms.

Non Linear Programming (NLP formulation for quantitative modeling of protein signal transduction pathways.

Directory of Open Access Journals (Sweden)

Alexander Mitsos

Full Text Available Modeling of signal transduction pathways plays a major role in understanding cells' function and predicting cellular response. Mathematical formalisms based on a logic formalism are relatively simple but can describe how signals propagate from one protein to the next and have led to the construction of models that simulate the cells response to environmental or other perturbations. Constrained fuzzy logic was recently introduced to train models to cell specific data to result in quantitative pathway models of the specific cellular behavior. There are two major issues in this pathway optimization: i excessive CPU time requirements and ii loosely constrained optimization problem due to lack of data with respect to large signaling pathways. Herein, we address both issues: the former by reformulating the pathway optimization as a regular nonlinear optimization problem; and the latter by enhanced algorithms to pre/post-process the signaling network to remove parts that cannot be identified given the experimental conditions. As a case study, we tackle the construction of cell type specific pathways in normal and transformed hepatocytes using medium and large-scale functional phosphoproteomic datasets. The proposed Non Linear Programming (NLP formulation allows for fast optimization of signaling topologies by combining the versatile nature of logic modeling with state of the art optimization algorithms.

Turbidite pathways in Cascadia Basin and Tufts abyssal plain, Part A, Astoria Channel, Blanco Valley, and Gorda Basin

Science.gov (United States)

Wolf, Stephen C.; Hamer, Michael R.

1999-01-01

studied; they are time and date coded, and color keyed to each ship ID data base listed at the bottom of each sheet. The first letter in the cruise ID is an abbreviation letter for the ship name, the following numbers represent the consecutive cruise number of that year, followed by the year number. The letters at the end of the ID represent the survey area, ie. NC- northern California, NP- north Pacific. Locations of selected sample seismic sections illustrated on sheets 3-5 also are shown. Scales for each of the sheets are the same as for sheets 3-5, which allows for overlaying of track data onto the interpretations shown on Maps A-C. Sheets 3 (MAP A), 4 (MAP B), and 5 (MAP C) show channel pathway location, bathymetric depth based on the USGS COW data base (Ca/Or/Wa), pathway morphology, and thickness of turbidite sediment fill at various locations. The interpreted turbidite sediments are color highlighted on the selected seismic sections to differentiate them from the typical deep sea sediments below and to the side of the turbidite pathways. Thickness of sediment fill, in meters, is shown along major pathways in white circular highlights. The data and interpretations rest on a background of USGS GLORIA side scan sonar imagery (1984) to illustrate the relationship of pathway position to sub sea features. Channel distance points are plotted along channel centerlines at 20,000 m intervals. These points begin at the start of each interpreted channel pathway. A bathymetric depth was assigned to each distance point. These data points were then used to construct channel gradient curves for the Astoria, Eel, Bear Valley, and Mendocino channel pathways. These gradients are plotted on sheet 6 of this report and illustrate the similarities and differences between each of the pathways. Sheet 7 shows various views of the Mendocino/Mattole Canyon heads as an example of useful derivative information of the Seabeam bathymetric data. These views illustrate that the Mendocino pathway

Symptoms of major depressive disorder subsequent to child maltreatment: Examining change across multiple levels of analysis to identify transdiagnostic risk pathways.

Science.gov (United States)

Shenk, Chad E; Griffin, Amanda M; O'Donnell, Kieran J

2015-11-01

Major depressive disorder (MDD) is a prevalent psychiatric condition in the child maltreatment population. However, not all children who have been maltreated will develop MDD or MDD symptoms, suggesting the presence of unique risk pathways that explain how certain children develop MDD symptoms when others do not. The current study tested several candidate risk pathways to MDD symptoms following child maltreatment: neuroendocrine, autonomic, affective, and emotion regulation. Female adolescents (N = 110; age range = 14-19) were recruited into a substantiated child maltreatment or comparison condition and completed a laboratory stressor, saliva samples, and measures of emotion regulation, negative affect, and MDD symptoms. MDD symptoms were reassessed 18 months later. Mediational modeling revealed that emotion regulation was the only significant indirect effect of the relationship between child maltreatment and subsequent MDD symptoms, demonstrating that children exposed to maltreatment had greater difficulties managing affective states that in turn led to more severe MDD symptoms. These results highlight the importance of emotion dysregulation as a central risk pathway to MDD following child maltreatment. Areas of future research and implications for optimizing prevention and clinical intervention through the direct targeting of transdiagnostic risk pathways are discussed.

Symptoms of Major Depressive Disorder Subsequent to Child Maltreatment: Examining Change across Multiple Levels of Analysis to Identify Transdiagnostic Risk Pathways

Science.gov (United States)

Shenk, Chad E.; Griffin, Amanda M.; O’Donnell, Kieran J.

2016-01-01

Major depressive disorder (MDD) is a prevalent psychiatric condition in the child maltreatment population. However, not all children who have been maltreated will develop MDD or MDD symptoms, suggesting the presence of unique risk pathways that explain how certain children develop MDD symptoms when others do not. The current study tested several candidate risk pathways to MDD symptoms following child maltreatment: 1) neuroendocrine, 2) autonomic, 3) affective, and 4) emotion regulation. Female adolescents (N=110; Age range: 14–19) were recruited into a substantiated child maltreatment or comparison condition and completed a laboratory stressor, saliva samples, and measures of emotion regulation, negative affect, and MDD symptoms. MDD symptoms were reassessed eighteen months later. Mediational modeling revealed that emotion regulation was the only significant indirect effect of the relationship between child maltreatment and subsequent MDD symptoms, demonstrating that children exposed to maltreatment had greater difficulties managing affective states that in turn led to more severe MDD symptoms. These results highlight the importance of emotion dysregulation as a central risk pathway to MDD following child maltreatment. Areas of future research and implications for optimizing prevention and clinical intervention through the direct targeting of transdiagnostic risk pathways are discussed. PMID:26535940

Women’s Work Pathways Across the Life Course1

Science.gov (United States)

Damaske, Sarah; Frech, Adrianne

2016-01-01

Despite numerous changes in women’s employment in the latter half of the 20th century, women’s employment continues to be uneven and stalled. Drawing from data on women’s weekly work hours in the National Longitudinal Survey of Youth (NLSY79), we identify significant inequality in women’s labor force experiences across adulthood. We find two pathways of stable fulltime work for women, three pathways of part-time employment, and a pathway of unpaid labor. A majority of women follow one of the two fulltime work pathways, while fewer than 10 percent follow a pathway of unpaid labor. Our findings provide evidence of the lasting influence of work-family conflict and early socio-economic advantages and disadvantages on women’s work pathways. Indeed, race, poverty, educational attainment, and early family characteristics significantly shaped women’s work careers. Work-family opportunities and constraints also were related to women’s work hours, as were a woman’s gendered beliefs and expectations. We conclude that women’s employment pathways are a product of both their resources and changing social environment as well as individual agency. Significantly, we point to social stratification, gender ideologies, and work-family constraints, working in concert, as key explanations for how women are “tracked” onto work pathways from an early age. PMID:27001314

Understanding trade pathways to target biosecurity surveillance

Directory of Open Access Journals (Sweden)

Manuel Colunga-Garcia

2013-09-01

Full Text Available Increasing trends in global trade make it extremely difficult to prevent the entry of all potential invasive species (IS. Establishing early detection strategies thus becomes an important part of the continuum used to reduce the introduction of invasive species. One part necessary to ensure the success of these strategies is the determination of priority survey areas based on invasion pressure. We used a pathway-centred conceptual model of pest invasion to address these questions: what role does global trade play in invasion pressure of plant ecosystems and how could an understanding of this role be used to enhance early detection strategies? We concluded that the relative level of invasion pressure for destination ecosystems can be influenced by the intensity of pathway usage (import volume and frequency, the number and type of pathways with a similar destination, and the number of different ecological regions that serve as the source for imports to the same destination. As these factors increase, pressure typically intensifies because of increasing a propagule pressure, b likelihood of transporting pests with higher intrinsic invasion potential, and c likelihood of transporting pests into ecosystems with higher invasibility. We used maritime containerized imports of live plants into the contiguous U.S. as a case study to illustrate the practical implications of the model to determine hotspot areas of relative invasion pressure for agricultural and forest ecosystems (two ecosystems with high potential invasibility. Our results illustrated the importance of how a pathway-centred model could be used to highlight potential target areas for early detection strategies for IS. Many of the hotspots in agricultural and forest ecosystems were within major U.S. metropolitan areas. Invasion ecologists can utilize pathway-centred conceptual models to a better understand the role of human-mediated pathways in pest establishment, b enhance current

Bipolar cell gap junctions serve major signaling pathways in the human retina.

Science.gov (United States)

Kántor, Orsolya; Varga, Alexandra; Nitschke, Roland; Naumann, Angela; Énzsöly, Anna; Lukáts, Ákos; Szabó, Arnold; Németh, János; Völgyi, Béla

2017-08-01

Connexin36 (Cx36) constituent gap junctions (GJ) throughout the brain connect neurons into functional syncytia. In the retina they underlie the transmission, averaging and correlation of signals prior conveying visual information to the brain. This is the first study that describes retinal bipolar cell (BC) GJs in the human inner retina, whose function is enigmatic even in the examined animal models. Furthermore, a number of unique features (e.g. fovea, trichromacy, midget system) necessitate a reexamination of the animal model results in the human retina. Well-preserved postmortem human samples of this study are allowed to identify Cx36 expressing BCs neurochemically. Results reveal that both rod and cone pathway interneurons display strong Cx36 expression. Rod BC inputs to AII amacrine cells (AC) appear in juxtaposition to AII GJs, thus suggesting a strategic AII cell targeting by rod BCs. Cone BCs serving midget, parasol or koniocellular signaling pathways display a wealth of Cx36 expression to form homologously coupled arrays. In addition, they also establish heterologous GJ contacts to serve an exchange of information between parallel signaling streams. Interestingly, a prominent Cx36 expression was exhibited by midget system BCs that appear to maintain intimate contacts with bistratified BCs serving other pathways. These findings suggest that BC GJs in parallel signaling streams serve both an intra- and inter-pathway exchange of signals in the human retina.

Two Pathways to Stimulus Encoding in Category Learning?

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Davis, Tyler; Love, Bradley C.; Maddox, W. Todd

2008-01-01

Category learning theorists tacitly assume that stimuli are encoded by a single pathway. Motivated by theories of object recognition, we evaluate a dual-pathway account of stimulus encoding. The part-based pathway establishes mappings between sensory input and symbols that encode discrete stimulus features, whereas the image-based pathway applies holistic templates to sensory input. Our experiments use rule-plus-exception structures in which one exception item in each category violates a salient regularity and must be distinguished from other items. In Experiment 1, we find that discrete representations are crucial for recognition of exceptions following brief training. Experiments 2 and 3 involve multi-session training regimens designed to encourage either part or image-based encoding. We find that both pathways are able to support exception encoding, but have unique characteristics. We speculate that one advantage of the part-based pathway is the ability to generalize across domains, whereas the image-based pathway provides faster and more effortless recognition. PMID:19460948

Enhancing microbial production of biofuels by expanding microbial metabolic pathways.

Science.gov (United States)

Yu, Ping; Chen, Xingge; Li, Peng

2017-09-01

Fatty acid, isoprenoid, and alcohol pathways have been successfully engineered to produce biofuels. By introducing three genes, atfA, adhE, and pdc, into Escherichia coli to expand fatty acid pathway, up to 1.28 g/L of fatty acid ethyl esters can be achieved. The isoprenoid pathway can be expanded to produce bisabolene with a high titer of 900 mg/L in Saccharomyces cerevisiae. Short- and long-chain alcohols can also be effectively biosynthesized by extending the carbon chain of ketoacids with an engineered "+1" alcohol pathway. Thus, it can be concluded that expanding microbial metabolic pathways has enormous potential for enhancing microbial production of biofuels for future industrial applications. However, some major challenges for microbial production of biofuels should be overcome to compete with traditional fossil fuels: lowering production costs, reducing the time required to construct genetic elements and to increase their predictability and reliability, and creating reusable parts with useful and predictable behavior. To address these challenges, several aspects should be further considered in future: mining and transformation of genetic elements related to metabolic pathways, assembling biofuel elements and coordinating their functions, enhancing the tolerance of host cells to biofuels, and creating modular subpathways that can be easily interconnected. © 2016 International Union of Biochemistry and Molecular Biology, Inc.

Curation and Computational Design of Bioenergy-Related Metabolic Pathways

Energy Technology Data Exchange (ETDEWEB)

Karp, Peter D. [SRI International, Menlo Park, CA (United States)

2014-09-12

Pathway Tools is a systems-biology software package written by SRI International (SRI) that produces Pathway/Genome Databases (PGDBs) for organisms with a sequenced genome. Pathway Tools also provides a wide range of capabilities for analyzing predicted metabolic networks and user-generated omics data. More than 5,000 academic, industrial, and government groups have licensed Pathway Tools. This user community includes researchers at all three DOE bioenergy centers, as well as academic and industrial metabolic engineering (ME) groups. An integral part of the Pathway Tools software is MetaCyc, a large, multiorganism database of metabolic pathways and enzymes that SRI and its academic collaborators manually curate. This project included two main goals: I. Enhance the MetaCyc content of bioenergy-related enzymes and pathways. II. Develop computational tools for engineering metabolic pathways that satisfy specified design goals, in particular for bioenergy-related pathways. In part I, SRI proposed to significantly expand the coverage of bioenergy-related metabolic information in MetaCyc, followed by the generation of organism-specific PGDBs for all energy-relevant organisms sequenced at the DOE Joint Genome Institute (JGI). Part I objectives included: 1: Expand the content of MetaCyc to include bioenergy-related enzymes and pathways. 2: Enhance the Pathway Tools software to enable display of complex polymer degradation processes. 3: Create new PGDBs for the energy-related organisms sequenced by JGI, update existing PGDBs with new MetaCyc content, and make these data available to JBEI via the BioCyc website. In part II, SRI proposed to develop an efficient computational tool for the engineering of metabolic pathways. Part II objectives included: 4: Develop computational tools for generating metabolic pathways that satisfy specified design goals, enabling users to specify parameters such as starting and ending compounds, and preferred or disallowed intermediate compounds

[Cell signaling pathways interaction in cellular proliferation: Potential target for therapeutic interventionism].

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Valdespino-Gómez, Víctor Manuel; Valdespino-Castillo, Patricia Margarita; Valdespino-Castillo, Víctor Edmundo

2015-01-01

Nowadays, cellular physiology is best understood by analysing their interacting molecular components. Proteins are the major components of the cells. Different proteins are organised in the form of functional clusters, pathways or networks. These molecules are ordered in clusters of receptor molecules of extracellular signals, transducers, sensors and biological response effectors. The identification of these intracellular signaling pathways in different cellular types has required a long journey of experimental work. More than 300 intracellular signaling pathways have been identified in human cells. They participate in cell homeostasis processes for structural and functional maintenance. Some of them participate simultaneously or in a nearly-consecutive progression to generate a cellular phenotypic change. In this review, an analysis is performed on the main intracellular signaling pathways that take part in the cellular proliferation process, and the potential use of some components of these pathways as target for therapeutic interventionism are also underlined. Copyright © 2015 Academia Mexicana de Cirugía A.C. Published by Masson Doyma México S.A. All rights reserved.

Pathway cross-talk network analysis identifies critical pathways in neonatal sepsis.

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Meng, Yu-Xiu; Liu, Quan-Hong; Chen, Deng-Hong; Meng, Ying

2017-06-01

Despite advances in neonatal care, sepsis remains a major cause of morbidity and mortality in neonates worldwide. Pathway cross-talk analysis might contribute to the inference of the driving forces in bacterial sepsis and facilitate a better understanding of underlying pathogenesis of neonatal sepsis. This study aimed to explore the critical pathways associated with the progression of neonatal sepsis by the pathway cross-talk analysis. By integrating neonatal transcriptome data with known pathway data and protein-protein interaction data, we systematically uncovered the disease pathway cross-talks and constructed a disease pathway cross-talk network for neonatal sepsis. Then, attract method was employed to explore the dysregulated pathways associated with neonatal sepsis. To determine the critical pathways in neonatal sepsis, rank product (RP) algorithm, centrality analysis and impact factor (IF) were introduced sequentially, which synthetically considered the differential expression of genes and pathways, pathways cross-talks and pathway parameters in the network. The dysregulated pathways with the highest IF values as well as RPpathways in neonatal sepsis. By integrating three kinds of data, only 6919 common genes were included to perform the pathway cross-talk analysis. By statistic analysis, a total of 1249 significant pathway cross-talks were selected to construct the pathway cross-talk network. Moreover, 47 dys-regulated pathways were identified via attract method, 20 pathways were identified under RPpathways with the highest IF were also screened from the pathway cross-talk network. Among them, we selected 8 common pathways, i.e. critical pathways. In this study, we systematically tracked 8 critical pathways involved in neonatal sepsis by integrating attract method and pathway cross-talk network. These pathways might be responsible for the host response in infection, and of great value for advancing diagnosis and therapy of neonatal sepsis. Copyright © 2017

Integrating parts of the APhA Career Pathway Evaluation Program for pharmacy professionals into a career development lab.

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Linn, Brooke A; Burton, Samantha J; Shepler, Brian M

To use parts of the APhA Career Pathway Evaluation Program for Pharmacy Professionals in a career development laboratory designed to provide students with relevant information that will help them prepare for successful careers across the profession of pharmacy. Students enrolled in the second professional year of pharmacy school participated in an interactive three-hour career development laboratory. Students completed the APhA Career Pathway Evaluation Program for Pharmacy Professionals Online Assessment Tool prior to the laboratory. In class, the students were randomized into eight groups. Two career profiles were assigned to each group for discussion during a thirty-minute brainstorming session. The groups reported their knowledge for each career profile to the entire class, and the instructors supplemented the discussion with details and more specific information about each profile. Two years of data were collected (n=300 students). One hundred and twenty four (41.3%) students responded to the voluntary post-laboratory survey questions. Overall, students rated the career pathway activities favorably with an average score of 8.13 out of 10. After participation in the discussion, 74 (59.7%) respondents indicated their career interests had been impacted. This career development laboratory is one example of how the APhA Career Pathway Evaluation Program for Pharmacy Professionals can be effectively incorporated into the PharmD curriculum in order to help students explore the various career options they might not have otherwise discovered on their own. Published by Elsevier Inc.

Alterations in leukocyte transcriptional control pathway activity associated with major depressive disorder and antidepressant treatment.

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Mellon, S H; Wolkowitz, O M; Schonemann, M D; Epel, E S; Rosser, R; Burke, H B; Mahan, L; Reus, V I; Stamatiou, D; Liew, C-C; Cole, S W

2016-05-24

Major depressive disorder (MDD) is associated with a significantly elevated risk of developing serious medical illnesses such as cardiovascular disease, immune impairments, infection, dementia and premature death. Previous work has demonstrated immune dysregulation in subjects with MDD. Using genome-wide transcriptional profiling and promoter-based bioinformatic strategies, we assessed leukocyte transcription factor (TF) activity in leukocytes from 20 unmedicated MDD subjects versus 20 age-, sex- and ethnicity-matched healthy controls, before initiation of antidepressant therapy, and in 17 of the MDD subjects after 8 weeks of sertraline treatment. In leukocytes from unmedicated MDD subjects, bioinformatic analysis of transcription control pathway activity indicated an increased transcriptional activity of cAMP response element-binding/activating TF (CREB/ATF) and increased activity of TFs associated with cellular responses to oxidative stress (nuclear factor erythroid-derived 2-like 2, NFE2l2 or NRF2). Eight weeks of antidepressant therapy was associated with significant reductions in Hamilton Depression Rating Scale scores and reduced activity of NRF2, but not in CREB/ATF activity. Several other transcriptional regulation pathways, including the glucocorticoid receptor (GR), nuclear factor kappa-B cells (NF-κB), early growth response proteins 1-4 (EGR1-4) and interferon-responsive TFs, showed either no significant differences as a function of disease or treatment, or activities that were opposite to those previously hypothesized to be involved in the etiology of MDD or effective treatment. Our results suggest that CREB/ATF and NRF2 signaling may contribute to MDD by activating immune cell transcriptome dynamics that ultimately influence central nervous system (CNS) motivational and affective processes via circulating mediators.

Policies built upon pathways

NARCIS (Netherlands)

Musterd, S.; Kovács, Z.; Musterd, S.; Kovács, Z.

2013-01-01

After the general introductions, the first substantive part of this volume (Part II) provides concise research-based discussions of policies developed in recognition of the important role played by the pathways along which city-regions have travelled. Our research has shown that it is highly

Evolution of the TOR Pathway.

NARCIS (Netherlands)

Dam, T.J.P. van; Zwartkruis, F.J.; Bos, J.L.; Snel, B.

2011-01-01

The TOR kinase is a major regulator of growth in eukaryotes. Many components of the TOR pathway are implicated in cancer and metabolic diseases in humans. Analysis of the evolution of TOR and its pathway may provide fundamental insight into the evolution of growth regulation in eukaryotes and

Balancing act: matching growth with environment by the TOR signalling pathway.

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Henriques, Rossana; Bögre, László; Horváth, Beátrix; Magyar, Zoltán

2014-06-01

One of the most fundamental aspects of growth in plants is its plasticity in relation to fluctuating environmental conditions. Growth of meristematic cells relies predominantly on protein synthesis, one of the most energy-consuming activities in cells, and thus is tightly regulated in accordance with the available nutrient and energy supplies. The Target of Rapamycin (TOR) signalling pathway takes a central position in this regulation. The core of the TOR signalling pathway is conserved throughout evolution, and can be traced back to the last eukaryotic common ancestor. In plants, a single complex constitutes the TOR signalling pathway. Manipulating the components of the TOR complex in Arabidopsis highlighted its common role as a major regulator of protein synthesis and metabolism, that is also involved in other biological functions such as cell-wall integrity, regulation of cell proliferation, and cell size. TOR, as an integral part of the auxin signalling pathway, connects hormonal and nutrient pathways. Downstream of TOR, S6 kinase and the ribosomal S6 protein have been shown to mediate several of these responses, although there is evidence of other complex non-linear TOR signalling pathway structures. © The Author 2014. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Cotton transformation via pollen tube pathway.

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Wang, Min; Zhang, Baohong; Wang, Qinglian

2013-01-01

Although many gene transfer methods have been employed for successfully obtaining transgenic cotton, the major constraint in cotton improvement is the limitation of genotype because the majority of transgenic methods require plant regeneration from a single transformed cell which is limited by cotton tissue culture. Comparing with other plant species, it is difficult to induce plant regeneration from cotton; currently, only a limited number of cotton cultivars can be cultured for obtaining regenerated plants. Thus, development of a simple and genotype-independent genetic transformation method is particularly important for cotton community. In this chapter, we present a simple, cost-efficient, and genotype-independent cotton transformation method-pollen tube pathway-mediated transformation. This method uses pollen tube pathway to deliver transgene into cotton embryo sacs and then insert foreign genes into cotton genome. There are three major steps for pollen tube pathway-mediated genetic transformation, which include injection of -foreign genes into pollen tube, integration of foreign genes into plant genome, and selection of transgenic plants.

Biomedical Science Undergraduate Major: A New Pathway to Advance Research and the Health Professions.

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Gunn, John S; Ledford, Cynthia H; Mousetes, Steven J; Grever, Michael R

2018-01-01

Many students entering professional degree programs, particularly M.D., Ph.D., and M.D./Ph.D., are not well prepared regarding the breadth of scientific knowledge required, communication skills, research experience, reading and understanding the scientific literature, and significant shadowing (for M.D.-related professions). In addition, physician scientists are a needed and necessary part of the academic research environment but are dwindling in numbers. In response to predictions of critical shortages of clinician investigators and the lack of proper preparation as undergraduates for these professions, the Biomedical Science (BMS) undergraduate major was created at The Ohio State University to attract incoming college freshmen with interests in scientific research and the healthcare professions. The intent of this major was to graduate an elite cohort of highly talented individuals who would pursue careers in the healthcare professions, biomedical research, or both. Students were admitted to the BMS major through an application and interview process. Admitted cohorts were small, comprising 22 to 26 students, and received a high degree of individualized professional academic advising and mentoring. The curriculum included a minimum of 4 semesters (or 2 years) of supervised research experience designed to enable students to gain skills in clinical and basic science investigation. In addition to covering the prerequisites for medicine and advanced degrees in health professions, the integrated BMS coursework emphasized research literacy as well as skills related to work as a healthcare professional, with additional emphasis on independent learning, teamwork to solve complex problems, and both oral and written communication skills. Supported by Ohio State's Department of Internal Medicine, a unique clinical internship provided selected students with insights into potential careers as physician scientists. In this educational case report, we describe the BMS

Novel metabolic pathways in Archaea.

Science.gov (United States)

Sato, Takaaki; Atomi, Haruyuki

2011-06-01

The Archaea harbor many metabolic pathways that differ to previously recognized classical pathways. Glycolysis is carried out by modified versions of the Embden-Meyerhof and Entner-Doudoroff pathways. Thermophilic archaea have recently been found to harbor a bi-functional fructose-1,6-bisphosphate aldolase/phosphatase for gluconeogenesis. A number of novel pentose-degrading pathways have also been recently identified. In terms of anabolic metabolism, a pathway for acetate assimilation, the methylaspartate cycle, and two CO2-fixing pathways, the 3-hydroxypropionate/4-hydroxybutyrate cycle and the dicarboxylate/4-hydroxybutyrate cycle, have been elucidated. As for biosynthetic pathways, recent studies have clarified the enzymes responsible for several steps involved in the biosynthesis of inositol phospholipids, polyamine, coenzyme A, flavin adeninedinucleotide and heme. By examining the presence/absence of homologs of these enzymes on genome sequences, we have found that the majority of these enzymes and pathways are specific to the Archaea. Copyright © 2011 Elsevier Ltd. All rights reserved.

Non-homologous end joining pathway is the major route of protection against 4β-hydroxywithanolide E-induced DNA damage in MCF-7 cells.

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You, B-J; Wu, Y-C; Lee, C-L; Lee, H-Z

2014-03-01

4β-Hydroxywithanolide E is a bioactive withanolide extracted from Physalis peruviana. 4β-Hydroxywithanolide E caused reactive oxygen species production and cell apoptosis in human breast cancer MCF-7 cells. We further found that 4β-hydroxywithanolide E induced DNA damage and regulated the DNA damage signaling in MCF-7 cells. The DNA damage sensors and repair proteins act promptly to remove DNA lesions by 4β-hydroxywithanolide E. The ataxia-telangiectasia mutated protein (ATM)-dependent DNA damage signaling pathway is involved in 4β-hydroxywithanolide E-induced apoptosis of MCF-7 cells. Non-homologous end joining pathway, but not homologous recombination, is the major route of protection of MCF-7 cells against 4β-hydroxywithanolide E-induced DNA damage. 4β-Hydroxywithanolide E had no significant impact on the base excision repair pathway. In this study, we examined the 4β-hydroxywithanolide E-induced DNA damage as a research tool in project investigating the DNA repair signaling in breast cancer cells. We also suggest that 4β-hydroxywithanolide E assert its anti-tumor activity in carcinogenic progression and develop into a dietary chemopreventive agent. Copyright © 2014 Elsevier Ltd. All rights reserved.

The methionine salvage pathway in Bacillus subtilis

Directory of Open Access Journals (Sweden)

Danchin Antoine

2002-04-01

Full Text Available Abstract Background Polyamine synthesis produces methylthioadenosine, which has to be disposed of. The cell recycles it into methionine through methylthioribose (MTR. Very little was known about MTR recycling for methionine salvage in Bacillus subtilis. Results Using in silico genome analysis and transposon mutagenesis in B. subtilis we have experimentally uncovered the major steps of the dioxygen-dependent methionine salvage pathway, which, although similar to that found in Klebsiella pneumoniae, recruited for its implementation some entirely different proteins. The promoters of the genes have been identified by primer extension, and gene expression was analyzed by Northern blotting and lacZ reporter gene expression. Among the most remarkable discoveries in this pathway is the role of an analog of ribulose diphosphate carboxylase (Rubisco, the plant enzyme used in the Calvin cycle which recovers carbon dioxide from the atmosphere as a major step in MTR recycling. Conclusions A complete methionine salvage pathway exists in B. subtilis. This pathway is chemically similar to that in K. pneumoniae, but recruited different proteins to this purpose. In particular, a paralogue or Rubisco, MtnW, is used at one of the steps in the pathway. A major observation is that in the absence of MtnW, MTR becomes extremely toxic to the cell, opening an unexpected target for new antimicrobial drugs. In addition to methionine salvage, this pathway protects B. subtilis against dioxygen produced by its natural biotope, the surface of leaves (phylloplane.

The major cellular sterol regulatory pathway is required for Andes virus infection.

Directory of Open Access Journals (Sweden)

Josiah Petersen

2014-02-01

Full Text Available The Bunyaviridae comprise a large family of RNA viruses with worldwide distribution and includes the pathogenic New World hantavirus, Andes virus (ANDV. Host factors needed for hantavirus entry remain largely enigmatic and therapeutics are unavailable. To identify cellular requirements for ANDV infection, we performed two parallel genetic screens. Analysis of a large library of insertionally mutagenized human haploid cells and a siRNA genomic screen converged on components (SREBP-2, SCAP, S1P and S2P of the sterol regulatory pathway as critically important for infection by ANDV. The significance of this pathway was confirmed using functionally deficient cells, TALEN-mediated gene disruption, RNA interference and pharmacologic inhibition. Disruption of sterol regulatory complex function impaired ANDV internalization without affecting virus binding. Pharmacologic manipulation of cholesterol levels demonstrated that ANDV entry is sensitive to changes in cellular cholesterol and raises the possibility that clinically approved regulators of sterol synthesis may prove useful for combating ANDV infection.

Cultural pathways through universal development.

Science.gov (United States)

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.

Bioinformatic Integration of Molecular Networks and Major Pathways Involved in Mice Cochlear and Vestibular Supporting Cells.

Science.gov (United States)

Requena, Teresa; Gallego-Martinez, Alvaro; Lopez-Escamez, Jose A

2018-01-01

Background : Cochlear and vestibular epithelial non-hair cells (ENHCs) are the supporting elements of the cellular architecture in the organ of Corti and the vestibular neuroepithelium in the inner ear. Intercellular and cell-extracellular matrix interactions are essential to prevent an abnormal ion redistribution leading to hearing and vestibular loss. The aim of this study is to define the main pathways and molecular networks in the mouse ENHCs. Methods : We retrieved microarray and RNA-seq datasets from mouse epithelial sensory and non-sensory cells from gEAR portal (http://umgear.org/index.html) and obtained gene expression fold-change between ENHCs and non-epithelial cells (NECs) against HCs for each gene. Differentially expressed genes (DEG) with a log2 fold change between 1 and -1 were discarded. The remaining genes were selected to search for interactions using Ingenuity Pathway Analysis and STRING platform. Specific molecular networks for ENHCs in the cochlea and the vestibular organs were generated and significant pathways were identified. Results : Between 1723 and 1559 DEG were found in the mouse cochlear and vestibular tissues, respectively. Six main pathways showed enrichment in the supporting cells in both tissues: (1) "Inhibition of Matrix Metalloproteases"; (2) "Calcium Transport I"; (3) "Calcium Signaling"; (4) "Leukocyte Extravasation Signaling"; (5) "Signaling by Rho Family GTPases"; and (6) "Axonal Guidance Si". In the mouse cochlea, ENHCs showed a significant enrichment in 18 pathways highlighting "axonal guidance signaling (AGS)" ( p = 4.37 × 10 -8 ) and "RhoGDI Signaling" ( p = 3.31 × 10 -8 ). In the vestibular dataset, there were 20 enriched pathways in ENHCs, the most significant being "Leukocyte Extravasation Signaling" ( p = 8.71 × 10 -6 ), "Signaling by Rho Family GTPases" ( p = 1.20 × 10 -5 ) and "Calcium Signaling" ( p = 1.20 × 10 -5 ). Among the top ranked networks, the most biologically significant network contained the

Pathways to youth homelessness.

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Martijn, Claudine; Sharpe, Louise

2006-01-01

Research documents high levels of psychopathology among homeless youth. Most research, however, has not distinguished between disorders that are present prior to homelessness and those that develop following homelessness. Hence whether psychological disorders are the cause or consequence of homelessness has not been established. The aim of this study is to investigate causal pathways to homelessness amongst currently homeless youth in Australia. The study uses a quasi-qualitative methodology to generate hypotheses for larger-scale research. High rates of psychological disorders were confirmed in the sample 35 homeless youth aged 14-25. The rates of psychological disorders at the point of homelessness were greater than in normative samples, but the rates of clinical disorder increased further once homeless. Further in-depth analyses were conducted to identify the temporal sequence for each individual with a view to establishing a set of causal pathways to homelessness and trajectories following homelessness that characterised the people in the sample. Five pathways to homelessness and five trajectories following homelessness were identified that accounted for the entire sample. Each pathway constituted a series of interactions between different factors similar to that described by Craig and Hodson (1998. Psychological Medicine, 28, 1379-1388) as "complex subsidiary pathways". The major findings were that (1) trauma is a common experience amongst homeless youth prior to homelessness and figured in the causal pathways to homelessness for over half of the sample; (2) once homeless, for the majority of youth there is an increase in the number of psychological diagnoses including drug and alcohol diagnoses; and (3) crime did not precede homelessness for all but one youth; however, following homelessness, involvement in criminal activity was common and became a distinguishing factor amongst youth. The implications of these findings for future research and service

Navigating the pathway to robotic competency in general thoracic surgery.

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Seder, Christopher W; Cassivi, Stephen D; Wigle, Dennis A

2013-01-01

Although robotic technology has addressed many of the limitations of traditional videoscopic surgery, robotic surgery has not gained widespread acceptance in the general thoracic community. We report our initial robotic surgery experience and propose a structured, competency-based pathway for the development of robotic skills. Between December 2008 and February 2012, a total of 79 robot-assisted pulmonary, mediastinal, benign esophageal, or diaphragmatic procedures were performed. Data on patient characteristics and perioperative outcomes were retrospectively collected and analyzed. During the study period, one surgeon and three residents participated in a triphasic, competency-based pathway designed to teach robotic skills. The pathway consisted of individual preclinical learning followed by mentored preclinical exercises and progressive clinical responsibility. The robot-assisted procedures performed included lung resection (n = 38), mediastinal mass resection (n = 19), hiatal or paraesophageal hernia repair (n = 12), and Heller myotomy (n = 7), among others (n = 3). There were no perioperative mortalities, with a 20% complication rate and a 3% readmission rate. Conversion to a thoracoscopic or open approach was required in eight pulmonary resections to facilitate dissection (six) or to control hemorrhage (two). Fewer major perioperative complications were observed in the later half of the experience. All residents who participated in the thoracic surgery robotic pathway perform robot-assisted procedures as part of their clinical practice. Robot-assisted thoracic surgery can be safely learned when skill acquisition is guided by a structured, competency-based pathway.

Putative transcriptomic biomarkers in the inflammatory cytokine pathway differentiate major depressive disorder patients from control subjects and bipolar disorder patients.

Directory of Open Access Journals (Sweden)

Timothy R Powell

Full Text Available Mood disorders consist of two etiologically related, but distinctly treated illnesses, major depressive disorder (MDD and bipolar disorder (BPD. These disorders share similarities in their clinical presentation, and thus show high rates of misdiagnosis. Recent research has revealed significant transcriptional differences within the inflammatory cytokine pathway between MDD patients and controls, and between BPD patients and controls, suggesting this pathway may possess important biomarker properties. This exploratory study attempts to identify disorder-specific transcriptional biomarkers within the inflammatory cytokine pathway, which can distinguish between control subjects, MDD patients and BPD patients. This is achieved using RNA extracted from subject blood and applying synthesized complementary DNA to quantitative PCR arrays containing primers for 87 inflammation-related genes. Initially, we use ANOVA to test for transcriptional differences in a 'discovery cohort' (total n = 90 and then we use t-tests to assess the reliability of any identified transcriptional differences in a 'validation cohort' (total n = 35. The two most robust and reliable biomarkers identified across both the discovery and validation cohort were Chemokine (C-C motif ligand 24 (CCL24 which was consistently transcribed higher amongst MDD patients relative to controls and BPD patients, and C-C chemokine receptor type 6 (CCR6 which was consistently more lowly transcribed amongst MDD patients relative to controls. Results detailed here provide preliminary evidence that transcriptional measures within inflammation-related genes might be useful in aiding clinical diagnostic decision-making processes. Future research should aim to replicate findings detailed in this exploratory study in a larger medication-free sample and examine whether identified biomarkers could be used prospectively to aid clinical diagnosis.

Metabolic pathways leading to detoxification of triptolide, a major active component of the herbal medicine Tripterygium wilfordii.

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Du, Fuying; Liu, Zhaohua; Li, Xinxiu; Xing, Jie

2014-08-01

Triptolide (TP) shows promising anti-inflammatory and antitumor activity but with severe toxicity. TP is a natural reactive electrophile containing three epoxide groups, which are usually linked to hepatotoxicity via their ability to covalently bind to cellular macromolecules. In this study, metabolic pathways leading to detoxification of TP were evaluated in glutathione (GSH)-depleted (treated with L-buthionine-S,R-sulfoxinine, BSO) and aminobenzotriazole (ABT; a non-specific inhibitor for P450s)-treated mice. The toxicity of TP in mice was evaluated in terms of mortality and levels of serum alanine transaminase (ALT). In incubates with NADPH- and GSH-supplemented liver microsomes, seven GSH conjugates derived from TP were detected. In mice, these hydrolytically unstable GSH conjugates underwent γ-glutamyltranspeptidase/dipeptidases-mediated hydrolysis leading to two major cysteinylglycine conjugates, which underwent further hydrolysis by dipeptidases to form two cysteine conjugates of TP. In ABT-treated mice, the hydroxylated metabolites of TP were found at a lower level than normal mice, and their subsequent conjugated metabolites were not found. The level of cysteinylglycine and cysteine conjugates derived from NADPH-independent metabolism increased in mice treated with both TP and BSO (or ABT), which could be the stress response to toxicity of TP. Compared with normal mice, mortality and ALT levels were significantly higher in TP-treated mice, indicating the toxicity of TP. Pretreatment of ABT increased the toxicity caused by TP, whereas the mortality decreased in GSH-depleted mice. Metabolism by cytochrome P450 enzymes to less reactive metabolites implied a high potential for detoxification of TP. The GSH conjugation pathway also contributed to TP's detoxification in mice. Copyright © 2013 John Wiley & Sons, Ltd.

Nitric Oxide-Related Biological Pathways in Patients with Major Depression.

Directory of Open Access Journals (Sweden)

Andreas Baranyi

Full Text Available Major depression is a well-known risk factor for cardiovascular diseases and increased mortality following myocardial infarction. However, biomarkers of depression and increased cardiovascular risk are still missing. The aim of this prospective study was to evaluate, whether nitric-oxide (NO related factors for endothelial dysfunction, such as global arginine bioavailability, arginase activity, L-arginine/ADMA ratio and the arginine metabolites asymmetric dimethylarginine (ADMA and symmetric dimethylarginine (SDMA might be biomarkers for depression-induced cardiovascular risk.In 71 in-patients with major depression and 48 healthy controls the Global Arginine Bioavailability Ratio (GABR, arginase activity (arginine/ornithine ratio, the L-arginine/ADMA ratio, ADMA, and SDMA were determined by high-pressure liquid chromatography. Psychiatric and laboratory assessments were obtained at baseline at the time of in-patient admittance and at the time of hospital discharge.The ADMA concentrations in patients with major depression were significantly elevated and the SDMA concentrations were significantly decreased in comparison with the healthy controls. Even after a first improvement of depression, ADMA and SDMA levels remained nearly unchanged. In addition, after a first improvement of depression at the time of hospital discharge, a significant decrease in arginase activity, an increased L-arginine/ADMA ratio and a trend for increased global arginine bioavailability were observed.Our study results are evidence that in patients with major depression ADMA and SDMA might be biomarkers to indicate an increased cardiovascular threat due to depression-triggered NO reduction. GABR, the L-arginine/ADMA ratio and arginase activity might be indicators of therapy success and increased NO production after remission.

Wnt and the Wnt signaling pathway in bone development and disease

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Wang, Yiping; Li, Yi-Ping; Paulson, Christie; Shao, Jian-Zhong; Zhang, Xiaoling; Wu, Mengrui; Chen, Wei

2014-01-01

Wnt signaling affects both bone modeling, which occurs during development, and bone remodeling, which is a lifelong process involving tissue renewal. Wnt signals are especially known to affect the differentiation of osteoblasts. In this review, we summarize recent advances in understanding the mechanisms of Wnt signaling, which is divided into two major branches: the canonical pathway and the noncanonical pathway. The canonical pathway is also called the Wnt/β-catenin pathway. There are two major noncanonical pathways: the Wnt-planar cell polarity pathway (Wnt-PCP pathway) and the Wnt-calcium pathway (Wnt-Ca2+ pathway). This review also discusses how Wnt ligands, receptors, intracellular effectors, transcription factors, and antagonists affect both the bone modeling and bone remodeling processes. We also review the role of Wnt ligands, receptors, intracellular effectors, transcription factors, and antagonists in bone as demonstrated in mouse models. Disrupted Wnt signaling is linked to several bone diseases, including osteoporosis, van Buchem disease, and sclerosteosis. Studying the mechanism of Wnt signaling and its interactions with other signaling pathways in bone will provide potential therapeutic targets to treat these bone diseases. PMID:24389191

Application for approval of the Cold Lake Expansion Project: volume 2: environmental impact assessment: Part 1: biophysical and resource use assessment. Part 2: impact model descriptions

International Nuclear Information System (INIS)

Green, J.; Eccles, R.; Hegmann, G.; Morrison, L.; Salter, R.; van Egmond, T.; Vonk, P.; Ash, G.; Crowther, R.; Dance, T.; Edwards, W.; Veldman, W.

1997-02-01

An environmental assessment of the Cold Lake Expansion Project has been conducted to identify major issues of concern by public and government agencies, to determine means to eliminate or reduce those impacts, and to recommend any further efforts required to obtain missing information or monitor impacts. Volume 2 of the environmental impact assessment is divided into two parts. Part 1 (biophysical and resource use assessment) constitutes the primary environmental impact assessment document for the Cold Lake expansion project. It includes technical support documentation in regard to: (1) an assessment of noise impacts, (2) an assessment of greenhouse gas emissions, (3) a conceptual conservation and reclamation plan, (4) a historical resource impact assessment, and (5) a description of effects of oil spills on fish. Part 2 (impact model description) serves a reference document for part 1. It describes the approach taken in developing and assessing the impact models, discusses proposed methods for mitigation and management of residual impacts, and the recommended monitoring requirements for each of the major resource disciplines. The impact models describe the specific pathways through which impacts will occur as a result of interactions between project-related activities and important environmental components. 476 refs., 58 tabs., 23 figs

Essential pathway identification: from in silico analysis to potential antifungal targets in Aspergillus fumigatus

DEFF Research Database (Denmark)

Thykær, Jette; Andersen, Mikael Rørdam; Baker, S. E.

2009-01-01

with the reactions, we identified orthologous candidate essential genes in Aspergillus fumigatus. Our predictions are validated in part by the modes of action for some antifungal drugs and by molecular genetic studies of essential genes in A. fumigatus and other fungi. The use of metabolic models to predict...... of 1190 biochemically unique reactions that are associated with 871 open reading frames. Through a systematic in silico deletion of single metabolic reactions using this model, several essential metabolic pathways were identified for A. niger. A total of 138 reactions were identified as being essential...... biochemical reactions during growth on a minimal glucose medium. The majority of the reactions grouped into essential biochemical pathways covering cell wall biosynthesis, amino acid biosynthesis, energy metabolism and purine and pyrimidine metabolism. Based on the A. niger open reading frames associated...

Therapeutic Potential of Thymoquinone in Glioblastoma Treatment: Targeting Major Gliomagenesis Signaling Pathways

Directory of Open Access Journals (Sweden)

Fabliha Ahmed Chowdhury

2018-01-01

Full Text Available Glioblastoma multiforme (GBM is one of the most devastating brain tumors with median survival of one year and presents unique challenges to therapy because of its aggressive behavior. Current treatment strategy involves surgery, radiotherapy, immunotherapy, and adjuvant chemotherapy even though optimal management requires a multidisciplinary approach and knowledge of potential complications from both the disease and its treatment. Thymoquinone (TQ, the main bioactive component of Nigella sativa L., has exhibited anticancer effects in numerous preclinical studies. Due to its multitargeting nature, TQ interferes in a wide range of tumorigenic processes and counteract carcinogenesis, malignant growth, invasion, migration, and angiogenesis. TQ can specifically sensitize tumor cells towards conventional cancer treatments and minimize therapy-associated toxic effects in normal cells. Its potential to enter brain via nasal pathway due to volatile nature of TQ adds another advantage in overcoming blood-brain barrier. In this review, we summarized the potential role of TQ in different signaling pathways in GBM that have undergone treatment with standard therapeutic modalities or with TQ. Altogether, we suggest further comprehensive evaluation of TQ in preclinical and clinical level to delineate its implied utility as novel therapeutics to combat the challenges for the treatment of GBM.

Cornelia de Lange Syndrome: NIPBL haploinsufficiency downregulates canonical Wnt pathway in zebrafish embryos and patients fibroblasts.

Science.gov (United States)

Pistocchi, A; Fazio, G; Cereda, A; Ferrari, L; Bettini, L R; Messina, G; Cotelli, F; Biondi, A; Selicorni, A; Massa, V

2013-10-17

Cornelia de Lange Syndrome is a severe genetic disorder characterized by malformations affecting multiple systems, with a common feature of severe mental retardation. Genetic variants within four genes (NIPBL (Nipped-B-like), SMC1A, SMC3, and HDAC8) are believed to be responsible for the majority of cases; all these genes encode proteins that are part of the 'cohesin complex'. Cohesins exhibit two temporally separated major roles in cells: one controlling the cell cycle and the other involved in regulating the gene expression. The present study focuses on the role of the zebrafish nipblb paralog during neural development, examining its expression in the central nervous system, and analyzing the consequences of nipblb loss of function. Neural development was impaired by the knockdown of nipblb in zebrafish. nipblb-loss-of-function embryos presented with increased apoptosis in the developing neural tissues, downregulation of canonical Wnt pathway genes, and subsequent decreased Cyclin D1 (Ccnd1) levels. Importantly, the same pattern of canonical WNT pathway and CCND1 downregulation was observed in NIPBL-mutated patient-specific fibroblasts. Finally, chemical activation of the pathway in nipblb-loss-of-function embryos rescued the adverse phenotype and restored the physiological levels of cell death.

CD40-CD40 Ligand Pathway is a Major Component of Acute Neuroinflammation and Contributes to Long-term Cognitive Dysfunction after Sepsis.

Science.gov (United States)

Michels, Monique; Danieslki, Lucinéia Gainski; Vieira, Andriele; Florentino, Drielly; Dall'Igna, Dhébora; Galant, Letícia; Sonai, Beatriz; Vuolo, Francieli; Mina, Franciele; Pescador, Bruna; Dominguini, Diogo; Barichello, Tatiana; Quevedo, João; Dal-Pizzol, Felipe; Petronilho, Fabrícia

2015-03-26

Sepsis-associated encephalopathy (SAE) is associated with an increased rate of morbidity and mortality. It is not understood what the exact mechanism is for the brain dysfunction that occurs in septic patients, but brain inflammation and oxidative stress are a possible theory. Such events can occur through the alteration of molecules that perpetuate the inflammatory response. Thus, it is possible to postulate that CD40 may be involved in this process. The aim of this work is to evaluate the role of CD40-CD40L pathway activation in brain dysfunction associated with sepsis in an animal model. Microglia activation induces the upregulation of CD40-CD40L, both in vitro and in vivo. The inhibition of microglia activation decreases levels of CD40-CD40L in the brain and decreases brain inflammation, oxidative damage and blood brain barrier dysfunction. Despite this, anti-CD40 treatment does not improve mortality in this model. However, it is able to improve long-term cognitive impairment in sepsis survivors. In conclusion, there is a major involvement of the CD40-CD40L signaling pathway in long-term brain dysfunction in an animal model of sepsis.

Altered Leukocyte Sphingolipid Pathway in Breast Cancer

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Larissa P. Maia

2017-11-01

Full Text Available Sphingolipid metabolism pathway is essential in membrane homeostasis, and its dysfunction has been associated with favorable tumor microenvironment, disease progression, and chemotherapy resistance. Its major components have key functions on survival and proliferation, with opposing effects. We have profiled the components of the sphingolipid pathway on leukocytes of breast cancer (BC patients undergoing chemotherapy treatment and without, including the five sphingosine 1-phosphate (S1P receptors, the major functional genes, and cytokines, in order to better understand the S1P signaling in the immune cells of these patients. To the best of our knowledge, this is the first characterization of the sphingolipid pathway in whole blood of BC patients. Skewed gene profiles favoring high SPHK1 expression toward S1P production during BC development was observed, which was reversed by chemotherapy treatment, and reached similar levels to those found in healthy donors. Such levels were also correlated with high levels of TNF-α. Our data revealed an important role of the sphingolipid pathway in immune cells in BC with skewed signaling of S1P receptors, which favored cancer development even under chemotherapy, and may probably be a trigger of cancer resistance. Thus, these molecules must be considered as a target pathway for combined BC therapeutics.

Intersection of autophagy with pathways of antigen presentation.

Science.gov (United States)

Patterson, Natalie L; Mintern, Justine D

2012-12-01

Traditionally, macroautophagy (autophagy) is viewed as a pathway of cell survival. Autophagy ensures the elimination of damaged or unwanted cytosolic components and provides a source of cellular nutrients during periods of stress. Interestingly, autophagy can also directly intersect with, and impact, other major pathways of cellular function. Here, we will review the contribution of autophagy to pathways of antigen presentation. The autophagy machinery acts to modulate both MHCI and MHCII antigen presentation. As such autophagy is an important participant in pathways that elicit host cell immunity and the elimination of infectious pathogens.

CMS completes major part of 3-D puzzle

CERN Multimedia

2002-01-01

The assembly of CMS in the giant SX5 surface building at Cessy has reached an important turning point. The magnet return yoke - whose red 'wheels' and 'disks' dominate the scene within the building - is completely assembled, including the central part that supports the huge outer shell of the solenoid vacuum tank. Now the focus is shifting towards installing the coil and sub-detectors within this structure..

New Pathways for Alimentary Mucositis

Directory of Open Access Journals (Sweden)

Joanne M. Bowen

2008-01-01

Full Text Available Alimentary mucositis is a major dose-limiting toxicity associated with anticancer treatment. It is responsible for reducing patient quality of life and represents a significant economic burden in oncology. The pathobiology of alimentary mucositis is extremely complex, and an increased understanding of mechanisms and pathway interactions is required to rationally design improved therapies. This review describes the latest advances in defining mechanisms of alimentary mucositis pathobiology in the context of pathway activation. It focuses particularly on the recent genome-wide analyses of regimen-related mucosal injury and the identification of specific regulatory pathways implicated in mucositis development. This review also discusses the currently known alimentary mucositis risk factors and the development of novel treatments. Suggestions for future research directions have been raised.

Evaluating options for balancing the water–electricity nexus in California: Part 2—Greenhouse gas and renewable energy utilization impacts

Energy Technology Data Exchange (ETDEWEB)

Tarroja, Brian; AghaKouchak, Amir; Sobhani, Reza; Feldman, David; Jiang, Sunny; Samuelsen, Scott, E-mail: gss@uci.edu

2014-11-01

A study was conducted to compare the technical potential and effectiveness of different water supply options for securing water availability in a large-scale, interconnected water supply system under historical and climate-change augmented inflow and demand conditions. Part 2 of the study focused on determining the greenhouse gas and renewable energy utilization impacts of different pathways to stabilize major surface reservoir levels. Using a detailed electric grid model and taking into account impacts on the operation of the water supply infrastructure, the greenhouse gas emissions and effect on overall grid renewable penetration level was calculated for each water supply option portfolio that successfully secured water availability from Part 1. The effects on the energy signature of water supply infrastructure were found to be just as important as that of the fundamental processes for each option. Under historical (baseline) conditions, many option portfolios were capable of securing surface reservoir levels with a net neutral or negative effect on emissions and a benefit for renewable energy utilization. Under climate change augmented conditions, however, careful selection of the water supply option portfolio was required to prevent imposing major emissions increases for the system. Overall, this analysis provided quantitative insight into the tradeoffs associated with choosing different pathways for securing California's water supply. - Highlights: • Part I presents a spatially and temporally resolved model of California’s surface reservoirs. • Part II presents GHG emissions and grid renewable penetration for water availability options. • In particular, the energy signature of water supply infrastructure is delineated. • Different pathways for securing California’s water supply are developed quantitatively. • Under baseline conditions, portfolios capable of securing surface reservoir levels emerge. • Under climate change conditions, the

Evaluating options for balancing the water–electricity nexus in California: Part 2—Greenhouse gas and renewable energy utilization impacts

International Nuclear Information System (INIS)

Tarroja, Brian; AghaKouchak, Amir; Sobhani, Reza; Feldman, David; Jiang, Sunny; Samuelsen, Scott

2014-01-01

A study was conducted to compare the technical potential and effectiveness of different water supply options for securing water availability in a large-scale, interconnected water supply system under historical and climate-change augmented inflow and demand conditions. Part 2 of the study focused on determining the greenhouse gas and renewable energy utilization impacts of different pathways to stabilize major surface reservoir levels. Using a detailed electric grid model and taking into account impacts on the operation of the water supply infrastructure, the greenhouse gas emissions and effect on overall grid renewable penetration level was calculated for each water supply option portfolio that successfully secured water availability from Part 1. The effects on the energy signature of water supply infrastructure were found to be just as important as that of the fundamental processes for each option. Under historical (baseline) conditions, many option portfolios were capable of securing surface reservoir levels with a net neutral or negative effect on emissions and a benefit for renewable energy utilization. Under climate change augmented conditions, however, careful selection of the water supply option portfolio was required to prevent imposing major emissions increases for the system. Overall, this analysis provided quantitative insight into the tradeoffs associated with choosing different pathways for securing California's water supply. - Highlights: • Part I presents a spatially and temporally resolved model of California’s surface reservoirs. • Part II presents GHG emissions and grid renewable penetration for water availability options. • In particular, the energy signature of water supply infrastructure is delineated. • Different pathways for securing California’s water supply are developed quantitatively. • Under baseline conditions, portfolios capable of securing surface reservoir levels emerge. • Under climate change conditions, the

Academic provenance: Investigation of pathways that lead students into the geosciences

Science.gov (United States)

Houlton, Heather R.

Pathways that lead students into the geosciences as a college major have not been fully explored in the current literature, despite the recent studies on the "geoscience pipeline model." Anecdotal evidence suggests low quality geoscience curriculum in K-12 education, lack of visibility of the discipline and lack of knowledge about geoscience careers contribute to low geoscience enrollments at universities. This study investigated the reasons why college students decided to major in the geosciences. Students' interests, experiences, motivations and desired future careers were examined to develop a pathway model. In addition, self-efficacy was used to inform pathway analyses, as it is an influential factor in academic major and career choice. These results and interpretations have strong implications for recruitment and retention in academia and industry. A semi-structured interview protocol was developed, which was informed by John Flanagan's critical incident theory. The responses to this interview were used to identify common experiences that diverse students shared for reasons they became geoscience majors. Researchers used self-efficacy theory by Alfred Bandura to assess students' pathways. Seventeen undergraduate geoscience majors from two U.S. Midwest research universities were sampled for cross-comparison and analysis. Qualitative analyses led to the development of six categorical steps for the geoscience pathway. The six pathway steps are: innate attributes/interest sources, pre-college critical incidents, college critical incidents, current/near future goals, expected career attributes and desired future careers. Although, how students traversed through each step was unique for individuals, similar patterns were identified between different populations in our participants: Natives, Immigrants and Refugees. In addition, critical incidents were found to act on behavior in two different ways: to support and confirm decision-making behavior (supportive critical

The Hippo Pathway: Immunity and Cancer.

Science.gov (United States)

Taha, Zaid; J Janse van Rensburg, Helena; Yang, Xiaolong

2018-03-28

Since its discovery, the Hippo pathway has emerged as a central signaling network in mammalian cells. Canonical signaling through the Hippo pathway core components (MST1/2, LATS1/2, YAP and TAZ) is important for development and tissue homeostasis while aberrant signaling through the Hippo pathway has been implicated in multiple pathologies, including cancer. Recent studies have uncovered new roles for the Hippo pathway in immunology. In this review, we summarize the mechanisms by which Hippo signaling in pathogen-infected or neoplastic cells affects the activities of immune cells that respond to these threats. We further discuss how Hippo signaling functions as part of an immune response. Finally, we review how immune cell-intrinsic Hippo signaling modulates the development/function of leukocytes and propose directions for future work.

Pharmacometabolomics of response to sertraline and to placebo in major depressive disorder - possible role for methoxyindole pathway.

Directory of Open Access Journals (Sweden)

Hongjie Zhu

Full Text Available Therapeutic response to selective serotonin (5-HT reuptake inhibitors in Major Depressive Disorder (MDD varies considerably among patients, and the onset of antidepressant therapeutic action is delayed until after 2 to 4 weeks of treatment. The objective of this study was to analyze changes within methoxyindole and kynurenine (KYN branches of tryptophan pathway to determine whether differential regulation within these branches may contribute to mechanism of variation in response to treatment. Metabolomics approach was used to characterize early biochemical changes in tryptophan pathway and correlated biochemical changes with treatment outcome. Outpatients with MDD were randomly assigned to sertraline (n = 35 or placebo (n = 40 in a double-blind 4-week trial; response to treatment was measured using the 17-item Hamilton Rating Scale for Depression (HAMD17. Targeted electrochemistry based metabolomic platform (LCECA was used to profile serum samples from MDD patients. The response rate was slightly higher for sertraline than for placebo (21/35 [60%] vs. 20/40 [50%], respectively, χ(2(1  = 0.75, p = 0.39. Patients showing a good response to sertraline had higher pretreatment levels of 5-methoxytryptamine (5-MTPM, greater reduction in 5-MTPM levels after treatment, an increase in 5-Methoxytryptophol (5-MTPOL and Melatonin (MEL levels, and decreases in the (KYN/MEL and 3-Hydroxykynurenine (3-OHKY/MEL ratios post-treatment compared to pretreatment. These changes were not seen in the patients showing poor response to sertraline. In the placebo group, more favorable treatment outcome was associated with increases in 5-MTPOL and MEL levels and significant decreases in the KYN/MEL and 3-OHKY/MEL; changes in 5-MTPM levels were not associated with the 4-week response. These results suggest that recovery from a depressed state due to treatment with drug or with placebo could be associated with preferential utilization of serotonin for

Pathways for impact: scientists' different perspectives on agricultural innovation

NARCIS (Netherlands)

Röling, N.G.

2009-01-01

This paper takes the viewpoint of a social scientist and looks at agricultural scientists' pathways for science impact. Awareness of these pathways is increasingly becoming part and parcel of the professionalism of the agricultural scientist, now that the pressure is on to mobilize smallholders and

The Competitiveness of Alternative Hydrogen Pathways

DEFF Research Database (Denmark)

Hansen, Anders Chr.

to transport services and in market competitiveness and societal competitiveness. The major societal competitive advantage of hydrogen is its convertibility to electricity and from any other source of energy. This enables a flexible use of natural gas and primary electricity as transport fuels. The major...... advantage in market competitiveness is the energy efficiency of the fuel cell. This advantage is, however, to some extent balanced by the costs associated with conversion, transport, and storage. The balance between these factors required for market competitiveness is identified.......The paper surveys the literature on the competitiveness of alternative hydrogen pathways in the transport sector. The competitiveness of the alternative systems can be differentiated in the “well-to-tank (WtT)” and “tank-to-wheel (TtW)” sections of the pathway transforming primary energy...

Signaling pathways activation profiles make better markers of cancer than expression of individual genes

OpenAIRE

Borisov, Nikolay M.; Terekhanova, Nadezhda V.; Aliper, Alexander M.; Venkova, Larisa S.; Smirnov, Philip Yu; Roumiantsev, Sergey; Korzinkin, Mikhail B.; Zhavoronkov, Alex A.; Buzdin, Anton A.

2014-01-01

Identification of reliable and accurate molecular markers remains one of the major challenges of contemporary biomedicine. We developed a new bioinformatic technique termed OncoFinder that for the first time enables to quantatively measure activation of intracellular signaling pathways basing on transcriptomic data. Signaling pathways regulate all major cellular events in health and disease. Here, we showed that the Pathway Activation Strength (PAS) value itself may serve as the biomarker for...

Distribution of events of positive selection and population differentiation in a metabolic pathway: the case of asparagine N-glycosylation

Directory of Open Access Journals (Sweden)

Dall’Olio Giovanni

2012-06-01

Full Text Available Abstract Background Asparagine N-Glycosylation is one of the most important forms of protein post-translational modification in eukaryotes. This metabolic pathway can be subdivided into two parts: an upstream sub-pathway required for achieving proper folding for most of the proteins synthesized in the secretory pathway, and a downstream sub-pathway required to give variability to trans-membrane proteins, and involved in adaptation to the environment and innate immunity. Here we analyze the nucleotide variability of the genes of this pathway in human populations, identifying which genes show greater population differentiation and which genes show signatures of recent positive selection. We also compare how these signals are distributed between the upstream and the downstream parts of the pathway, with the aim of exploring how forces of population differentiation and positive selection vary among genes involved in the same metabolic pathway but subject to different functional constraints. Results Our results show that genes in the downstream part of the pathway are more likely to show a signature of population differentiation, while events of positive selection are equally distributed among the two parts of the pathway. Moreover, events of positive selection are frequent on genes that are known to be at bifurcation points, and that are identified as being in key position by a network-level analysis such as MGAT3 and GCS1. Conclusions These findings indicate that the upstream part of the Asparagine N-Glycosylation pathway has lower diversity among populations, while the downstream part is freer to tolerate diversity among populations. Moreover, the distribution of signatures of population differentiation and positive selection can change between parts of a pathway, especially between parts that are exposed to different functional constraints. Our results support the hypothesis that genes involved in constitutive processes can be expected to show

Assessing patterns in introduction pathways of alien species by linking major invasion data bases

Czech Academy of Sciences Publication Activity Database

Saul, W.-C.; Roy, H. E.; Booy, O.; Carnevali, L.; Chen, H.-J.; Genovesi, P.; Harrower, C.; Hulme, P. E.; Pagad, S.; Pergl, Jan; Jeschke, J.M.

2017-01-01

Roč. 54, č. 2 (2017), s. 657-669 ISSN 0021-8901 R&D Projects: GA ČR(CZ) GAP504/11/1028 Grant - others:COST(XE) TD1209 Program:FA Institutional support: RVO:67985939 Keywords : invasions * pathways * databases Subject RIV: EH - Ecology, Behaviour OBOR OECD: Biodiversity conservation Impact factor: 5.301, year: 2016

Examination of tetrahydrobiopterin pathway genes in autism.

Science.gov (United States)

Schnetz-Boutaud, N C; Anderson, B M; Brown, K D; Wright, H H; Abramson, R K; Cuccaro, M L; Gilbert, J R; Pericak-Vance, M A; Haines, J L

2009-11-01

Autism is a complex disorder with a high degree of heritability and significant phenotypic and genotypic heterogeneity. Although candidate gene studies and genome-wide screens have failed to identify major causal loci associated with autism, numerous studies have proposed association with several variations in genes in the dopaminergic and serotonergic pathways. Because tetrahydrobiopterin (BH4) is the essential cofactor in the synthesis of these two neurotransmitters, we genotyped 25 SNPs in nine genes of the BH4 pathway in a total of 403 families. Significant nominal association was detected in the gene for 6-pyruvoyl-tetrahydropterin synthase, PTS (chromosome 11), with P = 0.009; this result was not restricted to an affected male-only subset. Multilocus interaction was detected in the BH4 pathway alone, but not across the serotonin, dopamine and BH4 pathways.

CD40–CD40 Ligand Pathway Is a Major Component of Acute Neuroinflammation and Contributes to Long-term Cognitive Dysfunction after Sepsis

Science.gov (United States)

Michels, Monique; Danieslki, Lucinéia Gainski; Vieira, Andriele; Florentino, Drielly; Dall’Igna, Dhébora; Galant, Letícia; Sonai, Beatriz; Vuolo, Francieli; Mina, Franciele; Pescador, Bruna; Dominguini, Diogo; Barichello, Tatiana; Quevedo, João; Dal-Pizzol, Felipe; Petronilho, Fabrícia

2015-01-01

Sepsis-associated encephalopathy (SAE) is associated with an increased rate of morbidity and mortality. It is not understood what the exact mechanism is for the brain dysfunction that occurs in septic patients, but brain inflammation and oxidative stress are a possible theory. Such events can occur through the alteration of molecules that perpetuate the inflammatory response. Thus, it is possible to postulate that CD40 may be involved in this process. The aim of this work is to evaluate the role of CD40–CD40L pathway activation in brain dysfunction associated with sepsis in an animal model. Microglia activation induces the upregulation of CD40–CD40L, both in vitro and in vivo. The inhibition of microglia activation decreases levels of CD40–CD40L in the brain and decreases brain inflammation, oxidative damage and blood brain barrier dysfunction. Despite this, anti-CD40 treatment does not improve mortality in this model. However, it is able to improve long-term cognitive impairment in sepsis survivors. In conclusion, there is a major involvement of the CD40–CD40L signaling pathway in long-term brain dysfunction in an animal model of sepsis. PMID:25822797

Thermodynamics in Gliomas: Interactions between the Canonical WNT/Beta-Catenin Pathway and PPAR Gamma

Directory of Open Access Journals (Sweden)

Alexandre Vallée

2017-05-01

Full Text Available Gliomas cells are the site of numerous metabolic and thermodynamics abnormalities with an increasing entropy rate which is characteristic of irreversible processes driven by changes in Gibbs energy, heat production, intracellular acidity, membrane potential gradient, and ionic conductance. We focus our review on the opposing interactions observed in glioma between the canonical WNT/beta-catenin pathway and PPAR gamma and their metabolic and thermodynamic implications. In gliomas, WNT/beta-catenin pathway is upregulated while PPAR gamma is downregulated. Upregulation of WNT/beta-catenin signaling induces changes in key metabolic enzyme that modify their thermodynamics behavior. This leads to activation pyruvate dehydrogenase kinase 1(PDK-1 and monocarboxylate lactate transporter 1 (MCT-1. Consequently, phosphorylation of PDK-1 inhibits pyruvate dehydrogenase complex (PDH. Thus, a large part of pyruvate cannot be converted into acetyl-CoA in mitochondria and in TCA (tricarboxylic acid cycle. This leads to aerobic glycolysis despite the availability of oxygen, named Warburg effect. Cytoplasmic pyruvate is, in major part, converted into lactate. The WNT/beta-catenin pathway induces also the transcription of genes involved in cell proliferation, cell invasiveness, nucleotide synthesis, tumor growth, and angiogenesis, such as c-Myc, cyclin D1, PDK. In addition, in gliomas cells, PPAR gamma is downregulated, leading to a decrease in insulin sensitivity and an increase in neuroinflammation. Moreover, PPAR gamma contributes to regulate some key circadian genes. Abnormalities in the regulation of circadian rhythms and dysregulation in circadian clock genes are observed in gliomas. Circadian rhythms are dissipative structures, which play a key role in far-from-equilibrium thermodynamics through their interactions with WNT/beta-catenin pathway and PPAR gamma. In gliomas, metabolism, thermodynamics, and circadian rhythms are tightly interrelated.

Pathway Distiller - multisource biological pathway consolidation.

Science.gov (United States)

Doderer, Mark S; Anguiano, Zachry; Suresh, Uthra; Dashnamoorthy, Ravi; Bishop, Alexander J R; Chen, Yidong

2012-01-01

One method to understand and evaluate an experiment that produces a large set of genes, such as a gene expression microarray analysis, is to identify overrepresentation or enrichment for biological pathways. Because pathways are able to functionally describe the set of genes, much effort has been made to collect curated biological pathways into publicly accessible databases. When combining disparate databases, highly related or redundant pathways exist, making their consolidation into pathway concepts essential. This will facilitate unbiased, comprehensive yet streamlined analysis of experiments that result in large gene sets. After gene set enrichment finds representative pathways for large gene sets, pathways are consolidated into representative pathway concepts. Three complementary, but different methods of pathway consolidation are explored. Enrichment Consolidation combines the set of the pathways enriched for the signature gene list through iterative combining of enriched pathways with other pathways with similar signature gene sets; Weighted Consolidation utilizes a Protein-Protein Interaction network based gene-weighting approach that finds clusters of both enriched and non-enriched pathways limited to the experiments' resultant gene list; and finally the de novo Consolidation method uses several measurements of pathway similarity, that finds static pathway clusters independent of any given experiment. We demonstrate that the three consolidation methods provide unified yet different functional insights of a resultant gene set derived from a genome-wide profiling experiment. Results from the methods are presented, demonstrating their applications in biological studies and comparing with a pathway web-based framework that also combines several pathway databases. Additionally a web-based consolidation framework that encompasses all three methods discussed in this paper, Pathway Distiller (http://cbbiweb.uthscsa.edu/PathwayDistiller), is established to allow

Geoscience Academic Provenance: A Theoretical Framework for Understanding Geoscience Students' Pathways

Science.gov (United States)

Houlton, H.; Keane, C.

2012-04-01

The demand and employment opportunities for geoscientists in the United States are projected to increase 23% from 2008 to 2018 (Gonzales, 2011). Despite this trend, there is a disconnect between undergraduate geoscience students and their desire to pursue geoscience careers. A theoretical framework was developed to understand the reasons why students decide to major in the geosciences and map those decisions to their career aspirations (Houlton, 2010). A modified critical incident study was conducted to develop the pathway model from 17, one-hour long semi-structured interviews of undergraduate geoscience majors from two Midwest Research Institutions (Houlton, 2010). Geoscience Academic Provenance maps geoscience students' initial interests, entry points into the major, critical incidents and future career goals as a pathway, which elucidates the relationships between each of these components. Analyses identified three geoscience student population groups that followed distinct pathways: Natives, Immigrants and Refugees. A follow up study was conducted in 2011 to ascertain whether these students continued on their predicted pathways, and if not, reasons for attrition. Geoscientists can use this framework as a guide to inform future recruitment and retention initiatives and target these geoscience population groups for specific employment sectors.

Aquatic pathway 2

International Nuclear Information System (INIS)

1977-01-01

This third part of the investigation discusses the preliminary results of sub-investigations concerning problems of the release of radioactive substances into the environment via the water pathway. On the basis of papers on the emission into the draining ditch and the exchange processes there, investigations of a possible incorporation via different exposure pathways are reported. Special regard is paid to drinking water supply aquatic foodstuffs, the river sediment, the utilisation of the agricultural surfaces and the draining ditch including its pre-pollution. The dynamics of contamination processes is reported on with regard to the problem of accidents. The colloquium will give an outline of the progress made so far and admit participants' suggestions for further work on the sub-investigations. The following colloquia will report further findings, in particular effects on aquatic ecosystems. (orig.) [de

14CO2 fixation and allocation of 14C into major biochemical fractions in different parts of Indian mustard (Brassica juncea)

International Nuclear Information System (INIS)

Subrahmanyam, D.; Rathore, V.S.

1993-01-01

14CO2 fixation and transport of 14C-photosynthates amongst different parts of Indian mustard (Brassica juncea) and the incorporation of 14C into major chemical fractions in different plant parts was studied at ripening stage. Stem and pod together contributed 70 % of the total 14C fixed by the plant. In all plant parts neutral saccharide fraction contained maximum radioactivity immediately after exposing plants to 14CO2. After 24 h, the radioactivity in this fraction declined considerably due to translocation or conversion into other fractions. Concomitantly radioactivity in lipids and pigments, residue and starch fractions increased after 24 h. The 14C allocation patterns in stem and leaves were similar. However, in pods very high radioactivity was recovered from amino and organic acid fractions indicating the presence of active phosphoenolpyruvate carboxylase in pod walls

Kynurenine pathway in psychosis: evidence of increased tryptophan degradation.

LENUS (Irish Health Repository)

Barry, Sandra

2009-05-01

The kynurenine pathway of tryptophan degradation may serve to integrate disparate abnormalities heretofore identified in research aiming to elucidate the complex aetiopathogenesis of psychotic disorders. Post-mortem brain tissue studies have reported elevated kynurenine and kynurenic acid in the frontal cortex and upregulation of the first step of the pathway in the anterior cingulate cortex of individuals with schizophrenia. In this study, we examined kynurenine pathway activity by measuring tryptophan breakdown, a number of pathway metabolites and interferon gamma (IFN-gamma), which is the preferential activator of the first-step enzyme, indoleamine dioxygenase (IDO), in the plasma of patients with major psychotic disorder. Plasma tryptophan, kynurenine pathway metabolites were measured using high-performance liquid chromatography (HPLC) in 34 patients with a diagnosis on the psychotic spectrum (schizophrenia or schizoaffective disorder) and in 36 healthy control subjects. IFN-gamma was measured using enzyme-linked immunosorbent assay (ELISA). The mean tryptophan breakdown index (kynurenine\\/tryptophan) was significantly higher in the patient group compared with controls (P < 0.05). IFN-gamma measures did not differ between groups (P = 0.23). No relationship was found between measures of psychopathology, symptom severity and activity in the first step in the pathway. A modest correlation was established between the tryptophan breakdown index and illness duration. These results provide evidence for kynurenine pathway upregulation, specifically involving the first enzymatic step, in patients with major psychotic disorder. Increased tryptophan degradation in psychoses may have potential consequences for the treatment of these disorders by informing the development of novel therapeutic compounds.

Developmental defects in zebrafish for classification of EGF pathway inhibitors

Energy Technology Data Exchange (ETDEWEB)

Pruvot, Benoist; Curé, Yoann; Djiotsa, Joachim; Voncken, Audrey; Muller, Marc, E-mail: m.muller@ulg.ac.be

2014-01-15

One of the major challenges when testing drug candidates targeted at a specific pathway in whole animals is the discrimination between specific effects and unwanted, off-target effects. Here we used the zebrafish to define several developmental defects caused by impairment of Egf signaling, a major pathway of interest in tumor biology. We inactivated Egf signaling by genetically blocking Egf expression or using specific inhibitors of the Egf receptor function. We show that the combined occurrence of defects in cartilage formation, disturbance of blood flow in the trunk and a decrease of myelin basic protein expression represent good indicators for impairment of Egf signaling. Finally, we present a classification of known tyrosine kinase inhibitors according to their specificity for the Egf pathway. In conclusion, we show that developmental indicators can help to discriminate between specific effects on the target pathway from off-target effects in molecularly targeted drug screening experiments in whole animal systems. - Highlights: • We analyze the functions of Egf signaling on zebrafish development. • Genetic blocking of Egf expression causes cartilage, myelin and circulatory defects. • Chemical inhibition of Egf receptor function causes similar defects. • Developmental defects can reveal the specificity of Egf pathway inhibitors.

Developmental defects in zebrafish for classification of EGF pathway inhibitors

International Nuclear Information System (INIS)

Pruvot, Benoist; Curé, Yoann; Djiotsa, Joachim; Voncken, Audrey; Muller, Marc

2014-01-01

One of the major challenges when testing drug candidates targeted at a specific pathway in whole animals is the discrimination between specific effects and unwanted, off-target effects. Here we used the zebrafish to define several developmental defects caused by impairment of Egf signaling, a major pathway of interest in tumor biology. We inactivated Egf signaling by genetically blocking Egf expression or using specific inhibitors of the Egf receptor function. We show that the combined occurrence of defects in cartilage formation, disturbance of blood flow in the trunk and a decrease of myelin basic protein expression represent good indicators for impairment of Egf signaling. Finally, we present a classification of known tyrosine kinase inhibitors according to their specificity for the Egf pathway. In conclusion, we show that developmental indicators can help to discriminate between specific effects on the target pathway from off-target effects in molecularly targeted drug screening experiments in whole animal systems. - Highlights: • We analyze the functions of Egf signaling on zebrafish development. • Genetic blocking of Egf expression causes cartilage, myelin and circulatory defects. • Chemical inhibition of Egf receptor function causes similar defects. • Developmental defects can reveal the specificity of Egf pathway inhibitors

Specialized prefrontal auditory fields: organization of primate prefrontal-temporal pathways

Directory of Open Access Journals (Sweden)

Maria eMedalla

2014-04-01

Full Text Available No other modality is more frequently represented in the prefrontal cortex than the auditory, but the role of auditory information in prefrontal functions is not well understood. Pathways from auditory association cortices reach distinct sites in the lateral, orbital, and medial surfaces of the prefrontal cortex in rhesus monkeys. Among prefrontal areas, frontopolar area 10 has the densest interconnections with auditory association areas, spanning a large antero-posterior extent of the superior temporal gyrus from the temporal pole to auditory parabelt and belt regions. Moreover, auditory pathways make up the largest component of the extrinsic connections of area 10, suggesting a special relationship with the auditory modality. Here we review anatomic evidence showing that frontopolar area 10 is indeed the main frontal auditory field as the major recipient of auditory input in the frontal lobe and chief source of output to auditory cortices. Area 10 is thought to be the functional node for the most complex cognitive tasks of multitasking and keeping track of information for future decisions. These patterns suggest that the auditory association links of area 10 are critical for complex cognition. The first part of this review focuses on the organization of prefrontal-auditory pathways at the level of the system and the synapse, with a particular emphasis on area 10. Then we explore ideas on how the elusive role of area 10 in complex cognition may be related to the specialized relationship with auditory association cortices.

MAP kinase pathways in the yeast Saccharomyces cerevisiae

Science.gov (United States)

Gustin, M. C.; Albertyn, J.; Alexander, M.; Davenport, K.; McIntire, L. V. (Principal Investigator)

1998-01-01

A cascade of three protein kinases known as a mitogen-activated protein kinase (MAPK) cascade is commonly found as part of the signaling pathways in eukaryotic cells. Almost two decades of genetic and biochemical experimentation plus the recently completed DNA sequence of the Saccharomyces cerevisiae genome have revealed just five functionally distinct MAPK cascades in this yeast. Sexual conjugation, cell growth, and adaptation to stress, for example, all require MAPK-mediated cellular responses. A primary function of these cascades appears to be the regulation of gene expression in response to extracellular signals or as part of specific developmental processes. In addition, the MAPK cascades often appear to regulate the cell cycle and vice versa. Despite the success of the gene hunter era in revealing these pathways, there are still many significant gaps in our knowledge of the molecular mechanisms for activation of these cascades and how the cascades regulate cell function. For example, comparison of different yeast signaling pathways reveals a surprising variety of different types of upstream signaling proteins that function to activate a MAPK cascade, yet how the upstream proteins actually activate the cascade remains unclear. We also know that the yeast MAPK pathways regulate each other and interact with other signaling pathways to produce a coordinated pattern of gene expression, but the molecular mechanisms of this cross talk are poorly understood. This review is therefore an attempt to present the current knowledge of MAPK pathways in yeast and some directions for future research in this area.

Pathway analysis: State of the art

Directory of Open Access Journals (Sweden)

Miguel Angel eGarcía-Campos

2015-12-01

Full Text Available Pathway analysis is a set of widely used tools for research in life sciences intended to give meaning to high-throughput biological data. The methodology of these tools settles in the gathering and usage of knowledge that comprise biomolecular functioning, coupled with statistical testing and other algorithms. Despite their wide employment, pathway analysis foundations and overall background may not be fully understood, leading to misinterpretation of analysis results. This review attempts to comprise the fundamental knowledge to take into consideration when using pathway analysis as a hypothesis generation tool. We discuss the key elements that are part of these methodologies, their capabilities and current deficiencies. We also present an overview of current and all-time popular methods, highlighting different classes across them. In doing so, we show the exploding diversity of methods that pathway analysis encompasses, point out commonly overlooked caveats, and direct attention to a potential new class of methods that attempt to zoom the analysis scope to the sample scale.

A global water scarcity assessment under Shared Socio-economic Pathways – Part 1: Water use

Directory of Open Access Journals (Sweden)

N. Hanasaki

2013-07-01

Full Text Available A novel global water scarcity assessment for the 21st century is presented in a two-part paper. In this first paper, water use scenarios are presented for the latest global hydrological models. The scenarios are compatible with the socio-economic scenarios of the Shared Socio-economic Pathways (SSPs, which are a part of the latest set of scenarios on global change developed by the integrated assessment, the IAV (climate change impact, adaptation, and vulnerability assessment, and the climate modeling community. The SSPs depict five global situations based on substantially different socio-economic conditions during the 21st century. Water use scenarios were developed to reflect not only quantitative socio-economic factors, such as population and electricity production, but also key qualitative concepts such as the degree of technological change and overall environmental consciousness. Each scenario consists of five factors: irrigated area, crop intensity, irrigation efficiency, and withdrawal-based potential industrial and municipal water demands. The first three factors are used to estimate the potential irrigation water demand. All factors were developed using simple models based on a literature review and analysis of historical records. The factors are grid-based at a spatial resolution of 0.5° × 0.5° and cover the whole 21st century in five-year intervals. Each factor shows wide variation among the different global situations depicted: the irrigated area in 2085 varies between 2.7 × 106 and 4.5 × 106 km2, withdrawal-based potential industrial water demand between 246 and 1714 km3 yr−1, and municipal water between 573 and 1280 km3 yr−1. The water use scenarios can be used for global water scarcity assessments that identify the regions vulnerable to water scarcity and analyze the timing and magnitude of scarcity conditions.

Research of the pre-launch powered lubrication device of major parts of the engine D-240

Science.gov (United States)

Korchuganova, M.; Syrbakov, A.; Tkachev, A.; Zorina, T.

2015-09-01

In the publication, the issues have been considered concerning combustion engine start wear of mobile machines in case of outside storage in the conditions of low environmental temperature. Based on the analysis of existing methods and constructions of powered lubrication devices for contact surfaces of engines, a design of a combined device has been suggested which unites the functions of hydraulic and heat accumulators. On the basis of the elaborated design, preparatory tests have been conducted in order to evaluate the effectiveness of pre-start oil circulation in the engine D-240, as well as the effectiveness rate of thermoinsulation and the heating device of the hydraulic accumulator. The findings of the survey have shown that the pre-start powered lubrication device for major parts of the engine is effective.

Radiation pathways and potential health impacts from inactive uranium mill tailings

International Nuclear Information System (INIS)

1978-07-01

Radiation exposure pathways and potential health impacts were estimated as part of the evaluation of radioactive uranium mill tailings at the sites of inactive mills in eight western states. The purpose of this report is to describe in detail the methodology used in performing the pathway analysis and health effects estimations. In addition, specific parameters are presented for each of the 22 uranium mill sites that were evaluated. A computer program, RADAD, developed as part of this program, is described and listed

Women and major depressive disorder: clinical perspectives on causal pathways.

Science.gov (United States)

Accortt, Eynav Elgavish; Freeman, Marlene P; Allen, John J B

2008-12-01

Epidemiological data on the prevalence of mood disorders demonstrate that major depressive disorder (MDD) is approximately twice as common in women as in men and that its first onset peaks during the reproductive years. We aimed to review key social, psychological, and biological factors that seem strongly implicated in the etiology of major depression and to focus on sex-specific aspects of depression, such as the role of a woman's reproductive life cycle in depressive symptomatology. A review of the literature, from 1965 to present, was conducted. An integrated etiological model best explains gender and sex differences in depression. Social, psychological, and biological variables must be simultaneously taken into account. These vulnerabilities include (but are not limited to) gender-specific roles in society, life stress such as trauma, a tendency toward ruminative coping strategies, and the effects of sex hormones and genetic factors. To effectively treat MDD in women and to prevent the recurrence of illness in vulnerable women, clinicians must understand the sex-specific aspects of mood disorders over the longitudinal course of women's reproductive lives. A biopsychosocial approach should, therefore, be the main focus of future research and practice, to eventually result in an integrated etiological model of depression in women. Based on the prevalence of MDD in women, timely screening, diagnosis, and intervention should be public health priorities.

Mycobacteria exploit three genetically distinct DNA double-strand break repair pathways.

Science.gov (United States)

Gupta, Richa; Barkan, Daniel; Redelman-Sidi, Gil; Shuman, Stewart; Glickman, Michael S

2011-01-01

Bacterial pathogens rely on their DNA repair pathways to resist genomic damage inflicted by the host. DNA double-strand breaks (DSBs) are especially threatening to bacterial viability. DSB repair by homologous recombination (HR) requires nucleases that resect DSB ends and a strand exchange protein that facilitates homology search. RecBCD and RecA perform these functions in Escherichia coli and constitute the major pathway of error-free DSB repair. Mycobacteria, including the human pathogen M. tuberculosis, elaborate an additional error-prone pathway of DSB repair via non-homologous end-joining (NHEJ) catalysed by Ku and DNA ligase D (LigD). Little is known about the relative contributions of HR and NHEJ to mycobacterial chromosome repair, the factors that dictate pathway choice, or the existence of additional DSB repair pathways. Here we demonstrate that Mycobacterium smegmatis has three DSB repair pathway options: HR, NHEJ and a novel mechanism of single-strand annealing (SSA). Inactivation of NHEJ or SSA is compensated by elevated HR. We find that mycobacterial RecBCD does not participate in HR or confer resistance to ionizing radiation (IR), but is required for the RecA-independent SSA pathway. In contrast, the mycobacterial helicase-nuclease AdnAB participates in the RecA-dependent HR pathway, and is a major determinant of resistance to IR and oxidative DNA damage. These findings reveal distinctive features of mycobacterial DSB repair, most notably the dedication of the RecBCD and AdnAB helicase-nuclease machines to distinct repair pathways. © 2010 Blackwell Publishing Ltd.

Alternative end-joining pathway(s): bricolage at DNA breaks.

Science.gov (United States)

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.

Proteomics of the rat myocardium during development of type 2 diabetes mellitus reveals progressive alterations in major metabolic pathways

DEFF Research Database (Denmark)

Edhager, Anders Valdemar; Povlsen, Jonas Agerlund; Løfgren, Bo

2018-01-01

in intracellular metabolic pathways in the Zucker diabetic fatty rat heart as T2DM develops using MS based proteomics. The pre-diabetic state only induced minor pathway changes, whereas onset and late T2DM caused pronounced perturbations. Two actin-associated proteins, ARPC2 and TPM3, were up-regulated at the pre...

Gene Expression Profiling Identifies Downregulation of the Neurotrophin-MAPK Signaling Pathway in Female Diabetic Peripheral Neuropathy Patients.

Science.gov (United States)

Luo, Lin; Zhou, Wen-Hua; Cai, Jiang-Jia; Feng, Mei; Zhou, Mi; Hu, Su-Pei; Xu, Jin; Ji, Lin-Dan

2017-01-01

Diabetic peripheral neuropathy (DPN) is a common complication of diabetes mellitus (DM). It is not diagnosed or managed properly in the majority of patients because its pathogenesis remains controversial. In this study, human whole genome microarrays identified 2898 and 4493 differentially expressed genes (DEGs) in DM and DPN patients, respectively. A further KEGG pathway analysis indicated that DPN and DM share four pathways, including apoptosis, B cell receptor signaling pathway, endocytosis, and Toll-like receptor signaling pathway. The DEGs identified through comparison of DPN and DM were significantly enriched in MAPK signaling pathway, NOD-like receptor signaling pathway, and neurotrophin signaling pathway, while the "neurotrophin-MAPK signaling pathway" was notably downregulated. Seven DEGs from the neurotrophin-MAPK signaling pathway were validated in additional 78 samples, and the results confirmed the initial microarray findings. These findings demonstrated that downregulation of the neurotrophin-MAPK signaling pathway may be the major mechanism of DPN pathogenesis, thus providing a potential approach for DPN treatment.

Pathways to deep decarbonization in India

DEFF Research Database (Denmark)

Shukla, P.; Dhar, Subash; Pathak, Minal

This report is a part of the global Deep Decarbonisation Pathways (DDP) Project. The analysis consider two development scenarios for India and assess alternate roadmaps for transiting to a low carbon economy consistent with the globally agreed 2°C stabilization target. The report does not conside...

Diverse Pathways of Psychology Majors: Vocational Interests, Self-Efficacy, and Intentions

Science.gov (United States)

Rottinghaus, Patrick J.; Gaffey, Abigail R.; Borgen, Fred H.; Ralston, Christopher A.

2006-01-01

The authors examine the differences in vocational interests and self-efficacy of 254 undergraduate psychology majors organized by 7 career intention groups (e.g., psychological research). The explanatory power of individual General Occupational Themes (GOTs), Basic Interest Scales (BISs), and Personal Style Scales (PPSs) of the Strong Interest…

Creatine Monohydrate Enhances Energy Status and Reduces Glycolysis via Inhibition of AMPK Pathway in Pectoralis Major Muscle of Transport-Stressed Broilers.

Science.gov (United States)

Zhang, Lin; Wang, Xiaofei; Li, Jiaolong; Zhu, Xudong; Gao, Feng; Zhou, Guanghong

2017-08-16

Creatine monohydrate (CMH) contributes to reduce transport-induced muscle rapid glycolysis and improve meat quality of broilers, but the underlying mechanism is still unknown. Therefore, this study aimed to investigate the molecular mechanisms underlying the ameliorative effects of CMH on muscle glycolysis metabolism of transported broilers during summer. The results showed that 3 h transport during summer elevated chicken live weight loss and plasma corticosterone concentration; decreased muscle concentrations of ATP, creatine, and energy charge value; increased muscle AMP concentration and AMP/ATP ratio; and upregulated muscle mRNA expression of LKB1 and AMPKα2, as well as protein expression of p-LKB1 Thr189 and p-AMPKα Thr172 , which subsequently resulted in rapid glycolysis in the pectoralis major muscle and consequent reduction of meat quality. Dietary addition of CMH at 1200 mg/kg ameliorated transport-induced rapid muscle glycolysis and reduction of meat quality via enhancement of the energy-buffering capacity of intramuscular phosphocreatine/creatine system and inhibition of AMPK pathway.

Cerebral insulin, insulin signaling pathway, and brain angiogenesis.

Science.gov (United States)

Zeng, Yi; Zhang, Le; Hu, Zhiping

2016-01-01

Insulin performs unique non-metabolic functions within the brain. Broadly speaking, two major areas of these functions are those related to brain endothelial cells and the blood-brain barrier (BBB) function, and those related to behavioral effects, like cognition in disease states (Alzheimer's disease, AD) and in health. Recent studies showed that both these functions are associated with brain angiogenesis. These findings raise interesting questions such as how they are linked to each other and whether modifying brain angiogenesis by targeting certain insulin signaling pathways could be an effective strategy to treat dementia as in AD, or even to help secure healthy longevity. The two canonical downstream pathways involved in mediating the insulin signaling pathway, the phosphoinositide-3 kinase (PI3K), and mitogen-activated protein kinase (MAPK) cascades, in the brain are supposed to be similar to those in the periphery. PI3K and MAPK pathways play important roles in angiogenesis. Both are involved in stimulating hypoxia inducible factor (HIF) in angiogenesis and could be activated by the insulin signaling pathway. This suggests that PI3K and MAPK pathways might act as cross-talk between the insulin signaling pathway and the angiogenesis pathway in brain. But the cerebral insulin, insulin signaling pathway, and the detailed mechanism in the connection of insulin signaling pathway, brain angiogenesis pathway, and healthy aging or dementias are still mostly not clear and need further studies.

Intercellular signaling pathways active during intervertebral disc growth, differentiation, and aging.

Science.gov (United States)

Dahia, Chitra Lekha; Mahoney, Eric J; Durrani, Atiq A; Wylie, Christopher

2009-03-01

Intervertebral discs at different postnatal ages were assessed for active intercellular signaling pathways. To generate a spatial and temporal map of the signaling pathways active in the postnatal intervertebral disc (IVD). The postnatal IVD is a complex structure, consisting of 3 histologically distinct components, the nucleus pulposus, fibrous anulus fibrosus, and endplate. These differentiate and grow during the first 9 weeks of age in the mouse. Identification of the major signaling pathways active during and after the growth and differentiation period will allow functional analysis using mouse genetics and identify targets for therapy for individual components of the disc. Antibodies specific for individual cell signaling pathways were used on cryostat sections of IVD at different postnatal ages to identify which components of the IVD were responding to major classes of intercellular signal, including sonic hedgehog, Wnt, TGFbeta, FGF, and BMPs. We present a spatial/temporal map of these signaling pathways during growth, differentiation, and aging of the disc. During growth and differentiation of the disc, its different components respond at different times to different intercellular signaling ligands. Most of these are dramatically downregulated at the end of disc growth.

On the usefulness of 'what' and 'where' pathways in vision.

Science.gov (United States)

de Haan, Edward H F; Cowey, Alan

2011-10-01

The primate visual brain is classically portrayed as a large number of separate 'maps', each dedicated to the processing of specific visual cues, such as colour, motion or faces and their many features. In order to understand this fractionated architecture, the concept of cortical 'pathways' or 'streams' was introduced. In the currently prevailing view, the different maps are organised hierarchically into two major pathways, one involved in recognition and memory (the ventral stream or 'what' pathway) and the other in the programming of action (the dorsal stream or 'where' pathway). In this review, we question this heuristically influential but potentially misleading linear hierarchical pathway model and argue instead for a 'patchwork' or network model. Copyright © 2011 Elsevier Ltd. All rights reserved.

Major Abdominal Surgical Complications : Innovative Approaches

NARCIS (Netherlands)

G.S.A. ter Hoeve-Boersema (Simone)

2017-01-01

markdownabstractIn this thesis the focus was on three major complications after abdominal surgery: incisional hernia (IH), prolonged postoperative ileus (PPOI), and colorectal anastomotic leakage (CAL). The results were summarized in three parts: _Part 1_ focused on prediction and detection of

The discovery of the tau lepton: Part 1, The early history through 1975; Part 2, Confirmation of the discovery and measurement of major properties, 1976--1982

International Nuclear Information System (INIS)

Perl, M.L.

1994-08-01

Several previous papers have given the history of the discovery of the τ lepton at the Stanford Linear Accelerator Center (SLAC). These papers emphasized (a) the experiments which led to our 1975 publication of the first evidence for the existence of the τ, (b) the subsequent experiments which confirmed the existence of the r, and (c) the experiments which elucidated the major properties of the τ. That history will be summarized in Part 2 of this talk. In this Part 1, I describe the earlier thoughts and work of myself and my colleagues at SLAC in the 1960's and early 1970's which led to the discovery. I also describe the theoretical and experimental events in particle physics in the 1960's in which our work was immersed. I will also try to describe for the younger generations of particle physicists, the atmosphere in the 1960's. That was before the elucidation of the quark model of hadrons, before the development of the concept of particle generations The experimental paths to program we hot as clear as they are today and we had to cast a wide experimental net

The Discovery of the Tau Lepton: Part 1, The Early History Through 1975; Part 2, Confirmation of the Discovery and Measurement of Major Properties, 1976--1982

Science.gov (United States)

Perl, M. L.

1994-08-01

Several previous papers have given the history of the discovery of the {tau} lepton at the Stanford Linear Accelerator Center (SLAC). These papers emphasized (a) the experiments which led to our 1975 publication of the first evidence for the existence of the {tau}, (b) the subsequent experiments which confirmed the existence of the r, and (c) the experiments which elucidated the major properties of the {tau}. That history will be summarized in Part 2 of this talk. In this Part 1, I describe the earlier thoughts and work of myself and my colleagues at SLAC in the 1960's and early 1970's which led to the discovery. I also describe the theoretical and experimental events in particle physics in the 1960's in which our work was immersed. I will also try to describe for the younger generations of particle physicists, the atmosphere in the 1960's. That was before the elucidation of the quark model of hadrons, before the development of the concept of particle generations The experimental paths to program we hot as clear as they are today and we had to cast a wide experimental net.

A peer review process as part of the implementation of clinical pathways in radiation oncology: Does it improve compliance?

Science.gov (United States)

Gebhardt, Brian J; Heron, Dwight E; Beriwal, Sushil

Clinical pathways are patient management plans that standardize evidence-based practices to ensure high-quality and cost-effective medical care. Implementation of a pathway is a collaborative process in our network, requiring the active involvement of physicians. This approach promotes acceptance of pathway recommendations, although a peer review process is necessary to ensure compliance and to capture and approve off-pathway selections. We investigated the peer review process and factors associated with time to completion of peer review. Our cancer center implemented radiation oncology pathways for every disease site throughout a large, integrated network. Recommendations are written based upon national guidelines, published literature, and institutional experience with evidence evaluated hierarchically in order of efficacy, toxicity, and then cost. Physicians enter decisions into an online, menu-driven decision support tool that integrates with medical records. Data were collected from the support tool and included the rate of on- and off-pathway selections, peer review decisions performed by disease site directors, and time to complete peer review. A total of 6965 treatment decisions were entered in 2015, and 605 (8.7%) were made off-pathway and were subject to peer review. The median time to peer review decision was 2 days (interquartile range, 0.2-6.8). Factors associated with time to peer review decision >48 hours on univariate analysis include disease site (P peer review (P 48 hours. Clinical pathways are an integral tool for standardizing evidence-based care throughout our large, integrated network, with 91.3% of all treatment decisions being made as per pathway. The peer review process was feasible, with peer review of treatment decisions encourages compliance with clinical pathway recommendations. Copyright © 2017 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.

Metabolism of cysteine by cyteinesulfinate-independent pathway(s) in rat hepatocytes

International Nuclear Information System (INIS)

Stipanuk, M.H.; De La Rosa, J.; Drake, M.R.

1986-01-01

The metabolism of cysteine (CYS) and that of cysteinesulfinate (CSA) were studied in freshly isolated hepatocytes from fed rats. In incubations of rat hepatocytes with either 1 or 25 mM CSA, over 90% of the 14 CO 2 formed from [1- 14 C]CSA could be accounted for by production of hypotaurine plus taurine. In similar incubations with 1 or 25 mM CYS, only 4% of 14 CO 2 evolution from [1- 14 C]CYS could be accounted for by production of hypotaurine plus taurine. Addition of unlabeled CSA inhibited recovery of label from [1- 14 C]CYS as 14 CO 2 by 33%. Metabolism of CYS and of CSA were affected differently by addition of α-ketoglutarate, a cosubstrate for transamination, or of propargylglycine, an inhibitor of cystathionase activity. These data suggest that a substantial proportion of CYS is catabolized by CSA-independent pathways in the rat hepatocyte. Although addition of α-ketoglutarate to incubations of hepatocytes with CSA resulted in a marked increase in CSA catabolism via the transamination pathway, addition of keto acids to incubation systems had little or no effect on production of any metabolite from CYS. Thus, CYS transamination does not appear to be a major pathway of CYS metabolism in the hepatocyte. Inhibition of cystathionase with propargylglycine reduced both 14 CO 2 production from [1- 14 C]CYS and ammonia plus urea nitrogen production from CYS by about 50%; CSA catabolism was not affected. Thus, cleavage of cyst(e)ine by cystathionase may be an important physiological pathway for CYS catabolism in the liver

PathText: a text mining integrator for biological pathway visualizations

Science.gov (United States)

Kemper, Brian; Matsuzaki, Takuya; Matsuoka, Yukiko; Tsuruoka, Yoshimasa; Kitano, Hiroaki; Ananiadou, Sophia; Tsujii, Jun'ichi

2010-01-01

Motivation: Metabolic and signaling pathways are an increasingly important part of organizing knowledge in systems biology. They serve to integrate collective interpretations of facts scattered throughout literature. Biologists construct a pathway by reading a large number of articles and interpreting them as a consistent network, but most of the models constructed currently lack direct links to those articles. Biologists who want to check the original articles have to spend substantial amounts of time to collect relevant articles and identify the sections relevant to the pathway. Furthermore, with the scientific literature expanding by several thousand papers per week, keeping a model relevant requires a continuous curation effort. In this article, we present a system designed to integrate a pathway visualizer, text mining systems and annotation tools into a seamless environment. This will enable biologists to freely move between parts of a pathway and relevant sections of articles, as well as identify relevant papers from large text bases. The system, PathText, is developed by Systems Biology Institute, Okinawa Institute of Science and Technology, National Centre for Text Mining (University of Manchester) and the University of Tokyo, and is being used by groups of biologists from these locations. Contact: brian@monrovian.com. PMID:20529930

Propofol reduced myocardial contraction of vertebrates partly by mediating the cyclic AMP-dependent protein kinase phosphorylation pathway

International Nuclear Information System (INIS)

Sun, Xiaotong; Zhang, Xinyu; Bo, Qiyu; Meng, Tao; Lei, Zhen; Li, Jingxin; Hou, Yonghao; Yu, Xiaoqian; Yu, Jingui

2016-01-01

Propofol inhibits myocardial contraction in a dose dependent manner. The present study is designed to examine the effect of propofol on PKA mediated myocardial contraction in the absence of adrenoreceptor agonist. The contraction of isolated rat heart was measured in the presence or absence of PKA inhibitor H89 or propofol, using a pressure transducer. The levels of cAMP and PKA kinase activity were detected by ELISA. The mRNA and total protein or phosphorylation level of PKA and downstream proteins were tested in the presence or absence of PKA inhibitor H89 or propofol, using RT-PCR, QPCR and western blotting. The phosphorylation level of PKA was examined thoroughly using immunofluorescence and PKA activity non-radioactive detection kit. Propofol induced a dose-dependent negative contractile response on the rat heart. The inhibitory effect of high concentration propofol (50 μM) with 45% decease of control could be partly reversed by the PKA inhibitor H89 (10 μM) and the depressant effect of propofol decreased from 45% to 10%. PKA kinase activity was inhibited by propofol in a dose-dependent manner. Propofol also induced a decrease in phosphorylation of PKA, which was also inhibited by H89, but did not alter the production of cAMP and the mRNA levels of PKA. The downstream proteins of PKA, PLN and RyR2 were phosphorylated to a lesser extent with propofol or H89 than control. These results demonstrated that propofol induced a negative myocardial contractile response partly by mediating the PKA phosphorylation pathway.

Evasion Mechanisms Used by Pathogens to Escape the Lectin Complement Pathway

DEFF Research Database (Denmark)

Rosbjerg, Anne; Genster, Ninette; Pilely, Katrine

2017-01-01

The complement system is a crucial defensive network that protects the host against invading pathogens. It is part of the innate immune system and can be initiated via three pathways: the lectin, classical and alternative activation pathway. Overall the network compiles a group of recognition...... the level of activity. The result is a pro-inflammatory response meant to combat foreign microbes. Microbial elimination is, however, not a straight forward procedure; pathogens have adapted to their environment by evolving a collection of evasion mechanisms that circumvent the human complement system....... Complement evasion strategies features different ways of exploiting human complement proteins and moreover features different pathogen-derived proteins that interfere with the normal processes. Accumulated, these mechanisms target all three complement activation pathways as well as the final common part...

Noncoding RNAs in protein clearance pathways: implications in ...

Indian Academy of Sciences (India)

Several studies from model organisms suggest upregulation of pathways that clear this toxic protein may provide .... part of UPS have been genetically linked to neurodegener- ... tionally modified or any other misfolded protein are poten-.

Pathways through the education and training system: Do we need a ...

African Journals Online (AJOL)

Analyses conducted by the Education, Science and Skills Development (ESSD) research programme at the Human Sciences Research Council (HSRC) reveal major areas of misalignment in the South African education pathway system. The majority of learners entering Further Education and Training (FET) colleges, ...

PathwayAccess: CellDesigner plugins for pathway databases.

Science.gov (United States)

Van Hemert, John L; Dickerson, Julie A

2010-09-15

CellDesigner provides a user-friendly interface for graphical biochemical pathway description. Many pathway databases are not directly exportable to CellDesigner models. PathwayAccess is an extensible suite of CellDesigner plugins, which connect CellDesigner directly to pathway databases using respective Java application programming interfaces. The process is streamlined for creating new PathwayAccess plugins for specific pathway databases. Three PathwayAccess plugins, MetNetAccess, BioCycAccess and ReactomeAccess, directly connect CellDesigner to the pathway databases MetNetDB, BioCyc and Reactome. PathwayAccess plugins enable CellDesigner users to expose pathway data to analytical CellDesigner functions, curate their pathway databases and visually integrate pathway data from different databases using standard Systems Biology Markup Language and Systems Biology Graphical Notation. Implemented in Java, PathwayAccess plugins run with CellDesigner version 4.0.1 and were tested on Ubuntu Linux, Windows XP and 7, and MacOSX. Source code, binaries, documentation and video walkthroughs are freely available at http://vrac.iastate.edu/~jlv.

Negative control of the HGF/c-MET pathway by TGF-β: a new look at the regulation of stemness in glioblastoma.

Science.gov (United States)

Papa, Eleanna; Weller, Michael; Weiss, Tobias; Ventura, Elisa; Burghardt, Isabel; Szabó, Emese

2017-12-13

Multiple target inhibition has gained considerable interest in combating drug resistance in glioblastoma, however, understanding the molecular mechanisms of crosstalk between signaling pathways and predicting responses of cancer cells to targeted interventions has remained challenging. Despite the significant role attributed to transforming growth factor (TGF)-β family and hepatocyte growth factor (HGF)/c-MET signaling in glioblastoma pathogenesis, their functional interactions have not been well characterized. Using genetic and pharmacological approaches to stimulate or antagonize the TGF-β pathway in human glioma-initiating cells (GIC), we observed that TGF-β exerts an inhibitory effect on c-MET phosphorylation. Inhibition of either mitogen-activated protein kinase (MAPK)/ extracellular signal-regulated kinase (ERK) or phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/AKT) signaling pathway attenuated this effect. A comparison of c-MET-driven and c-MET independent GIC models revealed that TGF-β inhibits stemness in GIC at least in part via its negative regulation of c-MET activity, suggesting that stem cell (SC) maintenance may be controlled by the balance between these two oncogenic pathways. Importantly, immunohistochemical analyses of human glioblastoma and ex vivo single-cell gene expression profiling of TGF-β and HGF confirm the negative interaction between both pathways. These novel insights into the crosstalk of two major pathogenic pathways in glioblastoma may explain some of the disappointing results when targeting either pathway alone in human glioblastoma patients and inform on potential future designs on targeted pharmacological or genetic intervention.

Gene expression meta-analysis identifies metastatic pathways and transcription factors in breast cancer

International Nuclear Information System (INIS)

Thomassen, Mads; Tan, Qihua; Kruse, Torben A

2008-01-01

Metastasis is believed to progress in several steps including different pathways but the determination and understanding of these mechanisms is still fragmentary. Microarray analysis of gene expression patterns in breast tumors has been used to predict outcome in recent studies. Besides classification of outcome, these global expression patterns may reflect biological mechanisms involved in metastasis of breast cancer. Our purpose has been to investigate pathways and transcription factors involved in metastasis by use of gene expression data sets. We have analyzed 8 publicly available gene expression data sets. A global approach, 'gene set enrichment analysis' as well as an approach focusing on a subset of significantly differently regulated genes, GenMAPP, has been applied to rank pathway gene sets according to differential regulation in metastasizing tumors compared to non-metastasizing tumors. Meta-analysis has been used to determine overrepresentation of pathways and transcription factors targets, concordant deregulated in metastasizing breast tumors, in several data sets. The major findings are up-regulation of cell cycle pathways and a metabolic shift towards glucose metabolism reflected in several pathways in metastasizing tumors. Growth factor pathways seem to play dual roles; EGF and PDGF pathways are decreased, while VEGF and sex-hormone pathways are increased in tumors that metastasize. Furthermore, migration, proteasome, immune system, angiogenesis, DNA repair and several signal transduction pathways are associated to metastasis. Finally several transcription factors e.g. E2F, NFY, and YY1 are identified as being involved in metastasis. By pathway meta-analysis many biological mechanisms beyond major characteristics such as proliferation are identified. Transcription factor analysis identifies a number of key factors that support central pathways. Several previously proposed treatment targets are identified and several new pathways that may

The N-end rule pathway catalyzes a major fraction of the protein degradation in skeletal muscle

Science.gov (United States)

Solomon, V.; Lecker, S. H.; Goldberg, A. L.

1998-01-01

In skeletal muscle, overall protein degradation involves the ubiquitin-proteasome system. One property of a protein that leads to rapid ubiquitin-dependent degradation is the presence of a basic, acidic, or bulky hydrophobic residue at its N terminus. However, in normal cells, substrates for this N-end rule pathway, which involves ubiquitin carrier protein (E2) E214k and ubiquitin-protein ligase (E3) E3alpha, have remained unclear. Surprisingly, in soluble extracts of rabbit muscle, we found that competitive inhibitors of E3alpha markedly inhibited the 125I-ubiquitin conjugation and ATP-dependent degradation of endogenous proteins. These inhibitors appear to selectively inhibit E3alpha, since they blocked degradation of 125I-lysozyme, a model N-end rule substrate, but did not affect the degradation of proteins whose ubiquitination involved other E3s. The addition of several E2s or E3alpha to the muscle extracts stimulated overall proteolysis and ubiquitination, but only the stimulation by E3alpha or E214k was sensitive to these inhibitors. A similar general inhibition of ubiquitin conjugation to endogenous proteins was observed with a dominant negative inhibitor of E214k. Certain substrates of the N-end rule pathway are degraded after their tRNA-dependent arginylation. We found that adding RNase A to muscle extracts reduced the ATP-dependent proteolysis of endogenous proteins, and supplying tRNA partially restored this process. Finally, although in muscle extracts the N-end rule pathway catalyzes most ubiquitin conjugation, it makes only a minor contribution to overall protein ubiquitination in HeLa cell extracts.

Crenothrix are major methane consumers in stratified lakes.

Science.gov (United States)

Oswald, Kirsten; Graf, Jon S; Littmann, Sten; Tienken, Daniela; Brand, Andreas; Wehrli, Bernhard; Albertsen, Mads; Daims, Holger; Wagner, Michael; Kuypers, Marcel Mm; Schubert, Carsten J; Milucka, Jana

2017-09-01

Methane-oxidizing bacteria represent a major biological sink for methane and are thus Earth's natural protection against this potent greenhouse gas. Here we show that in two stratified freshwater lakes a substantial part of upward-diffusing methane was oxidized by filamentous gamma-proteobacteria related to Crenothrix polyspora. These filamentous bacteria have been known as contaminants of drinking water supplies since 1870, but their role in the environmental methane removal has remained unclear. While oxidizing methane, these organisms were assigned an 'unusual' methane monooxygenase (MMO), which was only distantly related to 'classical' MMO of gamma-proteobacterial methanotrophs. We now correct this assignment and show that Crenothrix encode a typical gamma-proteobacterial PmoA. Stable isotope labeling in combination swith single-cell imaging mass spectrometry revealed methane-dependent growth of the lacustrine Crenothrix with oxygen as well as under oxygen-deficient conditions. Crenothrix genomes encoded pathways for the respiration of oxygen as well as for the reduction of nitrate to N 2 O. The observed abundance and planktonic growth of Crenothrix suggest that these methanotrophs can act as a relevant biological sink for methane in stratified lakes and should be considered in the context of environmental removal of methane.

The genetic makeup of the Drosophila piRNA pathway.

Science.gov (United States)

Handler, Dominik; Meixner, Katharina; Pizka, Manfred; Lauss, Kathrin; Schmied, Christopher; Gruber, Franz Sebastian; Brennecke, Julius

2013-06-06

The piRNA (PIWI-interacting RNA) pathway is a small RNA silencing system that acts in animal gonads and protects the genome against the deleterious influence of transposons. A major bottleneck in the field is the lack of comprehensive knowledge of the factors and molecular processes that constitute this pathway. We conducted an RNAi screen in Drosophila and identified ~50 genes that strongly impact the ovarian somatic piRNA pathway. Many identified genes fall into functional categories that indicate essential roles for mitochondrial metabolism, RNA export, the nuclear pore, transcription elongation, and chromatin regulation in the pathway. Follow-up studies on two factors demonstrate that components acting at distinct hierarchical levels of the pathway were identified. Finally, we define CG2183/Gasz as an essential primary piRNA biogenesis factor in somatic and germline cells. Based on the similarities between insect and vertebrate piRNA pathways, our results have far-reaching implications for the understanding of this conserved genome defense system. Copyright © 2013 Elsevier Inc. All rights reserved.

Kynurenine Pathway Metabolites in Humans: Disease and Healthy States

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Yiquan Chen

2009-01-01

Full Text Available Tryptophan is an essential amino acid that can be metabolised through different pathways, a major route being the kynurenine pathway. The first enzyme of the pathway, indoleamine-2,3-dioxygenase, is strongly stimulated by inflammatory molecules, particularly interferon gamma. Thus, the kynurenine pathway is often systematically up-regulated when the immune response is activated. The biological significance is that 1 the depletion of tryptophan and generation of kynurenines play a key modulatory role in the immune response; and 2 some of the kynurenines, such as quinolinic acid, 3-hydroxykynurenine and kynurenic acid, are neuroactive. The kynurenine pathway has been demonstrated to be involved in many diseases and disorders, including Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, AIDS dementia complex, malaria, cancer, depression and schizophrenia, where imbalances in tryptophan and kynurenines have been found. This review compiles most of these studies and provides an overview of how the kynurenine pathway might be contributing to disease development, and the concentrations of tryptophan and kynurenines in the serum, cerebrospinal fluid and brain tissues in control and patient subjects.

Gene Expression Dynamics in Major Endocrine Regulatory Pathways along the Transition from Solitary to Social Life in a Bumblebee, Bombus terrestris

Directory of Open Access Journals (Sweden)

Pavel Jedlička

2016-11-01

Full Text Available Understanding the social evolution leading to insect eusociality requires, among other, a detailed insight into endocrine regulatory mechanisms that have been co-opted from solitary ancestors to play new roles in the complex life histories of eusocial species. Bumblebees represent well-suited models of a relatively primitive social organization standing on the mid-way to highly advanced eusociality and their queens undergo both, a solitary and a social phase, separated by winter diapause.In the present paper, we characterize the gene expression levels of major endocrine regulatory pathways across tissues, sexes, and life-stages of the buff-tailed bumblebee, Bombus terrestris, with special emphasis on critical stages of the queen’s transition from solitary to social life. We focused on fundamental genes of three pathways: (1 Forkhead box protein O and insulin/insulin-like signaling, (2 Juvenile hormone signaling, and (3 Adipokinetic hormone signaling. Virgin queens were distinguished by higher expression of forkhead box protein O and downregulated insulin-like peptides and juvenile hormone (JH signaling, indicated by low expression of methyl farnesoate epoxidase (MFE and transcription factor Krüppel homolog 1 (Kr-h1. Diapausing queens showed the expected downregulation of JH signaling in terms of low MFE and vitellogenin (Vg expressions, but an unexpectedly high expression of Kr-h1. By contrast, reproducing queens revealed an upregulation of MFE and Vg together with insulin signaling. Surprisingly, the insulin growth factor 1 (IGF-1 turned out to be a queen-specific hormone. Workers exhibited an expression pattern of MFE and Vg similar to that of reproducing queens. Males were characterized by high Kr-h1 expression and low Vg level. The tissue comparison unveiled an unexpected resemblance between the fat body and hypopharyngeal glands across all investigated genes, sexes, and life stages.

Engineering of methionine chain elongation part of glucoraphanin pathway in E. coli

DEFF Research Database (Denmark)

Mirza, Nadia Muhammad Akram; Crocoll, Christoph; Olsen, Carl Erik

2016-01-01

The methionine-derived glucosinolate glucoraphanin is associated with the health-promoting properties of broccoli. This has developed a strong interest in producing this compound in high amounts from a microbial source. Glucoraphanin synthesis starts with a five-gene chain elongation pathway...

Integrating publicly-available data to generate computationally-predicted adverse outcome pathways for hepatic steatosis

Science.gov (United States)

The adverse outcome pathway (AOP) framework provides a way of organizing knowledge related to the key biological events that result in a particular health outcome. For the majority of environmental chemicals, the availability of curated pathways characterizing potential toxicity ...

ERβ induces the differentiation of cultured osteoblasts by both Wnt/β-catenin signaling pathway and estrogen signaling pathways

Energy Technology Data Exchange (ETDEWEB)

Yin, Xinhua [Department of Spine Surgery, Xiangya Hospital of Central South University, Changsha (China); Wang, Xiaoyuan [Department of Nephrology, Xi An Honghui Hospital, Xi an (China); Hu, Xiongke; Chen, Yong; Zeng, Kefeng [Department of Spine Surgery, Xiangya Hospital of Central South University, Changsha (China); Zhang, Hongqi, E-mail: zhq9699@126.com [Department of Spine Surgery, Xiangya Hospital of Central South University, Changsha (China)

2015-07-01

Although 17β-estradial (E2) is known to stimulate bone formation, the underlying mechanisms are not fully understood. Recent studies have implicated the Wnt/β-catenin pathway as a major signaling cascade in bone biology. The interactions between Wnt/β-catenin signaling pathway and estrogen signaling pathways have been reported in many tissues. In this study, E2 significantly increased the expression of β-catenin by inducing phosphorylations of GSK3β at serine 9. ERβ siRNAs were transfected into MC3T3-E1 cells and revealed that ERβ involved E2-induced osteoblasts proliferation and differentiation via Wnt/β-catenin signaling. The osteoblast differentiation genes (BGP, ALP and OPN) and proliferation related gene (cyclin D1) expression were significantly induced by E2-mediated ERβ. Furthermore immunofluorescence and immunoprecipitation analysis demonstrated that E2 induced the accumulation of β-catenin protein in the nucleus which leads to interaction with T-cell-specific transcription factor/lymphoid enhancer binding factor (TCF/LEF) transcription factors. Taken together, these findings suggest that E2 promotes osteoblastic proliferation and differentiation by inducing proliferation-related and differentiation-related gene expression via ERβ/GSK-3β-dependent Wnt/β-catenin signaling pathway. Our findings provide novel insights into the mechanisms of action of E2 in osteoblastogenesis. - Highlights: • 17β-estradial (E2) promotes GSK3-β phosphorylation. • E2 activates the Wnt/β-catenin signaling pathway. • The Wnt/β-catenin signaling pathway interacts with estrogen signaling pathways. • E2-mediated ER induced osteoblast differentiation and proliferation related genes expression.

ERβ induces the differentiation of cultured osteoblasts by both Wnt/β-catenin signaling pathway and estrogen signaling pathways

International Nuclear Information System (INIS)

Yin, Xinhua; Wang, Xiaoyuan; Hu, Xiongke; Chen, Yong; Zeng, Kefeng; Zhang, Hongqi

2015-01-01

Although 17β-estradial (E2) is known to stimulate bone formation, the underlying mechanisms are not fully understood. Recent studies have implicated the Wnt/β-catenin pathway as a major signaling cascade in bone biology. The interactions between Wnt/β-catenin signaling pathway and estrogen signaling pathways have been reported in many tissues. In this study, E2 significantly increased the expression of β-catenin by inducing phosphorylations of GSK3β at serine 9. ERβ siRNAs were transfected into MC3T3-E1 cells and revealed that ERβ involved E2-induced osteoblasts proliferation and differentiation via Wnt/β-catenin signaling. The osteoblast differentiation genes (BGP, ALP and OPN) and proliferation related gene (cyclin D1) expression were significantly induced by E2-mediated ERβ. Furthermore immunofluorescence and immunoprecipitation analysis demonstrated that E2 induced the accumulation of β-catenin protein in the nucleus which leads to interaction with T-cell-specific transcription factor/lymphoid enhancer binding factor (TCF/LEF) transcription factors. Taken together, these findings suggest that E2 promotes osteoblastic proliferation and differentiation by inducing proliferation-related and differentiation-related gene expression via ERβ/GSK-3β-dependent Wnt/β-catenin signaling pathway. Our findings provide novel insights into the mechanisms of action of E2 in osteoblastogenesis. - Highlights: • 17β-estradial (E2) promotes GSK3-β phosphorylation. • E2 activates the Wnt/β-catenin signaling pathway. • The Wnt/β-catenin signaling pathway interacts with estrogen signaling pathways. • E2-mediated ER induced osteoblast differentiation and proliferation related genes expression

Interaction Dynamics Determine Signaling and Output Pathway Responses

Directory of Open Access Journals (Sweden)

Klement Stojanovski

2017-04-01

Full Text Available The understanding of interaction dynamics in signaling pathways can shed light on pathway architecture and provide insights into targets for intervention. Here, we explored the relevance of kinetic rate constants of a key upstream osmosensor in the yeast high-osmolarity glycerol-mitogen-activated protein kinase (HOG-MAPK pathway to signaling output responses. We created mutant pairs of the Sln1-Ypd1 complex interface that caused major compensating changes in the association (kon and dissociation (koff rate constants (kinetic perturbations but only moderate changes in the overall complex affinity (Kd. Yeast cells carrying a Sln1-Ypd1 mutant pair with moderate increases in kon and koff displayed a lower threshold of HOG pathway activation than wild-type cells. Mutants with higher kon and koff rates gave rise to higher basal signaling and gene expression but impaired osmoadaptation. Thus, the kon and koff rates of the components in the Sln1 osmosensor determine proper signaling dynamics and osmoadaptation.

Part-Time Faculty Satisfaction at Two-Year Public Postsecondary Institutions: A Comparison of Involuntary Part-Time, Voluntary Part-Time, and Full-Time Faculty

Science.gov (United States)

Kinchen, Nancy Huval

2010-01-01

Part-time faculty members represent the majority of faculty at public two-year postsecondary institutions. Utilizing part-time faculty enables two-year institutions to control their instructional costs and maintain scheduling flexibility. However, part-time faculty are diverse in regards to their employment preference, some prefer part-time…

Transcriptome and metabolome analysis of Ferula gummosa Boiss. to reveal major biosynthetic pathways of galbanum compounds.

Science.gov (United States)

Sobhani Najafabadi, Ahmad; Naghavi, Mohammad Reza; Farahmand, Hamid; Abbasi, Alireza

2017-11-01

Ferula gummosa Boiss. is an industrial and pharmaceutical plant that has been highly recognized for its valuable oleo-gum-resin, namely galbanum. Despite the fabulous value of galbanum, very little information on the genetic and biochemical mechanisms of its production existed. In the present study, the oleo-gum-resin and four organs (root, flower, stem, and leaf) of F. gummosa were assessed in terms of metabolic compositions and the expression of genes involved in their biosynthetic pathways. Results showed that the most accumulation of resin and essential oils were occurred in the roots (13.99 mg/g) and flowers (6.01 mg/g), respectively. While the most dominant compound of the resin was β-amyrin from triterpenes, the most abundant compounds of the essential oils were α-pinene and β-pinene from monoterpenes and α-eudesmol and germacrene-D from sesquiterpenes. Transcriptome analysis was performed by RNA sequencing (RNA-seq) for the plant roots and flowers. Differential gene expression analysis showed that 1172 unigenes were differential between two organs that 934 (79.6%) of them were up-regulated in the flowers and 238 (20.4%) unigenes were up-regulated in the roots (FDR ≤0.001). The most important up-regulated unigenes in the roots were involved in the biosynthesis of the major components of galbanum, including myrcene, germacrene-D, α-terpineol, and β-amyrin. The results obtained by RNA-Seq were confirmed by qPCR. These analyses showed that different organs of F. gummosa are involved in the production of oleo-gum-resin, but the roots are more active than other organs in terms of the biosynthesis of triterpenes and some mono- and sesquiterpenes. This study provides rich molecular and biochemical resources for further studies on molecular genetics and functional genomics of oleo-gum-resin production in F. gummosa.

Major international sport profiles.

Science.gov (United States)

Patel, Dilip R; Stier, Bernhard; Luckstead, Eugene F

2002-08-01

Sports are part of the sociocultural fabric of all countries. Although different sports have their origins in different countries, many sports are now played worldwide. International sporting events bring athletes of many cultures together and provide the opportunity not only for athletic competition but also for sociocultural exchange and understanding among people. This article reviews five major sports with international appeal and participation: cricket, martial arts, field hockey, soccer, and tennis. For each sport, the major aspects of physiological and biomechanical demands, injuries, and prevention strategies are reviewed.

Impact of constitutional copy number variants on biological pathway evolution.

Science.gov (United States)

Poptsova, Maria; Banerjee, Samprit; Gokcumen, Omer; Rubin, Mark A; Demichelis, Francesca

2013-01-23

Inherited Copy Number Variants (CNVs) can modulate the expression levels of individual genes. However, little is known about how CNVs alter biological pathways and how this varies across different populations. To trace potential evolutionary changes of well-described biological pathways, we jointly queried the genomes and the transcriptomes of a collection of individuals with Caucasian, Asian or Yoruban descent combining high-resolution array and sequencing data. We implemented an enrichment analysis of pathways accounting for CNVs and genes sizes and detected significant enrichment not only in signal transduction and extracellular biological processes, but also in metabolism pathways. Upon the estimation of CNV population differentiation (CNVs with different polymorphism frequencies across populations), we evaluated that 22% of the pathways contain at least one gene that is proximal to a CNV (CNV-gene pair) that shows significant population differentiation. The majority of these CNV-gene pairs belong to signal transduction pathways and 6% of the CNV-gene pairs show statistical association between the copy number states and the transcript levels. The analysis suggested possible examples of positive selection within individual populations including NF-kB, MAPK signaling pathways, and Alu/L1 retrotransposition factors. Altogether, our results suggest that constitutional CNVs may modulate subtle pathway changes through specific pathway enzymes, which may become fixed in some populations.

[Targeting of the AKT/m-TOR Pathway: Biomarkers of Resistance to Cancer Therapy--
AKT/m-TOR Pathway and Resistance to Cancer Therapy].

Science.gov (United States)

Spirina, Liudmila V; Kondakova, Irina V; Tarasenko, Natalia V; Slonimskaya, Elena M; Usynin, Evgeny A; Gorbunov, Alexey K; Yurmazov, Zahar A; Chigevskaya, Svetlana Yu

2018-01-20

Resistance to cancer therapy continues to be a major limitation for the successful treatment of cancer. There are many published studies on therapy resistance in breast and prostate cancers; however, there are currently no data on molecular markers associated with resistance. The conflicting data were reported regarding the AKT/m-TOR signaling pathway components as markers predicting resistance. The AKT/m-TOR signaling pathway is involved in the development of many human cancers; its activation is related to cell proliferation, angiogenesis, apoptosis, as well as to therapy resistance. Molecular alterations in the AKT/m-TOR signaling pathway provide a platform to identify universal markers associated with the development of resistance to cancer therapy.

Overview of major hazards. Part 2: Source term; dispersion; combustion; blast, missiles, venting; fire; radiation; runaway reactions; toxic substances; dust explosions

Science.gov (United States)

Vilain, J.

Approaches to major hazard assessment and prediction are reviewed. Source term: (phenomenology/modeling of release, influence on early stages of dispersion); dispersion (atmospheric advection, diffusion and deposition, emphasis on dense/cold gases); combustion (flammable clouds and mists covering flash fires, deflagration, transition to detonation; mostly unconfined/partly confined situations); blast formation, propagation, interaction with structures; catastrophic fires (pool fires, torches and fireballs; highly reactive substances) runaway reactions; features of more general interest; toxic substances, excluding toxicology; and dust explosions (phenomenology and protective measures) are discussed.

Analysis of Chlorogenic Acid Oxidation Pathway in Simulated ...

African Journals Online (AJOL)

Keywords: Honeysuckle, Chlorogenic acid, Enzymatic browning, Mimic system, Oxidation pathway, ... enzymatic oxidation of CA is the major cause of ..... to the concentration of catechol, o-quinone and current at PPO-modified microcylinder biosensor for diffusion- kinetic model. J Electroanal Chem 2011; 660: 200-208.

Marine plastic pollution in waters around Australia: characteristics, concentrations, and pathways

OpenAIRE

Reisser, Julia Wiener; Shaw, Jeremy; Wilcox, Chris; Hardesty, Britta Denise; Proietti, Maíra Carneiro; Thums, Michele; Pattiaratchi, Charitha

2013-01-01

Plastics represent the vast majority of human-made debris present in the oceans. However, their characteristics, accumulation zones, and transport pathways remain poorly assessed. We characterised and estimated the concentration of marine plastics in waters around Australia using surface net tows, and inferred their potential pathways using particle-tracking models and real drifter trajectories. The 839 marine plastics recorded were predominantly small fragments ("microplastics", median lengt...

Building pathway graphs from BioPAX data in R.

Science.gov (United States)

Benis, Nirupama; Schokker, Dirkjan; Kramer, Frank; Smits, Mari A; Suarez-Diez, Maria

2016-01-01

Biological pathways are increasingly available in the BioPAX format which uses an RDF model for data storage. One can retrieve the information in this data model in the scripting language R using the package rBiopaxParser , which converts the BioPAX format to one readable in R. It also has a function to build a regulatory network from the pathway information. Here we describe an extension of this function. The new function allows the user to build graphs of entire pathways, including regulated as well as non-regulated elements, and therefore provides a maximum of information. This function is available as part of the rBiopaxParser distribution from Bioconductor.

Pathways to agility in the production of neutron generators

Energy Technology Data Exchange (ETDEWEB)

Stoltz, R.E. [Sandia National Labs., Livermore, CA (United States); Beavis, L.C.; Cutchen, J.T.; Garcia, P.; Gurule, G.A.; Harris, R.N.; McKey, P.C.; Williams, D.W. [Sandia National Labs., Albuquerque, NM (United States)

1994-02-01

This report is the result of a study team commissioned to explore pathways for increased agility in the manufacture of neutron generators. As a part of Sandia`s new responsibility for generator production, the goal of the study was to identify opportunities to reduce costs and increase flexibility in the manufacturing operation. Four parallel approaches (or pathways) were recommended: (1) Know the goal, (2) Use design leverage effectively, (3) Value simplicity, and (4) Configure for flexibility. Agility in neutron generator production can be enhanced if all of these pathways are followed. The key role of the workforce in achieving agility was also noted, with emphasis on ownership, continuous learning, and a supportive environment.

Alteration of renal excretion pathways in gentamicin-induced renal injury in rats.

Science.gov (United States)

Ma, Yan-Rong; Luo, Xuan; Wu, Yan-Fang; Zhang, Tiffany; Zhang, Fan; Zhang, Guo-Qiang; Wu, Xin-An

2018-02-20

The kidney plays a major part in the elimination of many drugs and their metabolites, and drug-induced kidney injury commonly alters either glomerular filtration or tubular transport, or both. However, the renal excretion pathway of drugs has not been fully elucidated at different stages of renal injury. This study aimed to evaluate the alteration of renal excretion pathways in gentamicin (GEN)-induced renal injury in rats. Results showed that serum cystatin C, creatinine and urea nitrogen levels were greatly increased by the exposure of GEN (100 mg kg -1 ), and creatinine concentration was increased by 39.7% by GEN (50 mg kg -1 ). GEN dose-dependently upregulated the protein expression of rOCT1, downregulated rOCT2 and rOAT1, but not affected rOAT2. Efflux transporters, rMRP2, rMRP4 and rBCRP expressions were significantly increased by GEN(100), and the rMATE1 level was markedly increased by GEN(50) but decreased by GEN(100). GEN(50) did not alter the urinary excretion of inulin, but increased metformin and furosemide excretion. However, GEN(100) resulted in a significant decrease of the urinary excretion of inulin, metformin and p-aminohippurate. In addition, urinary metformin excretions in vivo were significantly decreased by GEN(100), but slightly increased by GEN(50). These results suggested that GEN(50) resulted in the induction of rOCTs-rMATE1 and rOAT3-rMRPs pathway, but not changed the glomerular filtration rate, and GEN(100)-induced acute kidney injury caused the downregulated function of glomerular filtration -rOCTs-rMATE1 and -rOAT1-rMRPs pathway. Copyright © 2018 John Wiley & Sons, Ltd.

Semisubmersible oil platforms: understudied and potentially major vectors of biofouling-mediated invasions.

Science.gov (United States)

Yeo, Darren C J; Ahyong, Shane T; Lodge, David M; Ng, Peter K L; Naruse, Tohru; Lane, David J W

2010-01-01

Biofouling has long been recognised as a major pathway for the introduction of non-indigenous species. This study records the decapods and stomatopod crustaceans fouling a semisubmersible oil platform dry docked for hull cleaning in Jurong Port, Singapore. Of the 25 species of decapods identified, 13 were non-indigenous and represent new records to Singapore waters. Of these, the crabs Glabropilumnus seminudus and Carupa tenuipes are known to be invasive in other parts of the world. The stomatopod, Gonodactylaceus randalli, is the first mantis shrimp recorded in a biofouling community. The richness and diversity of this fouling community, consisting of many vagile species, highlights the difference between platforms and ships. With the expansion of maritime oil and gas exploration, the threat posed by an expanded fleet of semisubmersible oil platforms translocating non-indigenous fouling communities across biogeographical boundaries is very serious. Scientists, policy-makers, and stakeholders should turn their attention to this growing problem.

Personalized identification of differentially expressed pathways in pediatric sepsis.

Science.gov (United States)

Li, Binjie; Zeng, Qiyi

2017-10-01

Sepsis is a leading killer of children worldwide with numerous differentially expressed genes reported to be associated with sepsis. Identifying core pathways in an individual is important for understanding septic mechanisms and for the future application of custom therapeutic decisions. Samples used in the study were from a control group (n=18) and pediatric sepsis group (n=52). Based on Kauffman's attractor theory, differentially expressed pathways associated with pediatric sepsis were detected as attractors. When the distribution results of attractors are consistent with the distribution of total data assessed using support vector machine, the individualized pathway aberrance score (iPAS) was calculated to distinguish differences. Through attractor and Kyoto Encyclopedia of Genes and Genomes functional analysis, 277 enriched pathways were identified as attractors. There were 81 pathways with Ppathways with Ppathway clusters and four sample clusters. Thus, in the majority pediatric sepsis samples, core pathways can be detected as different from accumulated normal samples. In conclusion, a novel procedure that identified the dysregulated attractors in individuals with pediatric sepsis was constructed. Attractors can be markers to identify pathways involved in pediatric sepsis. iPAS may provide a correlation score for each of the signaling pathways present in an individual patient. This process may improve the personalized interpretation of disease mechanisms and may be useful in the forthcoming era of personalized medicine.

Crosstalk of Autophagy and the Secretory Pathway and Its Role in Diseases.

Science.gov (United States)

Zahoor, Muhammad; Farhan, Hesso

2018-01-01

The secretory and autophagic pathways are two fundamental, evolutionary highly conserved endomembrane processes. Typically, secretion is associated with biosynthesis and delivery of proteins. In contrast, autophagy is usually considered as a degradative pathway. Thus, an analogy to metabolic pathways is evident. Anabolic (biosynthetic) and catabolic (degradative) pathways are usually intimately linked and intertwined, and likewise, the secretory and autophagy pathways are intertwined. Investigation of this link is an emerging area of research, and we will provide an overview of some of the major advances that have been made to contribute to understanding of how secretion regulates autophagy and vice versa. Finally, we will highlight evidence that supports a potential involvement of the autophagy-secretion crosstalk in human diseases. © 2018 Elsevier Inc. All rights reserved.

Pathways of fish invasions in the Mid-Atlantic region of the United States

Science.gov (United States)

Lapointe, Nicolas W. R.; Fuller, Pam; Neilson, Matthew; Murphy, Brian R.; Angermeier, Paul

2016-01-01

Non-native fish introductions are a major threat to biodiversity and fisheries, and occur through numerous pathways that vary regionally in importance. A key strategy for managing invasions is to focus prevention efforts on pathways posing the greatest risk of future introductions. We identified high-risk pathways for fish establishment in the Mid-Atlantic region of the United States based on estimates of probability of establishment and records of previous introductions, which were considered in the context of emerging socioeconomic trends. We used estimates of propagule pressure, species’ environmental tolerance, and size of species pool to assess the risk of establishment by pathway. Pathways varied considerably in historic importance and species composition, with the majority of species introduced intentionally via stocking (primarily for sport, forage, or biocontrol) or bait release. Bait release, private stocking, illegal introductions intended to establish reproducing populations (e.g., of sport fish), aquaculture, and the sale of live organisms all create risks for future invasions in the Mid-Atlantic region. Of these pathways, bait release probably poses the greatest risk of introductions for the Mid-Atlantic region because propagule pressure is moderate, most released species are tolerant of local environmental conditions, and the pool of species available for transplantation is large. Our findings differ considerably from studies in other regions (e.g., bait release is a dominant pathway in the Mid-Atlantic region, whereas illegal introduction of sport fish is dominant in the western US and aquarium releases are dominant in Florida), demonstrating the need for regional-scale assessments of, and management strategies for, introduction pathways.

Performance profiles of major energy producers 1993

Energy Technology Data Exchange (ETDEWEB)

NONE

1995-01-01

Performance Profiles of Major Energy Producers 1993 is the seventeenth annual report of the Energy Information Administration`s (EIA) Financial Reporting System (FRS). The report examines financial and operating developments in energy markets, with particular reference to the 25 major US energy companies required to report annually on Form EIA-28. Financial information is reported by major liens of business, including oil and gas production, petroleum refining and marketing, other energy operations, and nonenergy businesses. Financial and operating results are presented in the context of energy market developments with a view toward identifying changing corporate strategies and measuring the performance of ongoing operations both in the US and abroad. This year`s report analyzes financial and operating developments for 1993 (Part 1: Developments in 1993) and also reviews key developments during the 20 years following the Arab Oil Embargo of 1973--1974 (Part 2: Major Energy Company Strategies Since the Arab Oil Embargo). 49 figs., 104 tabs.

Recent changes in sediment redistribution in the upper parts of the fluvial system of European Russia: regional aspects

Directory of Open Access Journals (Sweden)

O. P. Yermolaev

2015-03-01

Full Text Available Quantitative assessments of soil loss from cultivated land and sediment redistribution along pathways from cultivated fields to river channels have been undertaken using a range of different methods and techniques, including erosion models, detailed studies of sediment redistribution in representative catchments, monitoring of gully head retreat and evaluation of sediment deposition in ponds and small reservoirs. Most of the sediment eroded from arable land is deposited between the lower portions of the cultivated slopes and the river channels. Less than 15% of the eroded sediment is delivered to the river channels. Sediment redistribution rates in the upper parts of the fluvial system have declined during the last 25 years in both the western and eastern parts of the Russian Plain, because of a major reduction of surface runoff during snowmelt and a reduction of the area of arable land in some parts of the study area.

A first approximation for modeling the liquid diffusion pathway at the greater confinement disposal facilities

International Nuclear Information System (INIS)

Olague, N.E.; Price, L.L.

1991-01-01

The greater confinement disposal (GCD) project is an ongoing project examining the disposal of orphan wastes in Area 5 of the Nevada Test Site. One of the major tasks for the project is performance assessment. With regard to performance assessment, a preliminary conceptual model for ground-water flow and radionuclide transport to the accessible environment at the GCD facilities has been developed. One of the transport pathways that has been postulated is diffusion of radionuclides in the liquid phase upward to the land surface. This pathway is not usually considered in a performance assessment, but is included in the GCD conceptual model because of relatively low recharge estimates at the GCD site and the proximity of the waste to the land surface. These low recharge estimates indicate that convective flow downward to the water table may be negligible; thus, diffusion upward to the land surface may then become important. As part of a preliminary performance assessment which considered a basecase scenario and a climate-change scenario, a first approximation for modeling the liquid-diffusion pathway was formulated. The model includes an analytical solution that incorporates both diffusion and radioactivity decay. Overall, these results indicate that, despite the configuration of the GCD facilities that establishes the need for considering the liquid-diffusion pathway, the GCD disposal concept appears to be a technically feasible method for disposing of orphan wastes. Future analyses will consist of investigating the underlying assumptions of the liquid-diffusion model, refining the model is necessary, and reducing uncertainty in the input parameters. 11 refs., 6 figs

Is there a future for andrographolide to be an anti-inflammatory drug? Deciphering its major mechanisms of action.

Science.gov (United States)

Tan, W S Daniel; Liao, Wupeng; Zhou, Shuo; Wong, W S Fred

2017-09-01

Andrographis paniculata has long been part of the traditional herbal medicine system in Asia and in Scandinavia. Andrographolide was isolated as a major bioactive constituent of A. paniculata in 1951, and since 1984, andrographolide and its analogs have been scrutinized with modern drug discovery approach for anti-inflammatory properties. With this accumulated wealth of pre-clinical data, it is imperative to review and consolidate different sources of information, to decipher the major anti-inflammatory mechanisms of action in inflammatory diseases, and to provide direction for future studies. Andrographolide and its analogs have been shown to provide anti-inflammatory benefits in a variety of inflammatory disease models. Among the diverse signaling pathways investigated, inhibition of NF-κB activity is the prevailing anti-inflammatory mechanism elicited by andrographolide. There is also increasing evidence supporting endogenous antioxidant defense enhancement by andrographolide through Nrf2 activation. However, the exact pathway leading to NF-κB and Nrf2 activation by andrographolide has yet to be elucidated. Validation and consensus on the major mechanistic actions of andrographolide in different inflammatory conditions are required before translating current findings into clinical settings. There are a few clinical trials conducted using andrographolide in fixed combination formulation which have shown anti-inflammatory benefits and good safety profile. A concerted effort is definitely needed to identify potent andrographolide lead compounds with improved pharmacokinetics and toxicological properties. Taken together, andrographolide and its analogs have great potential to be the next new class of anti-inflammatory agents, and more andrographolide molecules are likely moving towards clinical study stage in the near future. Copyright © 2017 Elsevier Inc. All rights reserved.

Treating the Synapse in Major Psychiatric Disorders: The Role of Postsynaptic Density Network in Dopamine-Glutamate Interplay and Psychopharmacologic Drugs Molecular Actions

Directory of Open Access Journals (Sweden)

Carmine Tomasetti

2017-01-01

Full Text Available Dopamine-glutamate interplay dysfunctions have been suggested as pathophysiological key determinants of major psychotic disorders, above all schizophrenia and mood disorders. For the most part, synaptic interactions between dopamine and glutamate signaling pathways take part in the postsynaptic density, a specialized ultrastructure localized under the membrane of glutamatergic excitatory synapses. Multiple proteins, with the role of adaptors, regulators, effectors, and scaffolds compose the postsynaptic density network. They form structural and functional crossroads where multiple signals, starting at membrane receptors, are received, elaborated, integrated, and routed to appropriate nuclear targets. Moreover, transductional pathways belonging to different receptors may be functionally interconnected through postsynaptic density molecules. Several studies have demonstrated that psychopharmacologic drugs may differentially affect the expression and function of postsynaptic genes and proteins, depending upon the peculiar receptor profile of each compound. Thus, through postsynaptic network modulation, these drugs may induce dopamine-glutamate synaptic remodeling, which is at the basis of their long-term physiologic effects. In this review, we will discuss the role of postsynaptic proteins in dopamine-glutamate signals integration, as well as the peculiar impact of different psychotropic drugs used in clinical practice on postsynaptic remodeling, thereby trying to point out the possible future molecular targets of “synapse-based” psychiatric therapeutic strategies.

Enhanced Recovery After Surgery Protocols in Major Urologic Surgery

Directory of Open Access Journals (Sweden)

Natalija Vukovic

2018-04-01

Full Text Available The purpose of the reviewThe analysis of the components of enhanced recovery after surgery (ERAS protocols in urologic surgery.Recent findingsERAS protocols has been studied for over 20 years in different surgical procedures, mostly in colorectal surgery. The concept of improving patient care and reducing postoperative complications was also applied to major urologic surgery and especially procedure of radical cystectomy. This procedure is technically challenging, due to a major surgical resection and high postoperative complication rate that may reach 65%. Several clinical pathways were introduced to improve perioperative course and reduce the length of hospital stay. These protocols differ from ERAS modalities in other surgeries. The reasons for this are longer operative time, increased risk of perioperative transfusion and infection, and urinary diversion achieved using transposed intestinal segments. Previous studies in this area analyzed the need for mechanical bowel preparation, postoperative nasogastric tube decompression, as well as the duration of urinary drainage. Furthermore, the attention has also been drawn to perioperative fluid optimization, pain management, and bowel function.SummaryNotwithstanding partial resemblance between the pathways in major urologic surgery and other pelvic surgeries, there are still scarce guidelines for ERAS protocols in urology, which is why further studies should assess the importance of preoperative medical optimization, implementation of thoracic epidural anesthesia and analgesia, and perioperative nutritional management.

White matter pathways in persistent developmental stuttering: Lessons from tractography.

Science.gov (United States)

Kronfeld-Duenias, Vered; Civier, Oren; Amir, Ofer; Ezrati-Vinacour, Ruth; Ben-Shachar, Michal

2018-03-01

Fluent speech production relies on the coordinated processing of multiple brain regions. This highlights the role of neural pathways that connect distinct brain regions in producing fluent speech. Here, we aim to investigate the role of the white matter pathways in persistent developmental stuttering (PDS), where speech fluency is disrupted. We use diffusion weighted imaging and tractography to compare the white matter properties between adults who do and do not stutter. We compare the diffusion properties along 18 major cerebral white matter pathways. We complement the analysis with an overview of the methodology and a roadmap of the pathways implicated in PDS according to the existing literature. We report differences in the microstructural properties of the anterior callosum, the right inferior longitudinal fasciculus and the right cingulum in people who stutter compared with fluent controls. Persistent developmental stuttering is consistently associated with differences in bilateral distributed networks. We review evidence showing that PDS involves differences in bilateral dorsal fronto-temporal and fronto-parietal pathways, in callosal pathways, in several motor pathways and in basal ganglia connections. This entails an important role for long range white matter pathways in this disorder. Using a wide-lens analysis, we demonstrate differences in additional, right hemispheric pathways, which go beyond the replicable findings in the literature. This suggests that the affected circuits may extend beyond the known language and motor pathways. Copyright © 2017 Elsevier Inc. All rights reserved.

Aquatic pathway 1

International Nuclear Information System (INIS)

1976-01-01

This first part of the study discusses problems of exposure due to the emission of radioactive substances into the environment via the water pathway. Discussion is started with a paper on the fundamentals of calculation and another paper on the results of preliminary radiological model calculations. The colloquium will assess the present state of knowledge, helps to find an agreement between divergent opinions and determine open questions and possible solutions. Ten main problems have been raised, most of which pertain to site conditions. They are trated as sub-investigations by individual participants or working groups. The findings will be discussed in further colloquia. (orig.) [de

Logical knowledge representation of regulatory relations in biomedical pathways

DEFF Research Database (Denmark)

Zambach, Sine; Hansen, Jens Ulrik

2010-01-01

Knowledge on regulatory relations, in for example regulatory pathways in biology, is used widely in experiment design by biomedical researchers and in systems biology. The knowledge has typically either been represented through simple graphs or through very expressive differential equation...... simulations of smaller parts of a pathway. In this work we suggest a knowledge representation of the most basic relations in regulatory processes regulates, positively regulates and negatively regulates in logics based on a semantic analysis. We discuss the usage of these relations in biology and in articial...... intelligence for hypothesis development in drug discovery....

Pathway discovery in metabolic networks by subgraph extraction.

Science.gov (United States)

Faust, Karoline; Dupont, Pierre; Callut, Jérôme; van Helden, Jacques

2010-05-01

Subgraph extraction is a powerful technique to predict pathways from biological networks and a set of query items (e.g. genes, proteins, compounds, etc.). It can be applied to a variety of different data types, such as gene expression, protein levels, operons or phylogenetic profiles. In this article, we investigate different approaches to extract relevant pathways from metabolic networks. Although these approaches have been adapted to metabolic networks, they are generic enough to be adjusted to other biological networks as well. We comparatively evaluated seven sub-network extraction approaches on 71 known metabolic pathways from Saccharomyces cerevisiae and a metabolic network obtained from MetaCyc. The best performing approach is a novel hybrid strategy, which combines a random walk-based reduction of the graph with a shortest paths-based algorithm, and which recovers the reference pathways with an accuracy of approximately 77%. Most of the presented algorithms are available as part of the network analysis tool set (NeAT). The kWalks method is released under the GPL3 license.

Expression of protein-tyrosine phosphatases in the major insulin target tissues

DEFF Research Database (Denmark)

Norris, K; Norris, F; Kono, D H

1997-01-01

Protein-tyrosine phosphatases (PTPs) are key regulators of the insulin receptor signal transduction pathway. We have performed a detailed analysis of PTP expression in the major human insulin target tissues or cells (liver, adipose tissue, skeletal muscle and endothelial cells). To obtain a repre...

Disposition pathways and pharmacokinetics of herbal medicines in humans.

Science.gov (United States)

He, S-M; Li, C G; Liu, J-P; Chan, E; Duan, W; Zhou, S-F

2010-01-01

Pharmacokinetic studies have become an integral part of modern drug development, but these studies are not regulatory needs for herbal remedies. This paper updates our current knowledge on the disposition pathways and pharmacokinetic properties of commonly used herbal medicines in humans. To retrieve relevant data, the authors have searched through computer-based literatures by full text search in Medline (via Pubmed), ScienceDirect, Current Contents Connect (ISI), Cochrance Library, CINAHL (EBSCO), CrossRef Search and Embase (all from inception to May 2010). Many herbal compounds undergo Phase I and/or Phase II metabolism in vivo, with cytochrome P450s (CYPs) and uridine diphosphate glucuronosyltransferases (UGTs) playing a major role. Some herbal ingredients are substrates of P-glycoprotein (P-gp) which is highly expressed in the intestine, liver, brain and kidney. As such, the activities of these drug metabolizing enzymes and drug transporters are determining factors for the in vivo bioavailability, disposition and distribution of herbal remedies. There are increasing pharmacokinetic studies of herbal remedies, but these studies are mainly focused on a small number of herbal remedies including St John's wort, milk thistle, sculcap, curcumin, echinacea, ginseng, ginkgo, and ginger. The pharmacokinetic data of a small number of purified herbal ingredients, including anthocyanins, berberine, catechins, curcumin, lutein and quercetin, are available. For the majority of herbal remedies used in folk medicines, data on their disposition and biological fate in humans are lacking or in paucity. For a herbal medicine, the pharmacological effect is achieved when the bioactive agents or the metabolites reach and sustain proper levels at their sites of action. Both the dose levels and fates of active components in the body govern their target-site concentrations after administration of an herbal remedy. In this regard, a safe and optimal use of herbal medicines requires a

Safety assessment for deep underground disposal vault-pathways analysis

International Nuclear Information System (INIS)

Lyon, R.B.; Rosinger, E.L.J.

1980-01-01

The concept verification phase of the Canadian programme for the disposal of nuclear fuel waste encompasses a period of about three years before the start of site selection. During this time, the methodology for Environmental and Safety Assessment studies is being developed by focusing on a model site. Pathways analysis is an important component of these studies. It involves the prediction of the rate at which radionuclides might be released from a disposal vault and travel through the geosphere and biosphere to reach man. The pathways analysis studies cover three major topics: geosphere pathways analysis, biosphere pathways analysis and potentially-disruptive-phenomena analysis. Geosphere pathways analysis includes a total systems analysis, using the computer program GARD2, vault analysis, which considers container failure and waste leaching, hydrogeological modelling and geochemical modelling. Biosphere pathways analysis incorporates a compartmental modelling approach using the computer program RAMM, and a food chain analysis using the computer program FOOD II. Potentially-disruptive-phenomena analysis involves the estimation of the probability and consequences of events such as earthquakes which might reduce the effectiveness of the barriers preventing the release of radionuclides. The current stage of development of the required methodology and data is discussed in each of the three areas and preliminary results are presented. (author)

Evasion Mechanisms Used by Pathogens to Escape the Lectin Complement Pathway.

Science.gov (United States)

Rosbjerg, Anne; Genster, Ninette; Pilely, Katrine; Garred, Peter

2017-01-01

The complement system is a crucial defensive network that protects the host against invading pathogens. It is part of the innate immune system and can be initiated via three pathways: the lectin, classical and alternative activation pathway. Overall the network compiles a group of recognition molecules that bind specific patterns on microbial surfaces, a group of associated proteases that initiates the complement cascade, and a group of proteins that interact in proteolytic complexes or the terminal pore-forming complex. In addition, various regulatory proteins are important for controlling the level of activity. The result is a pro-inflammatory response meant to combat foreign microbes. Microbial elimination is, however, not a straight forward procedure; pathogens have adapted to their environment by evolving a collection of evasion mechanisms that circumvent the human complement system. Complement evasion strategies features different ways of exploiting human complement proteins and moreover features different pathogen-derived proteins that interfere with the normal processes. Accumulated, these mechanisms target all three complement activation pathways as well as the final common part of the cascade. This review will cover the currently known lectin pathway evasion mechanisms and give examples of pathogens that operate these to increase their chance of invasion, survival and dissemination.

minepath.org: a free interactive pathway analysis web server.

Science.gov (United States)

Koumakis, Lefteris; Roussos, Panos; Potamias, George

2017-07-03

( www.minepath.org ) is a web-based platform that elaborates on, and radically extends the identification of differentially expressed sub-paths in molecular pathways. Besides the network topology, the underlying MinePath algorithmic processes exploit exact gene-gene molecular relationships (e.g. activation, inhibition) and are able to identify differentially expressed pathway parts. Each pathway is decomposed into all its constituent sub-paths, which in turn are matched with corresponding gene expression profiles. The highly ranked, and phenotype inclined sub-paths are kept. Apart from the pathway analysis algorithm, the fundamental innovation of the MinePath web-server concerns its advanced visualization and interactive capabilities. To our knowledge, this is the first pathway analysis server that introduces and offers visualization of the underlying and active pathway regulatory mechanisms instead of genes. Other features include live interaction, immediate visualization of functional sub-paths per phenotype and dynamic linked annotations for the engaged genes and molecular relations. The user can download not only the results but also the corresponding web viewer framework of the performed analysis. This feature provides the flexibility to immediately publish results without publishing source/expression data, and get all the functionality of a web based pathway analysis viewer. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

Amino acids as regulators and components of nonproteinogenic pathways

NARCIS (Netherlands)

Meijer, Alfred J.

2003-01-01

Amino acids are not only important precursors for the synthesis of proteins and other N-containing compounds, but also participate in the regulation of major metabolic pathways. Glutamate and aspartate, for example, are components of the malate/aspartate shuttle and their concentrations control the

An Ixodes ricinus Tick Salivary Lectin Pathway Inhibitor Protects Borrelia burgdorferi sensu lato from Human Complement.

Science.gov (United States)

Wagemakers, Alex; Coumou, Jeroen; Schuijt, Tim J; Oei, Anneke; Nijhof, Ard M; van 't Veer, Cornelis; van der Poll, Tom; Bins, Adriaan D; Hovius, Joppe W R

2016-04-01

We previously identified tick salivary lectin pathway inhibitor (TSLPI) in Ixodes scapularis, a vector for Borrelia burgdorferi sensu stricto (s.s.) in North America. TSLPI is a salivary protein facilitating B. burgdorferi s.s. transmission and acquisition by inhibiting the host lectin complement pathway through interference with mannose binding lectin (MBL) activity. Since Ixodes ricinus is the predominant vector for Lyme borreliosis in Europe and transmits several complement sensitive B. burgdorferi sensu lato (s.l.) strains, we aimed to identify, describe, and characterize the I. ricinus ortholog of TSLPI. We performed (q)PCRs on I. ricinus salivary gland cDNA to identify a TSLPI ortholog. Next, we generated recombinant (r)TSLPI in a Drosophila expression system and examined inhibition of the MBL complement pathway and complement-mediated killing of B. burgdorferi s.l. in vitro. We identified a TSLPI ortholog in I. ricinus salivary glands with 93% homology at the RNA and 89% at the protein level compared to I. scapularis TSLPI, which was upregulated during tick feeding. In silico analysis revealed that TSLPI appears to be part of a larger family of Ixodes salivary proteins among which I. persulcatus basic tail salivary proteins and I. scapularis TSLPI and Salp14. I. ricinus rTSLPI inhibited the MBL complement pathway and protected B. burgdorferi s.s. and Borrelia garinii from complement-mediated killing. We have identified a TSLPI ortholog, which protects B. burgdorferi s.l. from complement-mediated killing in I. ricinus, the major vector for tick-borne diseases in Europe.

Parasubthalamic and calbindin nuclei in the posterior lateral hypothalamus are the major hypothalamic targets for projections from the central and anterior basomedial nuclei of the amygdala.

Science.gov (United States)

Barbier, Marie; Chometton, Sandrine; Peterschmitt, Yvan; Fellmann, Dominique; Risold, Pierre-Yves

2017-09-01

The parasubthalamic nucleus (PSTN) and the ventrally adjacent calbindin nucleus (CbN) form a nuclear complex in the posterior lateral hypothalamic area (LHA), recently characterized as connected with the central nucleus of the amygdala (CEA). The aim of the present work is to analyze in detail the projections from the amygdala into the PSTN/CbN, also focusing on pathways into the LHA. After fluorogold injections into the PSTN/CbN, the medial part of the CEA (CEAm) appears to be the main supplier of projections from the CEA. Other amygdalar nuclei contribute to the innervation of the PSTN/CbN complex, including the anterior part of the basomedial nucleus (BMAa). Injections of the anterograde tracer, Phaseolus vulgaris leucoagglutinin (PHAL), into the CEAm and BMAa revealed that projections from the CEAm follow two pathways into the LHA: a dorsal pathway formed by axons that also innervate the paraventricular hypothalamic nucleus, the anterior perifornical LHA and the PSTN, and a ventral pathway that runs laterally adjacent to the ventrolateral hypothalamic tract (vlt) and ends in the CbN. By contrast, the BMAa and other telencephalic structures, such as the fundus striatum project to the CbN via the ventral pathway. Confirming the microscopic observation, a semi-quantitative analysis of the density of these projections showed that the PSTN and the CbN are the major hypothalamic targets for the projections from the CEAm and the BMAa, respectively. PSTN and CbN receive these projections through distinct dorsal and ventral routes in the LHA. The ventral pathway forms a differentiated tract, named here the ventrolateral amygdalo-hypothalamic tract (vlah), that is distinct from, but runs adjacent to, the vlt. Both the vlt and the vlah had been previously described as forming an olfactory path into the LHA. These results help to better characterize the CbN within the PSTN/CbN complex and are discussed in terms of the functional organization of the network involving the

Observed and Modeled Pathways of the Iceland Scotland Overflow Water in the eastern North Atlantic

Science.gov (United States)

Zou, Sijia; Lozier, Susan; Zenk, Walter; Bower, Amy; Johns, William

2017-04-01

The Iceland Scotland Overflow Water (ISOW), one of the major components of the lower limb of the Atlantic Meridional Overturning Circulation (AMOC), is formed in the Nordic Seas and enters the eastern North Atlantic subpolar gyre via the Iceland-Scotland sill. After entraining the ambient waters, the relatively homogeneous ISOW spreads southward into the North Atlantic. An understanding of the distribution and variability of the spreading pathways of the ISOW is fundamental to our understanding of AMOC structure and variability. Three major ISOW pathways have been identified in the eastern North Atlantic by previous studies: 1) across the Reykjanes Ridge via deep gaps, 2) through the Charlie Gibbs Fracture Zone, and 3) southward along the eastern flank of the Mid Atlantic Ridge (MAR). However, most of these studies were conducted using an Eulerian frame with limited observations, especially for the third pathway along the eastern flank of the MAR. In this work, we give a comprehensive description of ISOW pathways in the Eulerian and Lagrangian frames, quantify the relative importance of each pathway and examine the temporal variability of these pathways. Our study distinguishes itself from past studies by using both Eulerian (current meter data) and Lagrangian (eddy-resolving RAFOS float data) observations in combination with modeling output (1/12° FLAME) to describe ISOW spreading pathways and their variability.

Improved fermentative L-cysteine overproduction by enhancing a newly identified thiosulfate assimilation pathway in Escherichia coli.

Science.gov (United States)

Kawano, Yusuke; Onishi, Fumito; Shiroyama, Maeka; Miura, Masashi; Tanaka, Naoyuki; Oshiro, Satoshi; Nonaka, Gen; Nakanishi, Tsuyoshi; Ohtsu, Iwao

2017-09-01

Sulfate (SO 4 2- ) is an often-utilized and well-understood inorganic sulfur source in microorganism culture. Recently, another inorganic sulfur source, thiosulfate (S 2 O 3 2- ), was proposed to be more advantageous in microbial growth and biotechnological applications. Although its assimilation pathway is known to depend on O-acetyl-L-serine sulfhydrylase B (CysM in Escherichia coli), its metabolism has not been extensively investigated. Therefore, we aimed to explore another yet-unidentified CysM-independent thiosulfate assimilation pathway in E. coli. ΔcysM cells could accumulate essential L-cysteine from thiosulfate as the sole sulfur source and could grow, albeit slowly, demonstrating that a CysM-independent thiosulfate assimilation pathway is present in E. coli. This pathway is expected to consist of the initial part of the thiosulfate to sulfite (SO 3 2- ) conversion, and the latter part might be shared with the final part of the known sulfate assimilation pathway [sulfite → sulfide (S 2- ) → L-cysteine]. This is because thiosulfate-grown ΔcysM cells could accumulate a level of sulfite and sulfide equivalent to that of wild-type cells. The catalysis of thiosulfate to sulfite is at least partly mediated by thiosulfate sulfurtransferase (GlpE), because its overexpression could enhance cellular thiosulfate sulfurtransferase activity in vitro and complement the slow-growth phenotype of thiosulfate-grown ΔcysM cells in vivo. GlpE is therefore concluded to function in the novel CysM-independent thiosulfate assimilation pathway by catalyzing thiosulfate to sulfite. We applied this insight to L-cysteine overproduction in E. coli and succeeded in enhancing it by GlpE overexpression in media containing glucose or glycerol as the main carbon source, by up to ~1.7-fold (1207 mg/l) or ~1.5-fold (1529 mg/l), respectively.

Aquatic pathways model to predict the fate of phenolic compounds

Energy Technology Data Exchange (ETDEWEB)

Aaberg, R.L.; Peloquin, R.A.; Strenge, D.L.; Mellinger, P.J.

1983-04-01

Organic materials released from energy-related activities could affect human health and the environment. To better assess possible impacts, we developed a model to predict the fate of spills or discharges of pollutants into flowing or static bodies of fresh water. A computer code, Aquatic Pathways Model (APM), was written to implement the model. The computer programs use compartmental analysis to simulate aquatic ecosystems. The APM estimates the concentrations of chemicals in fish tissue, water and sediment, and is therefore useful for assessing exposure to humans through aquatic pathways. The APM will consider any aquatic pathway for which the user has transport data. Additionally, APM will estimate transport rates from physical and chemical properties of chemicals between several key compartments. The major pathways considered are biodegradation, fish and sediment uptake, photolysis, and evaporation. The model has been implemented with parameters for distribution of phenols, an important class of compounds found in the water-soluble fractions of coal liquids. Current modeling efforts show that, in comparison with many pesticides and polyaromatic hydrocarbons (PAH), the lighter phenolics (the cresols) are not persistent in the environment. The properties of heavier molecular weight phenolics (indanols, naphthols) are not well enough understood at this time to make similar judgements. For the twelve phenolics studied, biodegradation appears to be the major pathway for elimination from aquatic environments. A pond system simulation (using APM) of a spill of solvent refined coal (SRC-II) materials indicates that phenol, cresols, and other single cyclic phenolics are degraded to 16 to 25 percent of their original concentrations within 30 hours. Adsorption of these compounds into sediments and accumulation by fish was minor.

Human cerebral venous outflow pathway depends on posture and central venous pressure

DEFF Research Database (Denmark)

Gisolf, J; van Lieshout, J J; van Heusden, K

2004-01-01

Internal jugular veins are the major cerebral venous outflow pathway in supine humans. In upright humans the positioning of these veins above heart level causes them to collapse. An alternative cerebral outflow pathway is the vertebral venous plexus. We set out to determine the effect of posture...... and during a Valsalva manoeuvre in both body positions, correlate highly with model simulation of the jugular cross-sectional area (R(2) = 0.97). The results suggest that the cerebral venous flow distribution depends on posture and CVP: in supine humans the internal jugular veins are the primary pathway...

The activation of the kynurenine pathway in a rat model with renovascular hypertension.

Science.gov (United States)

Bartosiewicz, Jacek; Kaminski, Tomasz; Pawlak, Krystyna; Karbowska, Malgorzata; Tankiewicz-Kwedlo, Anna; Pawlak, Dariusz

2017-04-01

Hypertension is a serious condition that can lead to many health problems. The mechanisms underlying this process are still not fully understood. The kynurenine pathway may be involved in the occurrence and progression of hypertension. The purpose of this study was to examine the activity of peripheral kynurenine pathway in rats with renovascular hypertension in Goldblatt 2K1C model. Hypertension was induced in the experimental groups by constricting the renal artery of the left kidney of the rats. Determination of tryptophan (Trp) and kynurenine pathway metabolites was assessed by high-performance liquid chromatography in plasma and tissues obtained at 4, 8, and 16 weeks after the surgical intervention or sham surgery. Levels of Ang II were evaluated using commercial immuno-enzymatic ELISA kits. Surgical treatment led to increased values of mean blood pressure and systolic blood pressure, whereas Trp concentrations were decreased in experimental animals compared to appropriate controls. Simultaneously, the considerable increment of kynurenine pathway components and a significant increase in the activity of tryptophan 2,3-dioxygenase were observed in rats with developed hypertension in comparison with controls. There were no differences between Ang II levels in controls and experimental groups. The inverse relationship was between plasma Trp and both SBP and Ang II values, and Trp independently affected Ang II concentrations in hypertensive rats. In contrast, tryptophan 2,3-dioxygenase activity and plasma kynurenine metabolites positively correlated with blood pressure values as well as with Ang II levels in these animals. Moreover, kynurenine was independently connected with MBP. Renovascular hypertension influences kynurenine pathway and leads to an imbalance in Trp and its metabolite levels. Tryptophan 2,3-dioxygenase and part of the kynurenine metabolites in plasma and tissues positively correlated with blood pressure values and Ang II levels. Although the

The Wnt signaling pathway in familial exudative vitreoretinopathy and Norrie disease.

Science.gov (United States)

Warden, Scott M; Andreoli, Christopher M; Mukai, Shizuo

2007-01-01

The Wnt signaling pathway is highly conserved among species and has an important role in many cell biological processes throughout the body. This signaling cascade is involved in regulating ocular growth and development, and recent findings indicate that this is particularly true in the retina. Mutations involving different aspects of the Wnt signaling pathway are being linked to several diseases of retinal development. The aim of this article is to first review the Wnt signaling pathway. We will then describe two conditions, familial exudative vitreoretinopathy (FEVR) and Norrie disease (ND), which have been shown to be caused in part by defects in the Wnt signaling cascade.

Pathways to improving the N efficiency of grazing bovines

NARCIS (Netherlands)

Hoekstra, N.J.; Schulte, R.P.O.; Struik, P.C.; Lantinga, E.A.

2007-01-01

Livestock production has been identified as a major source of nitrogen (N) losses. Therefore, it is important to reduce N output through animal excretions by improving N utilisation by the animal. The objective of this paper is to identify pathways for producing grass-based diets that maximise

Complex DNA repair pathways as possible therapeutic targets to overcome temozolomide resistance in glioblastoma

International Nuclear Information System (INIS)

Yoshimoto, Koji; Mizoguchi, Masahiro; Hata, Nobuhiro; Murata, Hideki; Hatae, Ryusuke; Amano, Toshiyuki; Nakamizo, Akira; Sasaki, Tomio

2012-01-01

Many conventional chemotherapeutic drugs exert their cytotoxic function by inducing DNA damage in the tumor cell. Therefore, a cell-inherent DNA repair pathway, which reverses the DNA-damaging effect of the cytotoxic drugs, can mediate therapeutic resistance to chemotherapy. The monofunctional DNA-alkylating agent temozolomide (TMZ) is a commonly used chemotherapeutic drug and the gold standard treatment for glioblastoma (GBM). Although the activity of DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) has been described as the main modulator to determine the sensitivity of GBM to TMZ, a subset of GBM does not respond despite MGMT inactivation, suggesting that another DNA repair mechanism may also modulate the tolerance to TMZ. Considerable interest has focused on MGMT, mismatch repair (MMR), and the base excision repair (BER) pathway in the mechanism of mediating TMZ resistance, but emerging roles for the DNA strand-break repair pathway have been demonstrated. In the first part of this review article, we briefly review the significant role of MGMT, MMR, and the BER pathway in the tolerance to TMZ; in the last part, we review the recent publications that demonstrate possible roles of DNA strand-break repair pathways, such as single-strand break repair and double-strand break repair, as well as the Fanconi anemia pathway in the repair process after alkylating agent-based therapy. It is possible that all of these repair pathways have a potential to modulate the sensitivity to TMZ and aid in overcoming the therapeutic resistance in the clinic.

Complex DNA repair pathways as possible therapeutic targets to overcome temozolomide resistance in glioblastoma

Energy Technology Data Exchange (ETDEWEB)

Yoshimoto, Koji; Mizoguchi, Masahiro; Hata, Nobuhiro; Murata, Hideki; Hatae, Ryusuke; Amano, Toshiyuki; Nakamizo, Akira; Sasaki, Tomio, E-mail: kyoshimo@ns.med.kyushu-u.ac.jp [Department of Neurosurgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka (Japan)

2012-12-05

Many conventional chemotherapeutic drugs exert their cytotoxic function by inducing DNA damage in the tumor cell. Therefore, a cell-inherent DNA repair pathway, which reverses the DNA-damaging effect of the cytotoxic drugs, can mediate therapeutic resistance to chemotherapy. The monofunctional DNA-alkylating agent temozolomide (TMZ) is a commonly used chemotherapeutic drug and the gold standard treatment for glioblastoma (GBM). Although the activity of DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) has been described as the main modulator to determine the sensitivity of GBM to TMZ, a subset of GBM does not respond despite MGMT inactivation, suggesting that another DNA repair mechanism may also modulate the tolerance to TMZ. Considerable interest has focused on MGMT, mismatch repair (MMR), and the base excision repair (BER) pathway in the mechanism of mediating TMZ resistance, but emerging roles for the DNA strand-break repair pathway have been demonstrated. In the first part of this review article, we briefly review the significant role of MGMT, MMR, and the BER pathway in the tolerance to TMZ; in the last part, we review the recent publications that demonstrate possible roles of DNA strand-break repair pathways, such as single-strand break repair and double-strand break repair, as well as the Fanconi anemia pathway in the repair process after alkylating agent-based therapy. It is possible that all of these repair pathways have a potential to modulate the sensitivity to TMZ and aid in overcoming the therapeutic resistance in the clinic.

Subcortical brain alterations in major depressive disorder : findings from the ENIGMA Major Depressive Disorder working group

NARCIS (Netherlands)

Schmaal, L.; Veltman, D. J.; van Erp, T. G. M.; Saemann, P. G.; Frodl, T.; Jahanshad, N.; Loehrer, E.; Tiemeier, H.; Hofman, A.; Niessen, W. J.; Vernooij, M. W.; Ikram, M. A.; Wittfeld, K.; Grabe, H. J.; Block, A.; Hegenscheid, K.; Voelzke, H.; Hoehn, D.; Czisch, M.; Lagopoulos, J.; Hatton, S. N.; Hickie, I. B.; Goya-Maldonado, R.; Kraemer, B.; Gruber, O.; Couvy-Duchesne, B.; Renteria, M. E.; Strike, L. T.; Mills, N. T.; de Zubicaray, G. I.; McMahon, K. L.; Medland, S. E.; Martin, N. G.; Gillespie, N. A.; Wright, M. J.; Hall, G.B.; MacQueen, G. M.; Frey, E. M.; Carballedo, A.; van Velzen, L. S.; van Tol, M. J.; van der Wee, N. J.; Veer, I. M.; Walter, H.; Schnell, K.; Schramm, E.; Normann, C.; Schoepf, D.; Konrad, C.; Penninx, B. W. J. H.

The pattern of structural brain alterations associated with major depressive disorder (MDD) remains unresolved. This is in part due to small sample sizes of neuroimaging studies resulting in limited statistical power, disease heterogeneity and the complex interactions between clinical

Histone Deacetylase Inhibitors Antagonize Distinct Pathways to Suppress Tumorigenesis of Embryonal Rhabdomyosarcoma.

Directory of Open Access Journals (Sweden)

Terra Vleeshouwer-Neumann

Full Text Available Embryonal rhabdomyosarcoma (ERMS is the most common soft tissue cancer in children. The prognosis of patients with relapsed or metastatic disease remains poor. ERMS genomes show few recurrent mutations, suggesting that other molecular mechanisms such as epigenetic regulation might play a major role in driving ERMS tumor biology. In this study, we have demonstrated the diverse roles of histone deacetylases (HDACs in the pathogenesis of ERMS by characterizing effects of HDAC inhibitors, trichostatin A (TSA and suberoylanilide hydroxamic acid (SAHA; also known as vorinostat in vitro and in vivo. TSA and SAHA suppress ERMS tumor growth and progression by inducing myogenic differentiation as well as reducing the self-renewal and migratory capacity of ERMS cells. Differential expression profiling and pathway analysis revealed downregulation of key oncogenic pathways upon HDAC inhibitor treatment. By gain-of-function, loss-of-function, and chromatin immunoprecipitation (ChIP studies, we show that Notch1- and EphrinB1-mediated pathways are regulated by HDACs to inhibit differentiation and enhance migratory capacity of ERMS cells, respectively. Our study demonstrates that aberrant HDAC activity plays a major role in ERMS pathogenesis. Druggable targets in the molecular pathways affected by HDAC inhibitors represent novel therapeutic options for ERMS patients.

Pathways to Retirement and Mortality Risk in The Netherlands

NARCIS (Netherlands)

Kalwij, Adriaan; Alessie, Rob; Knoef, Marike

The success of policies aimed at keeping older workers in employment until the statutory retirement age in part depends on the health of these workers. For this reason we examine to what extent pathways to statutory retirement other than employment are associated with adverse health conditions as

Sesquiterpene dimmer (DSF-27) inhibits the release of neuroinflammatory mediators from microglia by targeting spleen tyrosine kinase (Syk) and Janus kinase 2 (Jak2): Two major non-receptor tyrosine signaling proteins involved in inflammatory events

Energy Technology Data Exchange (ETDEWEB)

Zeng, Ke-Wu [State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191 (China); Wang, Shu [State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191 (China); Department of Medicinal Chemistry and Pharmaceutical Analysis, Logistics College of Chinese People' s Armed Police Forces, Tianjin 300162 (China); Dong, Xin; Jiang, Yong; Jin, Hong-Wei [State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191 (China); Tu, Peng-Fei, E-mail: pengfeitu@vip.163.com [State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191 (China)

2014-03-15

Non-receptor protein tyrosine kinases (NRPTKs)-dependent inflammatory signal transduction cascades play key roles in immunoregulation. However, drug intervention through NRPTKs-involved immunoregulation mechanism in microglia (the major immune cells of the central nervous system) has not been widely investigated. A main aim of the present study is to elucidate the contribution of two major NRPTKs (Syk and Jak2) in neuroinflammation suppression by a bioactive sesquiterpene dimmer (DSF-27). We found that LPS-stimulated BV-2 cells activated Syk and further initiated Akt/NF-κB inflammatory pathway. This Syk-dependent Akt/NF-κB inflammatory pathway can be effectively ameliorated by DSF-27. Moreover, Jak2 was activated by LPS, which was followed by transcriptional factor Stat3 activation. The Jak2/Stat3 signal was suppressed by DSF-27 through inhibition of Jak2 and Stat3 phosphorylation, promotion of Jak/Stat3 inhibitory factors PIAS3 expression, and down-regulation of ERK and p38 MAPK phosphorylation. Furthermore, DSF-27 protected cortical and mesencephalic dopaminergic neurons against neuroinflammatory injury. Taken together, our findings indicate NRPTK signaling pathways including Syk/NF-κB and Jak2/Stat3 cascades are potential anti-neuroinflammatory targets in microglia, and may also set the basis for the use of sesquiterpene dimmer as a therapeutic approach for neuroinflammation via interruption of these pathways. - Highlights: • Sesquiterpene dimmer DSF-27 inhibits inflammatory mediators' production in microglia. • Syk-dependent Akt/NF-κB pathway is important for DSF-27's anti-inflammation activity. • Jak2/Stat3 pathway is important for DSF-27's anti-inflammation activity. • Jak2/Stat3 signaling pathway is partly regulated by ERK and p38 MAPKs and PIAS3. • DSF-27 protects neurons against microglia-mediated neuroinflammatory injury.

Signal Transduction Pathways that Regulate CAB Gene Expression

Energy Technology Data Exchange (ETDEWEB)

Chory, Joanne

2004-12-31

The process of chloroplast differentiation, involves the coordinate regulation of many nuclear and chloroplast genes. The cues for the initiation of this developmental program are both extrinsic (e.g., light) and intrinsic (cell-type and plastid signals). During this project period, we utilized a molecular genetic approach to select for Arabidopsis mutants that did not respond properly to environmental light conditions, as well as mutants that were unable to perceive plastid damage. These latter mutants, called gun mutants, define two retrograde signaling pathways that regulate nuclear gene expression in response to chloroplasts. A major finding was to identify a signal from chloroplasts that regulates nuclear gene transcription. This signal is the build-up of Mg-Protoporphyrin IX, a key intermediate of the chlorophyll biosynthetic pathway. The signaling pathways downstream of this signal are currently being studied. Completion of this project has provided an increased understanding of the input signals and retrograde signaling pathways that control nuclear gene expression in response to the functional state of chloroplasts. These studies should ultimately influence our abilities to manipulate plant growth and development, and will aid in the understanding of the developmental control of photosynthesis.

Signal Transduction Pathways that Regulate CAB Gene Expression

Energy Technology Data Exchange (ETDEWEB)

Chory, Joanne

2006-01-16

The process of chloroplast differentiation, involves the coordinate regulation of many nuclear and chloroplast genes. The cues for the initiation of this developmental program are both extrinsic (e.g., light) and intrinsic (cell-type and plastid signals). During this project period, we utilized a molecular genetic approach to select for Arabidopsis mutants that did not respond properly to environmental light conditions, as well as mutants that were unable to perceive plastid damage. These latter mutants, called gun mutants, define two retrograde signaling pathways that regulate nuclear gene expression in response to chloroplasts. A major finding was to identify a signal from chloroplasts that regulates nuclear gene transcription. This signal is the build-up of Mg-Protoporphyrin IX, a key intermediate of the chlorophyll biosynthetic pathway. The signaling pathways downstream of this signal are currently being studied. Completion of this project has provided an increased understanding of the input signals and retrograde signaling pathways that control nuclear gene expression in response to the functional state of chloroplasts. These studies should ultimately influence our abilities to manipulate plant growth and development, and will aid in the understanding of the developmental control of photosynthesis.

Deciphering chemotaxis pathways using cross species comparisons

Directory of Open Access Journals (Sweden)

Armitage Judith P

2010-01-01

chemotaxis pathways, with grouping of che genes into operons likely to be a major factor in keeping signalling pathways distinct. Gene order is highly conserved with cheA-cheW and cheR-cheB blocks, perhaps reflecting functional linkage. CheY behaves differently to other Che proteins, both in its genomic location and its putative protein interactions, which should be considered when modelling chemotaxis pathways.

Differential bioaccumulation of "1"3"4Cs in tropical marine organisms and the relative importance of exposure pathways

International Nuclear Information System (INIS)

Metian, Marc; Pouil, Simon; Hédouin, Laetitia; Oberhänsli, François; Teyssié, Jean-Louis; Bustamante, Paco; Warnau, Michel

2016-01-01

located on the hard parts of the bivalves and shrimp, with the exception of G. pectinatum, where Cs was mainly distributed in the soft-parts. - Highlights: • Tropical marine species accumulate "1"3"4Cs similarly to species from temperate regions. • Absorption efficiencies of "1"3"4Cs in tropical marine species are relatively higher than species from temperate regions. • Food is generally the major uptake pathway of Cs in the tropical oysters clam and shrimp. • Interspecific differences exist for Cs accumulation capacities of tropical bivalves but are limited between studied oysters.

Genes encoding enzymes of the lignin biosynthesis pathway in Eucalyptus

Directory of Open Access Journals (Sweden)

Ricardo Harakava

2005-01-01

Full Text Available Eucalyptus ESTs libraries were screened for genes involved in lignin biosynthesis. This search was performed under the perspective of recent revisions on the monolignols biosynthetic pathway. Eucalyptus orthologues of all genes of the phenylpropanoid pathway leading to lignin biosynthesis reported in other plant species were identified. A library made with mRNAs extracted from wood was enriched for genes involved in lignin biosynthesis and allowed to infer the isoforms of each gene family that play a major role in wood lignin formation. Analysis of the wood library suggests that, besides the enzymes of the phenylpropanoids pathway, chitinases, laccases, and dirigent proteins are also important for lignification. Colocalization of several enzymes on the endoplasmic reticulum membrane, as predicted by amino acid sequence analysis, supports the existence of metabolic channeling in the phenylpropanoid pathway. This study establishes a framework for future investigations on gene expression level, protein expression and enzymatic assays, sequence polymorphisms, and genetic engineering.

The economic implications of a multimodal analgesic regimen for patients undergoing major orthopedic surgery: a comparative study of direct costs.

Science.gov (United States)

Duncan, Christopher M; Hall Long, Kirsten; Warner, David O; Hebl, James R

2009-01-01

Total knee and total hip arthoplasty (THA) are 2 of the most common surgical procedures performed in the United States and represent the greatest single Medicare procedural expenditure. This study was designed to evaluate the economic impact of implementing a multimodal analgesic regimen (Total Joint Regional Anesthesia [TJRA] Clinical Pathway) on the estimated direct medical costs of patients undergoing lower extremity joint replacement surgery. An economic cost comparison was performed on Mayo Clinic patients (n = 100) undergoing traditional total knee or total hip arthroplasty using the TJRA Clinical Pathway. Study patients were matched 1:1 with historical controls undergoing similar procedures using traditional anesthetic (non-TJRA) techniques. Matching criteria included age, sex, surgeon, type of procedure, and American Society of Anesthesiologists (ASA) physical status (PS) classification. Hospital-based direct costs were collected for each patient and analyzed in standardized inflation-adjusted constant dollars using cost-to-charge ratios, wage indexes, and physician services valued using Medicare reimbursement rates. The estimated mean direct hospital costs were compared between groups, and a subgroup analysis was performed based on ASA PS classification. The estimated mean direct hospital costs were significantly reduced among TJRA patients when compared with controls (cost difference, 1999 dollars; 95% confidence interval, 584-3231 dollars; P = 0.0004). A significant reduction in hospital-based (Medicare Part A) costs accounted for the majority of the total cost savings. Use of a comprehensive, multimodal analgesic regimen (TJRA Clinical Pathway) in patients undergoing lower extremity joint replacement surgery provides a significant reduction in the estimated total direct medical costs. The reduction in mean cost is primarily associated with lower hospital-based (Medicare Part A) costs, with the greatest overall cost difference appearing among patients

Construction of large signaling pathways using an adaptive perturbation approach with phosphoproteomic data.

Science.gov (United States)

Melas, Ioannis N; Mitsos, Alexander; Messinis, Dimitris E; Weiss, Thomas S; Rodriguez, Julio-Saez; Alexopoulos, Leonidas G

2012-04-01

Construction of large and cell-specific signaling pathways is essential to understand information processing under normal and pathological conditions. On this front, gene-based approaches offer the advantage of large pathway exploration whereas phosphoproteomic approaches offer a more reliable view of pathway activities but are applicable to small pathway sizes. In this paper, we demonstrate an experimentally adaptive approach to construct large signaling pathways from phosphoproteomic data within a 3-day time frame. Our approach--taking advantage of the fast turnaround time of the xMAP technology--is carried out in four steps: (i) screen optimal pathway inducers, (ii) select the responsive ones, (iii) combine them in a combinatorial fashion to construct a phosphoproteomic dataset, and (iv) optimize a reduced generic pathway via an Integer Linear Programming formulation. As a case study, we uncover novel players and their corresponding pathways in primary human hepatocytes by interrogating the signal transduction downstream of 81 receptors of interest and constructing a detailed model for the responsive part of the network comprising 177 species (of which 14 are measured) and 365 interactions.

Investigating multiple dysregulated pathways in rheumatoid arthritis based on pathway interaction network.

Science.gov (United States)

Song, Xian-Dong; Song, Xian-Xu; Liu, Gui-Bo; Ren, Chun-Hui; Sun, Yuan-Bo; Liu, Ke-Xin; Liu, Bo; Liang, Shuang; Zhu, Zhu

2018-03-01

The traditional methods of identifying biomarkers in rheumatoid arthritis (RA) have focussed on the differentially expressed pathways or individual pathways, which however, neglect the interactions between pathways. To better understand the pathogenesis of RA, we aimed to identify dysregulated pathway sets using a pathway interaction network (PIN), which considered interactions among pathways. Firstly, RA-related gene expression profile data, protein-protein interactions (PPI) data and pathway data were taken up from the corresponding databases. Secondly, principal component analysis method was used to calculate the pathway activity of each of the pathway, and then a seed pathway was identified using data gleaned from the pathway activity. A PIN was then constructed based on the gene expression profile, pathway data, and PPI information. Finally, the dysregulated pathways were extracted from the PIN based on the seed pathway using the method of support vector machines and an area under the curve (AUC) index. The PIN comprised of a total of 854 pathways and 1064 pathway interactions. The greatest change in the activity score between RA and control samples was observed in the pathway of epigenetic regulation of gene expression, which was extracted and regarded as the seed pathway. Starting with this seed pathway, one maximum pathway set containing 10 dysregulated pathways was extracted from the PIN, having an AUC of 0.8249, and the result indicated that this pathway set could distinguish RA from the controls. These 10 dysregulated pathways might be potential biomarkers for RA diagnosis and treatment in the future.

About miRNAs, miRNA seeds, target genes and target pathways.

Science.gov (United States)

Kehl, Tim; Backes, Christina; Kern, Fabian; Fehlmann, Tobias; Ludwig, Nicole; Meese, Eckart; Lenhof, Hans-Peter; Keller, Andreas

2017-12-05

miRNAs are typically repressing gene expression by binding to the 3' UTR, leading to degradation of the mRNA. This process is dominated by the eight-base seed region of the miRNA. Further, miRNAs are known not only to target genes but also to target significant parts of pathways. A logical line of thoughts is: miRNAs with similar (seed) sequence target similar sets of genes and thus similar sets of pathways. By calculating similarity scores for all 3.25 million pairs of 2,550 human miRNAs, we found that this pattern frequently holds, while we also observed exceptions. Respective results were obtained for both, predicted target genes as well as experimentally validated targets. We note that miRNAs target gene set similarity follows a bimodal distribution, pointing at a set of 282 miRNAs that seems to target genes with very high specificity. Further, we discuss miRNAs with different (seed) sequences that nonetheless regulate similar gene sets or pathways. Most intriguingly, we found miRNA pairs that regulate different gene sets but similar pathways such as miR-6886-5p and miR-3529-5p. These are jointly targeting different parts of the MAPK signaling cascade. The main goal of this study is to provide a general overview on the results, to highlight a selection of relevant results on miRNAs, miRNA seeds, target genes and target pathways and to raise awareness for artifacts in respective comparisons. The full set of information that allows to infer detailed results on each miRNA has been included in miRPathDB, the miRNA target pathway database (https://mpd.bioinf.uni-sb.de).

Integrated pathway clusters with coherent biological themes for target prioritisation.

Directory of Open Access Journals (Sweden)

Yi-An Chen

Full Text Available Prioritising candidate genes for further experimental characterisation is an essential, yet challenging task in biomedical research. One way of achieving this goal is to identify specific biological themes that are enriched within the gene set of interest to obtain insights into the biological phenomena under study. Biological pathway data have been particularly useful in identifying functional associations of genes and/or gene sets. However, biological pathway information as compiled in varied repositories often differs in scope and content, preventing a more effective and comprehensive characterisation of gene sets. Here we describe a new approach to constructing biologically coherent gene sets from pathway data in major public repositories and employing them for functional analysis of large gene sets. We first revealed significant overlaps in gene content between different pathways and then defined a clustering method based on the shared gene content and the similarity of gene overlap patterns. We established the biological relevance of the constructed pathway clusters using independent quantitative measures and we finally demonstrated the effectiveness of the constructed pathway clusters in comparative functional enrichment analysis of gene sets associated with diverse human diseases gathered from the literature. The pathway clusters and gene mappings have been integrated into the TargetMine data warehouse and are likely to provide a concise, manageable and biologically relevant means of functional analysis of gene sets and to facilitate candidate gene prioritisation.

Eliciting maize defense pathways aboveground attracts belowground biocontrol agents.

Science.gov (United States)

Filgueiras, Camila Cramer; Willett, Denis S; Pereira, Ramom Vasconcelos; Moino Junior, Alcides; Pareja, Martin; Duncan, Larry W

2016-11-04

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 of plant defense pathways on the interactions between corn, the aboveground herbivore adult Diabrotica speciosa, the belowground herbivore larval D. speciosa, and the subterranean ento-mopathogenic nematode natural enemy Heterorhabditis amazonensis. We show that adult D. speciosa recruit to aboveground herbivory and methyl salicylate treatment, that larval D. speciosa are relatively indiscriminate, and that H. amazonensis en-tomopathogenic nematodes recruit to corn fed upon by adult D. speciosa. These results suggest that entomopathogenicnematodes belowground can be highly attuned to changes in the aboveground parts of plants and that biological control can be enhanced with induced plant defense in this and similar systems.

Eliciting maize defense pathways aboveground attracts belowground biocontrol agents

Science.gov (United States)

Filgueiras, Camila Cramer; Willett, Denis S.; Pereira, Ramom Vasconcelos; Moino Junior, Alcides; Pareja, Martin; Duncan, Larry W.

2016-01-01

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 of plant defense pathways on the interactions between corn, the aboveground herbivore adult Diabrotica speciosa, the belowground herbivore larval D. speciosa, and the subterranean ento-mopathogenic nematode natural enemy Heterorhabditis amazonensis. We show that adult D. speciosa recruit to aboveground herbivory and methyl salicylate treatment, that larval D. speciosa are relatively indiscriminate, and that H. amazonensis en-tomopathogenic nematodes recruit to corn fed upon by adult D. speciosa. These results suggest that entomopathogenicnematodes belowground can be highly attuned to changes in the aboveground parts of plants and that biological control can be enhanced with induced plant defense in this and similar systems. PMID:27811992

Red blood cell distribution width: Genetic evidence for aging pathways in 116,666 volunteers.

Directory of Open Access Journals (Sweden)

Luke C Pilling

Full Text Available Variability in red blood cell volumes (distribution width, RDW increases with age and is strongly predictive of mortality, incident coronary heart disease and cancer. We investigated inherited genetic variation associated with RDW in 116,666 UK Biobank human volunteers.A large proportion RDW is explained by genetic variants (29%, especially in the older group (60+ year olds, 33.8%, <50 year olds, 28.4%. RDW was associated with 194 independent genetic signals; 71 are known for conditions including autoimmune disease, certain cancers, BMI, Alzheimer's disease, longevity, age at menopause, bone density, myositis, Parkinson's disease, and age-related macular degeneration. Exclusion of anemic participants did not affect the overall findings. Pathways analysis showed enrichment for telomere maintenance, ribosomal RNA, and apoptosis. The majority of RDW-associated signals were intronic (119 of 194, including SNP rs6602909 located in an intron of oncogene GAS6, an eQTL in whole blood.Although increased RDW is predictive of cardiovascular outcomes, this was not explained by known CVD or related lipid genetic risks, and a RDW genetic score was not predictive of incident disease. The predictive value of RDW for a range of negative health outcomes may in part be due to variants influencing fundamental pathways of aging.

PathScore: a web tool for identifying altered pathways in cancer data.

Science.gov (United States)

Gaffney, Stephen G; Townsend, Jeffrey P

2016-12-01

PathScore quantifies the level of enrichment of somatic mutations within curated pathways, applying a novel approach that identifies pathways enriched across patients. The application provides several user-friendly, interactive graphic interfaces for data exploration, including tools for comparing pathway effect sizes, significance, gene-set overlap and enrichment differences between projects. Web application available at pathscore.publichealth.yale.edu. Site implemented in Python and MySQL, with all major browsers supported. Source code available at: github.com/sggaffney/pathscore with a GPLv3 license. stephen.gaffney@yale.edu. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

A genomic pathway approach to a complex disease: axon guidance and Parkinson disease.

Directory of Open Access Journals (Sweden)

Timothy G Lesnick

2007-06-01

Full Text Available While major inroads have been made in identifying the genetic causes of rare Mendelian disorders, little progress has been made in the discovery of common gene variations that predispose to complex diseases. The single gene variants that have been shown to associate reproducibly with complex diseases typically have small effect sizes or attributable risks. However, the joint actions of common gene variants within pathways may play a major role in predisposing to complex diseases (the paradigm of complex genetics. The goal of this study was to determine whether polymorphism in a candidate pathway (axon guidance predisposed to a complex disease (Parkinson disease [PD]. We mined a whole-genome association dataset and identified single nucleotide polymorphisms (SNPs that were within axon-guidance pathway genes. We then constructed models of axon-guidance pathway SNPs that predicted three outcomes: PD susceptibility (odds ratio = 90.8, p = 4.64 x 10(-38, survival free of PD (hazards ratio = 19.0, p = 5.43 x 10(-48, and PD age at onset (R(2 = 0.68, p = 1.68 x 10(-51. By contrast, models constructed from thousands of random selections of genomic SNPs predicted the three PD outcomes poorly. Mining of a second whole-genome association dataset and mining of an expression profiling dataset also supported a role for many axon-guidance pathway genes in PD. These findings could have important implications regarding the pathogenesis of PD. This genomic pathway approach may also offer insights into other complex diseases such as Alzheimer disease, diabetes mellitus, nicotine and alcohol dependence, and several cancers.

Vitamin C degradation products and pathways in the human lens.

Science.gov (United States)

Nemet, Ina; Monnier, Vincent M

2011-10-28

Vitamin C and its degradation products participate in chemical modifications of proteins in vivo through non-enzymatic glycation (Maillard reaction) and formation of different products called advanced glycation end products. Vitamin C levels are particularly high in selected tissues, such as lens, brain and adrenal gland, and its degradation products can inflict substantial protein damage via formation of advanced glycation end products. However, the pathways of in vivo vitamin C degradation are poorly understood. Here we have determined the levels of vitamin C oxidation and degradation products dehydroascorbic acid, 2,3-diketogulonic acid, 3-deoxythreosone, xylosone, and threosone in the human lens using o-phenylenediamine to trap both free and protein-bound adducts. In the protein-free fraction and water-soluble proteins (WSP), all five listed degradation products were identified. Dehydroascorbic acid, 2,3-diketogulonic acid, and 3-deoxythreosone were the major products in the protein-free fraction, whereas in the WSP, 3-deoxythreosone was the most abundant measured dicarbonyl. In addition, 3-deoxythreosone in WSP showed positive linear correlation with age (p degradation product bound to human lens proteins provides in vivo evidence for the non-oxidative pathway of dehydroascorbate degradation into erythrulose as a major pathway for vitamin C degradation in vivo.

Ecosystem services for meeting sustainable development goals: Challenges and pathways

Directory of Open Access Journals (Sweden)

Huq Nazmul

2015-01-01

Full Text Available The paper summarizes four presentations of the session “Environment and Wellbeing: The Role of Ecosystems for Sustainable Development” at the international conference “Sustainability in the Water- Energy-Food Nexus” held on 19-20th May 2014 in Bonn, Germany. The aim of the session was to present current stresses on ecosystem services imposed by global development trajectory, potential impacts on Sustainable Development Goals (SDGs and pathways to achieve SDGs. All four presentations agreed that global ecosystem services are under increasing pressure from degradation and may not be able to meet the growing Water-Energy- Food (WEF demands especially for the developing world. Three examples from Tanzania, Cambodia and Niger made attempt to understand how governance policies attributed to natural resource depletion such as forestry and common grazing. The examples showed that governance policies favoring economic development are heavily contributing to clearing up natural resource bases. As a result, there were increasing conflicts among different resource user groups. Two other presentations introduce conceptual pathways to achieve the targets of Sustainable Development Goals (SDGs under current resource stressed regime. The pathways suggested global technologies, decentralized solutions and consumption changes as the major means of achieving global sustainability and poverty eradication without any major trade-offs.

Ecosystem services for meeting sustainable development goals: Challenges and pathways

Directory of Open Access Journals (Sweden)

Huq Nazmul

2015-01-01

Full Text Available The paper summarizes four presentations of the session “Environment and Wellbeing: The Role of Ecosystems for Sustainable Development” at the international conference “Sustainability in the Water- Energy-Food Nexus” held on 19-20th May 2014 in Bonn, Germany. The aim of the session was to present current stresses on ecosystem services imposed by global development trajectory, potential impacts on future Sustainable Development Goals (SDGs and pathways to achieve SDGs. All four presentations agreed that global ecosystem services are under increasing pressure from degradation and may not be able to meet the growing Water-Energy-Food (WEF demands especially for the developing world. Three examples from Tanzania, Cambodia and Niger made attempt to understand how government policies attributed to natural resource depletion such as forestry and common grazing. The examples showed that institutional policies favoring economic development contributing heavily to clearing up natural resource bases. As a result, there were increasing conflicts among different resource user groups. Two other presentations introduce conceptual pathways to achieve the targets of Sustainable Development Goals (SDGs under current resource stressed regime. The pathways suggested global technologies, decentralized solutions and consumption changes as the major means of achieving global sustainability and poverty eradication without any major trade-offs.

Latina Community College Leadership in California: Pathways to Executive Management

Science.gov (United States)

Delgadillo, Monica D.

2017-01-01

Purpose: The purpose of this qualitative study was to examine the learned experiences, challenges, and leadership pathways of Latinas currently in California community college management positions. Latinas have been underrepresented in community college leadership positions. Currently, women constitute a majority of those attending college, and…

Long-term athletic development- part 1: a pathway for all youth.

Science.gov (United States)

Lloyd, Rhodri S; Oliver, Jon L; Faigenbaum, Avery D; Howard, Rick; De Ste Croix, Mark B A; Williams, Craig A; Best, Thomas M; Alvar, Brent A; Micheli, Lyle J; Thomas, D Phillip; Hatfield, Disa L; Cronin, John B; Myer, Gregory D

2015-05-01

The concept of developing talent and athleticism in youth is the goal of many coaches and sports systems. Consequently, an increasing number of sporting organizations have adopted long-term athletic development models in an attempt to provide a structured approach to the training of youth. It is clear that maximizing sporting talent is an important goal of long-term athletic development models. However, ensuring that youth of all ages and abilities are provided with a strategic plan for the development of their health and physical fitness is also important to maximize physical activity participation rates, reduce the risk of sport- and activity-related injury, and to ensure long-term health and well-being. Critical reviews of independent models of long-term athletic development are already present within the literature; however, to the best of our knowledge, a comprehensive examination and review of the most prominent models does not exist. Additionally, considerations of modern day issues that may impact on the success of any long-term athletic development model are lacking, as are proposed solutions to address such issues. Therefore, within this 2-part commentary, Part 1 provides a critical review of existing models of practice for long-term athletic development and introduces a composite youth development model that includes the integration of talent, psychosocial and physical development across maturation. Part 2 identifies limiting factors that may restrict the success of such models and offers potential solutions.

Regulation and function of the cGAS-STING pathway of cytosolic DNA sensing.

Science.gov (United States)

Chen, Qi; Sun, Lijun; Chen, Zhijian J

2016-09-20

The recognition of microbial nucleic acids is a major mechanism by which the immune system detects pathogens. Cyclic GMP-AMP (cGAMP) synthase (cGAS) is a cytosolic DNA sensor that activates innate immune responses through production of the second messenger cGAMP, which activates the adaptor STING. The cGAS-STING pathway not only mediates protective immune defense against infection by a large variety of DNA-containing pathogens but also detects tumor-derived DNA and generates intrinsic antitumor immunity. However, aberrant activation of the cGAS pathway by self DNA can also lead to autoimmune and inflammatory disease. Thus, the cGAS pathway must be properly regulated. Here we review the recent advances in understanding of the cGAS-STING pathway, focusing on the regulatory mechanisms and roles of this pathway in heath and disease.

The hippo pathway in heart development, regeneration, and diseases.

Science.gov (United States)

Zhou, Qi; Li, Li; Zhao, Bin; Guan, Kun-Liang

2015-04-10

The heart is the first organ formed during mammalian development. A properly sized and functional heart is vital throughout the entire lifespan. Loss of cardiomyocytes because of injury or diseases leads to heart failure, which is a major cause of human morbidity and mortality. Unfortunately, regenerative potential of the adult heart is limited. The Hippo pathway is a recently identified signaling cascade that plays an evolutionarily conserved role in organ size control by inhibiting cell proliferation, promoting apoptosis, regulating fates of stem/progenitor cells, and in some circumstances, limiting cell size. Interestingly, research indicates a key role of this pathway in regulation of cardiomyocyte proliferation and heart size. Inactivation of the Hippo pathway or activation of its downstream effector, the Yes-associated protein transcription coactivator, improves cardiac regeneration. Several known upstream signals of the Hippo pathway such as mechanical stress, G-protein-coupled receptor signaling, and oxidative stress are known to play critical roles in cardiac physiology. In addition, Yes-associated protein has been shown to regulate cardiomyocyte fate through multiple transcriptional mechanisms. In this review, we summarize and discuss current findings on the roles and mechanisms of the Hippo pathway in heart development, injury, and regeneration. © 2015 American Heart Association, Inc.

Integrating nitric oxide into salicylic acid and jasmonic acid/ethylene plant defense pathways

DEFF Research Database (Denmark)

Mur, Luis A J; Prats, Elena; Pierre, Sandra

2013-01-01

to be tailored to particular biotic stresses. Nitric oxide (NO) has emerged as a major signal influencing resistance mediated by both signalling pathways but no attempt has been made to integrate NO into established SA/JA/ET interactions. NO has been shown to act as an inducer or suppressor of signalling along......Plant defence against pests and pathogens is known to be conferred by either salicylic acid (SA) or jasmonic acid (JA)/ethylene (ET) pathways, depending on infection or herbivore-grazing strategy. It is well attested that SA and JA/ET pathways are mutually antagonistic allowing defence responses...

Anthropogenic materials and products containing natural radionuclides. Pt. 1. Survey of the major exposure pathways

International Nuclear Information System (INIS)

Becker, D.E.; Reichelt, A.

1991-06-01

Knowledge of the possible exposure pathways permits to perform an overall assessment of the radiation doses and qualities affecting the population, as well as their inter-relations: A catalogue was established of products, raw materials and waste materials containing natural radioactivity that are processed, produced or dumped in Bavaria and that contribute above negligible level to the radiation exposure of the population and to occupational radiation doses. A literature study rounds up the information on anthropogenic sources containing natural radioactivity and thus representing a radiation source generally to be considered for assessments. Some of these sources are discussed in more detail, indicating their radiological significance for the population and the environment in Bavaria. (Orig./DG) [de

Dual career pathways of transnational athletes

DEFF Research Database (Denmark)

Ryba, T. V.; Stambulova, N. B.; Ronkainen, Noora J.

2015-01-01

Objectives: Transnationalism, as part of the globalization processes, has transformed the lifestyle and the course of athletes' careers. This presents previously unexplored challenges encountered by student-athletes in combining athletic and academic pursuits. In this article, we propose a concep......Objectives: Transnationalism, as part of the globalization processes, has transformed the lifestyle and the course of athletes' careers. This presents previously unexplored challenges encountered by student-athletes in combining athletic and academic pursuits. In this article, we propose...... patterns of transnational DC were discerned from the narratives based on the direction of geographic mobility and the core migration motive underpinning the storyline. Within the present dataset, the taxonomies are: (1) Within EU mobility: the sport exile DC pathway; (2) Mobility to the U.S.A.: the sport...

Pathway analysis for identification of potential biomarkers in severe ...

African Journals Online (AJOL)

It was found by geneMANIA database search that majority of these genes were coexpressed yielding 84.63 % co-expression. It was found that ten genes were in Physical interactions comprising almost 14.33 %. There were < 1 % pathway and genetic interactions with values of 0.97 and 0.06 %, respectively. Final analyses ...

A novel dysregulated pathway-identification analysis based on global influence of within-pathway effects and crosstalk between pathways

Science.gov (United States)

Han, Junwei; Li, Chunquan; Yang, Haixiu; Xu, Yanjun; Zhang, Chunlong; Ma, Jiquan; Shi, Xinrui; Liu, Wei; Shang, Desi; Yao, Qianlan; Zhang, Yunpeng; Su, Fei; Feng, Li; Li, Xia

2015-01-01

Identifying dysregulated pathways from high-throughput experimental data in order to infer underlying biological insights is an important task. Current pathway-identification methods focus on single pathways in isolation; however, consideration of crosstalk between pathways could improve our understanding of alterations in biological states. We propose a novel method of pathway analysis based on global influence (PAGI) to identify dysregulated pathways, by considering both within-pathway effects and crosstalk between pathways. We constructed a global gene–gene network based on the relationships among genes extracted from a pathway database. We then evaluated the extent of differential expression for each gene, and mapped them to the global network. The random walk with restart algorithm was used to calculate the extent of genes affected by global influence. Finally, we used cumulative distribution functions to determine the significance values of the dysregulated pathways. We applied the PAGI method to five cancer microarray datasets, and compared our results with gene set enrichment analysis and five other methods. Based on these analyses, we demonstrated that PAGI can effectively identify dysregulated pathways associated with cancer, with strong reproducibility and robustness. We implemented PAGI using the freely available R-based and Web-based tools (http://bioinfo.hrbmu.edu.cn/PAGI). PMID:25551156

Normal mode-guided transition pathway generation in proteins.

Directory of Open Access Journals (Sweden)

Byung Ho Lee

Full Text Available The biological function of proteins is closely related to its structural motion. For instance, structurally misfolded proteins do not function properly. Although we are able to experimentally obtain structural information on proteins, it is still challenging to capture their dynamics, such as transition processes. Therefore, we need a simulation method to predict the transition pathways of a protein in order to understand and study large functional deformations. Here, we present a new simulation method called normal mode-guided elastic network interpolation (NGENI that performs normal modes analysis iteratively to predict transition pathways of proteins. To be more specific, NGENI obtains displacement vectors that determine intermediate structures by interpolating the distance between two end-point conformations, similar to a morphing method called elastic network interpolation. However, the displacement vector is regarded as a linear combination of the normal mode vectors of each intermediate structure, in order to enhance the physical sense of the proposed pathways. As a result, we can generate more reasonable transition pathways geometrically and thermodynamically. By using not only all normal modes, but also in part using only the lowest normal modes, NGENI can still generate reasonable pathways for large deformations in proteins. This study shows that global protein transitions are dominated by collective motion, which means that a few lowest normal modes play an important role in this process. NGENI has considerable merit in terms of computational cost because it is possible to generate transition pathways by partial degrees of freedom, while conventional methods are not capable of this.

Doses in various parts of the biosphere due to long-lived radionuclides originating from deep geological repositories

International Nuclear Information System (INIS)

Bergstroem, U.; Karlsson, Sara; Nordlinder, S.

1999-01-01

Turnover of radionuclides and resulting doses to man were modelled for various parts of the biosphere. This was made for different scenarios of leakage of radionuclides from a deep geological repository for spent nuclear fuel and other waste. In previous studies, the emphasis was on doses from contaminated ground water represented by a well or various surface waters. This was because radionuclides were assumed to be released directly to surface water, the use of which subsequently formed the major pathway for radionuclides to agricultural areas. In the present study, radionuclides were considered to reach lakes, running waters, coastal areas, agricultural areas and peat areas. The inflow of radionuclides to agricultural areas was supposed to be from below. Doses due to direct use of contaminated ground water from a well were also considered. Altogether 44 radionuclides contained in the waste were assumed to be released during 10,000 years, with a rate of 1 Bq/year of each radionuclide, to each of the above mentioned biospheric parts. During that time, the biospheric conditions were assumed to be the same as they are today. Doses to the critical group were calculated by exposure pathways specific for each entry-point All calculations were performed with estimation of confidence due to time-dependent parameter variation and uncertainty in input values. The results indicate that drinking water from wells is not a critical exposure pathway for all studied radionuclides. Instead, inflow of contaminated water to soil and peat bogs may be crucial for illustration of doses for geological high-level waste disposal. Improved knowledge of processes at the geosphere-biosphere interface is therefore important

Major and minor axis kinematics of 22 ellipticals

International Nuclear Information System (INIS)

Franx, M.; Illingworth, G.; Heckman, T.

1989-01-01

Rotation curves and velocity dispersion profiles have been determined for the major and the minor axes of 22 elliptical galaxies. Rotation was detected in all but one galaxy, even though the sample was biased toward round ellipticals. Minor axis rotation larger than major axis rotation was measured in two galaxies, NGC 4406 and NGC 7507. Roughly 10 percent of ellipticals may show large minor axis velocities relative to those on the major axis. A simple model is used to derive a rotational axis from the observed minor and major axis velocities to a typical accuracy of 6 deg. The rotational and photometric minor axes aligned to better than 10 deg for 60 percent of the sample, implying that the direction of the angular momentum is related to the orientation of the figure of the galaxy. IC 1459 has a kinematically distinct core with its angular momentum opposite to the angular momentum of the outer parts, and NGC 4406 has a core with its angular momentum perpendicular to that of the outer parts. 46 refs

The relationships between mothers' work pathways and physical and mental health.

Science.gov (United States)

Frech, Adrianne; Damaske, Sarah

2012-01-01

We contribute to research on the relationships between gender, work, and health by using longitudinal, theoretically driven models of mothers' diverse work pathways and adjusting for unequal selection into these pathways. Using the National Longitudinal Study of Youth-1979 (N = 2,540), we find full-time, continuous employment following a first birth is associated with significantly better health at age 40 than part-time work, paid work interrupted by unemployment, and unpaid work in the home. Part-time workers with little unemployment report significantly better health at age 40 than mothers experiencing persistent unemployment. These relationships remain after accounting for the unequal selection of more advantaged mothers into full-time, continuous employment, suggesting full-time workers benefit from cumulating advantages across the life course and reiterating the need to disentangle health benefits associated with work from those associated with pre-pregnancy characteristics.

The Relationships between Mothers’ Work Pathways and Physical and Mental Health*

Science.gov (United States)

Frech, Adrianne; Damaske, Sarah

2014-01-01

We contribute to research on the relationships between gender, work and health by using longitudinal, theoretically driven models of mothers’ diverse work pathways and adjusting for unequal selection into these pathways. Using the NLSY79 (N=2,540), we find full-time, continuous employment following a first birth is associated with significantly better health at age forty than part-time work, paid work interrupted by unemployment, and unpaid work in the home. Part-time workers with little unemployment report significantly better health at age forty than mothers experiencing persistent unemployment. These relationships remain after accounting for the unequal selection of more advantaged mothers into full-time, continuous employment, suggesting full-time workers benefit from cumulating advantages across the life course and reiterating the need to disentangle health benefits associated with work from those associated with pre-pregnancy characteristics. PMID:23197483

B cell receptor pathway in chronic lymphocytic leukemia: specific role of CC-292

Directory of Open Access Journals (Sweden)

Arnason JE

2014-01-01

Full Text Available Jon E Arnason,1 Jennifer R Brown21Beth Israel Deaconess Medical Center, 2CLL Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USAAbstract: Chronic lymphocytic leukemia (CLL is the most common adult leukemia. The current treatment paradigm involves the use of chemoimmunotherapy, when patients develop an indication for therapy. With this strategy, a majority of patients will obtain a remission, though cure remains elusive. While treatable, the majority of CLL patients will die of complications of their disease. Recent advances in the understanding of the importance of the B cell receptor (BCR pathway in CLL have led to the development of a number of agents targeting this pathway. In this review, we discuss recent developments in the targeting of the BCR pathway, with a focus on CC-292. CC-292 covalently binds to Bruton's tyrosine kinase, a key mediator of BCR signaling, and has demonstrated preclinical and clinical activity in CLL, with acceptable tolerability. Based on the success of CC-292 and other inhibitors of the BCR pathway, these agents are being investigated in combination with standard therapy, with the hope that they will increase the depth and length of response, without significant toxicity.Keywords: Bruton's tyrosine kinase inhibitor, ibrutinib

Elite Destinations: Pathways to Attending an Ivy League University

Science.gov (United States)

Mullen, Ann L.

2009-01-01

As higher education expands and becomes more differentiated, patterns of class stratification remain deeply entrenched, in part due to class-based differences in college choice. A qualitative study of 50 Yale students shows the effects of social class, high schools and peers on students' pathways to college. For students from wealthy and highly…

Linking proteins to signaling pathways for experiment design and evaluation.

Directory of Open Access Journals (Sweden)

Illés J Farkas

Full Text Available Biomedical experimental work often focuses on altering the functions of selected proteins. These changes can hit signaling pathways, and can therefore unexpectedly and non-specifically affect cellular processes. We propose PathwayLinker, an online tool that can provide a first estimate of the possible signaling effects of such changes, e.g., drug or microRNA treatments. PathwayLinker minimizes the users' efforts by integrating protein-protein interaction and signaling pathway data from several sources with statistical significance tests and clear visualization. We demonstrate through three case studies that the developed tool can point out unexpected signaling bias in normal laboratory experiments and identify likely novel signaling proteins among the interactors of known drug targets. In our first case study we show that knockdown of the Caenorhabditis elegans gene cdc-25.1 (meant to avoid progeny may globally affect the signaling system and unexpectedly bias experiments. In the second case study we evaluate the loss-of-function phenotypes of a less known C. elegans gene to predict its function. In the third case study we analyze GJA1, an anti-cancer drug target protein in human, and predict for this protein novel signaling pathway memberships, which may be sources of side effects. Compared to similar services, a major advantage of PathwayLinker is that it drastically reduces the necessary amount of manual literature searches and can be used without a computational background. PathwayLinker is available at http://PathwayLinker.org. Detailed documentation and source code are available at the website.

Testing pathways linking exposure to community violence and sexual behaviors among African American youth.

Science.gov (United States)

Voisin, Dexter R; Hotton, Anna L; Neilands, Torsten B

2014-09-01

Exposure to community violence and HIV sexual risks are two major public health concerns among youth. This study tests various pathways linking exposure to community violence and sexual behaviors among African American adolescents. Using a sample of 563 (61% females) African American youth attending high school we examined whether problematic psychological symptoms, low school engagement, and/or negative perceptions of peer norms about safer sex functioned as pathways linking exposure to community violence and sexual behaviors. Major findings indicated that, for boys, the relationship between exposure to community violence and sexual début and sexual risk behaviors were linked by aggression. In addition, the relationship between exposure to community violence and sexual risk behaviors were linked by negative perceptions of peer attitudes about safer sex. For girls, the relationship between exposure to community violence and sexual début was linked by aggression and negative perceptions of peer attitudes about safer sex. These findings provide support for pathways linking exposure to community violence to sexual behaviors.

Molecular pathways and therapeutic targets in lung cancer

Science.gov (United States)

Shtivelman, Emma; Hensing, Thomas; Simon, George R.; Dennis, Phillip A.; Otterson, Gregory A.; Bueno, Raphael; Salgia, Ravi

2014-01-01

Lung cancer is still the leading cause of cancer death worldwide. Both histologically and molecularly lung cancer is heterogeneous. This review summarizes the current knowledge of the pathways involved in the various types of lung cancer with an emphasis on the clinical implications of the increasing number of actionable molecular targets. It describes the major pathways and molecular alterations implicated in the development and progression of non-small cell lung cancer (adenocarcinoma and squamous cancer), and of small cell carcinoma, emphasizing the molecular alterations comprising the specific blueprints in each group. The approved and investigational targeted therapies as well as the immune therapies, and clinical trials exploring the variety of targeted approaches to treatment of lung cancer are the main focus of this review. PMID:24722523

Neopositivism and the DSM psychiatric classification. An epistemological history. Part 2: Historical pathways, epistemological developments and present-day needs.

Science.gov (United States)

Aragona, Massimiliano

2013-12-01

Little is known about the concrete historical sources for the use of neopositivist operational criteria by the DSM-III. This paper suggests that distinct sources operated implicitly. The current usefulness of the operational approach is questioned. It is shown that: (a) in epistemology, neopositivism has been replaced by more adequate accounts; (b) psychologists rejected operational definitions because these were unable to define the majority of mental phenomena; (c) mental symptoms cannot be directly described as such, because they already make part of the psychiatric diagnosis to which they belong. In conclusion, diagnosing is based on the hermeneutical co-construction of mental symptoms. The failure of the neopositivist programme suggests that it is time to reconcile scientific formalization and semiotic activity.

Pathway analyses implicate glial cells in schizophrenia.

Directory of Open Access Journals (Sweden)

Laramie E Duncan

Full Text Available The quest to understand the neurobiology of schizophrenia and bipolar disorder is ongoing with multiple lines of evidence indicating abnormalities of glia, mitochondria, and glutamate in both disorders. Despite high heritability estimates of 81% for schizophrenia and 75% for bipolar disorder, compelling links between findings from neurobiological studies, and findings from large-scale genetic analyses, are only beginning to emerge.Ten publically available gene sets (pathways related to glia, mitochondria, and glutamate were tested for association to schizophrenia and bipolar disorder using MAGENTA as the primary analysis method. To determine the robustness of associations, secondary analyses were performed with: ALIGATOR, INRICH, and Set Screen. Data from the Psychiatric Genomics Consortium (PGC were used for all analyses. There were 1,068,286 SNP-level p-values for schizophrenia (9,394 cases/12,462 controls, and 2,088,878 SNP-level p-values for bipolar disorder (7,481 cases/9,250 controls.The Glia-Oligodendrocyte pathway was associated with schizophrenia, after correction for multiple tests, according to primary analysis (MAGENTA p = 0.0005, 75% requirement for individual gene significance and also achieved nominal levels of significance with INRICH (p = 0.0057 and ALIGATOR (p = 0.022. For bipolar disorder, Set Screen yielded nominally and method-wide significant associations to all three glial pathways, with strongest association to the Glia-Astrocyte pathway (p = 0.002.Consistent with findings of white matter abnormalities in schizophrenia by other methods of study, the Glia-Oligodendrocyte pathway was associated with schizophrenia in our genomic study. These findings suggest that the abnormalities of myelination observed in schizophrenia are at least in part due to inherited factors, contrasted with the alternative of purely environmental causes (e.g. medication effects or lifestyle. While not the primary purpose of our study

FindPath: a Matlab solution for in silico design of synthetic metabolic pathways.

Science.gov (United States)

Vieira, Gilles; Carnicer, Marc; Portais, Jean-Charles; Heux, Stéphanie

2014-10-15

Several methods and computational tools have been developed to design novel metabolic pathways. A major challenge is evaluating the metabolic efficiency of the designed pathways in the host organism. Here we present FindPath, a unified system to predict and rank possible pathways according to their metabolic efficiency in the cellular system. This tool uses a chemical reaction database to generate possible metabolic pathways and exploits constraint-based models (CBMs) to identify the most efficient synthetic pathway to achieve the desired metabolic function in a given host microorganism. FindPath can be used with common tools for CBM manipulation and uses the standard SBML format for both input and output files. http://metasys.insa-toulouse.fr/software/findpath/. heux@insa-toulouse.fr Supplementary data are available at Bioinformatics online. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Graph-representation of oxidative folding pathways

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Kaján László

2005-01-01

Full Text Available Abstract Background The process of oxidative folding combines the formation of native disulfide bond with conformational folding resulting in the native three-dimensional fold. Oxidative folding pathways can be described in terms of disulfide intermediate species (DIS which can also be isolated and characterized. Each DIS corresponds to a family of folding states (conformations that the given DIS can adopt in three dimensions. Results The oxidative folding space can be represented as a network of DIS states interconnected by disulfide interchange reactions that can either create/abolish or rearrange disulfide bridges. We propose a simple 3D representation wherein the states having the same number of disulfide bridges are placed on separate planes. In this representation, the shuffling transitions are within the planes, and the redox edges connect adjacent planes. In a number of experimentally studied cases (bovine pancreatic trypsin inhibitor, insulin-like growth factor and epidermal growth factor, the observed intermediates appear as part of contiguous oxidative folding pathways. Conclusions Such networks can be used to visualize folding pathways in terms of the experimentally observed intermediates. A simple visualization template written for the Tulip package http://www.tulip-software.org/ can be obtained from V.A.

Responses of Synechocystis sp. PCC 6803 to heterologous biosynthetic pathways

DEFF Research Database (Denmark)

Vavitsas, Konstantinos; Rue, Emil Østergaard; Stefánsdóttir, Lára Kristín

2017-01-01

BACKGROUND: There are an increasing number of studies regarding genetic manipulation of cyanobacteria to produce commercially interesting compounds. The majority of these works study the expression and optimization of a selected heterologous pathway, largely ignoring the wholeness and complexity...... different compounds, the cyanogenic glucoside dhurrin and the diterpenoid 13R-manoyl oxide in Synechocystis PCC 6803. We used genome-scale metabolic modelling to study fluxes in individual reactions and pathways, and we determined the concentrations of key metabolites, such as amino acids, carotenoids...

Interaction of Adverse Disease Related Pathways in Hypertrophic Cardiomyopathy.

Science.gov (United States)

Rowin, Ethan J; Maron, Martin S; Chan, Raymond H; Hausvater, Anais; Wang, Wendy; Rastegar, Hassan; Maron, Barry J

2017-12-15

Hypertrophic cardiomyopathy (HC) has been characterized as a generally progressive genetic heart disease, creating an ominous perspective for patients and managing cardiologists. We explored the HC disease burden and interaction of adverse clinical pathways to clarify patient expectations over long time periods in the contemporary therapeutic era. We studied 1,000 consecutive HC patients (52 ± 17 years) at Tufts Medical Center, followed 9.3 ± 8 years from diagnosis, employing a novel disease pathway model: 46% experienced a benign course free of adverse pathways, but 42% of patients progressed along 1 major pathway, most commonly refractory heart failure to New York Heart Association class III or IV requiring surgical myectomy (or alcohol ablation) or heart transplant; repetitive or permanent atrial fibrillation; and least commonly arrhythmic sudden death events. Eleven percent experienced 2 of these therapeutic end points at different times in their clinical course, most frequently the combination of advanced heart failure and atrial fibrillation, whereas only 1% incurred all 3 pathways. Freedom of progression from 1 to 2 disease pathways, or from 2 to 3 was 80% and 93% at 5 years, respectively. Annual HC-related mortality did not differ according to the number of pathways: 1 (0.8%), 2 (0.8%), or 3 (2.4%) (p = 0.56), and 93% of patients were in New York Heart Association classes I or II at follow-up. In conclusion, it is uncommon for HC patients to experience multiple adverse (but treatable) disease pathways, underscoring the principle that HC is not a uniformly progressive disease. These observations provide a measure of clarity and/or reassurance to patients regarding the true long-term disease burden of HC. Copyright © 2017 Elsevier Inc. All rights reserved.

Identifying alternate pathways for climate change to impact inland recreational fishers

Science.gov (United States)

Hunt, Len M.; Fenichel, Eli P.; Fulton, David C.; Mendelsohn, Robert; Smith, Jordan W.; Tunney, Tyler D.; Lynch, Abigail J.; Paukert, Craig P.; Whitney, James E.

2016-01-01

Fisheries and human dimensions literature suggests that climate change influences inland recreational fishers in North America through three major pathways. The most widely recognized pathway suggests that climate change impacts habitat and fish populations (e.g., water temperature impacting fish survival) and cascades to impact fishers. Climate change also impacts recreational fishers by influencing environmental conditions that directly affect fishers (e.g., increased temperatures in northern climates resulting in extended open water fishing seasons and increased fishing effort). The final pathway occurs from climate change mitigation and adaptation efforts (e.g., refined energy policies result in higher fuel costs, making distant trips more expensive). To address limitations of past research (e.g., assessing climate change impacts for only one pathway at a time and not accounting for climate variability, extreme weather events, or heterogeneity among fishers), we encourage researchers to refocus their efforts to understand and document climate change impacts to inland fishers.

BAD-mediated apoptotic pathway is associated with human cancer development.

Science.gov (United States)

Stickles, Xiaomang B; Marchion, Douglas C; Bicaku, Elona; Al Sawah, Entidhar; Abbasi, Forough; Xiong, Yin; Bou Zgheib, Nadim; Boac, Bernadette M; Orr, Brian C; Judson, Patricia L; Berry, Amy; Hakam, Ardeshir; Wenham, Robert M; Apte, Sachin M; Berglund, Anders E; Lancaster, Johnathan M

2015-04-01

The malignant transformation of normal cells is caused in part by aberrant gene expression disrupting the regulation of cell proliferation, apoptosis, senescence and DNA repair. Evidence suggests that the Bcl-2 antagonist of cell death (BAD)-mediated apoptotic pathway influences cancer chemoresistance. In the present study, we explored the role of the BAD-mediated apoptotic pathway in the development and progression of cancer. Using principal component analysis to derive a numeric score representing pathway expression, we evaluated clinico-genomic datasets (n=427) from corresponding normal, pre-invasive and invasive cancers of different types, such as ovarian, endometrial, breast and colon cancers in order to determine the associations between the BAD-mediated apoptotic pathway and cancer development. Immunofluorescence was used to compare the expression levels of phosphorylated BAD [pBAD (serine-112, -136 and -155)] in immortalized normal and invasive ovarian, colon and breast cancer cells. The expression of the BAD-mediated apoptotic pathway phosphatase, PP2C, was evaluated by RT-qPCR in the normal and ovarian cancer tissue samples. The growth-promoting effects of pBAD protein levels in the immortalized normal and cancer cells were assessed using siRNA depletion experiments with MTS assays. The expression of the BAD-mediated apoptotic pathway was associated with the development and/or progression of ovarian (n=106, pBAD-mediated apoptotic pathway is thus associated with the development of human cancers likely influenced by the protein levels of pBAD.

Endocytic Pathways Used by Andes Virus to Enter Primary Human Lung Endothelial Cells.

Directory of Open Access Journals (Sweden)

Cheng-Feng Chiang

Full Text Available Andes virus (ANDV is the major cause of hantavirus pulmonary syndrome (HPS in South America. Despite a high fatality rate (up to 40%, no vaccines or antiviral therapies are approved to treat ANDV infection. To understand the role of endocytic pathways in ANDV infection, we used 3 complementary approaches to identify cellular factors required for ANDV entry into human lung microvascular endothelial cells. We screened an siRNA library targeting 140 genes involved in membrane trafficking, and identified 55 genes required for ANDV infection. These genes control the major endocytic pathways, endosomal transport, cell signaling, and cytoskeleton rearrangement. We then used infectious ANDV and retroviral pseudovirions to further characterize the possible involvement of 9 of these genes in the early steps of ANDV entry. In addition, we used markers of cellular endocytosis along with chemical inhibitors of known endocytic pathways to show that ANDV uses multiple routes of entry to infect target cells. These entry mechanisms are mainly clathrin-, dynamin-, and cholesterol-dependent, but can also occur via a clathrin-independent manner.

Part-time Jobs : What Women Want?

NARCIS (Netherlands)

Booth, A.L.; van Ours, J.C.

2010-01-01

Part-time jobs are popular among partnered women in many countries. In the Netherlands the majority of partnered working women have a part-time job. Our paper investigates, from a supply-side perspective, if the current situation of abundant part-time work in the Netherlands is likely to be a

Cost-effectiveness analysis of a postoperative clinical care pathway in head and neck surgery with microvascular reconstruction

OpenAIRE

Dautremont, Jonathan F; Rudmik, Luke R; Yeung, Justin; Asante, Tiffany; Nakoneshny, Steve C; Hoy, Monica; Lui, Amanda; Chandarana, Shamir P; Matthews, Thomas W; Schrag, Christiaan; Dort, Joseph C

2013-01-01

Background The objective of this study is to evaluate the cost-effectiveness of a postoperative clinical care pathway for patients undergoing major head and neck oncologic surgery with microvascular reconstruction. Methods This is a comparative trial of a prospective treatment group managed on a postoperative clinical care pathway and a historical group managed prior to pathway implementation. Effectiveness outcomes evaluated were total hospital days, return to OR, readmission to ICU and rate...

Understanding Resolvin Signaling Pathways to Improve Oral Health

Directory of Open Access Journals (Sweden)

Laura De Oleo

2013-03-01

Full Text Available The discovery of resolvins has been a major breakthrough for understanding the processes involved in resolution of inflammation. Resolvins belong to a family of novel lipid mediators that possess dual anti-inflammatory and pro-resolution actions. Specifically, they protect healthy tissue during immune-inflammatory responses to infection or injury, thereby aiding inflammation resolution and promoting tissue healing. One of the major concerns in modern medicine is the management and treatment of oral diseases, as they are related to systemic outcomes impacting the quality of life of many patients. This review summarizes known signaling pathways utilized by resolvins to regulate inflammatory responses associated with the oral cavity.

DMPD: Regulatory pathways in inflammation. [Dynamic Macrophage Pathway CSML Database

Lifescience Database Archive (English)

Full Text Available 17967718 Regulatory pathways in inflammation. Mantovani A, Garlanda C, Locati M, Ro....html) (.csml) Show Regulatory pathways in inflammation. PubmedID 17967718 Title Regulatory pathways in infl

Characterization of new mutants in the early part of the yeast secretory pathway isolated by a [3H]mannose suicide selection

International Nuclear Information System (INIS)

Newman, A.P.; Ferro-Novick, S.

1987-01-01

We have adapted a [ 3 H]mannose suicide selection to identify mutations in additional genes which function in the early part of the yeast secretory pathway. Thus far this protocol has led to the identification of two new genes which are implicated in this process, as well as additional alleles of previously identified genes. The new mutants, bet1 and bet2, are temperature sensitive for growth and protein transport. Thin section analysis has revealed the accumulation of a network of endoplasmic reticulum (ER) at the restrictive temperature (37 0 C). Precursors of exported proteins that accumulate in the cell at 37 0 C are terminally core glycosylated. These observations suggest that the transport of precursors is blocked subsequent to translocation into the ER but before entry into the Golgi apparatus. The bet1 and bet2 mutants define two new complementation groups which have the same properties as previously identified ER-accumulating mutants. This and previous findings suggest that protein exit from the ER and entry into the Golgi apparatus is a complex process requiring at least 11 genes

Impacts of Four SO2 Oxidation Pathways on Wintertime Sulfate Concentrations

Science.gov (United States)

Sarwar, G.; Fahey, K.; Zhang, Y.; Kang, D.; Mathur, R.; Xing, J.; Wei, C.; Cheng, Y.

2017-12-01

Air quality models tend to under-estimate winter-time sulfate concentrations compared to observed data. Such under-estimations are particularly acute in China where very high concentrations of sulfate have been measured. Sulfate is produced by oxidation of sulfur dioxide (SO2) in gas-phase by hydroxyl radical and in aqueous-phase by hydrogen peroxide, ozone, etc. and most air quality models employ such typical reactions. Several additional SO2 oxidation pathways have recently been proposed. Heterogeneous reaction on dust has been suggested to be an important sink for SO2. Oxidation of SO2 on fine particles in presence of nitrogen dioxide (NO2) and ammonia (NH3) at high relative humidity has been implicated for sulfate formation in Chinese haze and London fog. Reactive nitrogen chemistry in aerosol water has also been suggested to produce winter-time sulfate in China. Specifically, high aerosol water can trap SO2 which can be subsequently oxidized by NO2 to form sulfate. Aqueous-phase (in-cloud) oxidation of SO2 by NO2 can also produce sulfate. Here, we use the hemispheric Community Multiscale Air Quality (CMAQ) modeling system to examine the potential impacts of these SO2 oxidation pathways on sulfate formation. We use anthropogenic emissions from the Emissions Database for Global Atmospheric Research and biogenic emissions from Global Emissions InitiAtive. We performed simulations without and with these SO2 oxidation pathways for October-December of 2014 using meteorological fields obtained from the Weather Research and Forecasting model. The standard CMAQ model contains one gas-phase chemical reaction and five aqueous-phase chemical reactions for SO2 oxidation. We implement four additional SO2 oxidation pathways into the CMAQ model. Our preliminary results suggest that the dust chemistry enhances mean sulfate over parts of China and Middle-East, the in-cloud SO2 oxidation by NO2 enhances sulfate over parts of western Europe, oxidation of SO2 by NO2 and NH3 on

C-Jun N-terminal kinase signalling pathway in response to cisplatin.

Science.gov (United States)

Yan, Dong; An, GuangYu; Kuo, Macus Tien

2016-11-01

Cisplatin (cis diamminedichloroplatinum II, cDDP) is one of the most effective cancer chemotherapeutic agents and is used in the treatment of many types of human malignancies. However, inherent tumour resistance is a major barrier to effective cisplatin therapy. So far, the mechanism of cDDP resistance has not been well defined. In general, cisplatin is considered to be a cytotoxic drug, for damaging DNA and inhibiting DNA synthesis, resulting in apoptosis via the mitochondrial death pathway or plasma membrane disruption. cDDP-induced DNA damage triggers signalling pathways that will eventually decide between cell life and death. As a member of the mitogen-activated protein kinases family, c-Jun N-terminal kinase (JNK) is a signalling pathway in response to extracellular stimuli, especially drug treatment, to modify the activity of numerous proteins locating in the mitochondria or the nucleus. Recent studies suggest that JNK signalling pathway plays a major role in deciding the fate of the cell and inducing resistance to cDDP-induced apoptosis in human tumours. c-Jun N-terminal kinase regulates several important cellular functions including cell proliferation, differentiation, survival and apoptosis while activating and inhibiting substrates for phosphorylation transcription factors (c-Jun, ATF2: Activating transcription factor 2, p53 and so on), which subsequently induce pro-apoptosis and pro-survival factors expression. Therefore, it is suggested that JNK signal pathway is a double-edged sword in cDDP treatment, simultaneously being a significant pro-apoptosis factor but also being associated with increased resistance to cisplatin-based chemotherapy. This review focuses on current knowledge concerning the role of JNK in cell response to cDDP, as well as their role in cisplatin resistance. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

The shared role of oxidative stress and inflammation in major depressive disorder and nicotine dependence.

Science.gov (United States)

Nunes, Sandra Odebrecht Vargas; Vargas, Heber Odebrecht; Prado, Eduardo; Barbosa, Decio Sabbatini; de Melo, Luiz Picoli; Moylan, Steven; Dodd, Seetal; Berk, Michael

2013-09-01

Nicotine dependence is common in people with mood disorders; however the operative pathways are not well understood. This paper reviews the contribution of inflammation and oxidative stress pathways to the co-association of depressive disorder and nicotine dependence, including increased levels of pro-inflammatory cytokines, increased acute phase proteins, decreased levels of antioxidants and increased oxidative stress. These could be some of the potential pathophysiological mechanisms involved in neuroprogression. The shared inflammatory and oxidative stress pathways by which smoking may increase the risk for development of depressive disorders are in part mediated by increased levels of pro-inflammatory cytokines, diverse neurotransmitter systems, activation the hypothalamic-pituitary-adrenal (HPA) axis, microglial activation, increased production of oxidative stress and decreased levels of antioxidants. Depressive disorder and nicotine dependence are additionally linked imbalance between neuroprotective and neurodegenerative metabolites in the kynurenine pathway that contribute to neuroprogression. These pathways provide a mechanistic framework for understanding the interaction between nicotine dependence and depressive disorder. Copyright © 2013. Published by Elsevier Ltd.

Alcohol resistance in Drosophila is modulated by the Toll innate immune pathway.

Science.gov (United States)

Troutwine, B R; Ghezzi, A; Pietrzykowski, A Z; Atkinson, N S

2016-04-01

A growing body of evidence has shown that alcohol alters the activity of the innate immune system and that changes in innate immune system activity can influence alcohol-related behaviors. Here, we show that the Toll innate immune signaling pathway modulates the level of alcohol resistance in Drosophila. In humans, a low level of response to alcohol is correlated with increased risk of developing an alcohol use disorder. The Toll signaling pathway was originally discovered in, and has been extensively studied in Drosophila. The Toll pathway is a major regulator of innate immunity in Drosophila, and mammalian Toll-like receptor signaling has been implicated in alcohol responses. Here, we use Drosophila-specific genetic tools to test eight genes in the Toll signaling pathway for effects on the level of response to ethanol. We show that increasing the activity of the pathway increases ethanol resistance whereas decreasing the pathway activity reduces ethanol resistance. Furthermore, we show that gene products known to be outputs of innate immune signaling are rapidly induced following ethanol exposure. The interaction between the Toll signaling pathway and ethanol is rooted in the natural history of Drosophila melanogaster. © 2016 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

Applying meta-pathway analyses through metagenomics to identify the functional properties of the major bacterial communities of a single spontaneous cocoa bean fermentation process sample.

Science.gov (United States)

Illeghems, Koen; Weckx, Stefan; De Vuyst, Luc

2015-09-01

A high-resolution functional metagenomic analysis of a representative single sample of a Brazilian spontaneous cocoa bean fermentation process was carried out to gain insight into its bacterial community functioning. By reconstruction of microbial meta-pathways based on metagenomic data, the current knowledge about the metabolic capabilities of bacterial members involved in the cocoa bean fermentation ecosystem was extended. Functional meta-pathway analysis revealed the distribution of the metabolic pathways between the bacterial members involved. The metabolic capabilities of the lactic acid bacteria present were most associated with the heterolactic fermentation and citrate assimilation pathways. The role of Enterobacteriaceae in the conversion of substrates was shown through the use of the mixed-acid fermentation and methylglyoxal detoxification pathways. Furthermore, several other potential functional roles for Enterobacteriaceae were indicated, such as pectinolysis and citrate assimilation. Concerning acetic acid bacteria, metabolic pathways were partially reconstructed, in particular those related to responses toward stress, explaining their metabolic activities during cocoa bean fermentation processes. Further, the in-depth metagenomic analysis unveiled functionalities involved in bacterial competitiveness, such as the occurrence of CRISPRs and potential bacteriocin production. Finally, comparative analysis of the metagenomic data with bacterial genomes of cocoa bean fermentation isolates revealed the applicability of the selected strains as functional starter cultures. Copyright © 2015 Elsevier Ltd. All rights reserved.

Policy Pathways: Monitoring, Verification and Enforcement

Energy Technology Data Exchange (ETDEWEB)

NONE

2010-07-01

The IEA estimates that, if implemented globally without delay, the 25 IEA Energy Efficiency recommendations could save 8.2 Gt CO2 per year by 2030. Yet many governments struggle with their implementation and thus miss a great part of the energy efficiency potential. The new IEA series Policy Pathways: Showing the way to energy efficiency implementation now aims to assist countries with improving energy efficiency policies. It features practical 'how-to' guides for designing, implementing and evaluating energy efficiency policies and achieving greater improvement.

Policy Pathways: Monitoring, Verification and Enforcement

Energy Technology Data Exchange (ETDEWEB)

NONE

2010-07-01

The IEA estimates that, if implemented globally without delay, the 25 IEA Energy Efficiency recommendations could save 8.2 Gt CO2 per year by 2030. Yet many governments struggle with their implementation and thus miss a great part of the energy efficiency potential. The new IEA series Policy Pathways: Showing the way to energy efficiency implementation now aims to assist countries with improving energy efficiency policies. It features practical 'how-to' guides for designing, implementing and evaluating energy efficiency policies and achieving greater improvement.

Examining the intersection between splicing, nuclear export and small RNA pathways.

Science.gov (United States)

Nabih, Amena; Sobotka, Julia A; Wu, Monica Z; Wedeles, Christopher J; Claycomb, Julie M

2017-11-01

Nuclear Argonaute/small RNA pathways in a variety of eukaryotic species are generally known to regulate gene expression via chromatin modulation and transcription attenuation in a process known as transcriptional gene silencing (TGS). However, recent data, including genetic screens, phylogenetic profiling, and molecular mechanistic studies, also point to a novel and emerging intersection between the splicing and nuclear export machinery with nuclear Argonaute/small RNA pathways in many organisms. In this review, we summarize the field's current understanding regarding the relationship between splicing, export and small RNA pathways, and consider the biological implications for coordinated regulation of transcripts by these pathways. We also address the importance and available approaches for understanding the RNA regulatory logic generated by the intersection of these particular pathways in the context of synthetic biology. The interactions between various eukaryotic RNA regulatory pathways, particularly splicing, nuclear export and small RNA pathways provide a type of combinatorial code that informs the identity ("self" versus "non-self") and dictates the fate of each transcript in a cell. Although the molecular mechanisms for how splicing and nuclear export impact small RNA pathways are not entirely clear at this early stage, the links between these pathways are widespread across eukaryotic phyla. The link between splicing, nuclear export, and small RNA pathways is emerging and establishes a new frontier for understanding the combinatorial logic of gene regulation across species that could someday be harnessed for therapeutic, biotechnology and agricultural applications. This article is part of a Special Issue entitled "Biochemistry of Synthetic Biology - Recent Developments" Guest Editor: Dr. Ilka Heinemann and Dr. Patrick O'Donoghue. Copyright © 2017 Elsevier B.V. All rights reserved.

NemaPath: online exploration of KEGG-based metabolic pathways for nematodes

Directory of Open Access Journals (Sweden)

Wang Zhengyuan

2008-11-01

Full Text Available Abstract Background Nematode.net http://www.nematode.net is a web-accessible resource for investigating gene sequences from parasitic and free-living nematode genomes. Beyond the well-characterized model nematode C. elegans, over 500,000 expressed sequence tags (ESTs and nearly 600,000 genome survey sequences (GSSs have been generated from 36 nematode species as part of the Parasitic Nematode Genomics Program undertaken by the Genome Center at Washington University School of Medicine. However, these sequencing data are not present in most publicly available protein databases, which only include sequences in Swiss-Prot. Swiss-Prot, in turn, relies on GenBank/Embl/DDJP for predicted proteins from complete genomes or full-length proteins. Description Here we present the NemaPath pathway server, a web-based pathway-level visualization tool for navigating putative metabolic pathways for over 30 nematode species, including 27 parasites. The NemaPath approach consists of two parts: 1 a backend tool to align and evaluate nematode genomic sequences (curated EST contigs against the annotated Kyoto Encyclopedia of Genes and Genomes (KEGG protein database; 2 a web viewing application that displays annotated KEGG pathway maps based on desired confidence levels of primary sequence similarity as defined by a user. NemaPath also provides cross-referenced access to nematode genome information provided by other tools available on Nematode.net, including: detailed NemaGene EST cluster information; putative translations; GBrowse EST cluster views; links from nematode data to external databases for corresponding synonymous C. elegans counterparts, subject matches in KEGG's gene database, and also KEGG Ontology (KO identification. Conclusion The NemaPath server hosts metabolic pathway mappings for 30 nematode species and is available on the World Wide Web at http://nematode.net/cgi-bin/keggview.cgi. The nematode source sequences used for the metabolic pathway

BAG3: a multifaceted protein that regulates major cell pathways

Science.gov (United States)

Rosati, A; Graziano, V; De Laurenzi, V; Pascale, M; Turco, M C

2011-01-01

Bcl2-associated athanogene 3 (BAG3) protein is a member of BAG family of co-chaperones that interacts with the ATPase domain of the heat shock protein (Hsp) 70 through BAG domain (110–124 amino acids). BAG3 is the only member of the family to be induced by stressful stimuli, mainly through the activity of heat shock factor 1 on bag3 gene promoter. In addition to the BAG domain, BAG3 contains also a WW domain and a proline-rich (PXXP) repeat, that mediate binding to partners different from Hsp70. These multifaceted interactions underlie BAG3 ability to modulate major biological processes, that is, apoptosis, development, cytoskeleton organization and autophagy, thereby mediating cell adaptive responses to stressful stimuli. In normal cells, BAG3 is constitutively present in a very few cell types, including cardiomyocytes and skeletal muscle cells, in which the protein appears to contribute to cell resistance to mechanical stress. A growing body of evidence indicate that BAG3 is instead expressed in several tumor types. In different tumor contexts, BAG3 protein was reported to sustain cell survival, resistance to therapy, and/or motility and metastatization. In some tumor types, down-modulation of BAG3 levels was shown, as a proof-of-principle, to inhibit neoplastic cell growth in animal models. This review attempts to outline the emerging mechanisms that can underlie some of the biological activities of the protein, focusing on implications in tumor progression. PMID:21472004

The cGAS/STING Pathway Detects Streptococcus pneumoniae but Appears Dispensable for Antipneumococcal Defense in Mice and Humans.

Science.gov (United States)

Ruiz-Moreno, Juan Sebastian; Hamann, Lutz; Jin, Lei; Sander, Leif E; Puzianowska-Kuznicka, Monika; Cambier, John; Witzenrath, Martin; Schumann, Ralf R; Suttorp, Norbert; Opitz, Bastian

2018-03-01

Streptococcus pneumoniae is a frequent colonizer of the upper respiratory tract and a leading cause of bacterial pneumonia. The innate immune system senses pneumococcal cell wall components, toxin, and nucleic acids, which leads to production of inflammatory mediators to initiate and control antibacterial defense. Here, we show that the cGAS (cyclic GMP-AMP [cGAMP] synthase)-STING pathway mediates detection of pneumococcal DNA in mouse macrophages to primarily stimulate type I interferon (IFN) responses. Cells of human individuals carrying HAQ TMEM173 , which encodes a common hypomorphic variant of STING, were largely or partly defective in inducing type I IFNs and proinflammatory cytokines upon infection. Subsequent analyses, however, revealed that STING was dispensable for restricting S. pneumoniae during acute pneumonia in mice. Moreover, explorative analyses did not find differences in the allele frequency of HAQ TMEM173 in nonvaccinated pneumococcal pneumonia patients and healthy controls or an association of HAQ TMEM173 carriage with disease severity. Together, our results indicate that the cGAS/STING pathway senses S. pneumoniae but plays no major role in antipneumococcal immunity in mice and humans. Copyright © 2018 American Society for Microbiology.

Distributions and natural levels of related metals in a trophic pathway

International Nuclear Information System (INIS)

Lemons, J.D.

1976-06-01

The first objective was to test the hypothesis that metal distributions and trends in organisms are, in part, a function of metal positions in the periodic table in unpolluted ecosystems. The data have shown that large soil crustal abundance differences of related elements (e.g. alkali metals) are proportionately approximated in higher organisms. Concentration factors for related nutritious and nonessential and toxic metals were determined along a trophic pathway. When the concentration factors were reported as the concentration of a particular metal by itself, all metal concentrations increased along the trophic pathway. The second objective of this study was to test the hypothesis that distributions and natural levels of chemically related nonessential and toxic metals can better be known when the metals are reported as a ratio, in ash, of the nonessential or toxic metal to its chemically related nutritious metal (e.g. strontium/calcium) as the metals are transferred through trophic pathways. The data have shown that when this method of reporting metal abundances in trophic levels is used, nonessential and toxic metals are discriminated against, relative to their chemically related nutritious metal, as the metals are transferred through the trophic pathway levels. The third objective was designed to test the hypothesis that surface deposition of toxic metals upon plants influences the trends of metal abundances through trophic pathways. This study indicates that metal pollution in the form of deposition upon plant surfaces bypasses the discrimination mechanisms in plants, and consequently elevates the total body burden in herbivores. It is likely that there is no herbivore defense for this type of metal exposure, because herbivores have probably come to rely, in part, upon the discriminatory mechanism of plants throughout the course of evolutionary history to keep toxic metal burdens low

A single point in protein trafficking by Plasmodium falciparum determines the expression of major antigens on the surface of infected erythrocytes targeted by human antibodies.

Science.gov (United States)

Chan, Jo-Anne; Howell, Katherine B; Langer, Christine; Maier, Alexander G; Hasang, Wina; Rogerson, Stephen J; Petter, Michaela; Chesson, Joanne; Stanisic, Danielle I; Duffy, Michael F; Cooke, Brian M; Siba, Peter M; Mueller, Ivo; Bull, Peter C; Marsh, Kevin; Fowkes, Freya J I; Beeson, James G

2016-11-01

Antibodies to blood-stage antigens of Plasmodium falciparum play a pivotal role in human immunity to malaria. During parasite development, multiple proteins are trafficked from the intracellular parasite to the surface of P. falciparum-infected erythrocytes (IEs). However, the relative importance of different proteins as targets of acquired antibodies, and key pathways involved in trafficking major antigens remain to be clearly defined. We quantified antibodies to surface antigens among children, adults, and pregnant women from different malaria-exposed regions. We quantified the importance of antigens as antibody targets using genetically engineered P. falciparum with modified surface antigen expression. Genetic deletion of the trafficking protein skeleton-binding protein-1 (SBP1), which is involved in trafficking the surface antigen PfEMP1, led to a dramatic reduction in antibody recognition of IEs and the ability of human antibodies to promote opsonic phagocytosis of IEs, a key mechanism of parasite clearance. The great majority of antibody epitopes on the IE surface were SBP1-dependent. This was demonstrated using parasite isolates with different genetic or phenotypic backgrounds, and among antibodies from children, adults, and pregnant women in different populations. Comparisons of antibody reactivity to parasite isolates with SBP1 deletion or inhibited PfEMP1 expression suggest that PfEMP1 is the dominant target of acquired human antibodies, and that other P. falciparum IE surface proteins are minor targets. These results establish SBP1 as part of a critical pathway for the trafficking of major surface antigens targeted by human immunity, and have key implications for vaccine development, and quantifying immunity in populations.

Interception and translocation of radionuclides in major food crops for Koreans

International Nuclear Information System (INIS)

Choi, Y. H.; Lim, K. M.; Park, H. G.; Choi, H. J.; Lee, H. S.

2002-01-01

In order to investigate the direct plant contamination pathway of 54 Mn, 57 Co, 85 Sr, 103 Ru and 134 Cs in major food crops for Koreans, rice, soybean and radish plants at different growth stages were sprayed with radioactive solutions in a greenhouse. The interception factor and the translocation factor were quantified as the fraction of the total deposition that is initially retained on the aboveground plant surface and the fraction of the total initial plant activity that is contained in the edible part at harvest, respectively. In rice and radish, interception factors increased as plants grew old to harvest. In soybean, however, rapid defoliation in old plants made interception factors decrease with increasing age during the later part of the growth. There was little difference in the interception factor among radionuclides. Translocation factors decreased in the order of 134 Cs ≥> 57 Co > 54 Mn ≥ 85 Sr > 103 Ru in general and varied with radionuclides by factors of 6-4000, depending on application time and plant species. Translocation factors for rice seeds were the highest when radionuclides were applied at the active seed growth stage and those for soybean seeds were the highest following the application at the early pod-filling stage except for 103 Ru. For radish roots, translocation factors were on the whole the highest following the early- growth-stage application. The obtained data can be used for parameter values in food-chain dose assessment models especially for Koreans and many other Asian people

Interception and translocation of radionuclides in major food crops for Koreans

Energy Technology Data Exchange (ETDEWEB)

Choi, Y. H.; Lim, K. M.; Park, H. G.; Choi, H. J.; Lee, H. S. [KAERI, Daejon (Korea, Republic of)

2002-07-01

In order to investigate the direct plant contamination pathway of {sup 54}Mn, {sup 57}Co, {sup 85}Sr, {sup 103}Ru and {sup 134}Cs in major food crops for Koreans, rice, soybean and radish plants at different growth stages were sprayed with radioactive solutions in a greenhouse. The interception factor and the translocation factor were quantified as the fraction of the total deposition that is initially retained on the aboveground plant surface and the fraction of the total initial plant activity that is contained in the edible part at harvest, respectively. In rice and radish, interception factors increased as plants grew old to harvest. In soybean, however, rapid defoliation in old plants made interception factors decrease with increasing age during the later part of the growth. There was little difference in the interception factor among radionuclides. Translocation factors decreased in the order of {sup 134}Cs {>=}> {sup 57}Co > {sup 54}Mn {>=} {sup 85}Sr >{sup 103}Ru in general and varied with radionuclides by factors of 6-4000, depending on application time and plant species. Translocation factors for rice seeds were the highest when radionuclides were applied at the active seed growth stage and those for soybean seeds were the highest following the application at the early pod-filling stage except for {sup 103}Ru. For radish roots, translocation factors were on the whole the highest following the early- growth-stage application. The obtained data can be used for parameter values in food-chain dose assessment models especially for Koreans and many other Asian people.

Ingestion Pathway Transfer Factors for Plutonium and Americium

International Nuclear Information System (INIS)

Blanchard, A.

1999-01-01

Overall transfer factors for major ingestion pathways are derived for plutonium and americium. These transfer factors relate the radionuclide concentration in a given foodstuff to deposition on the soil. Equations describing basic relationships consistent with Regulatory Guide 1.109 are followed. Updated values and coefficients from IAEA Technical Reports Series No. 364 are used when a available. Preference is given to using factors specific to the Savannah River Site

Petroleum migration pathways and charge concentration: A three-dimensional model

Energy Technology Data Exchange (ETDEWEB)

Hindle, A.D. [Anadarko Algeria Corp., Middlesex (United Kingdom)

1997-09-01

Petroleum migration pathways through a basin are determined by the three-dimensional distribution of discontinuous sealing surfaces, which are usually parallel to bedding. The petroleum migrates below the sealing surface, taking the structurally most advantageous route. The three-dimensional distribution of migration pathways within the petroleum system can be modeled on a personal computer using a program based on the parameters discussed in this paper. Application of the model to the Paris and Williston basins demonstrates that a good correlation between predicted pathways and discovered accumulations can be made using simple models. Pathways form a dense network overlying generating areas in the central parts of basins. Toward the basin margins these routes commonly become increasingly focused into discrete pathways by the sealing-surface morphologies. Eventually, these pathways may reach the surface as seepages. It is important to integrate surface outcrops of migration routes (surface seepages) into migration modeling. Deflection of the pathways from the structurally most advantageous route below the sealing surface may be caused by lateral sealing barriers due to faces variation in the carrier rock below the seal, fault juxtaposition, or cross-formational seals such as salt intrusions. Deflection of pathways also occurs where there are hydrodynamic conditions in response to topography-driven groundwater flow. Zones of vertical migration are associated with facies changes along the horizon of the sealing surface into a nonsealing facies, or juxtaposition to nonsealing strata by faults. Vertical migration from either normally or abnormally pressured strata is most likely to occur into normally or lesser pressured strata at intrabasinal highs where hydrocarbons can be stored and transferred at times of temporary seal rupture.

Signaling Pathways in Leiomyoma: Understanding Pathobiology and Implications for Therapy

Science.gov (United States)

Borahay, Mostafa A; Al-Hendy, Ayman; Kilic, Gokhan S; Boehning, Darren

2015-01-01

Uterine leiomyomas are the most common tumors of the female genital tract, affecting 50% to 70% of females by the age of 50. Despite their prevalence and enormous medical and economic impact, no effective medical treatment is currently available. This is, in part, due to the poor understanding of their underlying pathobiology. Although they are thought to start as a clonal proliferation of a single myometrial smooth muscle cell, these early cytogenetic alterations are considered insufficient for tumor development and additional complex signaling pathway alterations are crucial. These include steroids, growth factors, transforming growth factor-beta (TGF-β)/Smad; wingless-type (Wnt)/β-catenin, retinoic acid, vitamin D, and peroxisome proliferator-activated receptor γ (PPARγ). An important finding is that several of these pathways converge in a summative way. For example, mitogen-activated protein kinase (MAPK) and Akt pathways seem to act as signal integrators, incorporating input from several signaling pathways, including growth factors, estrogen and vitamin D. This underlines the multifactorial origin and complex nature of these tumors. In this review, we aim to dissect these pathways and discuss their interconnections, aberrations and role in leiomyoma pathobiology. We also aim to identify potential targets for development of novel therapeutics. PMID:25879625

15 CFR Supplement No. 7 to Part 742 - Description of Major Weapons Systems

Science.gov (United States)

2010-01-01

... Major Weapons Systems (1) Battle Tanks: Tracked or wheeled self-propelled armored fighting vehicles with...) Armored Combat Vehicles: Tracked, semi-tracked, or wheeled self-propelled vehicles, with armored..., including versions of these aircraft which perform specialized electronic warfare, suppression of air...

An Automated Pipeline for Engineering Many-Enzyme Pathways: Computational Sequence Design, Pathway Expression-Flux Mapping, and Scalable Pathway Optimization.

Science.gov (United States)

Halper, Sean M; Cetnar, Daniel P; Salis, Howard M

2018-01-01

Engineering many-enzyme metabolic pathways suffers from the design curse of dimensionality. There are an astronomical number of synonymous DNA sequence choices, though relatively few will express an evolutionary robust, maximally productive pathway without metabolic bottlenecks. To solve this challenge, we have developed an integrated, automated computational-experimental pipeline that identifies a pathway's optimal DNA sequence without high-throughput screening or many cycles of design-build-test. The first step applies our Operon Calculator algorithm to design a host-specific evolutionary robust bacterial operon sequence with maximally tunable enzyme expression levels. The second step applies our RBS Library Calculator algorithm to systematically vary enzyme expression levels with the smallest-sized library. After characterizing a small number of constructed pathway variants, measurements are supplied to our Pathway Map Calculator algorithm, which then parameterizes a kinetic metabolic model that ultimately predicts the pathway's optimal enzyme expression levels and DNA sequences. Altogether, our algorithms provide the ability to efficiently map the pathway's sequence-expression-activity space and predict DNA sequences with desired metabolic fluxes. Here, we provide a step-by-step guide to applying the Pathway Optimization Pipeline on a desired multi-enzyme pathway in a bacterial host.

Adverse Outcome Pathway Networks II: Network Analytics.

Science.gov (United States)

Villeneuve, Daniel L; Angrish, Michelle M; Fortin, Marie C; Katsiadaki, Ioanna; Leonard, Marc; Margiotta-Casaluci, Luigi; Munn, Sharon; O'Brien, Jason M; Pollesch, Nathan L; Smith, L Cody; Zhang, Xiaowei; Knapen, Dries

2018-02-28

Toxicological responses to stressors are more complex than the simple one biological perturbation to one adverse outcome model portrayed by individual adverse outcome pathways (AOPs). Consequently, the AOP framework was designed to facilitate de facto development of AOP networks that can aid understanding and prediction of pleiotropic and interactive effects more common to environmentally realistic, complex exposure scenarios. The present paper introduces nascent concepts related to the qualitative analysis of AOP networks. First, graph theory-based approaches for identifying important topological features are illustrated using two example AOP networks derived from existing AOP descriptions. Second, considerations for identifying the most significant path(s) through an AOP network from either a biological or risk assessment perspective are described. Finally, approaches for identifying interactions among AOPs that may result in additive, synergistic, or antagonistic responses, or previously undefined emergent patterns of response, are introduced. Along with a companion article (Knapen et al. part I), these concepts set the stage for development of tools and case studies that will facilitate more rigorous analysis of AOP networks, and the utility of AOP network-based predictions, for use in research and regulatory decision-making. Collectively, this work addresses one of the major themes identified through a SETAC Horizon Scanning effort focused on advancing the AOP framework. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Some Aspects of Part-Time Work.

Science.gov (United States)

Australian Dept. of Labour and National Service, Melbourne. Women's Bureau.

Of major importance to many married women seeking employment in Australia is the availability of part-time work. To describe the economic aspects of part-time employment for women, a review was made of statistics published by the Commonwealth Bureau of Census and Statistics and of research on part-time employment in overseas countries, and a…

Pathway Interaction Network Analysis Identifies Dysregulated Pathways in Human Monocytes Infected by Listeria monocytogenes

Directory of Open Access Journals (Sweden)

Wufeng Fan

2017-01-01

Full Text Available In our study, we aimed to extract dysregulated pathways in human monocytes infected by Listeria monocytogenes (LM based on pathway interaction network (PIN which presented the functional dependency between pathways. After genes were aligned to the pathways, principal component analysis (PCA was used to calculate the pathway activity for each pathway, followed by detecting seed pathway. A PIN was constructed based on gene expression profile, protein-protein interactions (PPIs, and cellular pathways. Identifying dysregulated pathways from the PIN was performed relying on seed pathway and classification accuracy. To evaluate whether the PIN method was feasible or not, we compared the introduced method with standard network centrality measures. The pathway of RNA polymerase II pretranscription events was selected as the seed pathway. Taking this seed pathway as start, one pathway set (9 dysregulated pathways with AUC score of 1.00 was identified. Among the 5 hub pathways obtained using standard network centrality measures, 4 pathways were the common ones between the two methods. RNA polymerase II transcription and DNA replication owned a higher number of pathway genes and DEGs. These dysregulated pathways work together to influence the progression of LM infection, and they will be available as biomarkers to diagnose LM infection.

HIV-1 RNAs are Not Part of the Argonaute 2 Associated RNA Interference Pathway in Macrophages.

Directory of Open Access Journals (Sweden)

Valentina Vongrad

Full Text Available MiRNAs and other small noncoding RNAs (sncRNAs are key players in post-transcriptional gene regulation. HIV-1 derived small noncoding RNAs (sncRNAs have been described in HIV-1 infected cells, but their biological functions still remain to be elucidated. Here, we approached the question whether viral sncRNAs may play a role in the RNA interference (RNAi pathway or whether viral mRNAs are targeted by cellular miRNAs in human monocyte derived macrophages (MDM.The incorporation of viral sncRNAs and/or their target RNAs into RNA-induced silencing complex was investigated using photoactivatable ribonucleoside-induced cross-linking and immunoprecipitation (PAR-CLIP as well as high-throughput sequencing of RNA isolated by cross-linking immunoprecipitation (HITS-CLIP, which capture Argonaute2-bound miRNAs and their target RNAs. HIV-1 infected monocyte-derived macrophages (MDM were chosen as target cells, as they have previously been shown to express HIV-1 sncRNAs. In addition, we applied small RNA deep sequencing to study differential cellular miRNA expression in HIV-1 infected versus non-infected MDMs.PAR-CLIP and HITS-CLIP data demonstrated the absence of HIV-1 RNAs in Ago2-RISC, although the presence of a multitude of HIV-1 sncRNAs in HIV-1 infected MDMs was confirmed by small RNA sequencing. Small RNA sequencing revealed that 1.4% of all sncRNAs were of HIV-1 origin. However, neither HIV-1 derived sncRNAs nor putative HIV-1 target sequences incorporated into Ago2-RISC were identified suggesting that HIV-1 sncRNAs are not involved in the canonical RNAi pathway nor is HIV-1 targeted by this pathway in HIV-1 infected macrophages.

DEGAS: de novo discovery of dysregulated pathways in human diseases.

Directory of Open Access Journals (Sweden)

Igor Ulitsky

Full Text Available BACKGROUND: Molecular studies of the human disease transcriptome typically involve a search for genes whose expression is significantly dysregulated in sick individuals compared to healthy controls. Recent studies have found that only a small number of the genes in human disease-related pathways show consistent dysregulation in sick individuals. However, those studies found that some pathway genes are affected in most sick individuals, but genes can differ among individuals. While a pathway is usually defined as a set of genes known to share a specific function, pathway boundaries are frequently difficult to assign, and methods that rely on such definition cannot discover novel pathways. Protein interaction networks can potentially be used to overcome these problems. METHODOLOGY/PRINCIPAL FINDINGS: We present DEGAS (DysrEgulated Gene set Analysis via Subnetworks, a method for identifying connected gene subnetworks significantly enriched for genes that are dysregulated in specimens of a disease. We applied DEGAS to seven human diseases and obtained statistically significant results that appear to home in on compact pathways enriched with hallmarks of the diseases. In Parkinson's disease, we provide novel evidence for involvement of mRNA splicing, cell proliferation, and the 14-3-3 complex in the disease progression. DEGAS is available as part of the MATISSE software package (http://acgt.cs.tau.ac.il/matisse. CONCLUSIONS/SIGNIFICANCE: The subnetworks identified by DEGAS can provide a signature of the disease potentially useful for diagnosis, pinpoint possible pathways affected by the disease, and suggest targets for drug intervention.

A CCR2 macrophage endocytic pathway mediates extravascular fibrin clearance in vivo

DEFF Research Database (Denmark)

Motley, Michael P; Madsen, Daniel H; Jürgensen, Henrik J

2016-01-01

cellular endocytosis and lysosomal targeting, revealing a novel intracellular pathway for extravascular fibrin degradation. A C-C chemokine receptor type 2 (CCR2)-positive macrophage subpopulation constituted the majority of fibrin-uptaking cells. Consequently, cellular fibrin uptake was diminished...... by elimination of CCR2-expressing cells. The CCR2-positive macrophage subtype was different from collagen-internalizing M2-like macrophages. Cellular fibrin uptake was strictly dependent on plasminogen and plasminogen activator. Surprisingly, however, fibrin endocytosis was unimpeded by the absence of the fibrin...... subsets of macrophages employing distinct molecular pathways....

Identification of altered pathways in breast cancer based on individualized pathway aberrance score.

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Shi, Sheng-Hong; Zhang, Wei; Jiang, Jing; Sun, Long

2017-08-01

The objective of the present study was to identify altered pathways in breast cancer based on the individualized pathway aberrance score (iPAS) method combined with the normal reference (nRef). There were 4 steps to identify altered pathways using the iPAS method: Data preprocessing conducted by the robust multi-array average (RMA) algorithm; gene-level statistics based on average Z ; pathway-level statistics according to iPAS; and a significance test dependent on 1 sample Wilcoxon test. The altered pathways were validated by calculating the changed percentage of each pathway in tumor samples and comparing them with pathways from differentially expressed genes (DEGs). A total of 688 altered pathways with Ppathways were involved in the total 688 altered pathways, which may validate the present results. In addition, there were 324 DEGs and 155 common genes between DEGs and pathway genes. DEGs and common genes were enriched in the same 9 significant terms, which also were members of altered pathways. The iPAS method was suitable for identifying altered pathways in breast cancer. Altered pathways (such as KIF and PLK mediated events) were important for understanding breast cancer mechanisms and for the future application of customized therapeutic decisions.

Assembly and Multiplex Genome Integration of Metabolic Pathways in Yeast Using CasEMBLR

DEFF Research Database (Denmark)

Jakočiūnas, Tadas; Jensen, Emil D.; Jensen, Michael Krogh

2018-01-01

and marker-free integration of the carotenoid pathway from 15 exogenously supplied DNA parts into three targeted genomic loci. As a second proof-of-principle, a total of ten DNA parts were assembled and integrated in two genomic loci to construct a tyrosine production strain, and at the same time knocking......Genome integration is a vital step for implementing large biochemical pathways to build a stable microbial cell factory. Although traditional strain construction strategies are well established for the model organism Saccharomyces cerevisiae, recent advances in CRISPR/Cas9-mediated genome...... engineering allow much higher throughput and robustness in terms of strain construction. In this chapter, we describe CasEMBLR, a highly efficient and marker-free genome engineering method for one-step integration of in vivo assembled expression cassettes in multiple genomic sites simultaneously. Cas...

Volunteering as a community mother--a pathway to lifelong learning.

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Molloy, Mary

2007-05-01

This paper describes a study that was undertaken to investigate the effects of participating in a community volunteering programme (the Community Mothers Programme) on volunteers (Community Mothers). The aim of the study was to investigate if volunteering in this programme acted as a pathway to lifelong learning; did the volunteers recognise the learning of new knowledge and/or skills, and did their participation in the programme trigger them to progress to further education in other settings? A self-administered questionnaire method was used for data collection: 115 questionnaires being distributed to volunteers, with a response rate of eighty-two (71 per cent). Findings show that the majority of the respondents cited the learning of new knowledge and/or skills as a result of their participation in the Community Mothers Programme. Learning appeared to stem from the various training and activities, suggesting an educational process within the volunteer setting. Findings also show that the majority of respondents had progressed to further education. In this instance, therefore, volunteering did appear to act as a pathway to lifelong learning.

Network pharmacology-based identification of key pharmacological pathways of Yin-Huang-Qing-Fei capsule acting on chronic bronchitis.

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Yu, Guohua; Zhang, Yanqiong; Ren, Weiqiong; Dong, Ling; Li, Junfang; Geng, Ya; Zhang, Yi; Li, Defeng; Xu, Haiyu; Yang, Hongjun

2017-01-01

For decades in China, the Yin-Huang-Qing-Fei capsule (YHQFC) has been widely used in the treatment of chronic bronchitis, with good curative effects. Owing to the complexity of traditional Chinese herbal formulas, the pharmacological mechanism of YHQFC remains unclear. To address this problem, a network pharmacology-based strategy was proposed in this study. At first, the putative target profile of YHQFC was predicted using MedChem Studio, based on structural and functional similarities of all available YHQFC components to the known drugs obtained from the DrugBank database. Then, an interaction network was constructed using links between putative YHQFC targets and known therapeutic targets of chronic bronchitis. Following the calculation of four topological features (degree, betweenness, closeness, and coreness) of each node in the network, 475 major putative targets of YHQFC and their topological importance were identified. In addition, a pathway enrichment analysis based on the Kyoto Encyclopedia of Genes and Genomes pathway database indicated that the major putative targets of YHQFC are significantly associated with various pathways involved in anti-inflammation processes, immune responses, and pathological changes caused by asthma. More interestingly, eight major putative targets of YHQFC (interleukin [IL]-3, IL-4, IL-5, IL-10, IL-13, FCER1G, CCL11, and EPX) were demonstrated to be associated with the inflammatory process that occurs during the progression of asthma. Finally, a molecular docking simulation was performed and the results exhibited that 17 pairs of chemical components and candidate YHQFC targets involved in asthma pathway had strong binding efficiencies. In conclusion, this network pharmacology-based investigation revealed that YHQFC may attenuate the inflammatory reaction of chronic bronchitis by regulating its candidate targets, which may be implicated in the major pathological processes of the asthma pathway.

Lectin Pathway of Complement Activation Is Associated with Vulnerability of Atherosclerotic Plaques

DEFF Research Database (Denmark)

Fumagalli, Stefano; Perego, Carlo; Zangari, Rosalia

2017-01-01

Inflammatory mechanisms may be involved in atherosclerotic plaque rupture. By using a novel histology-based method to quantify plaque instability here, we assess whether lectin pathway (LP) of complement activation, a major inflammation arm, could represent an index of plaque instability. Plaques...

The Hedgehog-GLI pathway in embryonic development and cancer: implications for pulmonary oncology therapy

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Armas-López, Leonel; Zúñiga, Joaquín; Arrieta, Oscar; Ávila-Moreno, Federico

2017-01-01

Transcriptional regulation and epigenetic mechanisms closely control gene expression through diverse physiological and pathophysiological processes. These include the development of germ layers and post-natal epithelial cell-tissue differentiation, as well as, involved with the induction, promotion and/or progression of human malignancies. Diverse studies have shed light on the molecular similarities and differences involved in the stages of embryological epithelial development and dedifferentiation processes in malignant tumors of epithelial origin, of which many focus on lung carcinomas. In lung cancer, several transcriptional, epigenetic and genetic aberrations have been described to partly arise from environmental risk factors, but ethnic genetic predisposition factors may also play a role. The classification of the molecular hallmarks of cancer has been essential to study and achieve a comprehensive view of the interaction networks between cell signaling pathways and functional roles of the transcriptional and epigenetic regulatory mechanisms. This has in turn increased understanding on how these molecular networks are involved in embryo-layers and malignant diseases development. Ultimately, a major biomedicine goal is to achieve a thorough understanding of their roles as diagnostic, prognostic and treatment response indicators in lung oncological patients. Recently, several notable cell-signaling pathways have been studied based on their contribution to promoting and/or regulating the engagement of different cancer hallmarks, among them genome instability, exacerbated proliferative signaling, replicative immortality, tumor invasion-metastasis, inflammation, and immune-surveillance evasion mechanisms. Of these, the Hedgehog-GLI (Hh) cell-signaling pathway has been identified as a main molecular contribution into several of the abovementioned functional embryo-malignancy processes. Nonetheless, the systematic study of the regulatory epigenetic and

A benefit-risk review of systemic haemostatic agents - Part 1 : In major surgery

NARCIS (Netherlands)

Fraser, Ian S.; Porte, Robert J.; Kouides, Peter A.; Lukes, Andrea S.

2008-01-01

Systemic haemostatic agents play an important role in the management of blood loss during major surgery where significant blood loss is likely and their use has increased in recent times as a consequence of demand for blood products outstripping supply and the risks associated with transfusions.

Long Non-Coding RNAs Embedded in the Rb and p53 Pathways

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Subramanian, Murugan; Jones, Matthew F.; Lal, Ashish, E-mail: ashish.lal@nih.gov [Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 (United States)

2013-12-04

In recent years, long non-coding RNAs (lncRNAs) have gained significant attention as a novel class of gene regulators. Although a small number of lncRNAs have been shown to regulate gene expression through diverse mechanisms including transcriptional regulation, mRNA splicing and translation, the physiological function and mechanism of action of the vast majority are not known. Profiling studies in cell lines and tumor samples have suggested a potential role of lncRNAs in cancer. Indeed, distinct lncRNAs have been shown to be embedded in the p53 and Rb networks, two of the major tumor suppressor pathways that control cell cycle progression and survival. Given the fact that inactivation of Rb and p53 is a hallmark of human cancer, in this review we discuss recent evidence on the function of lncRNAs in the Rb and p53 signaling pathways.

Long Non-Coding RNAs Embedded in the Rb and p53 Pathways

International Nuclear Information System (INIS)

Subramanian, Murugan; Jones, Matthew F.; Lal, Ashish

2013-01-01

In recent years, long non-coding RNAs (lncRNAs) have gained significant attention as a novel class of gene regulators. Although a small number of lncRNAs have been shown to regulate gene expression through diverse mechanisms including transcriptional regulation, mRNA splicing and translation, the physiological function and mechanism of action of the vast majority are not known. Profiling studies in cell lines and tumor samples have suggested a potential role of lncRNAs in cancer. Indeed, distinct lncRNAs have been shown to be embedded in the p53 and Rb networks, two of the major tumor suppressor pathways that control cell cycle progression and survival. Given the fact that inactivation of Rb and p53 is a hallmark of human cancer, in this review we discuss recent evidence on the function of lncRNAs in the Rb and p53 signaling pathways

Imaging of orbital and visual pathway pathology

International Nuclear Information System (INIS)

Mueller-Forell, W.S.

2006-01-01

This is one of the first books to deal with imaging of pathology of the entire visual system. It is divided into two parts, general and special. In the general part, the most important basics of modern imaging methods are discussed, but with less emphasis on the physical background than in purely neuro-/radiological textbooks. Chapters are devoted to the meticulous presentation of imaging anatomy of the orbit and intracranial visual pathway. The latest knowledge on the indication, technique, and results of functional MR imaging is presented. Visual system impairment in the pediatric age group is also discussed. The special part of the book provides detailed descriptions of the symptoms and clinical and imaging findings in individual patients with orbital and intracranial pathologies. This book is specifically designed to be of value not only to neuroradiologists but also to ophthalmologists, neurosurgeons, oto-/rhino-laryngologists, and neurologists who require more detailed information on these special diseases. (orig.)

Imaging of orbital and visual pathway pathology

Energy Technology Data Exchange (ETDEWEB)

Mueller-Forell, W.S. (ed.) [Medical School Univ. of Mainz (Germany). Inst. of Neuroradiology

2006-07-01

This is one of the first books to deal with imaging of pathology of the entire visual system. It is divided into two parts, general and special. In the general part, the most important basics of modern imaging methods are discussed, but with less emphasis on the physical background than in purely neuro-/radiological textbooks. Chapters are devoted to the meticulous presentation of imaging anatomy of the orbit and intracranial visual pathway. The latest knowledge on the indication, technique, and results of functional MR imaging is presented. Visual system impairment in the pediatric age group is also discussed. The special part of the book provides detailed descriptions of the symptoms and clinical and imaging findings in individual patients with orbital and intracranial pathologies. This book is specifically designed to be of value not only to neuroradiologists but also to ophthalmologists, neurosurgeons, oto-/rhino-laryngologists, and neurologists who require more detailed information on these special diseases. (orig.)

Milk distribution and feeding practice data for the PATHWAY model

International Nuclear Information System (INIS)

Ward, G.M.; Whicker, F.W.

1990-01-01

Milk is a major source for ingestion of several radionuclides, particularly when it is produced from fresh forage. Estimation of radionuclide ingestion via milk from Nevada Test Site fallout events in the 1950s required information on the sources of milk, feeding practices for cows, and elapsed time between milking and consumption for various geographic areas. These data were essential input to the food-chain model, PATHWAY. A data base was compiled from personal interviews. Milk sources included private cows, local dairies, and regional plants that collected from and distributed to wide geographic areas. Estimates of the contribution of each source were made for communities in a nine-state area. Pasture seasons varied from 3 to 6 mo. Pasture use varied from zero to 80% of the cows' diet. Pasture use declined during the 1950s, as did the number of family cows and local dairy plants. Regional distributors captured a larger portion of the market, and improved technologies increased the shelf life of milk. These factors tended to reduce the human intake of fallout radionuclides from milk in the latter part of the 1950s

78 FR 1991 - Major Capital Investment Projects

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2013-01-09

... Administration 49 CFR Part 611 Major Capital Investment Projects; Notice of Availability of Proposed New Starts... Capital Investment Projects AGENCY: Federal Transit Administration (FTA), DOT. ACTION: Final rule. SUMMARY... capital investments seeking funding under the discretionary ``New Starts'' and ``Small Starts'' programs...

Managing nuclear liabilities: 'hospital pass' or major opportunity?

International Nuclear Information System (INIS)

May, D.

1995-01-01

This paper sets out to start changing the perception that liabilities management is an unattractive part of the UK Nuclear Industry. The paper describes BNFL's successes and long term challenges in this area and concludes that liabilities management presents a major opportunity to:-Remove an Achilles heel of the industry; Create value for the companies concerned by successfully driving down costs; Sustain and exploit internationally a major UK competitive edge. (Author)

WikiPathways: a multifaceted pathway database bridging metabolomics to other omics research.

Science.gov (United States)

Slenter, Denise N; Kutmon, Martina; Hanspers, Kristina; Riutta, Anders; Windsor, Jacob; Nunes, Nuno; Mélius, Jonathan; Cirillo, Elisa; Coort, Susan L; Digles, Daniela; Ehrhart, Friederike; Giesbertz, Pieter; Kalafati, Marianthi; Martens, Marvin; Miller, Ryan; Nishida, Kozo; Rieswijk, Linda; Waagmeester, Andra; Eijssen, Lars M T; Evelo, Chris T; Pico, Alexander R; Willighagen, Egon L

2018-01-04

WikiPathways (wikipathways.org) captures the collective knowledge represented in biological pathways. By providing a database in a curated, machine readable way, omics data analysis and visualization is enabled. WikiPathways and other pathway databases are used to analyze experimental data by research groups in many fields. Due to the open and collaborative nature of the WikiPathways platform, our content keeps growing and is getting more accurate, making WikiPathways a reliable and rich pathway database. Previously, however, the focus was primarily on genes and proteins, leaving many metabolites with only limited annotation. Recent curation efforts focused on improving the annotation of metabolism and metabolic pathways by associating unmapped metabolites with database identifiers and providing more detailed interaction knowledge. Here, we report the outcomes of the continued growth and curation efforts, such as a doubling of the number of annotated metabolite nodes in WikiPathways. Furthermore, we introduce an OpenAPI documentation of our web services and the FAIR (Findable, Accessible, Interoperable and Reusable) annotation of resources to increase the interoperability of the knowledge encoded in these pathways and experimental omics data. New search options, monthly downloads, more links to metabolite databases, and new portals make pathway knowledge more effortlessly accessible to individual researchers and research communities. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

Neurophysiology and itch pathways.

Science.gov (United States)

Schmelz, Martin

2015-01-01

As we all can easily differentiate the sensations of itch and pain, the most straightforward neurophysiologic concept would consist of two specific pathways that independently encode itch and pain. Indeed, a neuronal pathway for histamine-induced itch in the peripheral and central nervous system has been described in animals and humans, and recently several non-histaminergic pathways for itch have been discovered in rodents that support a dichotomous concept differentiated into a pain and an itch pathway, with both pathways being composed of different "flavors." Numerous markers and mediators have been found that are linked to itch processing pathways. Thus, the delineation of neuronal pathways for itch from pain pathways seemingly proves that all sensory aspects of itch are based on an itch-specific neuronal pathway. However, such a concept is incomplete as itch can also be induced by the activation of the pain pathway in particular when the stimulus is applied in a highly localized spatial pattern. These opposite views reflect the old dispute between specificity and pattern theories of itch. Rather than only being of theoretic interest, this conceptual problem has key implication for the strategy to treat chronic itch as key therapeutic targets would be either itch-specific pathways or unspecific nociceptive pathways.

Radiolabeling as a tool to study uptake pathways in plants

Energy Technology Data Exchange (ETDEWEB)

Schymura, Stefan; Hildebrand, Heike; Franke, Karsten [Helmholtz-Zentrum Dresden-Rossendorf e.V., Dresden (Germany). Reactive Transport; Fricke, T. [Vita34 BioPlanta, Leipzig (Germany)

2017-06-01

The identification of major uptake pathways in plants is an important factor when evaluation the fate of manufactured nanoparticles in the environment and the associated risks. Using different radiolabeling techniques we were able to show a predominantly particulate uptake for CeO{sub 2} nanoparticles (NPs) in contrast to a possible uptake in the form of ionic cerium.

A simple biosynthetic pathway for large product generation from small substrate amounts

Science.gov (United States)

Djordjevic, Marko; Djordjevic, Magdalena

2012-10-01

A recently emerging discipline of synthetic biology has the aim of constructing new biosynthetic pathways with useful biological functions. A major application of these pathways is generating a large amount of the desired product. However, toxicity due to the possible presence of toxic precursors is one of the main problems for such production. We consider here the problem of generating a large amount of product from a potentially toxic substrate. To address this, we propose a simple biosynthetic pathway, which can be induced in order to produce a large number of the product molecules, by keeping the substrate amount at low levels. Surprisingly, we show that the large product generation crucially depends on fast non-specific degradation of the substrate molecules. We derive an optimal induction strategy, which allows as much as three orders of magnitude increase in the product amount through biologically realistic parameter values. We point to a recently discovered bacterial immune system (CRISPR/Cas in E. coli) as a putative example of the pathway analysed here. We also argue that the scheme proposed here can be used not only as a stand-alone pathway, but also as a strategy to produce a large amount of the desired molecules with small perturbations of endogenous biosynthetic pathways.

A simple biosynthetic pathway for large product generation from small substrate amounts

Energy Technology Data Exchange (ETDEWEB)

Djordjevic, Marko [Institute of Physiology and Biochemistry, Faculty of Biology, University of Belgrade (Serbia); Djordjevic, Magdalena [Institute of Physics Belgrade, University of Belgrade (Serbia)

2012-10-01

A recently emerging discipline of synthetic biology has the aim of constructing new biosynthetic pathways with useful biological functions. A major application of these pathways is generating a large amount of the desired product. However, toxicity due to the possible presence of toxic precursors is one of the main problems for such production. We consider here the problem of generating a large amount of product from a potentially toxic substrate. To address this, we propose a simple biosynthetic pathway, which can be induced in order to produce a large number of the product molecules, by keeping the substrate amount at low levels. Surprisingly, we show that the large product generation crucially depends on fast non-specific degradation of the substrate molecules. We derive an optimal induction strategy, which allows as much as three orders of magnitude increase in the product amount through biologically realistic parameter values. We point to a recently discovered bacterial immune system (CRISPR/Cas in E. coli) as a putative example of the pathway analysed here. We also argue that the scheme proposed here can be used not only as a stand-alone pathway, but also as a strategy to produce a large amount of the desired molecules with small perturbations of endogenous biosynthetic pathways. (paper)

A simple biosynthetic pathway for large product generation from small substrate amounts

International Nuclear Information System (INIS)

Djordjevic, Marko; Djordjevic, Magdalena

2012-01-01

A recently emerging discipline of synthetic biology has the aim of constructing new biosynthetic pathways with useful biological functions. A major application of these pathways is generating a large amount of the desired product. However, toxicity due to the possible presence of toxic precursors is one of the main problems for such production. We consider here the problem of generating a large amount of product from a potentially toxic substrate. To address this, we propose a simple biosynthetic pathway, which can be induced in order to produce a large number of the product molecules, by keeping the substrate amount at low levels. Surprisingly, we show that the large product generation crucially depends on fast non-specific degradation of the substrate molecules. We derive an optimal induction strategy, which allows as much as three orders of magnitude increase in the product amount through biologically realistic parameter values. We point to a recently discovered bacterial immune system (CRISPR/Cas in E. coli) as a putative example of the pathway analysed here. We also argue that the scheme proposed here can be used not only as a stand-alone pathway, but also as a strategy to produce a large amount of the desired molecules with small perturbations of endogenous biosynthetic pathways. (paper)

Agriculture and nutrition in India: mapping evidence to pathways.

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Kadiyala, Suneetha; Harris, Jody; Headey, Derek; Yosef, Sivan; Gillespie, Stuart

2014-12-01

In India, progress against undernutrition has been slow. Given its importance for income generation, improving diets, care practices, and maternal health, the agriculture sector is widely regarded as playing an important role in accelerating the reduction in undernutrition. This paper comprehensively maps existing evidence along agriculture-nutrition pathways in India and assesses both the quality and coverage of the existing literature. We present a conceptual framework delineating six key pathways between agriculture and nutrition. Three pathways pertain to the nutritional impacts of farm production, farm incomes, and food prices. The other three pertain to agriculture-gender linkages. After an extensive search, we found 78 research papers that provided evidence to populate these pathways. The literature suggests that Indian agriculture has a range of important influences on nutrition. Agriculture seems to influence diets even when controlling for income, and relative food prices could partly explain observed dietary changes in recent decades. The evidence on agriculture-gender linkages to nutrition is relatively weak. Sizeable knowledge gaps remain. The root causes of these gaps include an interdisciplinary disconnect between nutrition and economics/agriculture, a related problem of inadequate survey data, and limited policy-driven experimentation. Closing these gaps is essential to strengthening the agriculture sector's contribution to reducing undernutrition. © 2014 New York Academy of Sciences.

Comparative TEA for Indirect Liquefaction Pathways to Distillate-Range Fuels via Oxygenated Intermediates

Energy Technology Data Exchange (ETDEWEB)

Tan, Eric; Snowden-Swan, Lesley J.; Talmadge, Michael; Dutta, Abhijit; Jones, Susanne; Ramasamy, Karthikeyan; Gray, Michael; Dagle, Robert; Padmaperuma, Asanga; Gerber, Mark; Sahir, Asad; Tao, Ling; Zhang, Yanan

2017-03-03

This paper presents a comparative techno-economic analysis of five conversion pathways from biomass to gasoline-, jet-, and diesel-range hydrocarbons via indirect liquefaction with specific focus on pathways utilizing oxygenated intermediates (derived either via thermochemical or biochemical conversion steps). The four emerging pathways of interest are compared with one conventional pathway (Fischer-Tropsch) for the production of the hydrocarbon blendstocks. The processing steps of the four emerging pathways include: biomass-to-syngas via indirect gasification, gas cleanup, conversion of syngas to alcohols/oxygenates, followed by conversion of alcohols/oxygenates to hydrocarbon blendstocks via dehydration, oligomerization, and hydrogenation. We show that the emerging pathways via oxygenated intermediates have the potential to be cost competitive with the conventional Fischer-Tropsch process. The evaluated pathways and the benchmark process generally exhibit similar fuel yields and carbon conversion efficiencies. The resulting minimum fuel selling prices are comparable to the benchmark at approximately $3.60 per gallon-gasoline equivalent, with potential for two new pathways to be more economically competitive. Additionally, the coproduct values can play an important role in the economics of the processes with oxygenated intermediates derived via syngas fermentation. Major cost drivers for the integrated processes are tied to achievable fuel yields and conversion efficiency of the intermediate steps, i.e., the production of oxygenates/alcohols from syngas and the conversion of oxygenates/alcohols to hydrocarbon fuels.

Small molecule screening identifies targetable zebrafish pigmentation pathways

DEFF Research Database (Denmark)

Colanesi, Sarah; Taylor, Kerrie L; Temperley, Nicholas D

2012-01-01

Small molecules complement genetic mutants and can be used to probe pigment cell biology by inhibiting specific proteins or pathways. Here, we present the results of a screen of active compounds for those that affect the processes of melanocyte and iridophore development in zebrafish and investig......Small molecules complement genetic mutants and can be used to probe pigment cell biology by inhibiting specific proteins or pathways. Here, we present the results of a screen of active compounds for those that affect the processes of melanocyte and iridophore development in zebrafish...... and investigate the effects of a few of these compounds in further detail. We identified and confirmed 57 compounds that altered pigment cell patterning, number, survival, or differentiation. Additional tissue targets and toxicity of small molecules are also discussed. Given that the majority of cell types...

Bioinformatic evaluation of L-arginine catabolic pathways in 24 cyanobacteria and transcriptional analysis of genes encoding enzymes of L-arginine catabolism in the cyanobacterium Synechocystis sp. PCC 6803

Directory of Open Access Journals (Sweden)

Pistorius Elfriede K

2007-11-01

Full Text Available Abstract Background So far very limited knowledge exists on L-arginine catabolism in cyanobacteria, although six major L-arginine-degrading pathways have been described for prokaryotes. Thus, we have performed a bioinformatic analysis of possible L-arginine-degrading pathways in cyanobacteria. Further, we chose Synechocystis sp. PCC 6803 for a more detailed bioinformatic analysis and for validation of the bioinformatic predictions on L-arginine catabolism with a transcript analysis. Results We have evaluated 24 cyanobacterial genomes of freshwater or marine strains for the presence of putative L-arginine-degrading enzymes. We identified an L-arginine decarboxylase pathway in all 24 strains. In addition, cyanobacteria have one or two further pathways representing either an arginase pathway or L-arginine deiminase pathway or an L-arginine oxidase/dehydrogenase pathway. An L-arginine amidinotransferase pathway as a major L-arginine-degrading pathway is not likely but can not be entirely excluded. A rather unusual finding was that the cyanobacterial L-arginine deiminases are substantially larger than the enzymes in non-photosynthetic bacteria and that they are membrane-bound. A more detailed bioinformatic analysis of Synechocystis sp. PCC 6803 revealed that three different L-arginine-degrading pathways may in principle be functional in this cyanobacterium. These are (i an L-arginine decarboxylase pathway, (ii an L-arginine deiminase pathway, and (iii an L-arginine oxidase/dehydrogenase pathway. A transcript analysis of cells grown either with nitrate or L-arginine as sole N-source and with an illumination of 50 μmol photons m-2 s-1 showed that the transcripts for the first enzyme(s of all three pathways were present, but that the transcript levels for the L-arginine deiminase and the L-arginine oxidase/dehydrogenase were substantially higher than that of the three isoenzymes of L-arginine decarboxylase. Conclusion The evaluation of 24

Activation of the PI3K/AKT pathway in Merkel cell carcinoma.

Directory of Open Access Journals (Sweden)

Christian Hafner

Full Text Available Merkel cell carcinoma (MCC is a highly aggressive skin cancer with an increasing incidence. The understanding of the molecular carcinogenesis of MCC is limited. Here, we scrutinized the PI3K/AKT pathway, one of the major pathways activated in human cancer, in MCC. Immunohistochemical analysis of 41 tumor tissues and 9 MCC cell lines revealed high levels of AKT phosphorylation at threonine 308 in 88% of samples. Notably, the AKT phosphorylation was not correlated with the presence or absence of the Merkel cell polyoma virus (MCV. Accordingly, knock-down of the large and small T antigen by shRNA in MCV positive MCC cells did not affect phosphorylation of AKT. We also analyzed 46 MCC samples for activating PIK3CA and AKT1 mutations. Oncogenic PIK3CA mutations were found in 2/46 (4% MCCs whereas mutations in exon 4 of AKT1 were absent. MCC cell lines demonstrated a high sensitivity towards the PI3K inhibitor LY-294002. This finding together with our observation that the PI3K/AKT pathway is activated in the majority of human MCCs identifies PI3K/AKT as a potential new therapeutic target for MCC patients.

Catalase plays an important role in a genotoxic pathway of methylated arsenicals

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Arsenic is a common contaminant of drinking water in many parts of the world. Consumption of arsenic-contaminated drinking water has been implicated in both cancerous and non-cancerous health conditions. However, the pathways that lead to arsenic-induced health conditions have no...

75 FR 39492 - Major Capital Investment Projects

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2010-07-09

... DEPARTMENT OF TRANSPORTATION Federal Transit Administration 49 CFR Part 611 [Docket No. FTA-2010-0009] RIN 2132-AB02 Major Capital Investment Projects AGENCY: Federal Transit Administration (FTA), DOT. ACTION: Public meetings on ANPRM. SUMMARY: This document announces the date, time, and location of an...

75 FR 33757 - Major Capital Investment Projects

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2010-06-15

... DEPARTMENT OF TRANSPORTATION Federal Transit Administration 49 CFR Part 611 [Docket No. FTA-2010-0009] RIN 2132-AB02 Major Capital Investment Projects AGENCY: Federal Transit Administration (FTA), DOT. ACTION: Public meetings on ANPRM. SUMMARY: This document announces the dates, times, and locations of...

Determination of the contribution of livestock water ingestion to dose from the cow-milk pathway

International Nuclear Information System (INIS)

Ikenberry, T.A.

1992-12-01

As part of the Hanford Environmental Dose Reconstruction (HEDR) Project, a series of calculations has been undertaken to evaluate the absolute and relative contribution of different exposure pathways to thyroid doses that may have been received by individuals living in the vicinity of the Hanford Site. These evaluations include some pathways that were included in the Phase I air-pathway dose evaluations (HEDR staff 1991, page xx), as well as other potential exposure pathways being evaluated for possible inclusion in the future HEDR modeling efforts. This calculation (002) examined the possible doses that may have been received by individuals who drank milk from cows that drank from sources of water (stock tanks and farm ponds) exposed to iodine-131 in the atmosphere during 1945

Predicting pathway cross-talks in ankylosing spondylitis through investigating the interactions among pathways.

Science.gov (United States)

Gu, Xiang; Liu, Cong-Jian; Wei, Jian-Jie

2017-11-13

Given that the pathogenesis of ankylosing spondylitis (AS) remains unclear, the aim of this study was to detect the potentially functional pathway cross-talk in AS to further reveal the pathogenesis of this disease. Using microarray profile of AS and biological pathways as study objects, Monte Carlo cross-validation method was used to identify the significant pathway cross-talks. In the process of Monte Carlo cross-validation, all steps were iterated 50 times. For each run, detection of differentially expressed genes (DEGs) between two groups was conducted. The extraction of the potential disrupted pathways enriched by DEGs was then implemented. Subsequently, we established a discriminating score (DS) for each pathway pair according to the distribution of gene expression levels. After that, we utilized random forest (RF) classification model to screen out the top 10 paired pathways with the highest area under the curve (AUCs), which was computed using 10-fold cross-validation approach. After 50 bootstrap, the best pairs of pathways were identified. According to their AUC values, the pair of pathways, antigen presentation pathway and fMLP signaling in neutrophils, achieved the best AUC value of 1.000, which indicated that this pathway cross-talk could distinguish AS patients from normal subjects. Moreover, the paired pathways of SAPK/JNK signaling and mitochondrial dysfunction were involved in 5 bootstraps. Two paired pathways (antigen presentation pathway and fMLP signaling in neutrophil, as well as SAPK/JNK signaling and mitochondrial dysfunction) can accurately distinguish AS and control samples. These paired pathways may be helpful to identify patients with AS for early intervention.

Crosstalk between the Tor and Gcn2 pathways in response to different stresses.

Science.gov (United States)

Rødland, Gro Elise; Tvegård, Tonje; Boye, Erik; Grallert, Beáta

2014-01-01

Regulating growth and the cell cycle in response to environmental fluctuations is important for all organisms in order to maintain viability. Two major pathways for translational regulation are found in higher eukaryotes: the Tor signaling pathway and those operating through the eIF2α kinases. Studies from several organisms indicate that the two pathways are interlinked, in that Tor complex 1 (TORC1) negatively regulates the Gcn2 kinase. Furthermore, inactivation of TORC1 may be required for activation of Gcn2 in response to stress. Here, we use the model organism Schizosaccharomyces pombe to investigate this crosstalk further. We find that the relationship is more complex than previously thought. First, in response to UV irradiation and oxidative stress, Gcn2 is fully activated in the presence of TORC1 signaling. Second, during amino-acid starvation, activation of Gcn2 is dependent on Tor2 activity, and Gcn2 is required for timely inactivation of the Tor pathway. Our data show that the crosstalk between the two pathways varies with the actual stress applied.

A metalloproteinase karilysin present in the majority of Tannerella forsythia isolates inhibits all pathways of the complement system

DEFF Research Database (Denmark)

Jusko, Monika; Potempa, Jan; Karim, Abdulkarim Y

2012-01-01

Tannerella forsythia is a poorly studied pathogen despite being one of the main causes of periodontitis, which is an inflammatory disease of the supporting structures of the teeth. We found that despite being recognized by all complement pathways, T. forsythia is resistant to killing by human....... forsythia obtained from patients with periodontitis. Taken together, the newly characterized karilysin appears to be an important virulence factor of T. forsythia and might have several important implications for immune evasion....

Targeting inflammatory pathways by dietary agents for prevention and treatment of cancer

International Nuclear Information System (INIS)

Aggarwal, Bharat B.

2016-01-01

Chronic infections, obesity, alcohol, tobacco, radiation, environmental pollutants and high-calorie diet have been recognized as major risk factors for the most common types of cancer. All these risk factors are linked to cancer through inflammation. While acute inflammation that persists for short-term mediates host defense against infections, chronic inflammation that lasts for long-term can predispose the host to various chronic illnesses, including cancer. Linkage between cancer and inflammation is indicated by numerous lines of evidence; first, transcription factors NF-kB and STAT3, two major pathways for inflammation, are activated by most cancer risk factors; second, an inflammatory condition precedes most cancers; third, NFkB and STAT3 are constitutively active in most cancers; fourth, hypoxia and acidic conditions found in solid tumors activate NF-kB; fifth, chemotherapeutic agents and γ-irradiation activate NF-kB and lead to chemoresistance and radioresistance; sixth, most gene products linked to inflammation, survival, proliferation, invasion, angiogenesis and metastasis are regulated by NF-kB and STAT3; seventh, suppression of NF-kB and STAT3 inhibits the proliferation and invasion of tumors; and eighth, most chemopreventive agents mediate their effects through inhibition of NF-kB and STAT3 activation pathways. Thus, the suppression of these proinflammatory pathways may provide opportunities for both prevention and treatment of cancer. We will discuss the potential of nutraceuticals derived from spices and from traditional Indian medicine in suppression of inflammatory pathways and their role inprevention and therapy of cancer. (author)

Metabolic pathway redundancy within the apicomplexan-dinoflagellate radiation argues against an ancient chromalveolate plastid

KAUST Repository

Waller, Ross F.

2015-12-08

The chromalveolate hypothesis presents an attractively simple explanation for the presence of red algal-derived secondary plastids in 5 major eukaryotic lineages: “chromista” phyla, cryptophytes, haptophytes and ochrophytes; and alveolate phyla, dinoflagellates and apicomplexans. It posits that a single secondary endosymbiotic event occurred in a common ancestor of these diverse groups, and that this ancient plastid has since been maintained by vertical inheritance only. Substantial testing of this hypothesis by molecular phylogenies has, however, consistently failed to provide support for the predicted monophyly of the host organisms that harbour these plastids—the “chromalveolates.” This lack of support does not disprove the chromalveolate hypothesis per se, but rather drives the proposed endosymbiosis deeper into the eukaryotic tree, and requires multiple plastid losses to have occurred within intervening aplastidic lineages. An alternative perspective on plastid evolution is offered by considering the metabolic partnership between the endosymbiont and its host cell. A recent analysis of metabolic pathways in a deep-branching dinoflagellate indicates a high level of pathway redundancy in the common ancestor of apicomplexans and dinoflagellates, and differential losses of these pathways soon after radiation of the major extant lineages. This suggests that vertical inheritance of an ancient plastid in alveolates is highly unlikely as it would necessitate maintenance of redundant pathways over very long evolutionary timescales.

Metabolic pathway redundancy within the apicomplexan-dinoflagellate radiation argues against an ancient chromalveolate plastid

KAUST Repository

Waller, Ross F.; Gornik, Sebastian G.; Koreny, Ludek; Pain, Arnab

2015-01-01

The chromalveolate hypothesis presents an attractively simple explanation for the presence of red algal-derived secondary plastids in 5 major eukaryotic lineages: “chromista” phyla, cryptophytes, haptophytes and ochrophytes; and alveolate phyla, dinoflagellates and apicomplexans. It posits that a single secondary endosymbiotic event occurred in a common ancestor of these diverse groups, and that this ancient plastid has since been maintained by vertical inheritance only. Substantial testing of this hypothesis by molecular phylogenies has, however, consistently failed to provide support for the predicted monophyly of the host organisms that harbour these plastids—the “chromalveolates.” This lack of support does not disprove the chromalveolate hypothesis per se, but rather drives the proposed endosymbiosis deeper into the eukaryotic tree, and requires multiple plastid losses to have occurred within intervening aplastidic lineages. An alternative perspective on plastid evolution is offered by considering the metabolic partnership between the endosymbiont and its host cell. A recent analysis of metabolic pathways in a deep-branching dinoflagellate indicates a high level of pathway redundancy in the common ancestor of apicomplexans and dinoflagellates, and differential losses of these pathways soon after radiation of the major extant lineages. This suggests that vertical inheritance of an ancient plastid in alveolates is highly unlikely as it would necessitate maintenance of redundant pathways over very long evolutionary timescales.

Synergy between methylerythritol phosphate pathway and mevalonate pathway for isoprene production in Escherichia coli.

Science.gov (United States)

Yang, Chen; Gao, Xiang; Jiang, Yu; Sun, Bingbing; Gao, Fang; Yang, Sheng

2016-09-01

Isoprene, a key building block of synthetic rubber, is currently produced entirely from petrochemical sources. In this work, we engineered both the methylerythritol phosphate (MEP) pathway and the mevalonate (MVA) pathway for isoprene production in E. coli. The synergy between the MEP pathway and the MVA pathway was demonstrated by the production experiment, in which overexpression of both pathways improved the isoprene yield about 20-fold and 3-fold, respectively, compared to overexpression of the MEP pathway or the MVA pathway alone. The (13)C metabolic flux analysis revealed that simultaneous utilization of the two pathways resulted in a 4.8-fold increase in the MEP pathway flux and a 1.5-fold increase in the MVA pathway flux. The synergy of the dual pathway was further verified by quantifying intracellular flux responses of the MEP pathway and the MVA pathway to fosmidomycin treatment and mevalonate supplementation. Our results strongly suggest that coupling of the complementary reducing equivalent demand and ATP requirement plays an important role in the synergy of the dual pathway. Fed-batch cultivation of the engineered strain overexpressing the dual pathway resulted in production of 24.0g/L isoprene with a yield of 0.267g/g of glucose. The synergy of the MEP pathway and the MVA pathway also successfully increased the lycopene productivity in E. coli, which demonstrates that it can be used to improve the production of a broad range of terpenoids in microorganisms. Copyright © 2016 International Metabolic Engineering Society. Published by Elsevier Inc. All rights reserved.

Methanogenic pathways of coal-bed gas in the Powder River Basin, United States: The geologic factor

Energy Technology Data Exchange (ETDEWEB)

Flores, Romeo M.; Rice, Cynthia A.; Stricker, Gary D.; Warden, Augusta; Ellis, Margaret S. [U.S. Geological Survey, Box 25046, MS 939, Denver, Colorado 80225 (United States)

2008-10-02

Coal-bed gas of the Tertiary Fort Union and Wasatch Formations in the Powder River Basin in Wyoming and Montana, U.S. was interpreted as microbial in origin by previous studies based on limited data on the gas and water composition and isotopes associated with the coal beds. To fully evaluate the microbial origin of the gas and mechanisms of methane generation, additional data for 165 gas and water samples from 7 different coal-bed methane-bearing coal-bed reservoirs were collected basinwide and correlated to the coal geology and stratigraphy. The C{sub 1}/(C{sub 2} + C{sub 3}) ratio and vitrinite reflectance of coal and organic shale permitted differentiation between microbial gas and transitional thermogenic gas in the central part of the basin. Analyses of methane {delta}{sup 13}C and {delta}D, carbon dioxide {delta}{sup 13}C, and water {delta}D values indicate gas was generated primarily from microbial CO{sub 2} reduction, but with significant gas generated by microbial methyl-type fermentation (aceticlastic) in some areas of the basin. Microbial CO{sub 2} reduction occurs basinwide, but is generally dominant in Paleocene Fort Union Formation coals in the central part of the basin, whereas microbial methyl-type fermentation is common along the northwest and east margins. Isotopically light methane {delta}{sup 13}C is distributed along the basin margins where {delta}D is also depleted, indicating that both CO{sub 2}-reduction and methyl-type fermentation pathways played major roles in gas generation, but gas from the latter pathway overprinted gas from the former pathway. More specifically, along the northwest basin margin gas generation by methyl-type fermentation may have been stimulated by late-stage infiltration of groundwater recharge from clinker areas, which flowed through highly fractured and faulted coal aquifers. Also, groundwater recharge controlled a change in gas composition in the shallow Eocene Wasatch Formation with the increase of nitrogen and

DNA methylation in a Scottish family multiply affected by bipolar disorder and major depressive disorder.

Science.gov (United States)

Walker, Rosie May; Christoforou, Andrea Nikie; McCartney, Daniel L; Morris, Stewart W; Kennedy, Nicholas A; Morten, Peter; Anderson, Susan Maguire; Torrance, Helen Scott; Macdonald, Alix; Sussmann, Jessika Elizabeth; Whalley, Heather Clare; Blackwood, Douglas H R; McIntosh, Andrew Mark; Porteous, David John; Evans, Kathryn Louise

2016-01-01

Bipolar disorder (BD) is a severe, familial psychiatric condition. Progress in understanding the aetiology of BD has been hampered by substantial phenotypic and genetic heterogeneity. We sought to mitigate these confounders by studying a multi-generational family multiply affected by BD and major depressive disorder (MDD), who carry an illness-linked haplotype on chromosome 4p. Within a family, aetiological heterogeneity is likely to be reduced, thus conferring greater power to detect illness-related changes. As accumulating evidence suggests that altered DNA methylation confers risk for BD and MDD, we compared genome-wide methylation between (i) affected carriers of the linked haplotype (ALH) and married-in controls (MIs), (ii) well unaffected haplotype carriers (ULH) and MI, (iii) ALH and ULH and (iv) all haplotype carriers (LH) and MI. Nominally significant differences in DNA methylation were observed in all comparisons, with differences withstanding correction for multiple testing when the ALH or LH group was compared to the MIs. In both comparisons, we observed increased methylation at a locus in FANCI, which was accompanied by increased FANCI expression in the ALH group. FANCI is part of the Fanconi anaemia complementation (FANC) gene family, which are mutated in Fanconi anaemia and participate in DNA repair. Interestingly, several FANC genes have been implicated in psychiatric disorders. Regional analyses of methylation differences identified loci implicated in psychiatric illness by genome-wide association studies, including CACNB2 and the major histocompatibility complex. Gene ontology analysis revealed enrichment for methylation differences in neurologically relevant genes. Our results highlight altered DNA methylation as a potential mechanism by which the linked haplotype might confer risk for mood disorders. Differences in the phenotypic outcome of haplotype carriers might, in part, arise from additional changes in DNA methylation that converge on

Pathways linking parental divorce with adolescent depression.

Science.gov (United States)

Aseltine, R H

1996-06-01

This article examines the intervening pathways linking parental divorce with adolescent depression, using both cross-sectional and prospective data from a study of high school students in the Boston metropolitan area. Overall, findings reveal that parental divorce is linked with adolescent depression in two ways: (1) it is a source of numerous secondary problems and stresses that are causally related to depression, and (2) it alters youths' reactivity to these stresses, in some cases enhancing, but in other cases mitigating, their depressive effects. Analyses demonstrated the central role of economic hardship in linking family status with depression, with the strength of this indirect pathway partly attributable to the greater vulnerability of youths in single-parent families to financial stresses. In contrast, family conflict did not account for the distress of youths in single-parent families, largely because of their immunity to the effects of such conflict. Finally, prospective data failed to support the hypothesis that differences between youths in single-parent and intact families predate the divorce.

Policy Pathways: A Tale of Renewed Cities

Energy Technology Data Exchange (ETDEWEB)

NONE

2013-08-01

Transport currently accounts for half of global oil consumption and nearly 20% of world energy use, of which approximately 40% is used in urban transport alone. The IEA expects urban transport energy consumption to double by 2050, despite ongoing vehicle technology and fuel-economy improvements. While increased mobility brings many benefits, the staggering rate of this increase creates new challenges. Urgent energy-efficiency policy attention will be needed to mitigate associated negative noise, air pollution, congestion, climate and economic impacts, all of which can cost countries billions of dollars per year. This report highlights lessons learned and examples of good practice from countries with experience implementing a wide range of measures to improve energy efficiency in urban transport systems. Part of the IEA Policy Pathway series, A Tale of Renewed Cities sets out key steps in planning, implementation, monitoring and evaluation to achieve improved energy efficiency in urban transport systems. The Policy Pathway series aims to help policy makers implement the IEA 25 Energy Efficiency Policy Recommendations.

Human oocyte chromosome analysis: complicated cases and major ...

Indian Academy of Sciences (India)

Human oocyte chromosome analysis: complicated cases and major ... dardized even after more than 20 years of research, making it difficult to draw .... (c) Part of a metaphase with a chromosome break in the centromeric region (arrows).

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

Science.gov (United States)

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.

European Regulation on Major Shareholdings and Takeovers

DEFF Research Database (Denmark)

Sørensen, Karsten Engsig; Clausen, Nis Jul

2002-01-01

Even though the rules on disclosure of major shareholdings in listed companies has been partly harmonised in the EU large difference remains. This is documented in the article and it is further debated whether these difference are acceptable, especially in light of the ongoing efforts to harmonise...

Arginine deiminase pathway enzymes: evolutionary history in metamonads and other eukaryotes.

Science.gov (United States)

Novák, Lukáš; Zubáčová, Zuzana; Karnkowska, Anna; Kolisko, Martin; Hroudová, Miluše; Stairs, Courtney W; Simpson, Alastair G B; Keeling, Patrick J; Roger, Andrew J; Čepička, Ivan; Hampl, Vladimír

2016-10-06

Multiple prokaryotic lineages use the arginine deiminase (ADI) pathway for anaerobic energy production by arginine degradation. The distribution of this pathway among eukaryotes has been thought to be very limited, with only two specialized groups living in low oxygen environments (Parabasalia and Diplomonadida) known to possess the complete set of all three enzymes. We have performed an extensive survey of available sequence data in order to map the distribution of these enzymes among eukaryotes and to reconstruct their phylogenies. We have found genes for the complete pathway in almost all examined representatives of Metamonada, the anaerobic protist group that includes parabasalids and diplomonads. Phylogenetic analyses indicate the presence of the complete pathway in the last common ancestor of metamonads and heterologous transformation experiments suggest its cytosolic localization in the metamonad ancestor. Outside Metamonada, the complete pathway occurs rarely, nevertheless, it was found in representatives of most major eukaryotic clades. Phylogenetic relationships of complete pathways are consistent with the presence of the Archaea-derived ADI pathway in the last common ancestor of all eukaryotes, although other evolutionary scenarios remain possible. The presence of the incomplete set of enzymes is relatively common among eukaryotes and it may be related to the fact that these enzymes are involved in other cellular processes, such as the ornithine-urea cycle. Single protein phylogenies suggest that the evolutionary history of all three enzymes has been shaped by frequent gene losses and horizontal transfers, which may sometimes be connected with their diverse roles in cellular metabolism.

A Bayesian method for identifying missing enzymes in predicted metabolic pathway databases

Directory of Open Access Journals (Sweden)

Karp Peter D

2004-06-01

Full Text Available Abstract Background The PathoLogic program constructs Pathway/Genome databases by using a genome's annotation to predict the set of metabolic pathways present in an organism. PathoLogic determines the set of reactions composing those pathways from the enzymes annotated in the organism's genome. Most annotation efforts fail to assign function to 40–60% of sequences. In addition, large numbers of sequences may have non-specific annotations (e.g., thiolase family protein. Pathway holes occur when a genome appears to lack the enzymes needed to catalyze reactions in a pathway. If a protein has not been assigned a specific function during the annotation process, any reaction catalyzed by that protein will appear as a missing enzyme or pathway hole in a Pathway/Genome database. Results We have developed a method that efficiently combines homology and pathway-based evidence to identify candidates for filling pathway holes in Pathway/Genome databases. Our program not only identifies potential candidate sequences for pathway holes, but combines data from multiple, heterogeneous sources to assess the likelihood that a candidate has the required function. Our algorithm emulates the manual sequence annotation process, considering not only evidence from homology searches, but also considering evidence from genomic context (i.e., is the gene part of an operon? and functional context (e.g., are there functionally-related genes nearby in the genome? to determine the posterior belief that a candidate has the required function. The method can be applied across an entire metabolic pathway network and is generally applicable to any pathway database. The program uses a set of sequences encoding the required activity in other genomes to identify candidate proteins in the genome of interest, and then evaluates each candidate by using a simple Bayes classifier to determine the probability that the candidate has the desired function. We achieved 71% precision at a

Insulin signaling pathways in lepidopteran steroidogenesis

Directory of Open Access Journals (Sweden)

Wendy eSmith

2014-02-01

Full Text Available Molting and metamorphosis are stimulated by the secretion of ecdysteroid hormones from the prothoracic glands. Insulin-like hormones have been found to enhance prothoracic gland activity, providing a mechanism to link molting to nutritional state. In silk moths (Bombyx mori, the prothoracic glands are directly stimulated by insulin and the insulin-like hormone bombyxin. Further, in Bombyx , the neuropeptide prothoracicotropic hormone (PTTH appears to act at least in part through the insulin-signaling pathway. In the prothoracic glands of Manduca sexta, while insulin stimulates the phosphorylation of the insulin receptor and Akt, neither insulin nor bombyxin II stimulate ecdysone secretion. Involvement of the insulin-signaling pathway in Manduca prothoracic glands was explored using two inhibitors of phosphatidylinositol-3-kinase (PI3K, LY294002 and wortmannin. PI3K inhibitors block the phosphorylation of Akt and 4EBP but have no effect on ecdysone secretion, or on the phosphorylation of the MAPkinase, ERK. Inhibitors that block phosphorylation of ERK, including the MEK inhibitor U0126, and high doses of the RSK inhibitor SL0101, effectively inhibit ecdysone secretion. The results highlight differences between the two lepidopteran insects most commonly used to directly study ecdysteroid secretion. In Bombyx, the PTTH and insulin-signaling pathways intersect; both insulin and PTTH enhance the phosphorylation of Akt and stimulate ecdysteroid secretion, and inhibition of PI3K reduces ecdysteroid secretion. By contrast, in Manduca, the action of PTTH is distinct from insulin. The results highlight species differences in the roles of translational regulators such as 4EBP, and members of the MAPkinase pathway such as ERK and RSK, in the effects of nutritionally-sensitive hormones such as insulin on ecdysone secretion and molting.

Pathways from and Crises after Communism: the Case of Central Eastern Europe

Directory of Open Access Journals (Sweden)

SZELENYI, Ivan

2014-12-01

Full Text Available The transition from socialist redistributive economy to capitalist markets has proved to be a rockier road that anticipated. The degree and character of difficulties that the countries faced during the transition depended on the nature of the pathways taken. In this paper I distinguish three major trajectories various countries followed: Central European neo-liberalism; post USSR neo-patrimonial regime and the East Asian (Chinese and Vietnamese transformation from below. Rather than distinguishing the “right way” from the “wrong way” I explore what the different costs and benefits of the various pathways were at various stages of the transformation.

Cost-effectiveness analysis of a postoperative clinical care pathway in head and neck surgery with microvascular reconstruction.

Science.gov (United States)

Dautremont, Jonathan F; Rudmik, Luke R; Yeung, Justin; Asante, Tiffany; Nakoneshny, Steve C; Hoy, Monica; Lui, Amanda; Chandarana, Shamir P; Matthews, Thomas W; Schrag, Christiaan; Dort, Joseph C

2013-12-19

The objective of this study is to evaluate the cost-effectiveness of a postoperative clinical care pathway for patients undergoing major head and neck oncologic surgery with microvascular reconstruction. This is a comparative trial of a prospective treatment group managed on a postoperative clinical care pathway and a historical group managed prior to pathway implementation. Effectiveness outcomes evaluated were total hospital days, return to OR, readmission to ICU and rate of pulmonary complications. Costing perspective was from the government payer. 118 patients were included in the study. All outcomes demonstrated that the postoperative pathway group was both more effective and less costly, and is therefore a dominant clinical intervention. The overall mean pre- and post-pathway costs are $22,733 and $16,564 per patient, respectively. The incremental cost reduction associated with the postoperative pathway was $6,169 per patient. Implementing the postoperative clinical care pathway in patients undergoing head and neck oncologic surgery with reconstruction resulted in improved clinical outcomes and reduced costs.

Discovery of new enzymes and metabolic pathways using structure and genome context

Science.gov (United States)

Zhao, Suwen; Kumar, Ritesh; Sakai, Ayano; Vetting, Matthew W.; Wood, B. McKay; Brown, Shoshana; Bonanno, Jeffery B.; Hillerich, Brandan S.; Seidel, Ronald D.; Babbitt, Patricia C.; Almo, Steven C.; Sweedler, Jonathan V.; Gerlt, John A.; Cronan, John E.; Jacobson, Matthew P.

2014-01-01

Assigning valid functions to proteins identified in genome projects is challenging, with over-prediction and database annotation errors major concerns1. We, and others2, are developing computation-guided strategies for functional discovery using “metabolite docking” to experimentally derived3 or homology-based4 three-dimensional structures. Bacterial metabolic pathways often are encoded by “genome neighborhoods” (gene clusters and/or operons), which can provide important clues for functional assignment. We recently demonstrated the synergy of docking and pathway context by “predicting” the intermediates in the glycolytic pathway in E. coli5. Metabolite docking to multiple binding proteins/enzymes in the same pathway increases the reliability of in silico predictions of substrate specificities because the pathway intermediates are structurally similar. We report that structure-guided approaches for predicting the substrate specificities of several enzymes encoded by a bacterial gene cluster allowed i) the correct prediction of the in vitro activity of a structurally characterized enzyme of unknown function (PDB 2PMQ), 2-epimerization of trans-4-hydroxy-L-proline betaine (tHyp-B) and cis-4-hydroxy-D-proline betaine (cHyp-B), and ii) the correct identification of the catabolic pathway in which Hyp-B 2-epimerase participates. The substrate-liganded pose predicted by virtual library screening (docking) was confirmed experimentally. The enzymatic activities in the predicted pathway were confirmed by in vitro assays and genetic analyses; the intermediates were identified by metabolomics; and repression of the genes encoding the pathway by high salt was established by transcriptomics, confirming the osmolyte role of tHyp-B. This study establishes the utility of structure-guide functional predictions to enable the discovery of new metabolic pathways. PMID:24056934

A novel method to identify hub pathways of rheumatoid arthritis based on differential pathway networks.

Science.gov (United States)

Wei, Shi-Tong; Sun, Yong-Hua; Zong, Shi-Hua

2017-09-01

The aim of the current study was to identify hub pathways of rheumatoid arthritis (RA) using a novel method based on differential pathway network (DPN) analysis. The present study proposed a DPN where protein‑protein interaction (PPI) network was integrated with pathway‑pathway interactions. Pathway data was obtained from background PPI network and the Reactome pathway database. Subsequently, pathway interactions were extracted from the pathway data by building randomized gene‑gene interactions and a weight value was assigned to each pathway interaction using Spearman correlation coefficient (SCC) to identify differential pathway interactions. Differential pathway interactions were visualized using Cytoscape to construct a DPN. Topological analysis was conducted to identify hub pathways that possessed the top 5% degree distribution of DPN. Modules of DPN were mined according to ClusterONE. A total of 855 pathways were selected to build pathway interactions. By filtrating pathway interactions of weight values >0.7, a DPN with 312 nodes and 791 edges was obtained. Topological degree analysis revealed 15 hub pathways, such as heparan sulfate/heparin‑glycosaminoglycan (HS‑GAG) degradation, HS‑GAG metabolism and keratan sulfate degradation for RA based on DPN. Furthermore, hub pathways were also important in modules, which validated the significance of hub pathways. In conclusion, the proposed method is a computationally efficient way to identify hub pathways of RA, which identified 15 hub pathways that may be potential biomarkers and provide insight to future investigation and treatment of RA.

Aberrations of the p53 pathway components p53, MDM2 and CDKN2A appear independent in diffuse large B cell lymphoma

DEFF Research Database (Denmark)

Møller, Michael Boe; Ino, Y; Gerdes, A M

1999-01-01

The two gene products of the CDKN2A gene, p16 and p19ARF, have recently been linked to each of two major tumour suppressor pathways in human carcinogenesis, the RB1 pathway and the p53 pathway. p16 inhibits the phosphorylation of the retinoblastoma gene product by cyclin D-dependent kinases...

Major histocompatibility complex-restricted self-recognition in responses to trinitrophenyl-Ficoll. A novel cell interaction pathway requiring self-recognition of accessory cell H-2 determinants by both T cells and B cells

International Nuclear Information System (INIS)

Hodes, R.J.; Hathcock, K.S.; Singer, A.

1983-01-01

In vitro primary antibody responses to limiting concentrations of trinitrophenyl (TNP)-Ficoll were shown to be T cell dependent, requiring the cooperation of T helper (TH) cells, B cells, and accessory cells. Under these conditions, TH cells derived from long-term radiation bone marrow chimeras were major histocompatibility complex (MHC) restricted in their ability to cooperate with accessory cells expressing host-type MHC determinants. The requirement for MHC-restricted self-recognition by TNP-Ficoll-reactive B cells was assessed under these T-dependent conditions. In the presence of competent TH cells, chimeric B cells were found to be MHC restricted, cooperating only with accessory cells that expressed host-type MHC products. In contrast, the soluble products of certain monoclonal T cell lines were able to directly activate B cells in response to TNP-Ficoll, bypassing any requirement for MHC-restricted self-recognition. These findings demonstrate the existence of a novel cell interaction pathway in which B cells as well as TH cells are each required to recognize self-MHC determinants on accessory cells, but are not required to recognize each other. They further demonstrate that the requirement for self-recognition by B cells may be bypassed in certain T-dependent activation pathways

The functional interplay between the HIF pathway and the ubiquitin system - more than a one-way road.

Science.gov (United States)

Günter, Julia; Ruiz-Serrano, Amalia; Pickel, Christina; Wenger, Roland H; Scholz, Carsten C

2017-07-15

The hypoxia inducible factor (HIF) pathway and the ubiquitin system represent major cellular processes that are involved in the regulation of a plethora of cellular signaling pathways and tissue functions. The ubiquitin system controls the ubiquitination of proteins, which is the covalent linkage of one or several ubiquitin molecules to specific targets. This ubiquitination is catalyzed by approximately 1000 different E3 ubiquitin ligases and can lead to different effects, depending on the type of internal ubiquitin chain linkage. The best-studied function is the targeting of proteins for proteasomal degradation. The activity of E3 ligases is antagonized by proteins called deubiquitinases (or deubiquitinating enzymes), which negatively regulate ubiquitin chains. This is performed in most cases by the catalytic removal of these chains from the targeted protein. The HIF pathway is regulated in an oxygen-dependent manner by oxygen-sensing hydroxylases. Covalent modification of HIFα subunits leads to the recruitment of an E3 ligase complex via the von Hippel-Lindau (VHL) protein and the subsequent polyubiquitination and proteasomal degradation of HIFα subunits, demonstrating the regulation of the HIF pathway by the ubiquitin system. This unidirectional effect of an E3 ligase on the HIF pathway is the best-studied example for the interplay between these two important cellular processes. However, additional regulatory mechanisms of the HIF pathway through the ubiquitin system are emerging and, more recently, also the reciprocal regulation of the ubiquitin system through components of the HIF pathway. Understanding these mechanisms and their relevance for the activity of each other is of major importance for the comprehensive elucidation of the oxygen-dependent regulation of cellular processes. This review describes the current knowledge of the functional bidirectional interplay between the HIF pathway and the ubiquitin system on the protein level. Copyright © 2017

Omega-oxidation is the major pathway for the catabolism of leukotriene B4 in human polymorphonuclear leukocytes.

Science.gov (United States)

Shak, S; Goldstein, I M

1984-08-25

Leukotriene B4 (LTB4), formed by the 5-lipoxygenase pathway in human polymorphonuclear leukocytes (PMN), may be an important mediator of inflammation. Recent studies suggest that human leukocytes can convert LTB4 to products that are less biologically active. To examine the catabolism of LTB4, we developed (using high performance liquid chromatography) a sensitive, reproducible assay for this mediator and its omega-oxidation products (20-OH- and 20-COOH-LTB4). With this assay, we have found that human PMN (but not human monocytes, lymphocytes, or platelets) convert exogenous LTB4 almost exclusively to 20-OH- and 20-COOH-LTB4 (identified by gas chromatography-mass spectrometry). Catabolism of exogenous LTB4 by omega-oxidation is rapid (t1/2 approximately 4 min at 37 degrees C in reaction mixtures containing 1.0 microM LTB4 and 20 X 10(6) PMN/ml), temperature-dependent (negligible at 0 degrees C), and varies with cell number as well as with initial substrate concentration. The pathway for omega-oxidation in PMN is specific for LTB4 and 5(S),12(S)-dihydroxy-6,8,10,14-eicosatetraenoic acid (only small amounts of other dihydroxylated-derivatives of arachidonic acid are converted to omega-oxidation products). Even PMN that are stimulated by phorbol myristate acetate to produce large amounts of superoxide anion radicals catabolize exogenous leukotriene B4 primarily by omega-oxidation. Finally, LTB4 that is generated when PMN are stimulated with the calcium ionophore, A23187, is rapidly catabolized by omega-oxidation. Thus, human PMN not only generate and respond to LTB4, but also rapidly and specifically catabolize this mediator by omega-oxidation.

DMPD: Parallel pathways of virus recognition. [Dynamic Macrophage Pathway CSML Database

Lifescience Database Archive (English)

Full Text Available 16713969 Parallel pathways of virus recognition. Tenoever BR, Maniatis T. Immunity.... 2006 May;24(5):510-2. (.png) (.svg) (.html) (.csml) Show Parallel pathways of virus recognition. PubmedID 1...6713969 Title Parallel pathways of virus recognition. Authors Tenoever BR, Maniatis T. Publication Immunity.

Simulation of a major tokamak disruption

International Nuclear Information System (INIS)

White, R.B.; Monticello, D.A.; Rosenbluth, M.N.

1977-08-01

It is known that the internal tokamak disruption leads to a current profile which is flattened inside the surface where the safety factor equals unity. It is shown that such a profile can lead to m = 2 magnetic islands which grow to fill a substantial part of the tokamak cross section in a time consistent with the observations of the major disruption

DMPD: Signaling pathways activated by microorganisms. [Dynamic Macrophage Pathway CSML Database

Lifescience Database Archive (English)

Full Text Available 17303405 Signaling pathways activated by microorganisms. Takeuchi O, Akira S. Curr ...Opin Cell Biol. 2007 Apr;19(2):185-91. Epub 2007 Feb 15. (.png) (.svg) (.html) (.csml) Show Signaling pathways activated by microorg...anisms. PubmedID 17303405 Title Signaling pathways activated by microorganisms. Auth

Efficiency and CO[sub 2] emission analysis of pathways by which methane can provide transportation services

Energy Technology Data Exchange (ETDEWEB)

Crane, P; Scott, D S [Victoria Univ., BC (Canada). Inst. for Integrated Energy Systems Victoria Univ., BC (Canada). Dept. of Mechanical Engineering

1992-07-01

Methane is expected to have an increasingly important role as an energy source in the future. As a result, methane will become a major energy source for the transportation sector. Future energy systems will also be selected for efficiency and environmental gentility. Six candidate pathways by which the energy for service transportation can be provided, using methane as the sole energy source, are proposed and are compared with the use of gasoline from petroleum. These pathways involve methanol, methane and hydrogen used in spark ignition engines and solid polymer fuel cells. The energy conversion processes in each pathway are analysed based on the second law of thermodynamics. Two performance criteria are used: total exergy input to the pathway and total carbon dioxide produced along the pathway. All results are normalized to a unit of transportation service, in this case 1 km of city driving. A surprising result is that the methanol spark ignition engine pathway is the least efficient and produces the greatest amount of carbon dioxide, of the pathways examined. Hydrogen and fuel cell pathways are found to be optimal using the criteria of this paper. (author)

Genome wide expression analysis in HPV16 Cervical Cancer: identification of altered metabolic pathways

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Salcedo Mauricio

2007-09-01

Full Text Available Abstract Background Cervical carcinoma (CC is a leading cause of death among women worldwide. Human papilloma virus (HPV is a major etiological factor in CC and HPV 16 is the more frequent viral type present. Our aim was to characterize metabolic pathways altered in HPV 16 tumor samples by means of transcriptome wide analysis and bioinformatics tools for visualizing expression data in the context of KEGG biological pathways. Results We found 2,067 genes significantly up or down-modulated (at least 2-fold in tumor clinical samples compared to normal tissues, representing ~3.7% of analyzed genes. Cervical carcinoma was associated with an important up-regulation of Wnt signaling pathway, which was validated by in situ hybridization in clinical samples. Other up-regulated pathways were those of calcium signaling and MAPK signaling, as well as cell cycle-related genes. There was down-regulation of focal adhesion, TGF-β signaling, among other metabolic pathways. Conclusion This analysis of HPV 16 tumors transcriptome could be useful for the identification of genes and molecular pathways involved in the pathogenesis of cervical carcinoma. Understanding the possible role of these proteins in the pathogenesis of CC deserves further studies.

Revealing the cerebello-ponto-hypothalamic pathway in the human brain.

Science.gov (United States)

Kamali, Arash; Karbasian, Niloofar; Rabiei, Pejman; Cano, Andres; Riascos, Roy F; Tandon, Nitin; Arevalo, Octavio; Ocasio, Laura; Younes, Kyan; Khayat-Khoei, Mahsa; Mirbagheri, Saeedeh; Hasan, Khader M

2018-04-16

The cerebellum is shown to be involved in some limbic functions of the human brain such as emotion and affect. The major connection of the cerebellum with the limbic system is known to be through the cerebello-hypothalamic pathways. The consensus is that the projections from the cerebellar nuclei to the limbic system, and particularly the hypothalamus, or from the hypothalamus to the cerebellar nuclei, are through multisynaptic pathways in the bulbar reticular formation. The detailed anatomy of the pathways responsible for mediating these responses, however, is yet to be determined. Diffusion tensor imaging may be helpful in better visualizing the surgical anatomy of the cerebello-ponto-hypothalamic (CPH) pathway. This study aimed to investigate the utility of high-spatial-resolution diffusion tensor tractography for mapping the trajectory of the CPH tract in the human brain. Fifteen healthy adults were studied. We delineated, for the first time, the detailed trajectory of the CPH tract of the human brain in fifteen normal adult subjects using high-spatial-resolution diffusion tensor tractography. We further revealed the close relationship of the CPH tract with the optic tract, temporo-pontine tract, amygdalofugal tract and the fornix in the human brain. Copyright © 2018. Published by Elsevier B.V.

Molecular and cellular pathways associated with chromosome 1p deletions during colon carcinogenesis

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Payne CM

2011-05-01

Full Text Available Claire M Payne, Cheray Crowley-Skillicorn, Carol Bernstein, Hana Holubec, Harris BernsteinDepartment of Cell Biology and Anatomy, College of Medicine, University of Arizona Tucson, AZ, USAAbstract: Chromosomal instability is a major pathway of sporadic colon carcinogenesis. Chromosome arm 1p appears to be one of the “hot spots” in the non-neoplastic mucosa that, when deleted, is associated with the initiation of carcinogenesis. Chromosome arm 1p contains genes associated with DNA repair, spindle checkpoint function, apoptosis, multiple microRNAs, the Wnt signaling pathway, tumor suppression, antioxidant activities, and defense against environmental toxins. Loss of 1p is dangerous since it would likely contribute to genomic instability leading to tumorigenesis. The 1p deletion-associated colon carcinogenesis pathways are reviewed at the molecular and cellular levels. Sporadic colon cancer is strongly linked to a high-fat/low-vegetable/low-micronutrient, Western-style diet. We also consider how selected dietary-related compounds (eg, excess hydrophobic bile acids, and low levels of folic acid, niacin, plant-derived antioxidants, and other modulatory compounds might affect processes leading to chromosomal deletions, and to the molecular and cellular pathways specifically altered by chromosome 1p loss.Keywords: chromosome 1p, colon carcinogenesis, molecular pathways, cellular pathways

Evolution of JAK-STAT pathway components: mechanisms and role in immune system development.

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Clifford Liongue

Full Text Available BACKGROUND: Lying downstream of a myriad of cytokine receptors, the Janus kinase (JAK-Signal transducer and activator of transcription (STAT pathway is pivotal for the development and function of the immune system, with additional important roles in other biological systems. To gain further insight into immune system evolution, we have performed a comprehensive bioinformatic analysis of the JAK-STAT pathway components, including the key negative regulators of this pathway, the SH2-domain containing tyrosine phosphatase (SHP, Protein inhibitors against Stats (PIAS, and Suppressor of cytokine signaling (SOCS proteins across a diverse range of organisms. RESULTS: Our analysis has demonstrated significant expansion of JAK-STAT pathway components co-incident with the emergence of adaptive immunity, with whole genome duplication being the principal mechanism for generating this additional diversity. In contrast, expansion of upstream cytokine receptors appears to be a pivotal driver for the differential diversification of specific pathway components. CONCLUSION: Diversification of JAK-STAT pathway components during early vertebrate development occurred concurrently with a major expansion of upstream cytokine receptors and two rounds of whole genome duplications. This produced an intricate cell-cell communication system that has made a significant contribution to the evolution of the immune system, particularly the emergence of adaptive immunity.

Aerosol penetration of leak pathways : an examination of the available data and models.

Energy Technology Data Exchange (ETDEWEB)

Powers, Dana Auburn

2009-04-01

Data and models of aerosol particle deposition in leak pathways are described. Pathways considered include capillaries, orifices, slots and cracks in concrete. The Morewitz-Vaughan criterion for aerosol plugging of leak pathways is shown to be applicable only to a limited range of particle settling velocities and Stokes numbers. More useful are sampling efficiency criteria defined by Davies and by Liu and Agarwal. Deposition of particles can be limited by bounce from surfaces defining leak pathways and by resuspension of particles deposited on these surfaces. A model of the probability of particle bounce is described. Resuspension of deposited particles can be triggered by changes in flow conditions, particle impact on deposits and by shock or vibration of the surfaces. This examination was performed as part of the review of the AP1000 Standard Combined License Technical Report, APP-GW-GLN-12, Revision 0, 'Offsite and Control Room Dose Changes' (TR-112) in support of the USNRC AP1000 Standard Combined License Pre-Application Review.

The functional anatomy of psychomotor disturbances in major depressive disorder

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Benny eLiberg

2015-03-01

Full Text Available Psychomotor disturbances (PMD are a classic feature of depressive disorder that provide rich clinical information. The aim our narrative review was to characterize the functional anatomy of PMD by summarizing findings from neuroimaging studies. We found evidence across several neuroimaging modalities that suggest involvement of fronto-striatal neurocircuitry, and monoaminergic pathways and metabolism. We suggest that PMD in major depressive disorder emerge from an alteration of limbic signals, which influence emotion, volition, higher-order cognitive functions, and movement.

Anatomical study of the final common pathway for vocalization in the cat

Science.gov (United States)

Holstege, Gert

1989-01-01

Results are presented of an anatomical study of the neuronal pathways in the cat, via which the periaqueductal gray (PAG) produces excitation of motoneurons involved in vocalization. It is shown that a specific cell group in the lateral part of the caudal PAG and in the tegmentum just lateral to it projects bilaterally to the nucleus retroambiguus (NRA) in the caudal medulla oblongata. Neurons in the NRA in turn project, via a contralateral pathway through the ventral funiculus of the spinal cord, to the motoneuronal cell groups innervating intercostal and abdominal muscles. In the brainstem, the NRA neurons project to the motoneuronal cell groups innervating mouth-opening and perioral muscles as well as to motoneurons innervating the pharynx, soft palate, and tongue. These results indicate that the projections from PAG via NRA to vocalization motoneurons form the final common pathway in vocalization.

Pathways Intern Report

Science.gov (United States)

Huggett, Daniel James

2017-01-01

The National Aeronautics and Space Administration (NASA) provides a formal training program for prospective employees titled, Pathways Intern Employment. The Pathways program targets graduate and undergraduate students who strive to become an active contributor to NASA's goal of space exploration. The report herein provides an account of Daniel Huggett's Pathways experience for the Spring and Summer 2017 semesters.

Malaria parasite evasion of classical complement pathway attack

DEFF Research Database (Denmark)

Larsen, Mads Delbo; Ditlev, Sisse; Olmos, Rafael Bayarri

2017-01-01

of the protective antibodies that are gradually acquired in response to P. falciparum-IEs. Although this response is dominated by IgG1 and IgG3, complement-mediated attack following activation of the classical pathway does not appear to be a major effector mechanism. We hypothesized that this is related to the knob...... is that the knob-restricted expression of PfEMP1 on the IE surface may serve as a hitherto unappreciated immune evasion mechanism employed by P. falciparum parasites....

Interleukins and their signaling pathways in the Reactome biological pathway database.

Science.gov (United States)

Jupe, Steve; Ray, Keith; Roca, Corina Duenas; Varusai, Thawfeek; Shamovsky, Veronica; Stein, Lincoln; D'Eustachio, Peter; Hermjakob, Henning

2018-04-01

There is a wealth of biological pathway information available in the scientific literature, but it is spread across many thousands of publications. Alongside publications that contain definitive experimental discoveries are many others that have been dismissed as spurious, found to be irreproducible, or are contradicted by later results and consequently now considered controversial. Many descriptions and images of pathways are incomplete stylized representations that assume the reader is an expert and familiar with the established details of the process, which are consequently not fully explained. Pathway representations in publications frequently do not represent a complete, detailed, and unambiguous description of the molecules involved; their precise posttranslational state; or a full account of the molecular events they undergo while participating in a process. Although this might be sufficient to be interpreted by an expert reader, the lack of detail makes such pathways less useful and difficult to understand for anyone unfamiliar with the area and of limited use as the basis for computational models. Reactome was established as a freely accessible knowledge base of human biological pathways. It is manually populated with interconnected molecular events that fully detail the molecular participants linked to published experimental data and background material by using a formal and open data structure that facilitates computational reuse. These data are accessible on a Web site in the form of pathway diagrams that have descriptive summaries and annotations and as downloadable data sets in several formats that can be reused with other computational tools. The entire database and all supporting software can be downloaded and reused under a Creative Commons license. Pathways are authored by expert biologists who work with Reactome curators and editorial staff to represent the consensus in the field. Pathways are represented as interactive diagrams that include as

A board game to assist pharmacy students in learning metabolic pathways.

Science.gov (United States)

Rose, Tyler M

2011-11-10

To develop and evaluate a board game designed to increase students' enjoyment of learning metabolic pathways; their familiarity with pathway reactions, intermediates, and regulation; and, their understanding of how pathways relate to one another and to selected biological conditions. The board game, entitled Race to Glucose, was created as a team activity for first-year pharmacy students in the biochemistry curriculum. A majority of respondents agreed that the game was helpful for learning regulation, intermediates, and interpathway relationships but not for learning reactions, formation of energetic molecules, or relationships, to biological conditions. There was a significant increase in students' scores on game-related examination questions (68.8% pretest vs. 81.3% posttest), but the improvement was no greater than that for examination questions not related to the game (12.5% vs. 10.9%). First-year pharmacy students considered Race to Glucose to be an enjoyable and helpful tool for learning intermediates, regulation, and interpathway relationships.

Endocrine-disrupting Chemicals: Review of Toxicological Mechanisms Using Molecular Pathway Analysis

Science.gov (United States)

Yang, Oneyeol; Kim, Hye Lim; Weon, Jong-Il; Seo, Young Rok

2015-01-01

Endocrine disruptors are known to cause harmful effects to human through various exposure routes. These chemicals mainly appear to interfere with the endocrine or hormone systems. As importantly, numerous studies have demonstrated that the accumulation of endocrine disruptors can induce fatal disorders including obesity and cancer. Using diverse biological tools, the potential molecular mechanisms related with these diseases by exposure of endocrine disruptors. Recently, pathway analysis, a bioinformatics tool, is being widely used to predict the potential mechanism or biological network of certain chemicals. In this review, we initially summarize the major molecular mechanisms involved in the induction of the above mentioned diseases by endocrine disruptors. Additionally, we provide the potential markers and signaling mechanisms discovered via pathway analysis under exposure to representative endocrine disruptors, bisphenol, diethylhexylphthalate, and nonylphenol. The review emphasizes the importance of pathway analysis using bioinformatics to finding the specific mechanisms of toxic chemicals, including endocrine disruptors. PMID:25853100

An in silico platform for the design of heterologous pathways in nonnative metabolite production

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Chatsurachai Sunisa

2012-05-01

Full Text Available Abstract Background Microorganisms are used as cell factories to produce valuable compounds in pharmaceuticals, biofuels, and other industrial processes. Incorporating heterologous metabolic pathways into well-characterized hosts is a major strategy for obtaining these target metabolites and improving productivity. However, selecting appropriate heterologous metabolic pathways for a host microorganism remains difficult owing to the complexity of metabolic networks. Hence, metabolic network design could benefit greatly from the availability of an in silico platform for heterologous pathway searching. Results We developed an algorithm for finding feasible heterologous pathways by which nonnative target metabolites are produced by host microorganisms, using Escherichia coli, Corynebacterium glutamicum, and Saccharomyces cerevisiae as templates. Using this algorithm, we screened heterologous pathways for the production of all possible nonnative target metabolites contained within databases. We then assessed the feasibility of the target productions using flux balance analysis, by which we could identify target metabolites associated with maximum cellular growth rate. Conclusions This in silico platform, designed for targeted searching of heterologous metabolic reactions, provides essential information for cell factory improvement.

Major Accidents (Gray Swans) Likelihood Modeling Using Accident Precursors and Approximate Reasoning.

Science.gov (United States)

Khakzad, Nima; Khan, Faisal; Amyotte, Paul

2015-07-01

Compared to the remarkable progress in risk analysis of normal accidents, the risk analysis of major accidents has not been so well-established, partly due to the complexity of such accidents and partly due to low probabilities involved. The issue of low probabilities normally arises from the scarcity of major accidents' relevant data since such accidents are few and far between. In this work, knowing that major accidents are frequently preceded by accident precursors, a novel precursor-based methodology has been developed for likelihood modeling of major accidents in critical infrastructures based on a unique combination of accident precursor data, information theory, and approximate reasoning. For this purpose, we have introduced an innovative application of information analysis to identify the most informative near accident of a major accident. The observed data of the near accident were then used to establish predictive scenarios to foresee the occurrence of the major accident. We verified the methodology using offshore blowouts in the Gulf of Mexico, and then demonstrated its application to dam breaches in the United Sates. © 2015 Society for Risk Analysis.

Supply Chain Sustainability Analysis of Three Biofuel Pathways

Energy Technology Data Exchange (ETDEWEB)

Jacob J. Jacobson; Erin Searcy; Kara Cafferty; Jennifer B. Dunn; Michael Johnson; Zhichao Wang; Michael Wang; Mary Biddy; Abhijit Dutta; Daniel Inman; Eric Tan; Sue Jones; Lesley Snowden-Swan

2013-11-01

The Department of Energy’s (DOE) Bioenergy Technologies Office (BETO) collaborates with industrial, agricultural, and non-profit partners to develop and deploy biofuels and other biologically-derived products. As part of this effort, BETO and its national laboratory teams conduct in-depth techno-economic assessments (TEA) of technologies to produce biofuels as part state of technology (SOT) analyses. An SOT assesses progress within and across relevant technology areas based on actual experimental results relative to technical targets and cost goals from design cases and includes technical, economic, and environmental criteria as available. Overall assessments of biofuel pathways begin with feedstock production and the logistics of transporting the feedstock from the farm or plantation to the conversion facility or biorefinery. The conversion process itself is modeled in detail as part of the SOT analysis. The teams then develop an estimate of the biofuel minimum selling price (MSP) and assess the cost competitiveness of the biofuel with conventional fuels such as gasoline.

Application of R to investigate common gene regulatory network pathway among bipolar disorder and associate diseases

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Nahida Habib

2016-12-01

Full Text Available Depression, Major Depression or mental disorder creates severe diseases. Mental illness such as Unipolar Major Depression, Bipolar Disorder, Dysthymia, Schizophrenia, Cardiovascular Diseases (Hypertension, Coronary Heart Disease, Stroke etc., are known as Major Depression. Several studies have revealed the possibilities about the association among Bipolar Disorder, Schizophrenia, Coronary Heart Diseases and Stroke with each other. The current study aimed to investigate the relationships between genetic variants in the above four diseases and to create a common pathway or PPI network. The associated genes of each disease are collected from different gene database with verification using R. After performing some preprocessing, mining and operations using R on collected genes, seven (7 common associated genes are discovered on selected four diseases (SZ, BD, CHD and Stroke. In each of the iteration, the numbers of collected genes are reduced up to 51%, 36%, 10%, 2% and finally less than 1% respectively. Moreover, common pathway on selected diseases has been investigated in this research.

Decreased bone uptake of technetium-99m polyphosphate in thalassemia major

International Nuclear Information System (INIS)

Valdez, V.A.; Jacobstein, J.G.

1980-01-01

Bone scans were performed with Tc-99m stannous polyphosphate on four patients with thalassemia major. Three of the scans show generalized decrease in skeletal uptake of the radiopharmaceutical, associated with renal enlargement and markedly increased renal radioactivity. The skeletal findings are consistent with the known bone abnormalities in thalassemia major, which are secondary to the extensive marrow hyperplasia and include loss of trabeculae and cortical thinning with consequent loss of bone mass. The increased renal uptake is probably due in part to the increased renal excretion (secondary to the poor bone uptake) and in part to the tubular dilatation and renal enlargement associated with thalassemia major. In addition, the presence of excessive amounts of iron in these patients may play a role in both the skeletal and renal findings

The Impact of climate change on heat-related mortality in six major cities, South Korea, under representative concentration pathways (RCPs

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Youngmin eKim

2014-02-01

Full Text Available Background: We aimed to quantify the excess mortality associated with increased temperature due to climate change in six major Korean cities under Representative Concentration Pathways (RCPs which are new emission scenarios designed for the fifth assessment report of the Intergovernmental Panel on Climate Change (IPCC. Methods: We first examined the association between daily mean temperature and mortality in each during the summertime (June to September from 2001 to 2008. This was done using a generalized linear Poisson model with adjustment for a long-term time trend, relative humidity, air pollutants, and day of the week. We then computed heat-related mortality attributable to future climate change using estimated mortality risks, projected future populations, and temperature increments for both future years 2041-2070 and 2071-2100 under RCP 4.5 and 8.5. We considered effects from added days with high temperatures over thresholds and shifted effects from high to higher temperature.Results: Estimated excess all-cause mortalities for six cities in Korea ranged from 500 (95% CI: 313-703 for 2041-2070 to 2,320 (95% CI: 1,430-3,281 deaths per year for 2071-2100 under two RCPs. Excess cardiovascular mortality was estimated to range from 192 (95% CI: 41-351 to 896 (95% CI: 185-1,694 deaths per year, covering about 38.5% of all-cause excess mortality. Increased rates of heat-related mortality were higher in cities located at relatively lower latitude than cities with higher latitude. Estimated excess mortality under RCP 8.5, a fossil fuel-intensive emission scenario, was more than twice as high compared with RCP 4.5, low to medium emission scenario.Conclusions: Excess mortality due to climate change is expected to be profound in the future showing spatial variation. Efforts to mitigate climate change can cause substantial health benefits via reducing heat-related mortality.

On the deduction of chemical reaction pathways from measurements of time series of concentrations.

Science.gov (United States)

Samoilov, Michael; Arkin, Adam; Ross, John

2001-03-01

We discuss the deduction of reaction pathways in complex chemical systems from measurements of time series of chemical concentrations of reacting species. First we review a technique called correlation metric construction (CMC) and show the construction of a reaction pathway from measurements on a part of glycolysis. Then we present two new improved methods for the analysis of time series of concentrations, entropy metric construction (EMC), and entropy reduction method (ERM), and illustrate (EMC) with calculations on a model reaction system. (c) 2001 American Institute of Physics.

Is There Volume Transmission Along Extracellular Fluid Pathways Corresponding to the Acupuncture Meridians?

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Weibo Zhang

2017-02-01

Full Text Available Volume transmission is a new major communication signaling via extracellular fluid (interstitial fluid pathways. It was proposed by the current authors that such pathways can explain the meridian phenomena and acupuncture effects. To investigate whether meridian-like structures exist in fish body and operate via volume transmission in extracellular fluid pathways, we injected alcian blue (AB under anesthesia into Gephyrocharax melanocheir, which has a translucent body. The migration of AB could be seen directly and was recorded by a digital camera. The fish was then embedded and cut transversely to observe the position of tracks in three dimensions. Eight longitudinal threadlike blue tracks were recognized on the fish. The positions of these threadlike tracks were similar to meridians on the human body. Transverse sections showed that these tracks distributed to different layers of distinct subcutaneous loose connective tissues and intermuscular septa. Lymphatic vessels were sometimes associated with the extracellular blue tracks where the migration of AB occurred. Extracellular fluid pathways were found on fish through their transport of AB. These pathways operating via volume transmission appeared to be similar in positions and functions to the acupuncture meridians in Chinese medicine.

Metabolic-flux analysis of hydrogen production pathway in Citrobacter amalonaticus Y19

Energy Technology Data Exchange (ETDEWEB)

Oh, You-Kwan; Kim, Mi-Sun [Bioenergy Research Center, Korea Institute of Energy Research, Daejeon 305-343 (Korea); Kim, Heung-Joo; Park, Sunghoon [Department of Chemical and Biochemical Engineering and Institute for Environmental Technology and Industry, Pusan National University, Busan 609-735 (Korea); Ryu, Dewey D.Y. [Biochemical Engineering Program, Department of Chemical Engineering and Material Science, University of California, Davis, CA 95616 (United States)

2008-03-15

For the newly isolated chemoheterotrophic bacterium Citrobacter amalonaticus Y19, anaerobic glucose metabolism and hydrogen (H{sub 2}) production pathway were studied using batch cultivation and an in silico metabolic-flux analysis. Batch cultivation was conducted under varying initial glucose concentration between 1.5 and 9.5 g/L with quantitative measurement of major metabolites to obtain accurate carbon material balance. The metabolic flux of Y19 was analyzed using a metabolic-pathway model which was constructed from 81 biochemical reactions. The linear optimization program MetaFluxNet was employed for the analysis. When the specific growth rate of cells was chosen as an objective function, the model described the batch culture characteristics of Ci. amalonaticus Y19 reasonably well. When the specific H{sub 2} production rate was selected as an objective function, on the other hand, the achievable maximal H{sub 2} production yield (8.7molH{sub 2}/mol glucose) and the metabolic pathway enabling the high H{sub 2} yield were identified. The pathway involved non-native NAD(P)-linked hydrogenase and H{sub 2} production from NAD(P)H which were supplied at a high rate from glucose degradation through the pentose phosphate pathway. (author)

The photovoltaic pathway

International Nuclear Information System (INIS)

Jourde, P.; Guerin de Montgareuil, A.; Mattera, F.; Jaussaud, C.; Boulanger, P.; Veriat, G.; Firon, M.

2004-01-01

Photovoltaic conversion, the direct transformation of light into electricity, is, of the three pathways for solar energy, the one experiencing most rapid growth, and for which scientific and technological advances are most promising, as regards significant improvements in its economic balance. While the long-term trend, in Europe, is favorable, with annual growth set at 30%, the cost per photovoltaic kilowatt-hour remains some ten times higher than that achieved with natural gas or nuclear energy (after connection to the grid), this being a handicap, at first blush, for high power ratings. For remote locations, where its advantage is unquestionable, in spite of the added cost of storage between insolation periods (this more than compensating for savings in terms of connection costs), this pathway sets its future prospects on marked module cost reductions. Such reduction may only be achieved by way of technological breakthroughs, to which CEA, active as it has been, in this area, for some thirty years, intends making a contribution, as linchpin of French research and technology, and a key protagonist on the European scene. One of the avenues being pursued concerns fabrication of high-efficiency cells from mineral or organic thin films, with particularly strong expectations with respect to the all-polymer path, complementary of the silicon pathway. Concurrently, device reliability needs must be improved, this being another factor making for an improved overall balance. To achieve easier transfer to industry of laboratory outcomes, CEA is relying, in particular, on the new cell fabrication platform set up in Grenoble, this complementing its other R and D resources, including those installed at Cadarache, allowing testing of cells and entire photovoltaic systems in actual operating conditions. Another path for cost reductions being explored by CEA research workers consists in construction of systems integrated into the built environment: this affords new prospects

MIPPA: First Broad Changes to Medicare Part D Plan Operations.

Science.gov (United States)

LeMasurier, Jean D; Edgar, Babette

2009-04-01

In July 2008, as part of broad Medicare reform, Congress passed the first major legislative changes to Medicare Part D since its enactment in 2003-the Medicare Improvements for Patients and Providers Act. This new legislation has significant implications for how Part D plans can market and enroll Medicare beneficiaries. The new legislation also strengthened beneficiary protections, expanded the low-income subsidy provisions originally included in Part D, and expanded Part D coverage. These changes have significant implications for the operation of Part D plans and can affect those involved in benefit design, including specialty pharmacy coverage. This article discusses the major changes that took effect on January 1, 2009, and have immediate implications for Part D plan sponsors, including Medicare Advantage plans and stand-alone prescription drug plans.

Surface heat loads during major disruptions in INTOR

International Nuclear Information System (INIS)

Mioduszewski, P.

1981-01-01

The thermal energy contained in the INTOR plasma is assumed to be about 200 MJ. In a major plasma disruption this energy is dumped into parts of the first wall in a time short compared to the energy confinement time. To estimate the surface heat load due to this energy dump, two major parameters are not sufficiently well known at present: the disruption time and the affected first wall surface area. To get a certain idea of the heat loads to be expected, we have employed the model of conserved flux tubes which are successively scraped-off at the first wall. The results reveal that even for a homogeneous deposition in the toroidal direction the heat load is too high for some parts of the first wall. Since, however, the presumptions are very uncertain to date, experiments will have to be set up to study the energy deposition during disruptions. (author)

Binocular depth processing in the ventral visual pathway.

Science.gov (United States)

Verhoef, Bram-Ernst; Vogels, Rufin; Janssen, Peter

2016-06-19

One of the most powerful forms of depth perception capitalizes on the small relative displacements, or binocular disparities, in the images projected onto each eye. The brain employs these disparities to facilitate various computations, including sensori-motor transformations (reaching, grasping), scene segmentation and object recognition. In accordance with these different functions, disparity activates a large number of regions in the brain of both humans and monkeys. Here, we review how disparity processing evolves along different regions of the ventral visual pathway of macaques, emphasizing research based on both correlational and causal techniques. We will discuss the progression in the ventral pathway from a basic absolute disparity representation to a more complex three-dimensional shape code. We will show that, in the course of this evolution, the underlying neuronal activity becomes progressively more bound to the global perceptual experience. We argue that these observations most probably extend beyond disparity processing per se, and pertain to object processing in the ventral pathway in general. We conclude by posing some important unresolved questions whose answers may significantly advance the field, and broaden its scope.This article is part of the themed issue 'Vision in our three-dimensional world'. © 2016 The Author(s).

Evasion Mechanisms Used by Pathogens to Escape the Lectin Complement Pathway

DEFF Research Database (Denmark)

Rosbjerg, Anne; Genster, Ninette; Pilely, Katrine

2017-01-01

the level of activity. The result is a pro-inflammatory response meant to combat foreign microbes. Microbial elimination is, however, not a straight forward procedure; pathogens have adapted to their environment by evolving a collection of evasion mechanisms that circumvent the human complement system....... Complement evasion strategies features different ways of exploiting human complement proteins and moreover features different pathogen-derived proteins that interfere with the normal processes. Accumulated, these mechanisms target all three complement activation pathways as well as the final common part...... of the cascade. This review will cover the currently known lectin pathway evasion mechanisms and give examples of pathogens that operate these to increase their chance of invasion, survival and dissemination....

Organization of ascending auditory pathways in the pigeon (Columba livia) as determined by autoradiographic methods

International Nuclear Information System (INIS)

Correia, M.J.; Eden, A.R.; Westlund, K.N.; Coulter, J.D.

1982-01-01

A mixture of tritiated proline and fucose was injected into the labyrinthine endolymphatic space of 5 white king pigeons (Columba livia). Using standard autoradiographic techniques, the authors observed transsynaptic labeling in ascending auditory pathways to the level of the mesencephalon. Auditory system structures, ipsilateral to the injection site, which labeled heavily were the cochlear nerve, the magnocellular and angular nuclei, and the superior olive. Those ipsilateral structures which were slightly labeled were the lateral lemniscus and the dorsal part of the lateral mesencephalic nucleus. Contralateral structures which labeled were the superior olive, lateral lemniscus, and dorsal part of the lateral mesencephalic nucleus. The results of this study suggest that ascending auditory pathways (to the level of mesencephalon) in the pigeon are more similar to those described for mammals in general than previously thought. (Auth.)

Organization of ascending auditory pathways in the pigeon (Columba livia) as determined by autoradiographic methods

Energy Technology Data Exchange (ETDEWEB)

Correia, M.J.; Eden, A.R.; Westlund, K.N.; Coulter, J.D. (Texas Univ., Galveston (USA). Medical Branch)

1982-02-25

A mixture of tritiated proline and fucose was injected into the labyrinthine endolymphatic space of 5 white king pigeons (Columba livia). Using standard autoradiographic techniques, the authors observed transsynaptic labeling in ascending auditory pathways to the level of the mesencephalon. Auditory system structures, ipsilateral to the injection site, which labeled heavily were the cochlear nerve, the magnocellular and angular nuclei, and the superior olive. Those ipsilateral structures which were slightly labeled were the lateral lemniscus and the dorsal part of the lateral mesencephalic nucleus. Contralateral structures which labeled were the superior olive, lateral lemniscus, and dorsal part of the lateral mesencephalic nucleus. The results of this study suggest that ascending auditory pathways (to the level of mesencephalon) in the pigeon are more similar to those described for mammals in general than previously thought.

DMPD: Regulation of mitochondrial antiviral signaling pathways. [Dynamic Macrophage Pathway CSML Database

Lifescience Database Archive (English)

Full Text Available 18549796 Regulation of mitochondrial antiviral signaling pathways. Moore CB, Ting J...P. Immunity. 2008 Jun;28(6):735-9. (.png) (.svg) (.html) (.csml) Show Regulation of mitochondrial antiviral ...signaling pathways. PubmedID 18549796 Title Regulation of mitochondrial antiviral signaling pathways. Author

The Tyndall decarbonisation scenarios-Part I: Development of a backcasting methodology with stakeholder participation

International Nuclear Information System (INIS)

Mander, Sarah L.; Bows, Alice; Anderson, Kevin L.; Shackley, Simon; Agnolucci, Paolo; Ekins, Paul

2008-01-01

The Tyndall decarbonisation scenarios project has outlined alternative pathways whereby a 60% reduction in CO 2 emissions from 1990 levels by 2050, a goal adopted by the UK Government, can be achieved. This paper, Part I of a two part paper, describes the methodology used to develop the scenarios and outlines the motivations for the project. The study utilised a backcasting approach, applied in three phases. In phase one, a set of credible and consistent end-points that described a substantially decarbonised energy system in 2050 were generated and reviewed by stakeholders. In phase two, pathways were developed to achieve the transition to the desired end-point. The impacts of the scenarios were assessed in phase three, by means of a deliberative multi-criteria assessment framework. The scenarios to emerge from this process are elaborated in Part II, and conclusions drawn in relation to the feasibility of achieving the 60% target

Interactions Between the Canonical WNT/Beta-Catenin Pathway and PPAR Gamma on Neuroinflammation, Demyelination, and Remyelination in Multiple Sclerosis.

Science.gov (United States)

Vallée, Alexandre; Vallée, Jean-Noël; Guillevin, Rémy; Lecarpentier, Yves

2018-05-01

Multiple sclerosis (MS) is marked by neuroinflammation and demyelination with loss of oligodendrocytes in the central nervous system. The immune response is regulated by WNT/beta-catenin pathway in MS. Activated NF-kappaB, a major effector of neuroinflammation, and upregulated canonical WNT/beta-catenin pathway positively regulate each other. Demyelinating events present an upregulation of WNT/beta-catenin pathway, whereas proper myelinating phases show a downregulation of WNT/beta-catenin pathway essential for the promotion of oligodendrocytes precursors cells proliferation and differentiation. The activation of WNT/beta-catenin pathway results in differentiation failure and impairment in remyelination. However, PI3K/Akt pathway and TCF7L2, two downstream targets of WNT/beta-catenin pathway, are upregulated and promote proper remyelination. The interactions of these signaling pathways remain unclear. PPAR gamma activation can inhibit NF-kappaB, and can also downregulate the WNT/beta-catenin pathway. PPAR gamma and canonical WNT/beta-catenin pathway act in an opposite manner. PPAR gamma agonists appear as a promising treatment for the inhibition of demyelination and the promotion of proper remyelination through the control of both NF-kappaB activity and canonical WNT/beta-catenin pathway.

A Theory of Intellectual Development: Part 1.

Science.gov (United States)

Confrey, Jere

1994-01-01

Part 1 of a three-part article analyzing radical constructivism (as one interpretation of Piaget) and the socio-cultural perspective (as one interpretation of Vygotsky), including major principles, primary contributions to mathematics education, and potential limitations. Introduces an integration of the two theories through a feminist…

Speech parts as Poisson processes.

Science.gov (United States)

Badalamenti, A F

2001-09-01

This paper presents evidence that six of the seven parts of speech occur in written text as Poisson processes, simple or recurring. The six major parts are nouns, verbs, adjectives, adverbs, prepositions, and conjunctions, with the interjection occurring too infrequently to support a model. The data consist of more than the first 5000 words of works by four major authors coded to label the parts of speech, as well as periods (sentence terminators). Sentence length is measured via the period and found to be normally distributed with no stochastic model identified for its occurrence. The models for all six speech parts but the noun significantly distinguish some pairs of authors and likewise for the joint use of all words types. Any one author is significantly distinguished from any other by at least one word type and sentence length very significantly distinguishes each from all others. The variety of word type use, measured by Shannon entropy, builds to about 90% of its maximum possible value. The rate constants for nouns are close to the fractions of maximum entropy achieved. This finding together with the stochastic models and the relations among them suggest that the noun may be a primitive organizer of written text.

Consistent genomic alterations in carcinoma in situ of the urinary bladder confirm the presence of two major pathways in bladder cancer development

DEFF Research Database (Denmark)

Zieger, Karsten; Marcussen, Niels; Borre, Michael

2009-01-01

Bladder cancer develops through different pathways, provisionally entitled "papillary" and "invasive." Carcinoma in situ (CIS) is thought to be the precursor of invasive bladder cancer. However, little is known about chromosomal alterations of these clinically important lesions......, and the relationship between chromosomal alterations and the different pathways. We laser-microdissected 12 CIS and 4 dysplasia samples concomitant to invasive bladder cancer. We determined genome-wide chromosome copy number changes and loss of heterozygosity (LOH) using Mapping 10K SNP microarrays. We further...... examined 48 high-risk non-muscle-invasive bladder cancers using SNP microarrays to reveal characteristic changes correlated with the CIS-phenotype. DNA copy-number changes were further validated using QPCR in 77 independent tumor samples. CIS was found to be chromosomal unstable in 8 of 12 cases...

Descending motor pathways and the spinal motor system. Limbic and non-limbic components

NARCIS (Netherlands)

G. Holstege (Gert)

1990-01-01

textabstractFor a thorough understanding of the descending pathways of the motor system originating in the forebrain, knowledge about the anatomy and function of the structures in the more caudally located parts of the central nervous system is indispensable. In this paper an overview will be

Evaluation of the Auditory Pathway in Traffic Policemen

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Vipul Indora

2017-04-01

Full Text Available Background: Traffic policemen working at heavy traffic junctions are continuously exposed to high level of noise and its health consequences. Objective: To assess the hearing pathway in traffic policemen by means of brainstem evoked response audiometry (BERA, mid-latency response (MLR, and slow vertex response (SVR. Methods: In this observational comparative study, BERA, MLR, and SVR were tested in 35 male traffic policemen with field posting of more than 3 years. 35 age-matched men working in our college served as controls. Results: Increase in the latencies of waves I and III of BERA, and IPL I-III were observed. Compared to controls, the MLR and SVR waves showed no significant changes in studied policemen. Conclusion: We found that chronic exposure of traffic policemen to noise resulted in delayed conduction in peripheral part of the auditory pathway, ie, auditory nerve up to the level of superior olivary nucleus; no impairment was observed at the level of sub-cortical, cortical, or the association areas.

Quadrupolar transfer pathways

Science.gov (United States)

Antonijevic, Sasa; Bodenhausen, Geoffrey

2006-06-01

A set of graphical conventions called quadrupolar transfer pathways is proposed to describe a wide range of experiments designed for the study of quadrupolar nuclei with spin quantum numbers I = 1, 3/2, 2, 5/2, etc. These pathways, which inter alea allow one to appreciate the distinction between quadrupolar and Zeeman echoes, represent a generalization of the well-known coherence transfer pathways. Quadrupolar transfer pathways not merely distinguish coherences with different orders -2 I ⩽ p ⩽ +2 I, but allow one to follow the fate of coherences associated with single transitions that have the same coherence orderp=mIr-mIs but can be distinguished by a satellite orderq=(mIr)2-(mIs)2.

Pathway-specific differences between tumor cell lines and normal and tumor tissue cells

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Tozeren Aydin

2006-11-01

Full Text Available Abstract Background Cell lines are used in experimental investigation of cancer but their capacity to represent tumor cells has yet to be quantified. The aim of the study was to identify significant alterations in pathway usage in cell lines in comparison with normal and tumor tissue. Methods This study utilized a pathway-specific enrichment analysis of publicly accessible microarray data and quantified the gene expression differences between cell lines, tumor, and normal tissue cells for six different tissue types. KEGG pathways that are significantly different between cell lines and tumors, cell lines and normal tissues and tumor and normal tissue were identified through enrichment tests on gene lists obtained using Significance Analysis of Microarrays (SAM. Results Cellular pathways that were significantly upregulated in cell lines compared to tumor cells and normal cells of the same tissue type included ATP synthesis, cell communication, cell cycle, oxidative phosphorylation, purine, pyrimidine and pyruvate metabolism, and proteasome. Results on metabolic pathways suggested an increase in the velocity nucleotide metabolism and RNA production. Pathways that were downregulated in cell lines compared to tumor and normal tissue included cell communication, cell adhesion molecules (CAMs, and ECM-receptor interaction. Only a fraction of the significantly altered genes in tumor-to-normal comparison had similar expressions in cancer cell lines and tumor cells. These genes were tissue-specific and were distributed sparsely among multiple pathways. Conclusion Significantly altered genes in tumors compared to normal tissue were largely tissue specific. Among these genes downregulation was a major trend. In contrast, cell lines contained large sets of significantly upregulated genes that were common to multiple tissue types. Pathway upregulation in cell lines was most pronounced over metabolic pathways including cell nucleotide metabolism and oxidative

Computed tomographic characteristics of collateral venous pathways in dogs with caudal vena cava obstruction.

Science.gov (United States)

Specchi, Swan; d'Anjou, Marc-André; Carmel, Eric Norman; Bertolini, Giovanna

2014-01-01

Collateral venous pathways develop in dogs with obstruction or increased blood flow resistance at any level of the caudal vena cava in order to maintain venous drainage to the right atrium. The purpose of this retrospective study was to describe the sites, causes of obstruction, and configurations of venous collateral pathways for a group of dogs with caudal vena cava obstruction. Computed tomography databases from two veterinary hospitals were searched for dogs with a diagnosis of caudal vena cava obstruction and multidetector row computed tomographic angiographic (CTA) scans that included the entire caudal vena cava. Images for each included dog were retrieved and collateral venous pathways were characterized using image postprocessing and a classification system previously reported for humans. A total of nine dogs met inclusion criteria and four major collateral venous pathways were identified: deep (n = 2), portal (n = 2), intermediate (n = 7), and superficial (n = 5). More than one collateral venous pathway was present in 5 dogs. An alternative pathway consisting of renal subcapsular collateral veins, arising mainly from the caudal pole of both kidneys, was found in three dogs. In conclusion, findings indicated that collateral venous pathway patterns similar to those described in humans are also present in dogs with caudal vena cava obstruction. These collateral pathways need to be distinguished from other vascular anomalies in dogs. Postprocessing of multidetector-row CTA images allowed delineation of the course of these complicated venous pathways and may be a helpful adjunct for treatment planning in future cases. © 2014 American College of Veterinary Radiology.

Suppression of the auxin response pathway enhances susceptibility to Phytophthora cinnamomi while phosphite-mediated resistance stimulates the auxin signalling pathway

Science.gov (United States)

2014-01-01

elongation, and increased root hair formation in plants with sufficient Pi. Conclusions The auxin response pathway, particularly auxin sensitivity and transport, plays an important role in resistance to P. cinnamomi in Arabidopsis, and phosphite-mediated resistance may in some part be through its effect on the stimulation of the PSR and auxin response pathways. PMID:24649892

Effects of clinical pathways in the joint replacement: a meta-analysis

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Faggiano F

2009-07-01

Full Text Available Abstract Background A meta-analysis was performed to evaluate the use of clinical pathways for hip and knee joint replacements when compared with standard medical care. The impact of clinical pathways was evaluated assessing the major outcomes of in-hospital hip and knee joint replacement processes: postoperative complications, number of patients discharged at home, length of in-hospital stay and direct costs. Methods Medline, Cinahl, Embase and the Cochrane Central Register of Controlled Trials were searched. The search was performed from 1975 to 2007. Each study was assessed independently by two reviewers. The assessment of methodological quality of the included studies was based on the Jadad methodological approach and on the New Castle Ottawa Scale. Data analysis abided by the guidelines set out by The Cochrane Collaboration regarding statistical methods. Meta-analyses were performed using RevMan software, version 4.2. Results Twenty-two studies met the study inclusion criteria and were included in the meta-analysis for a total sample of 6,316 patients. The aggregate overall results showed significantly fewer patients suffering postoperative complications in the clinical pathways group when compared with the standard care group. A shorter length of stay in the clinical pathway group was also observed and lower costs during hospital stay were associated with the use of the clinical pathways. No significant differences were found in the rates of discharge to home. Conclusion The results of this meta-analysis show that clinical pathways can significantly improve the quality of care even if it is not possible to conclude that the implementation of clinical pathways is a cost-effective process, because none of the included studies analysed the cost of the development and implementation of the pathways. Based on the results we assume that pathways have impact on the organisation of care if the care process is structured in a standardised way

Glycinergic Pathways of the Central Auditory System and Adjacent Reticular Formation of the Rat.

Science.gov (United States)

Hunter, Chyren

The development of techniques to visualize and identify specific transmitters of neuronal circuits has stimulated work on the characterization of pathways in the rat central nervous system that utilize the inhibitory amino acid glycine as its neurotransmitter. Glycine is a major inhibitory transmitter in the spinal cord and brainstem of vertebrates where it satisfies the major criteria for neurotransmitter action. Some of these characteristics are: uneven distribution in brain, high affinity reuptake mechanisms, inhibitory neurophysiological actions on certain neuronal populations, uneven receptor distribution and the specific antagonism of its actions by the convulsant alkaloid strychnine. Behaviorally, antagonism of glycinergic neurotransmission in the medullary reticular formation is linked to the development of myoclonus and seizures which may be initiated by auditory as well as other stimuli. In the present study, decreases in the concentration of glycine as well as the density of glycine receptors in the medulla with aging were found and may be responsible for the lowered threshold for strychnine seizures observed in older rats. Neuroanatomical pathways in the central auditory system and medullary and pontine reticular formation (RF) were investigated using retrograde transport of tritiated glycine to identify glycinergic pathways; immunohistochemical techniques were used to corroborate the location of glycine neurons. Within the central auditory system, retrograde transport studies using tritiated glycine demonstrated an ipsilateral glycinergic pathway linking nuclei of the ascending auditory system. This pathway has its cell bodies in the medial nucleus of the trapezoid body (MNTB) and projects to the ventrocaudal division of the ventral nucleus of the lateral lemniscus (VLL). Collaterals of this glycinergic projection terminate in the ipsilateral lateral superior olive (LSO). Other glycinergic pathways found were afferent to the VLL and have their origin

In Silico Analysis of Putrefaction Pathways in Bacteria and Its Implication in Colorectal Cancer

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Harrisham Kaur

2017-11-01

Full Text Available Fermentation of undigested proteins in human gastrointestinal tract (gut by the resident microbiota, a process called bacterial putrefaction, can sometimes disrupt the gut homeostasis. In this process, essential amino acids (e.g., histidine, tryptophan, etc. that are required by the host may be utilized by the gut microbes. In addition, some of the products of putrefaction, like ammonia, putrescine, cresol, indole, phenol, etc., have been implicated in the disease pathogenesis of colorectal cancer (CRC. We have investigated bacterial putrefaction pathways that are known to be associated with such metabolites. Results of the comprehensive in silico analysis of the selected putrefaction pathways across bacterial genomes revealed presence of these pathways in limited bacterial groups. Majority of these bacteria are commonly found in human gut. These include Bacillus, Clostridium, Enterobacter, Escherichia, Fusobacterium, Salmonella, etc. Interestingly, while pathogens utilize almost all the analyzed pathways, commensals prefer putrescine and H2S production pathways for metabolizing the undigested proteins. Further, comparison of the putrefaction pathways in the gut microbiomes of healthy, carcinoma and adenoma datasets indicate higher abundances of putrefying bacteria in the carcinoma stage of CRC. The insights obtained from the present study indicate utilization of possible microbiome-based therapies to minimize the adverse effects of gut microbiome in enteric diseases.

G Protein-Linked Signaling Pathways in Bipolar and Major Depressive Disorders

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Hiroaki eTomita

2013-12-01

Full Text Available The G-protein linked signaling system (GPLS comprises a large number of G-proteins, G protein-coupled receptors (GPCRs, GPCR ligands, and downstream effector molecules. G-proteins interact with both GPCRs and downstream effectors such as cyclic adenosine monophosphate (cAMP, phosphatidylinositols, and ion channels. The GPLS is implicated in the pathophysiology and pharmacology of both major depressive disorder (MDD and bipolar disorder (BPD. This study evaluated whether GPLS is altered at the transcript level. The gene expression in the dorsolateral prefrontal (DLPFC and anterior cingulate (ACC were compared from MDD, BPD, and control subjects using Affymetrix Gene Chips and real time quantitative PCR. High quality brain tissue was used in the study to control for confounding effects of agonal events, tissue pH, RNA integrity, gender, and age. GPLS signaling transcripts were altered especially in the ACC of BPD and MDD subjects. Transcript levels of molecules which repress cAMP activity were increased in BPD and decreased in MDD. Two orphan GPCRs, GPRC5B and GPR37, showed significantly decreased expression levels in MDD, and significantly increased expression levels in BPD. Our results suggest opposite changes in BPD and MDD in the GPLS, ‘activated’ cAMP signaling activity in BPD and ‘blunted’ cAMP signaling activity in MDD. GPRC5B and GPR37 both appear to have behavioral effects, and are also candidate genes for neurodegenerative disorders. In the context of the opposite changes observed in BPD and MDD, these GPCRs warrant further study of their brain effects.

Partial activation of SA- and JA-defensive pathways in strawberry upon Colletotrichum acutatum interaction

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FRANCISCO AMIL-RUIZ

2016-07-01

Full Text Available Understanding the nature of pathogen host interaction may help improve strawberry (Fragaria × ananassa cultivars. Plant resistance to pathogenic agents usually operates through a complex network of defense mechanisms mediated by a diverse array of signaling molecules. In strawberry, resistance to a variety of pathogens has been reported to be mostly polygenic and quantitatively inherited, making it difficult to associate molecular markers with disease resistance genes. Colletotrichum acutatum spp. is a major strawberry pathogen, and completely resistant cultivars have not been reported. Moreover, strawberry defense network components and mechanisms remain largely unknown and poorly understood. Assessment of the strawberry response to C. acutatum included a global transcript analysis, and acidic hormones SA and JA measurements were analyzed after challenge with the pathogen. Induction of transcripts corresponding to the SA and JA signaling pathways and key genes controlling major steps within these defense pathways was detected. Accordingly, SA and JA accumulated in strawberry after infection. Contrastingly, induction of several important SA, JA, and oxidative stress-responsive defense genes, including FaPR1-1, FaLOX2, FaJAR1, FaPDF1, and FaGST1, was not detected, which suggests that specific branches in these defense pathways (those leading to FaPR1-2, FaPR2-1, FaPR2-2, FaAOS, FaPR5 and FaPR10 were activated. Our results reveal that specific aspects in SA and JA dependent signaling pathways are activated in strawberry upon interaction with C. acutatum. Certain described defense-associated transcripts related to these two known signaling pathways do not increase in abundance following infection. This finding suggests new insight into a specific putative molecular strategy for defense against this pathogen.

The Impact of Hedgehog Signaling Pathway on DNA Repair Mechanisms in Human Cancer

International Nuclear Information System (INIS)

Meng, Erhong; Hanna, Ann; Samant, Rajeev S.; Shevde, Lalita A.

2015-01-01

Defined cellular mechanisms have evolved that recognize and repair DNA to protect the integrity of its structure and sequence when encountering assaults from endogenous and exogenous sources. There are five major DNA repair pathways: mismatch repair, nucleotide excision repair, direct repair, base excision repair and DNA double strand break repair (including non-homologous end joining and homologous recombination repair). Aberrant activation of the Hedgehog (Hh) signaling pathway is a feature of many cancer types. The Hh pathway has been documented to be indispensable for epithelial-mesenchymal transition, invasion and metastasis, cancer stemness, and chemoresistance. The functional transcription activators of the Hh pathway include the GLI proteins. Inhibition of the activity of GLI can interfere with almost all DNA repair types in human cancer, indicating that Hh/GLI functions may play an important role in enabling tumor cells to survive lethal types of DNA damage induced by chemotherapy and radiotherapy. Thus, Hh signaling presents an important therapeutic target to overcome DNA repair-enabled multi-drug resistance and consequently increase chemotherapeutic response in the treatment of cancer

The Impact of Hedgehog Signaling Pathway on DNA Repair Mechanisms in Human Cancer

Energy Technology Data Exchange (ETDEWEB)

Meng, Erhong; Hanna, Ann; Samant, Rajeev S.; Shevde, Lalita A., E-mail: lsamant@uab.edu [Department of Pathology, Comprehensive Cancer Center, University of Alabama at Birmingham, WTI320D, 1824 6th Avenue South, Birmingham, AL 35233 (United States)

2015-07-21

Defined cellular mechanisms have evolved that recognize and repair DNA to protect the integrity of its structure and sequence when encountering assaults from endogenous and exogenous sources. There are five major DNA repair pathways: mismatch repair, nucleotide excision repair, direct repair, base excision repair and DNA double strand break repair (including non-homologous end joining and homologous recombination repair). Aberrant activation of the Hedgehog (Hh) signaling pathway is a feature of many cancer types. The Hh pathway has been documented to be indispensable for epithelial-mesenchymal transition, invasion and metastasis, cancer stemness, and chemoresistance. The functional transcription activators of the Hh pathway include the GLI proteins. Inhibition of the activity of GLI can interfere with almost all DNA repair types in human cancer, indicating that Hh/GLI functions may play an important role in enabling tumor cells to survive lethal types of DNA damage induced by chemotherapy and radiotherapy. Thus, Hh signaling presents an important therapeutic target to overcome DNA repair-enabled multi-drug resistance and consequently increase chemotherapeutic response in the treatment of cancer.

Simultaneous modulation of the intrinsic and extrinsic pathways by simvastatin in mediating prostate cancer cell apoptosis

International Nuclear Information System (INIS)

Goc, Anna; Kochuparambil, Samith T; Al-Husein, Belal; Al-Azayzih, Ahmad; Mohammad, Shuaib; Somanath, Payaningal R

2012-01-01

Recent studies suggest the potential benefits of statins as anti-cancer agents. Mechanisms by which statins induce apoptosis in cancer cells are not clear. We previously showed that simvastatin inhibit prostate cancer cell functions and tumor growth. Molecular mechanisms by which simvastatin induce apoptosis in prostate cancer cells is not completely understood. Effect of simvastatin on PC3 cell apoptosis was compared with docetaxel using apoptosis, TUNEL and trypan blue viability assays. Protein expression of major candidates of the intrinsic pathway downstream of simvastatin-mediated Akt inactivation was analyzed. Gene arrays and western analysis of PC3 cells and tumor lysates were performed to identify the candidate genes mediating extrinsic apoptosis pathway by simvastatin. Data indicated that simvastatin inhibited intrinsic cell survival pathway in PC3 cells by enhancing phosphorylation of Bad, reducing the protein expression of Bcl-2, Bcl-xL and cleaved caspases 9/3. Over-expression of PC3 cells with Bcl-2 or DN-caspase 9 did not rescue the simvastatin-induced apoptosis. Simvastatin treatment resulted in increased mRNA and protein expression of molecules such as TNF, Fas-L, Traf1 and cleaved caspase 8, major mediators of intrinsic apoptosis pathway and reduced protein levels of pro-survival genes Lhx4 and Nme5. Our study provides the first report that simvastatin simultaneously modulates intrinsic and extrinsic pathways in the regulation of prostate cancer cell apoptosis in vitro and in vivo, and render reasonable optimism that statins could become an attractive anti-cancer agent

BMP pathway regulation of and by macrophages.

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Megha Talati

Full Text Available Pulmonary arterial hypertension (PAH is a disease of progressively increasing pulmonary vascular resistance, associated with mutations of the type 2 receptor for the BMP pathway, BMPR2. The canonical signaling pathway for BMPR2 is through the SMAD family of transcription factors. BMPR2 is expressed in every cell type, but the impact of BMPR2 mutations affecting SMAD signaling, such as Bmpr2delx4+, had only previously been investigated in smooth muscle and endothelium. In the present study, we created a mouse with universal doxycycline-inducible expression of Bmpr2delx4+ in order to determine if broader expression had an impact relevant to the development of PAH. We found that the most obvious phenotype was a dramatic, but patchy, increase in pulmonary inflammation. We crossed these double transgenic mice onto an NF-κB reporter strain, and by luciferase assays on live mice, individual organs and isolated macrophages, we narrowed down the origin of the inflammatory phenotype to constitutive activation of tissue macrophages. Study of bone marrow-derived macrophages from mutant and wild-type mice suggested a baseline difference in differentiation state in Bmpr2 mutants. When activated with LPS, both mutant and wild-type macrophages secrete BMP pathway inhibitors sufficient to suppress BMP pathway activity in smooth muscle cells (SMC treated with conditioned media. Functionally, co-culture with macrophages results in a BMP signaling-dependent increase in scratch closure in cultured SMC. We conclude that SMAD signaling through BMP is responsible, in part, for preventing macrophage activation in both live animals and in cells in culture, and that activated macrophages secrete BMP inhibitors in sufficient quantity to cause paracrine effect on vascular smooth muscle.

Care Pathways in Persistent Orofacial Pain: Qualitative Evidence from the DEEP Study.

Science.gov (United States)

Breckons, M; Bissett, S M; Exley, C; Araujo-Soares, V; Durham, J

2017-01-01

Persistent orofacial pain is relatively common and known to have an adverse effect on quality of life. Previous studies suggest that the current care pathway may be problematic, but it is not well understood which health services patients access and what their experience is. The aim of this study was to explore care pathways and their impact from the perspective of patients. Qualitative interviews were conducted with a maximum variation sample of patients recruited from primary (community based) and secondary (specialist hospital based) care in the United Kingdom. Questions focused on the stages in their pathway and the impact of the care that they had received. Interviews were digitally recorded and transcribed verbatim, and analysis followed principles of the constant comparative method. NVivo 10 was used to help organize and analyze data. Twenty-two patients were interviewed at baseline, and 18 took part in a second interview at 12 mo. Three main themes emerged from the data: the "fluidity of the care pathway," in which patients described moving among health care providers in attempts to have their pain diagnosed and managed, occurring alongside a "failure to progress," where despite multiple appointments, patients described frustration at delays in obtaining a diagnosis and effective treatment for their pain. Throughout their care pathways, patients described the "effects of unmanaged pain," where the longer the pain went unmanaged, the greater its potential to negatively affect their lives. Findings of this study suggest that the current care pathway is inefficient and fails to meet patient needs. Future work needs to focus on working with stakeholder groups to redesign patient-centered care pathways. Knowledge Transfer Statement: Data from qualitative interviews conducted with patients with persistent orofacial pain suggest significant problems with the existing care pathway, consisting of delays to diagnosis, treatment, and referral. Patients describing

Activation of sorbitol pathway in metabolic syndrome and increased susceptibility to cataract in Wistar-Obese rats.

Science.gov (United States)

Reddy, Paduru Yadagiri; Giridharan, Nappan Veettil; Reddy, Geereddy Bhanuprakash

2012-01-01

Obesity is a major public health problem worldwide, and of late, epidemiological studies indicate a preponderance of cataracts under obesity conditions. Although cataract is a multifactorial disorder and various biochemical mechanisms have been proposed, the influence of obesity on cataractogenesis has yet to be investigated. In such a scenario, a suitable animal model that develops cataract following the onset of obesity will be a welcome tool for biomedical research. Therefore, we investigated the molecular and biochemical basis for predisposition to cataract in the obese mutant rat models established in our institute because 15%-20% of these rats develop cataracts spontaneously as they reach 12-15 months of age. We analyzed the major biochemical pathways in the normal lenses of different age groups of our obese mutant rat strains, Wistar/Obese (WNIN/Ob) and WNIN/GR-Ob, the former with euglycemia and the latter with an additional impaired glucose tolerance trait. In addition, sorbitol levels were estimated in the cataractous lenses of the obese rats. Except for the polyol pathway, all the principal pathways of the lens remained unaltered. Therefore, sorbitol levels were found to be high in the normal eye lenses of obese rats (WNIN/Ob and WNIN/GR-Ob) compared to their lean controls from three months of age onwards. Between WNIN/Ob and WNIN/GR-Ob, the levels of sorbitol were higher in the latter, suggesting a synergistic effect of impaired glucose tolerance along with obesity in the activation of the sorbitol pathway. Either way, an elevated sorbitol pathway seemed to be the predisposing factor responsible for cataract formation in these mutant rats. Activation of the sorbitol pathway indeed enhances the risk of cataract development in conditions such as metabolic syndrome. These rat models thus may be valuable tools for investigating obesity-associated cataract and for developing intervention strategies, based on these findings.

Descending motor pathways and the spinal motor system. Limbic and non-limbic components

NARCIS (Netherlands)

Holstege, G.

1991-01-01

For a thorough understanding of the descending pathways of the motor system originating in the forebrain, knowledge about the anatomy and function of the structures in the more caudally located parts of the central nervous system is indispensable. In this paper an overview will be presented of these

Building integrated pathways to independence for diverse biomedical researchers: Project Pathways, the BUILD program at Xavier University of Louisiana.

Science.gov (United States)

Foroozesh, Maryam; Giguette, Marguerite; Morgan, Kathleen; Johanson, Kelly; D'Amour, Gene; Coston, Tiera; Wilkins-Green, Clair

2017-01-01

Xavier University of Louisiana is a historically Black and Catholic university that is nationally recognized for its science, technology, engineering and mathematics (STEM) curricula. Approximately 73% of Xavier's students are African American, and about 77% major in the biomedical sciences. Xavier is a national leader in the number of STEM majors who go on to receive M.D. degrees and Ph.D. degrees in science and engineering. Despite Xavier's advances in this area, African Americans still earn about 7.5% of the Bachelor's degrees, less than 8% of the Master's degrees, and less than 5% of the doctoral degrees conferred in STEM disciplines in the United States. Additionally, although many well-prepared, highly-motivated students are attracted by Xavier's reputation in the sciences, many of these students, though bright and capable, come from underperforming public school systems and receive substandard preparation in STEM disciplines. The purpose of this article is to describe how Xavier works to overcome unequal education backgrounds and socioeconomic challenges to develop student talent through expanding biomedical training opportunities and build on an established reputation in science education. The National Institutes of Health (NIH)/National Institute of General Medical Sciences (NIGMS)-funded BUILD (Building Infrastructure Leading to Diversity) Program at Xavier University of Louisiana, Project Pathways , is a highly-innovative program designed to broaden the career interests of students early on, and to engage them in activities that entice them to continue their education towards biomedical research careers. Project strategies involve a transformation of Xavier's academic and non-academic programs through the redesign, supplementation and integration of academic advising, tutoring, career services, personal counseling, undergraduate research training, faculty research mentoring, and development of new biomedical and research skills courses. The Program also

Analysis of porcine granulosa cell death signaling pathways induced by vinclozolin.

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Knet, Malgorzata; Wartalski, Kamil; Hoja-Lukowicz, Dorota; Tabarowski, Zbigniew; Slomczynska, Maria; Duda, Malgorzata

2015-10-01

Recent studies suggest that disturbing androgen-signaling pathways in porcine ovarian follicles may cause granulosa cell (GC) death. For this reason, we investigated which apoptotic pathway is initiated after GC exposure to an environmental antiandrogen, vinclozolin (Vnz), in vitro. Immunocytochemistry, Western blots, and fluorometric assays were used to quantify caspase-3 and -9 expression and activity. To elucidate the specific mechanism of Vnz action and toxicity, GCs were assessed for viability, cytotoxicity, and apoptotic activity using the ApoTox-Glo Triplex Assay. To further determine the mechanism of GC death induced by Vnz, we used the Apoptosis Antibody Array Kit. In response to Vnz stimulus, we found an increased level of caspase-3 protein expression (P ≤ 0.001) and an increase in caspase-3 proteolytic activity (P ≤ 0.001), confirming that Vnz is a potent proapoptotic factor. The strong immunoreaction of caspase-9 after Vnz treatment (P ≤ 0.001) suggests that intrinsic mitochondrial apoptosis pathway was activated during GC death. On the other hand, caspase-8, being a part of the extrinsic receptor pathway, was also activated (P ≤ 0.001). Therefore, it is possible that Vnz induces porcine granulosal apoptosis also through a parallel pathway. Activation of these two pathways was confirmed by the Apoptosis Antibody Array Kit. In conclusion, it is possible that the intrinsic signaling pathway may not act as an initial trigger for GC apoptosis but might contribute to the amplification and propagation of apoptotic cell death in the granulosa layer after treatment with this antiandrogen. Moreover, Vnz disturbs the physiological process of programmed cell death. Consequently, this could explain why atretic follicles are rapidly removed and suggests that normal function of the ovarian follicle may be destroyed. Copyright © 2015 Elsevier Inc. All rights reserved.

Dysregulated Pathway Identification of Alzheimer's Disease Based on Internal Correlation Analysis of Genes and Pathways.

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Kong, Wei; Mou, Xiaoyang; Di, Benteng; Deng, Jin; Zhong, Ruxing; Wang, Shuaiqun

2017-11-20

Dysregulated pathway identification is an important task which can gain insight into the underlying biological processes of disease. Current pathway-identification methods focus on a set of co-expression genes and single pathways and ignore the correlation between genes and pathways. The method proposed in this study, takes into account the internal correlations not only between genes but also pathways to identifying dysregulated pathways related to Alzheimer's disease (AD), the most common form of dementia. In order to find the significantly differential genes for AD, mutual information (MI) is used to measure interdependencies between genes other than expression valves. Then, by integrating the topology information from KEGG, the significant pathways involved in the feature genes are identified. Next, the distance correlation (DC) is applied to measure the pairwise pathway crosstalks since DC has the advantage of detecting nonlinear correlations when compared to Pearson correlation. Finally, the pathway pairs with significantly different correlations between normal and AD samples are known as dysregulated pathways. The molecular biology analysis demonstrated that many dysregulated pathways related to AD pathogenesis have been discovered successfully by the internal correlation detection. Furthermore, the insights of the dysregulated pathways in the development and deterioration of AD will help to find new effective target genes and provide important theoretical guidance for drug design. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

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

Science.gov (United States)

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.

Pathway Processor 2.0: a web resource for pathway-based analysis of high-throughput data.

Science.gov (United States)

Beltrame, Luca; Bianco, Luca; Fontana, Paolo; Cavalieri, Duccio

2013-07-15

Pathway Processor 2.0 is a web application designed to analyze high-throughput datasets, including but not limited to microarray and next-generation sequencing, using a pathway centric logic. In addition to well-established methods such as the Fisher's test and impact analysis, Pathway Processor 2.0 offers innovative methods that convert gene expression into pathway expression, leading to the identification of differentially regulated pathways in a dataset of choice. Pathway Processor 2.0 is available as a web service at http://compbiotoolbox.fmach.it/pathwayProcessor/. Sample datasets to test the functionality can be used directly from the application. duccio.cavalieri@fmach.it Supplementary data are available at Bioinformatics online.

Probabilistic pathway construction.

Science.gov (United States)

Yousofshahi, Mona; Lee, Kyongbum; Hassoun, Soha

2011-07-01

Expression of novel synthesis pathways in host organisms amenable to genetic manipulations has emerged as an attractive metabolic engineering strategy to overproduce natural products, biofuels, biopolymers and other commercially useful metabolites. We present a pathway construction algorithm for identifying viable synthesis pathways compatible with balanced cell growth. Rather than exhaustive exploration, we investigate probabilistic selection of reactions to construct the pathways. Three different selection schemes are investigated for the selection of reactions: high metabolite connectivity, low connectivity and uniformly random. For all case studies, which involved a diverse set of target metabolites, the uniformly random selection scheme resulted in the highest average maximum yield. When compared to an exhaustive search enumerating all possible reaction routes, our probabilistic algorithm returned nearly identical distributions of yields, while requiring far less computing time (minutes vs. years). The pathways identified by our algorithm have previously been confirmed in the literature as viable, high-yield synthesis routes. Prospectively, our algorithm could facilitate the design of novel, non-native synthesis routes by efficiently exploring the diversity of biochemical transformations in nature. Copyright © 2011 Elsevier Inc. All rights reserved.

Well-to-wheels analysis of hydrogen based fuel-cell vehicle pathways in Shanghai

International Nuclear Information System (INIS)

Huang Zhijia; Zhang Xu

2006-01-01

Due to high energy efficiency and zero emissions, some believe fuel cell vehicles (FCVs) could revolutionize the automobile industry by replacing internal combustion engine technology, and first boom in China. However, hydrogen infrastructure is one of the major barriers. Because different H 2 pathways have very different energy and emissions effects, the well-to-wheels (WTW) analyses are necessary for adequately evaluating fuel/vehicle systems. The pathways used to supply H 2 for FCVs must be carefully examined by their WTW energy use, greenhouse gases (GHGs) emissions, total criteria pollutions emissions, and urban criteria pollutions emissions. Ten hydrogen pathways in Shanghai have been simulated. The results include well-to-wheels energy use, GHGs emissions, total criteria pollutions and urban criteria pollutions. A fuel-cycle model developed at Argonne National Laboratory-called the Greenhouse gases, Regulated Emissions, and Energy use in Transportation (GREET) model-was used to evaluate well-to-wheels energy and emissions impacts of hydrogen pathways in this study. Because the initial GREET model had no coal and naphtha-based hydrogen pathways, four hydrogen pathway computer programs were added to GREET in the research. To analyze uncertain impacts, commercial software, Crystal Ball(TM) was used to conduct Monte Carlo simulations. Hence, instead of point estimates, the results of this study were probability distributions. Through the research of H 2 pathways in Shanghai, the following conclusions were achieved:(1)All the pathways have significant reductions in WTW petroleum use, except two H 2 pathways from naphtha, which achieve about 20% reductions in WTW petroleum. (2)All the pathways have significant reductions in WTW urban criteria pollutions emissions, except two H 2 pathways from coal, which result in significant increases in WTW urban SO X emissions. (3)The NG-based H 2 pathways have the best WTW energy efficiencies, and the electrolysis H 2 pathways

Review of the chronic exposure pathways models in MACCS [MELCOR Accident Consequence Code System] and several other well-known probabilistic risk assessment models

International Nuclear Information System (INIS)

Tveten, U.

1990-06-01

The purpose of this report is to document the results of the work performed by the author in connection with the following task, performed for US Nuclear Regulatory Commission, (USNRC) Office of Nuclear Regulatory Research, Division of Systems Research: MACCS Chronic Exposure Pathway Models: Review the chronic exposure pathway models implemented in the MELCOR Accident Consequence Code System (MACCS) and compare those models to the chronic exposure pathway models implemented in similar codes developed in countries that are members of the OECD. The chronic exposures concerned are via: the terrestrial food pathways, the water pathways, the long-term groundshine pathway, and the inhalation of resuspended radionuclides pathway. The USNRC has indicated during discussions of the task that the major effort should be spent on the terrestrial food pathways. There is one chapter for each of the categories of chronic exposure pathways listed above

Activation of the hedgehog pathway in advanced prostate cancer

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McCormick Frank

2004-10-01

Full Text Available Abstract Background The hedgehog pathway plays a critical role in the development of prostate. However, the role of the hedgehog pathway in prostate cancer is not clear. Prostate cancer is the second most prevalent cause of cancer death in American men. Therefore, identification of novel therapeutic targets for prostate cancer has significant clinical implications. Results Here we report that activation of the hedgehog pathway occurs frequently in advanced human prostate cancer. We find that high levels of hedgehog target genes, PTCH1 and hedgehog-interacting protein (HIP, are detected in over 70% of prostate tumors with Gleason scores 8–10, but in only 22% of tumors with Gleason scores 3–6. Furthermore, four available metastatic tumors all have high expression of PTCH1 and HIP. To identify the mechanism of the hedgehog signaling activation, we examine expression of Su(Fu protein, a negative regulator of the hedgehog pathway. We find that Su(Fu protein is undetectable in 11 of 27 PTCH1 positive tumors, two of them contain somatic loss-of-function mutations of Su(Fu. Furthermore, expression of sonic hedgehog protein is detected in majority of PTCH1 positive tumors (24 out of 27. High levels of hedgehog target genes are also detected in four prostate cancer cell lines (TSU, DU145, LN-Cap and PC3. We demonstrate that inhibition of hedgehog signaling by smoothened antagonist, cyclopamine, suppresses hedgehog signaling, down-regulates cell invasiveness and induces apoptosis. In addition, cancer cells expressing Gli1 under the CMV promoter are resistant to cyclopamine-mediated apoptosis. All these data suggest a significant role of the hedgehog pathway for cellular functions of prostate cancer cells. Conclusion Our data indicate that activation of the hedgehog pathway, through loss of Su(Fu or overexpression of sonic hedgehog, may involve tumor progression and metastases of prostate cancer. Thus, targeted inhibition of hedgehog signaling may have

The dominant acetate degradation pathway/methanogenic composition in full-scale anaerobic digesters operating under different ammonia levels

DEFF Research Database (Denmark)

Fotidis, Ioannis; Karakashev, Dimitar Borisov; Angelidaki, Irini

2014-01-01

Ammonia is a major environmental factor influencing biomethanation in full-scale anaerobic digesters. In this study, the effect of different ammonia levels on methanogenic pathways and methanogenic community composition of full-scale biogas plants was investigated. Eight full-scale digesters...... operating under different ammonia levels were sampled, and the residual biogas production was followed in fed-batch reactors. Acetate, labelled in the methyl group, was used to determine the methanogenic pathway by following the 14CH4 and 14CO2 production. Fluorescence in situ hybridisation was used...... to determine the methanogenic communities’ composition. Results obtained clearly demonstrated that syntrophic acetate oxidation coupled with hydrogenotrophic methanogenesis was the dominant pathway in all digesters with high ammonia levels (2.8–4.57 g NH4 +-N L−1), while acetoclastic methanogenic pathway...

Src kinase conformational activation: thermodynamics, pathways, and mechanisms.

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Sichun Yang

2008-03-01

Full Text Available Tyrosine kinases of the Src-family are large allosteric enzymes that play a key role in cellular signaling. Conversion of the kinase from an inactive to an active state is accompanied by substantial structural changes. Here, we construct a coarse-grained model of the catalytic domain incorporating experimental structures for the two stable states, and simulate the dynamics of conformational transitions in kinase activation. We explore the transition energy landscapes by constructing a structural network among clusters of conformations from the simulations. From the structural network, two major ensembles of pathways for the activation are identified. In the first transition pathway, we find a coordinated switching mechanism of interactions among the alphaC helix, the activation-loop, and the beta strands in the N-lobe of the catalytic domain. In a second pathway, the conformational change is coupled to a partial unfolding of the N-lobe region of the catalytic domain. We also characterize the switching mechanism for the alphaC helix and the activation-loop in detail. Finally, we test the performance of a Markov model and its ability to account for the structural kinetics in the context of Src conformational changes. Taken together, these results provide a broad framework for understanding the main features of the conformational transition taking place upon Src activation.

Supporting the Academic Majority: Policies and Practices Related to Part-Time Faculty's Job Satisfaction

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Eagan, M. Kevin, Jr.; Jaeger, Audrey J.; Grantham, Ashley

2015-01-01

The academic workforce in higher education has shifted in the last several decades from consisting of mostly full-time, tenure-track faculty to one comprised predominantly of contingent, non-tenure-track faculty. This substantial shift toward part-time academic labor has not corresponded with institutions implementing more supportive policies and…

RhoA/ROCK pathway is the major molecular determinant of basal tone in intact human internal anal sphincter.

Science.gov (United States)

Rattan, Satish; Singh, Jagmohan

2012-04-01

The knowledge of molecular control mechanisms underlying the basal tone in the intact human internal anal sphincter (IAS) is critical for the pathophysiology and rational therapy for a number of debilitating rectoanal motility disorders. We determined the role of RhoA/ROCK and PKC pathways by comparing the effects of ROCK- and PKC-selective inhibitors Y 27632 and Gö 6850 (10(-8) to 10(-4) M), respectively, on the basal tone in the IAS vs. the rectal smooth muscle (RSM). Western blot studies were performed to determine the levels of RhoA/ROCK II, PKC-α, MYPT1, CPI-17, and MLC(20) in the unphosphorylated and phosphorylated forms, in the IAS vs. RSM. Confocal microscopic studies validated the membrane distribution of ROCK II. Finally, to confirm a direct relationship, we examined the enzymatic activities and changes in the basal IAS tone and p-MYPT1, p-CPI-17, and p-MLC(20), before and after Y 27632 and Gö 6850. Data show higher levels of RhoA/ROCK II and related downstream signal transduction proteins in the IAS vs. RSM. In addition, data show a significant correlation between the active RhoA/ROCK levels, ROCK enzymatic activity, downstream proteins, and basal IAS tone, before and after ROCK inhibitor. From these data we conclude 1) RhoA/ROCK and downstream signaling are constitutively active in the IAS, and this pathway (in contrast with PKC) is the critical determinant of the basal tone in intact human IAS; and 2) RhoA and ROCK are potential therapeutic targets for a number of rectoanal motility disorders for which currently there is no satisfactory treatment.

A Simple Geotracer Compositional Correlation Analysis Reveals Oil Charge and Migration Pathways

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Yang, Yunlai; Arouri, Khaled

2016-03-01

A novel approach, based on geotracer compositional correlation analysis is reported, which reveals the oil charge sequence and migration pathways for five oil fields in Saudi Arabia. The geotracers utilised are carbazoles, a family of neutral pyrrolic nitrogen compounds known to occur naturally in crude oils. The approach is based on the concept that closely related fields, with respect to filling sequence, will show a higher carbazole compositional correlation, than those fields that are less related. That is, carbazole compositional correlation coefficients can quantify the charge and filling relationships among different fields. Consequently, oil migration pathways can be defined based on the established filling relationships. The compositional correlation coefficients of isomers of C1 and C2 carbazoles, and benzo[a]carbazole for all different combination pairs of the five fields were found to vary extremely widely (0.28 to 0.94). A wide range of compositional correlation coefficients allows adequate differentiation of separate filling relationships. Based on the established filling relationships, three distinct migration pathways were inferred, with each apparently being charged from a different part of a common source kitchen. The recognition of these charge and migration pathways will greatly aid the search for new accumulations.

A Simple Geotracer Compositional Correlation Analysis Reveals Oil Charge and Migration Pathways.

Science.gov (United States)

Yang, Yunlai; Arouri, Khaled

2016-03-11

A novel approach, based on geotracer compositional correlation analysis is reported, which reveals the oil charge sequence and migration pathways for five oil fields in Saudi Arabia. The geotracers utilised are carbazoles, a family of neutral pyrrolic nitrogen compounds known to occur naturally in crude oils. The approach is based on the concept that closely related fields, with respect to filling sequence, will show a higher carbazole compositional correlation, than those fields that are less related. That is, carbazole compositional correlation coefficients can quantify the charge and filling relationships among different fields. Consequently, oil migration pathways can be defined based on the established filling relationships. The compositional correlation coefficients of isomers of C1 and C2 carbazoles, and benzo[a]carbazole for all different combination pairs of the five fields were found to vary extremely widely (0.28 to 0.94). A wide range of compositional correlation coefficients allows adequate differentiation of separate filling relationships. Based on the established filling relationships, three distinct migration pathways were inferred, with each apparently being charged from a different part of a common source kitchen. The recognition of these charge and migration pathways will greatly aid the search for new accumulations.

Responsive eLearning exercises to enhance student interaction with metabolic pathways.

Science.gov (United States)

Roesler, William J; Dreaver-Charles, Kristine

2018-05-01

Successful learning of biochemistry requires students to engage with the material. In the past this often involved students writing out pathways by hand, and more recently directing students to online resources such as videos, songs, and animated slide presentations. However, even these latter resources do not really provide students an opportunity to engage with the material in an active fashion. As part of an online introductory metabolism course that was developed at our university, we created a series of twelve online interactive activities using Adobe Captivate 9. These activities targeted glycolysis, gluconeogenesis, the pentose phosphate pathway, glycogen metabolism, the citric acid cycle, and fatty acid oxidation. The interactive exercises consisted of two types. One involved dragging objects such as names of enzymes or allosteric modifiers to their correct drop locations such as a particular point in a metabolic pathway, a specific enzyme, and so forth. A second type involved clicking on objects, locations within a pathway, and so forth, in response to a particular question. In both types of exercises, students received feedback on their decisions in order to enhance learning. The student feedback received on these activities was very positive, and indicated that they found them to increase their confidence in the material and that they had learned the key principles of each pathway. © 2018 by The International Union of Biochemistry and Molecular Biology, 46(3):223-229, 2018. © 2018 The International Union of Biochemistry and Molecular Biology.

Seasonal precipitation patterns along pathways of South American low-level jets and aerial rivers

Science.gov (United States)

Poveda, Germán.; Jaramillo, Liliana; Vallejo, Luisa F.

2014-01-01

We study the seasonal dynamics of the eastern Pacific (CHOCO) and Caribbean low-level jets (LLJ), and aerial rivers (AR) acting on tropical and subtropical South America. Using the ERA-Interim reanalysis (1979-2012), we show that the convergence of both LLJs over the eastern Pacific-western Colombia contributes to the explanation of the region's world-record rainfall. Diverse variables involved in the transport and storage of moisture permit the identification of an AR over northern South America involving a midtropospheric easterly jet that connects the Atlantic and Pacific Oceans across the Andes, with stronger activity in April to August. Other major seasonal AR pathways constitute part of a large gyre originating over the tropical North Atlantic, veering to the southeast over the eastern Andes and reaching regions of northern Argentina and southeastern Brazil. We illustrate the distribution of average seasonal precipitation along the LLJs and AR pathways with data from the Tropical Rainfall Measuring Mission (1998-2011), combined with considerations of CAPE, topography, and land cover. In addition, the theory of the biotic pump of atmospheric moisture (BiPAM) is tested at seasonal time scales, and found to hold in 8 out of 12 ARs, and 22 out of 32 forest-covered tracks (64% in distance) along the ARs. Deviations from BiPAM's predictions of rainfall distribution are explained by the effects of topography, orography, and land cover types different from forests. Our results lend a strong observational support to the BiPAM theory at seasonal time scales over South American forested flat lands.

Solubility of indium-tin oxide in simulated lung and gastric fluids: Pathways for human intake.

Science.gov (United States)

Andersen, Jens Christian Østergård; Cropp, Alastair; Paradise, Diane Caroline

2017-02-01

From being a metal with very limited natural distribution, indium (In) has recently become disseminated throughout the human society. Little is known of how In compounds behave in the natural environment, but recent medical studies link exposure to In compounds to elevated risk of respiratory disorders. Animal tests suggest that exposure may lead to more widespread damage in the body, notably the liver, kidneys and spleen. In this paper, we investigate the solubility of the most widely used In compound, indium-tin oxide (ITO) in simulated lung and gastric fluids in order to better understand the potential pathways for metals to be introduced into the bloodstream. Our results show significant potential for release of In and tin (Sn) in the deep parts of the lungs (artificial lysosomal fluid) and digestive tract, while the solubility in the upper parts of the lungs (the respiratory tract or tracheobronchial tree) is very low. Our study confirms that ITO is likely to remain as solid particles in the upper parts of the lungs, but that particles are likely to slowly dissolve in the deep lungs. Considering the prolonged residence time of inhaled particles in the deep lung, this environment is likely to provide the major route for uptake of In and Sn from inhaled ITO nano- and microparticles. Although dissolution through digestion may also lead to some uptake, the much shorter residence time is likely to lead to much lower risk of uptake. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Combining chemoinformatics with bioinformatics: in silico prediction of bacterial flavor-forming pathways by a chemical systems biology approach "reverse pathway engineering".

Science.gov (United States)

Liu, Mengjin; Bienfait, Bruno; Sacher, Oliver; Gasteiger, Johann; Siezen, Roland J; Nauta, Arjen; Geurts, Jan M W

2014-01-01

The incompleteness of genome-scale metabolic models is a major bottleneck for systems biology approaches, which are based on large numbers of metabolites as identified and quantified by metabolomics. Many of the revealed secondary metabolites and/or their derivatives, such as flavor compounds, are non-essential in metabolism, and many of their synthesis pathways are unknown. In this study, we describe a novel approach, Reverse Pathway Engineering (RPE), which combines chemoinformatics and bioinformatics analyses, to predict the "missing links" between compounds of interest and their possible metabolic precursors by providing plausible chemical and/or enzymatic reactions. We demonstrate the added-value of the approach by using flavor-forming pathways in lactic acid bacteria (LAB) as an example. Established metabolic routes leading to the formation of flavor compounds from leucine were successfully replicated. Novel reactions involved in flavor formation, i.e. the conversion of alpha-hydroxy-isocaproate to 3-methylbutanoic acid and the synthesis of dimethyl sulfide, as well as the involved enzymes were successfully predicted. These new insights into the flavor-formation mechanisms in LAB can have a significant impact on improving the control of aroma formation in fermented food products. Since the input reaction databases and compounds are highly flexible, the RPE approach can be easily extended to a broad spectrum of applications, amongst others health/disease biomarker discovery as well as synthetic biology.

genome-wide association and metabolic pathway analysis of corn earworm resistance in maize

Science.gov (United States)

Marilyn L. Warburton; Erika D. Womack; Juliet D. Tang; Adam Thrash; J. Spencer Smith; Wenwei Xu; Seth C. Murray; W. Paul Williams

2018-01-01

Maize (Zea mays mays L.) is a staple crop of economic, industrial, and food security importance. Damage to the growing ears by corn earworm [Helicoverpa zea (Boddie)] is a major economic burden and increases secondary fungal infections and mycotoxin levels. To identify biochemical pathways associated with native resistance mechanisms, a genome-wide...

Cis-acting pathways selectively enforce the non-immunogenicity of shed placental antigen for maternal CD8 T cells.

Directory of Open Access Journals (Sweden)

Chin-Siean Tay

Full Text Available Maternal immune tolerance towards the fetus and placenta is thought to be established in part by pathways that attenuate T cell priming to antigens released from the placenta into maternal blood. These pathways remain largely undefined and their existence, at face value, seems incompatible with a mother's need to maintain a functional immune system during pregnancy. A particular conundrum is evident if we consider that maternal antigen presenting cells, activated in order to prime T cells to pathogen-derived antigens, would also have the capacity to prime T cells to co-ingested placental antigens. Here, we address this paradox using a transgenic system in which placental membranes are tagged with a strong surrogate antigen (ovalbumin. We find that although a remarkably large quantity of acellular ovalbumin-containing placental material is released into maternal blood, splenic CD8 T cells in pregnant mice bearing unmanipulated T cell repertoires are not primed to ovalbumin even if the mice are intravenously injected with adjuvants. This failure was largely independent of regulatory T cells, and instead was linked to the intrinsic characteristics of the released material that rendered it selectively non-immunogenic, potentially by sequestering it from CD8α(+ dendritic cells. The release of ovalbumin-containing placental material into maternal blood thus had no discernable impact on CD8 T cell priming to soluble ovalbumin injected intravenously during pregnancy, nor did it induce long-term tolerance to ovalbumin. Together, these results outline a major pathway governing the maternal immune response to the placenta, and suggest how tolerance to placental antigens can be maintained systemically without being detrimental to host defense.

Cis-Acting Pathways Selectively Enforce the Non-Immunogenicity of Shed Placental Antigen for Maternal CD8 T Cells

Science.gov (United States)

Tay, Chin-Siean; Tagliani, Elisa; Collins, Mary K.; Erlebacher, Adrian

2013-01-01

Maternal immune tolerance towards the fetus and placenta is thought to be established in part by pathways that attenuate T cell priming to antigens released from the placenta into maternal blood. These pathways remain largely undefined and their existence, at face value, seems incompatible with a mother's need to maintain a functional immune system during pregnancy. A particular conundrum is evident if we consider that maternal antigen presenting cells, activated in order to prime T cells to pathogen-derived antigens, would also have the capacity to prime T cells to co-ingested placental antigens. Here, we address this paradox using a transgenic system in which placental membranes are tagged with a strong surrogate antigen (ovalbumin). We find that although a remarkably large quantity of acellular ovalbumin-containing placental material is released into maternal blood, splenic CD8 T cells in pregnant mice bearing unmanipulated T cell repertoires are not primed to ovalbumin even if the mice are intravenously injected with adjuvants. This failure was largely independent of regulatory T cells, and instead was linked to the intrinsic characteristics of the released material that rendered it selectively non-immunogenic, potentially by sequestering it from CD8α+ dendritic cells. The release of ovalbumin-containing placental material into maternal blood thus had no discernable impact on CD8 T cell priming to soluble ovalbumin injected intravenously during pregnancy, nor did it induce long-term tolerance to ovalbumin. Together, these results outline a major pathway governing the maternal immune response to the placenta, and suggest how tolerance to placental antigens can be maintained systemically without being detrimental to host defense. PMID:24391885

Dynamics and control of the ERK signaling pathway: Sensitivity, bistability, and oscillations.

Science.gov (United States)

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.

Phosphoproteomic Analysis Identifies Signaling Pathways Regulated by Curcumin in Human Colon Cancer Cells.

Science.gov (United States)

Sato, Tatsuhiro; Higuchi, Yutaka; Shibagaki, Yoshio; Hattori, Seisuke

2017-09-01

Curcumin, a major polyphenol of the spice turmeric, acts as a potent chemopreventive and chemotherapeutic agent in several cancer types, including colon cancer. Although various proteins have been shown to be affected by curcumin, how curcumin exerts its anticancer activity is not fully understood. Phosphoproteomic analyses were performed using SW480 and SW620 human colon cancer cells to identify curcumin-affected signaling pathways. Curcumin inhibited the growth of the two cell lines in a dose-dependent manner. Thirty-nine curcumin-regulated phosphoproteins were identified, five of which are involved in cancer signaling pathways. Detailed analyses revealed that the mTORC1 and p53 signaling pathways are main targets of curcumin. Our results provide insight into the molecular mechanisms of the anticancer activities of curcumin and future molecular targets for its clinical application. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Assessing quality and completeness of human transcriptional regulatory pathways on a genome-wide scale

Directory of Open Access Journals (Sweden)

Aifantis Iannis

2011-02-01

Full Text Available Abstract Background Pathway databases are becoming increasingly important and almost omnipresent in most types of biological and translational research. However, little is known about the quality and completeness of pathways stored in these databases. The present study conducts a comprehensive assessment of transcriptional regulatory pathways in humans for seven well-studied transcription factors: MYC, NOTCH1, BCL6, TP53, AR, STAT1, and RELA. The employed benchmarking methodology first involves integrating genome-wide binding with functional gene expression data to derive direct targets of transcription factors. Then the lists of experimentally obtained direct targets are compared with relevant lists of transcriptional targets from 10 commonly used pathway databases. Results The results of this study show that for the majority of pathway databases, the overlap between experimentally obtained target genes and targets reported in transcriptional regulatory pathway databases is surprisingly small and often is not statistically significant. The only exception is MetaCore pathway database which yields statistically significant intersection with experimental results in 84% cases. Additionally, we suggest that the lists of experimentally derived direct targets obtained in this study can be used to reveal new biological insight in transcriptional regulation and suggest novel putative therapeutic targets in cancer. Conclusions Our study opens a debate on validity of using many popular pathway databases to obtain transcriptional regulatory targets. We conclude that the choice of pathway databases should be informed by solid scientific evidence and rigorous empirical evaluation. Reviewers This article was reviewed by Prof. Wing Hung Wong, Dr. Thiago Motta Venancio (nominated by Dr. L Aravind, and Prof. Geoff J McLachlan.

Creating and analyzing pathway and protein interaction compendia for modelling signal transduction networks

Directory of Open Access Journals (Sweden)

Kirouac Daniel C

2012-05-01

Full Text Available Abstract Background Understanding the information-processing capabilities of signal transduction networks, how those networks are disrupted in disease, and rationally designing therapies to manipulate diseased states require systematic and accurate reconstruction of network topology. Data on networks central to human physiology, such as the inflammatory signalling networks analyzed here, are found in a multiplicity of on-line resources of pathway and interactome databases (Cancer CellMap, GeneGo, KEGG, NCI-Pathway Interactome Database (NCI-PID, PANTHER, Reactome, I2D, and STRING. We sought to determine whether these databases contain overlapping information and whether they can be used to construct high reliability prior knowledge networks for subsequent modeling of experimental data. Results We have assembled an ensemble network from multiple on-line sources representing a significant portion of all machine-readable and reconcilable human knowledge on proteins and protein interactions involved in inflammation. This ensemble network has many features expected of complex signalling networks assembled from high-throughput data: a power law distribution of both node degree and edge annotations, and topological features of a “bow tie” architecture in which diverse pathways converge on a highly conserved set of enzymatic cascades focused around PI3K/AKT, MAPK/ERK, JAK/STAT, NFκB, and apoptotic signaling. Individual pathways exhibit “fuzzy” modularity that is statistically significant but still involving a majority of “cross-talk” interactions. However, we find that the most widely used pathway databases are highly inconsistent with respect to the actual constituents and interactions in this network. Using a set of growth factor signalling networks as examples (epidermal growth factor, transforming growth factor-beta, tumor necrosis factor, and wingless, we find a multiplicity of network topologies in which receptors couple to downstream

Transcriptomic analysis of genes in the nitrogen recycling pathway of meat-type chickens divergently selected for feed efficiency.

Science.gov (United States)

Aggrey, S E; Lee, J; Karnuah, A B; Rekaya, R

2014-04-01

The understanding of the dynamics of ammonia detoxification and excretion in uricotelic species is lagging behind ureotelic species. The relative expression of genes involved in nitrogen recycling and feed efficiency in chickens is unknown. The objective of this study was to investigate the transcriptomics differences in key genes in the nitrogen (N) metabolism and purine biosynthesis pathway in a chicken population divergently selected for low (LRFI) or high (HRFI) residual feed intake at days 35 and 42 using duodenum, liver, pectoralis major (P. major) and kidney. There was a significant positive correlation between RFI and fecal N. The purine salvage pathway was activated in the LRFI compared with HRFI at days 42. The birds in the LRFI population attained greater feed efficiency by having lower FI, increasing their protein retention and producing adequate glutamine to maintain growth compared with the HRFI line. To maintain growth, excess N is deaminated mostly to generate purine nucleotides. Generating purine nucleotides primarily from the purine biosynthesis pathway is energetically costly, and to preserve energy, they preferentially generate nucleotides from the purine salvage pathway. The LRFI birds need to generate sufficient nucleotides to maintain growth despite reduced FI that then results in reduced fecal N. © 2013 Stichting International Foundation for Animal Genetics.

Policy Pathways: Modernising Building Energy Codes

Energy Technology Data Exchange (ETDEWEB)

NONE

2013-08-01

Buildings are the largest consumers of energy worldwide and will continue to be a source of increasing energy demand in the future. Globally, the sector’s final energy consumption doubled between 1971 and 2010 to reach 2 794 million tonnes of oil equivalent (Mtoe), driven primarily by population increase and economic growth. Under current policies, the global energy demand of buildings is projected by the IEA experts to grow by an additional 838 Mtoe by 2035 compared to 2010. The challenges of the projected increase of energy consumption due to the built environment vary by country. In IEA member countries, much of the future buildings stock is already in place, and so the main challenge is to renovate existing buildings stock. In non-IEA countries, more than half of the buildings stock needed by 2050 has yet to be built. The IEA and the UNDP partnered to analyse current practices in the design and implementation of building energy codes. The aim is to consolidate existing efforts and to encourage more attention to the role of the built environment in a low-carbon and climate-resilient world. This joint IEA-UNDP Policy Pathway aims to share lessons learned between IEA member countries and non-IEA countries. The objective is to spread best practices, limit pressures on global energy supply, improve energy security, and contribute to environmental sustainability. Part of the IEA Policy Pathway series, Modernising building energy codes to secure our global energy future sets out key steps in planning, implementation, monitoring and evaluation. The Policy Pathway series aims to help policy makers implement the IEA 25 Energy Efficiency Policy Recommendations endorsed by IEA Ministers (2011).

Transcriptomics and metabolite analysis reveals the molecular mechanism of anthocyanin biosynthesis branch pathway in different Senecio cruentus cultivars

Directory of Open Access Journals (Sweden)

Xuehua Jin

2016-09-01

Full Text Available The cyanidin (Cy, pelargonidin (Pg and delphinidin (Dp pathways are the three major branching anthocyanin biosynthesis pathways that regulate flavonoid metabolic flux and are responsible for red, orange and blue flower colors, respectively. Different species have evolved to develop multiple regulation mechanisms that form the branched pathways. In the current study, five Senecio cruentus cultivars with different colors were investigated. We found that the white and yellow cultivars do not accumulate anthocyanin and that the blue, pink and carmine cultivars mainly accumulate Dp, Pg and Cy in differing densities. Subsequent transcriptome analysis determined that there were 43 unigenes encoding anthocyanin biosynthesis genes in the blue cultivar. We also combined chemical and transcriptomic analyses to investigate the major metabolic pathways that are related to the observed differences in flower pigmentation in the series of S. cruentus. The results showed that mutations of the ScbHLH17 and ScCHI1/2 coding regions abolish anthocyanin formation in the white and the yellow cultivars; the competition of the ScF3’H1, ScF3’5’H and ScDFR1/2 genes for naringenin determines the differences in branching metabolic flux of the Cy, Dp and Pg pathways. Our findings provide new insights into the regulation of anthocyanin branching and also supplement gene resources (including ScF3’5’H, ScF3’H and ScDFRs for flower color modification of ornamentals.

Alveolar Soft Part Sarcoma.

Science.gov (United States)

Jaber, Omar I; Kirby, Patricia A

2015-11-01

Alveolar soft part sarcoma is a rare neoplasm usually arising in the soft tissues of the lower limbs in adults and in the head and neck region in children. It presents primarily as a slowly growing mass or as metastatic disease. It is characterized by a specific chromosomal alteration, der(17)t(X:17)(p11:q25), resulting in fusion of the transcription factor E3 (TFE3) with alveolar soft part sarcoma critical region 1 (ASPSCR1) at 17q25. This translocation is diagnostically useful because the tumor nuclei are positive for TFE3 by immunohistochemistry. Real-time polymerase chain reaction to detect the ASPSCR1-TFE3 fusion transcript on paraffin-embedded tissue blocks has been shown to be more sensitive and specific than detection of TFE3 by immunohistochemical stain. Cathepsin K is a relatively recent immunohistochemical stain that can aid in the diagnosis. The recent discovery of the role of the ASPSCR1-TFE3 fusion protein in the MET proto-oncogene signaling pathway promoting angiogenesis and cell proliferation offers a promising targeted molecular therapy.

Neuroradiology in the ocular motility disorders : II. nuclear and infranuclear pathway

International Nuclear Information System (INIS)

Kim, Hyung Jin; Kim, Jae Hyoung; Ha, Choong Gun; Lim, Myung Kwan; Cho, Young Kuk; Suh, Chang Hae

1999-01-01

The nuclear and infranuclear pathway of eye movement begins from the ocular motor nuclei situated in the brain stem, where the axons originate and form three ocular motor nerves. Although each of the ocular motor nerves follows a distinct route to reach the end organ, the extraocular muscles, they also have common housings in the cavernous sinus and at the orbital apex, where part or all of them are frequently and simultaneously affected by a common disease process. Since the fine details of normal and diseased structures can frequently be seen on radiologic imaging, especially magnetic resonance (MR) imaging, a knowledge of the basic anatomy involved in nuclear and infranuclear eye movement is important. In this description, in addition to the normal nuclear and infranuclear pathway of eye movement, we have noted the radiologic findings of typical diseases involving each segment of the nuclear and infranuclear pathway, particularly as seen on magnetic resonance images. Brief comments on ocular motor pseudopalsy, which mimics ocular motor palsy, are also included

Non-Smad signaling pathways.

Science.gov (United States)

Mu, Yabing; Gudey, Shyam Kumar; Landström, Maréne

2012-01-01

Transforming growth factor-beta (TGFβ) is a key regulator of cell fate during embryogenesis and has also emerged as a potent driver of the epithelial-mesenchymal transition during tumor progression. TGFβ signals are transduced by transmembrane type I and type II serine/threonine kinase receptors (TβRI and TβRII, respectively). The activated TβR complex phosphorylates Smad2 and Smad3, converting them into transcriptional regulators that complex with Smad4. TGFβ also uses non-Smad signaling pathways such as the p38 and Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) pathways to convey its signals. Ubiquitin ligase tumor necrosis factor (TNF)-receptor-associated factor 6 (TRAF6) and TGFβ-associated kinase 1 (TAK1) have recently been shown to be crucial for the activation of the p38 and JNK MAPK pathways. Other TGFβ-induced non-Smad signaling pathways include the phosphoinositide 3-kinase-Akt-mTOR pathway, the small GTPases Rho, Rac, and Cdc42, and the Ras-Erk-MAPK pathway. Signals induced by TGFβ are tightly regulated and specified by post-translational modifications of the signaling components, since they dictate the subcellular localization, activity, and duration of the signal. In this review, we discuss recent findings in the field of TGFβ-induced responses by non-Smad signaling pathways.

Carbohydrate Metabolism in Archaea: Current Insights into Unusual Enzymes and Pathways and Their Regulation

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Esser, Dominik; Rauch, Bernadette

2014-01-01

SUMMARY The metabolism of Archaea, the third domain of life, resembles in its complexity those of Bacteria and lower Eukarya. However, this metabolic complexity in Archaea is accompanied by the absence of many “classical” pathways, particularly in central carbohydrate metabolism. Instead, Archaea are characterized by the presence of unique, modified variants of classical pathways such as the Embden-Meyerhof-Parnas (EMP) pathway and the Entner-Doudoroff (ED) pathway. The pentose phosphate pathway is only partly present (if at all), and pentose degradation also significantly differs from that known for bacterial model organisms. These modifications are accompanied by the invention of “new,” unusual enzymes which cause fundamental consequences for the underlying regulatory principles, and classical allosteric regulation sites well established in Bacteria and Eukarya are lost. The aim of this review is to present the current understanding of central carbohydrate metabolic pathways and their regulation in Archaea. In order to give an overview of their complexity, pathway modifications are discussed with respect to unusual archaeal biocatalysts, their structural and mechanistic characteristics, and their regulatory properties in comparison to their classic counterparts from Bacteria and Eukarya. Furthermore, an overview focusing on hexose metabolic, i.e., glycolytic as well as gluconeogenic, pathways identified in archaeal model organisms is given. Their energy gain is discussed, and new insights into different levels of regulation that have been observed so far, including the transcript and protein levels (e.g., gene regulation, known transcription regulators, and posttranslational modification via reversible protein phosphorylation), are presented. PMID:24600042

Compilation of poultry and egg parameters for the PATHWAY code

International Nuclear Information System (INIS)

Ikenberry, T.A.

1982-08-01

The PATHWAY computer code was developed as a part of the foodchain pathway analysis task. The objective was to estimate radionuclide ingestion rates of residents of Lincoln (Nevada), Washington (Utah), and Iron (Utah) counties during the period 1951-1962, which resulted from explosion of nuclear devices at the Nevada Test Site (NTS). Estimation of radionuclide ingestion rates involves determination of radionuclide concentrations in dietary items as a function of time and geographic area, and consumption rates of such items as a function of age and lifestyle. Poultry and eggs may have been relatively significant dose contributors to humans, because of the fairly large consumption rates of these products, and because of potential radionuclide concentration in them. This paper describes nuclide-dependent and nuclide-independent parameters related to poultry products, and the determination of specific values of these parameters. 17 figs., 10 tabs

Multiple repair pathways mediate tolerance to chemotherapeutic cross-linking agents in vertebrate cells.

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Nojima, Kuniharu; Hochegger, Helfrid; Saberi, Alihossein; Fukushima, Toru; Kikuchi, Koji; Yoshimura, Michio; Orelli, Brian J; Bishop, Douglas K; Hirano, Seiki; Ohzeki, Mioko; Ishiai, Masamichi; Yamamoto, Kazuhiko; Takata, Minoru; Arakawa, Hiroshi; Buerstedde, Jean-Marie; Yamazoe, Mitsuyoshi; Kawamoto, Takuo; Araki, Kasumi; Takahashi, Jun A; Hashimoto, Nobuo; Takeda, Shunichi; Sonoda, Eiichiro

2005-12-15

Cross-linking agents that induce DNA interstrand cross-links (ICL) are widely used in anticancer chemotherapy. Yeast genetic studies show that nucleotide excision repair (NER), Rad6/Rad18-dependent postreplication repair, homologous recombination, and cell cycle checkpoint pathway are involved in ICL repair. To study the contribution of DNA damage response pathways in tolerance to cross-linking agents in vertebrates, we made a panel of gene-disrupted clones from chicken DT40 cells, each defective in a particular DNA repair or checkpoint pathway, and measured the sensitivities to cross-linking agents, including cis-diamminedichloroplatinum (II) (cisplatin), mitomycin C, and melphalan. We found that cells harboring defects in translesion DNA synthesis (TLS), Fanconi anemia complementation groups (FANC), or homologous recombination displayed marked hypersensitivity to all the cross-linking agents, whereas NER seemed to play only a minor role. This effect of replication-dependent repair pathways is distinctively different from the situation in yeast, where NER seems to play a major role in dealing with ICL. Cells deficient in Rev3, the catalytic subunit of TLS polymerase Polzeta, showed the highest sensitivity to cisplatin followed by fanc-c. Furthermore, epistasis analysis revealed that these two mutants work in the same pathway. Our genetic comprehensive study reveals a critical role for DNA repair pathways that release DNA replication block at ICLs in cellular tolerance to cross-linking agents and could be directly exploited in designing an effective chemotherapy.

KeyPathwayMinerWeb

DEFF Research Database (Denmark)

List, Markus; Alcaraz, Nicolas; Dissing-Hansen, Martin

2016-01-01

, for instance), KeyPathwayMiner extracts connected sub-networks containing a high number of active or differentially regulated genes (proteins, metabolites) in the molecular profiles. The web interface at (http://keypathwayminer.compbio.sdu.dk) implements all core functionalities of the KeyPathwayMiner tool set......We present KeyPathwayMinerWeb, the first online platform for de novo pathway enrichment analysis directly in the browser. Given a biological interaction network (e.g. protein-protein interactions) and a series of molecular profiles derived from one or multiple OMICS studies (gene expression...... such as data integration, input of background knowledge, batch runs for parameter optimization and visualization of extracted pathways. In addition to an intuitive web interface, we also implemented a RESTful API that now enables other online developers to integrate network enrichment as a web service...

Identifying pathways affected by cancer mutations.

Science.gov (United States)

Iengar, Prathima

2017-12-16

Mutations in 15 cancers, sourced from the COSMIC Whole Genomes database, and 297 human pathways, arranged into pathway groups based on the processes they orchestrate, and sourced from the KEGG pathway database, have together been used to identify pathways affected by cancer mutations. Genes studied in ≥15, and mutated in ≥10 samples of a cancer have been considered recurrently mutated, and pathways with recurrently mutated genes have been considered affected in the cancer. Novel doughnut plots have been presented which enable visualization of the extent to which pathways and genes, in each pathway group, are targeted, in each cancer. The 'organismal systems' pathway group (including organism-level pathways; e.g., nervous system) is the most targeted, more than even the well-recognized signal transduction, cell-cycle and apoptosis, and DNA repair pathway groups. The important, yet poorly-recognized, role played by the group merits attention. Pathways affected in ≥7 cancers yielded insights into processes affected. Copyright © 2017 Elsevier Inc. All rights reserved.

Magnocellular pathway for rotation invariant Neocognitron.

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Ting, C H

1993-03-01

In the mammalian visual system, magnocellular pathway and parvocellular pathway cooperatively process visual information in parallel. The magnocellular pathway is more global and less particular about the details while the parvocellular pathway recognizes objects based on the local features. In many aspects, Neocognitron may be regarded as the artificial analogue of the parvocellular pathway. It is interesting then to model the magnocellular pathway. In order to achieve "rotation invariance" for Neocognitron, we propose a neural network model after the magnocellular pathway and expand its roles to include surmising the orientation of the input pattern prior to recognition. With the incorporation of the magnocellular pathway, a basic shift in the original paradigm has taken place. A pattern is now said to be recognized when and only when one of the winners of the magnocellular pathway is validified by the parvocellular pathway. We have implemented the magnocellular pathway coupled with Neocognitron parallel on transputers; our simulation programme is now able to recognize numerals in arbitrary orientation.

Transcriptional Responses of Escherichia coli to a Small-Molecule Inhibitor of LolCDE, an Essential Component of the Lipoprotein Transport Pathway

Science.gov (United States)

Lorenz, Christian; Dougherty, Thomas J.

2016-01-01

ABSTRACT In Gram-negative bacteria, a dedicated machinery consisting of LolABCDE components targets lipoproteins to the outer membrane. We used a previously identified small-molecule inhibitor of the LolCDE complex of Escherichia coli to assess the global transcriptional consequences of interference with lipoprotein transport. Exposure of E. coli to the LolCDE inhibitor at concentrations leading to minimal and significant growth inhibition, followed by transcriptome sequencing, identified a small group of genes whose transcript levels were decreased and a larger group whose mRNA levels increased 10- to 100-fold compared to those of untreated cells. The majority of the genes whose mRNA concentrations were reduced were part of the flagellar assembly pathway, which contains an essential lipoprotein component. Most of the genes whose transcript levels were elevated encode proteins involved in selected cell stress pathways. Many of these genes are involved with envelope stress responses induced by the mislocalization of outer membrane lipoproteins. Although several of the genes whose RNAs were induced have previously been shown to be associated with the general perturbation of the cell envelope by antibiotics, a small subset was affected only by LolCDE inhibition. Findings from this work suggest that the efficiency of the Lol system function may be coupled to a specific monitoring system, which could be exploited in the development of reporter constructs suitable for use for screening for additional inhibitors of lipoprotein trafficking. IMPORTANCE Inhibition of the lipoprotein transport pathway leads to E. coli death and subsequent lysis. Early significant changes in the levels of RNA for a subset of genes identified to be associated with some periplasmic and envelope stress responses were observed. Together these findings suggest that disruption of this key pathway can have a severe impact on balanced outer membrane synthesis sufficient to affect viability. PMID

Transcriptional Responses of Escherichia coli to a Small-Molecule Inhibitor of LolCDE, an Essential Component of the Lipoprotein Transport Pathway.

Science.gov (United States)

Lorenz, Christian; Dougherty, Thomas J; Lory, Stephen

2016-12-01

In Gram-negative bacteria, a dedicated machinery consisting of LolABCDE components targets lipoproteins to the outer membrane. We used a previously identified small-molecule inhibitor of the LolCDE complex of Escherichia coli to assess the global transcriptional consequences of interference with lipoprotein transport. Exposure of E. coli to the LolCDE inhibitor at concentrations leading to minimal and significant growth inhibition, followed by transcriptome sequencing, identified a small group of genes whose transcript levels were decreased and a larger group whose mRNA levels increased 10- to 100-fold compared to those of untreated cells. The majority of the genes whose mRNA concentrations were reduced were part of the flagellar assembly pathway, which contains an essential lipoprotein component. Most of the genes whose transcript levels were elevated encode proteins involved in selected cell stress pathways. Many of these genes are involved with envelope stress responses induced by the mislocalization of outer membrane lipoproteins. Although several of the genes whose RNAs were induced have previously been shown to be associated with the general perturbation of the cell envelope by antibiotics, a small subset was affected only by LolCDE inhibition. Findings from this work suggest that the efficiency of the Lol system function may be coupled to a specific monitoring system, which could be exploited in the development of reporter constructs suitable for use for screening for additional inhibitors of lipoprotein trafficking. Inhibition of the lipoprotein transport pathway leads to E. coli death and subsequent lysis. Early significant changes in the levels of RNA for a subset of genes identified to be associated with some periplasmic and envelope stress responses were observed. Together these findings suggest that disruption of this key pathway can have a severe impact on balanced outer membrane synthesis sufficient to affect viability. Copyright © 2016 Lorenz et al.

Modeling of nitrous oxide production by autotrophic ammonia-oxidizing bacteria with multiple production pathways.

Science.gov (United States)

Ni, Bing-Jie; Peng, Lai; Law, Yingyu; Guo, Jianhua; Yuan, Zhiguo

2014-04-01

Autotrophic ammonia oxidizing bacteria (AOB) have been recognized as a major contributor to N2O production in wastewater treatment systems. However, so far N2O models have been proposed based on a single N2O production pathway by AOB, and there is still a lack of effective approach for the integration of these models. In this work, an integrated mathematical model that considers multiple production pathways is developed to describe N2O production by AOB. The pathways considered include the nitrifier denitrification pathway (N2O as the final product of AOB denitrification with NO2(-) as the terminal electron acceptor) and the hydroxylamine (NH2OH) pathway (N2O as a byproduct of incomplete oxidation of NH2OH to NO2(-)). In this model, the oxidation and reduction processes are modeled separately, with intracellular electron carriers introduced to link the two types of processes. The model is calibrated and validated using experimental data obtained with two independent nitrifying cultures. The model satisfactorily describes the N2O data from both systems. The model also predicts shifts of the dominating pathway at various dissolved oxygen (DO) and nitrite levels, consistent with previous hypotheses. This unified model is expected to enhance our ability to predict N2O production by AOB in wastewater treatment systems under varying operational conditions.

Mining pathway associations for disease-related pathway activity analysis based on gene expression and methylation data.

Science.gov (United States)

Lee, Hyeonjeong; Shin, Miyoung

2017-01-01

The problem of discovering genetic markers as disease signatures is of great significance for the successful diagnosis, treatment, and prognosis of complex diseases. Even if many earlier studies worked on identifying disease markers from a variety of biological resources, they mostly focused on the markers of genes or gene-sets (i.e., pathways). However, these markers may not be enough to explain biological interactions between genetic variables that are related to diseases. Thus, in this study, our aim is to investigate distinctive associations among active pathways (i.e., pathway-sets) shown each in case and control samples which can be observed from gene expression and/or methylation data. The pathway-sets are obtained by identifying a set of associated pathways that are often active together over a significant number of class samples. For this purpose, gene expression or methylation profiles are first analyzed to identify significant (active) pathways via gene-set enrichment analysis. Then, regarding these active pathways, an association rule mining approach is applied to examine interesting pathway-sets in each class of samples (case or control). By doing so, the sets of associated pathways often working together in activity profiles are finally chosen as our distinctive signature of each class. The identified pathway-sets are aggregated into a pathway activity network (PAN), which facilitates the visualization of differential pathway associations between case and control samples. From our experiments with two publicly available datasets, we could find interesting PAN structures as the distinctive signatures of breast cancer and uterine leiomyoma cancer, respectively. Our pathway-set markers were shown to be superior or very comparable to other genetic markers (such as genes or gene-sets) in disease classification. Furthermore, the PAN structure, which can be constructed from the identified markers of pathway-sets, could provide deeper insights into

Patient navigation pathway and barriers to treatment seeking in cancer in India: a qualitative inquiry.

Science.gov (United States)

Pati, Sanghamitra; Hussain, Mohammad Akhtar; Chauhan, Abhimanyu Singh; Mallick, Diptimayee; Nayak, Sukdev

2013-12-01

Cancer is a leading cause of mortality worldwide. Early diagnosis and treatment of cancer may curb the growing burden of the disease. Understanding cancer patients' navigation pathways for seeking treatment is important in order to facilitate early diagnosis and treatment. With this background we conducted a hospital-based cross-sectional study comprising 68 randomly selected cancer inpatients in a tertiary cancer specialty hospital in Odisha, India, to explore the treatment-seeking pathways of the cancer patients and the barriers and enablers in seeking treatment. Financial constraint is one of the major reasons for the delay in accessing treatment, even when patients are suspected of or diagnosed with cancer. Low awareness of the presenting signs and symptoms of cancer and limited knowledge of the availability of cancer diagnosis and treatment facilities are major factors contributing to delay. Family and friends' support is found to be the major enabling factor toward seeking treatment. Generation of awareness of cancer among the general population and primary-care practitioners - including those in alternative systems of medicine - is important. Information on diagnostic and treatment services appears to be a felt need. Copyright © 2013 Elsevier Ltd. All rights reserved.

Disorders of dysregulated signal traffic through the RAS-MAPK pathway: phenotypic spectrum and molecular mechanisms.

Science.gov (United States)

Tartaglia, Marco; Gelb, Bruce D

2010-12-01

RAS GTPases control a major signaling network implicated in several cellular functions, including cell fate determination, proliferation, survival, differentiation, migration, and senescence. Within this network, signal flow through the RAF-MEK-ERK pathway-the first identified mitogen-associated protein kinase (MAPK) cascade-mediates early and late developmental processes controlling morphology determination, organogenesis, synaptic plasticity, and growth. Signaling through the RAS-MAPK cascade is tightly controlled; and its enhanced activation represents a well-known event in oncogenesis. Unexpectedly, in the past few years, inherited dysregulation of this pathway has been recognized as the cause underlying a group of clinically related disorders sharing facial dysmorphism, cardiac defects, reduced postnatal growth, ectodermal anomalies, variable cognitive deficits, and susceptibility to certain malignancies as major features. These disorders are caused by heterozygosity for mutations in genes encoding RAS proteins, regulators of RAS function, modulators of RAS interaction with effectors, or downstream signal transducers. Here, we provide an overview of the phenotypic spectrum associated with germline mutations perturbing RAS-MAPK signaling, the unpredicted molecular mechanisms converging toward the dysregulation of this signaling cascade, and major genotype-phenotype correlations. © 2010 New York Academy of Sciences.

Bioengineering natural product biosynthetic pathways for therapeutic applications.

Science.gov (United States)

Wu, Ming-Cheng; Law, Brian; Wilkinson, Barrie; Micklefield, Jason

2012-12-01

With the advent of next-generation DNA sequencing technologies, the number of microbial genome sequences has increased dramatically, revealing a vast array of new biosynthetic gene clusters. Genomics data provide a tremendous opportunity to discover new natural products, and also to guide the bioengineering of new and existing natural product scaffolds for therapeutic applications. Notably, it is apparent that the vast majority of biosynthetic gene clusters are either silent or produce very low quantities of the corresponding natural products. It is imperative therefore to devise methods for activating unproductive biosynthetic pathways to provide the quantities of natural products needed for further development. Moreover, on the basis of our expanding mechanistic and structural knowledge of biosynthetic assembly-line enzymes, new strategies for re-programming biosynthetic pathways have emerged, resulting in focused libraries of modified products with potentially improved biological properties. In this review we will focus on the latest bioengineering approaches that have been utilised to optimise yields and increase the structural diversity of natural product scaffolds for future clinical applications. Copyright © 2012 Elsevier Ltd. All rights reserved.

Are part timers real GPs? Attitudes of general practitioners toward those who work part time.

Science.gov (United States)

Mazza, D; Northfield, S

2000-09-01

Current attitudes within the medical profession suggest that one cannot be a 'real' doctor unless one works full time. The aim of this study was to determine the views and attitudes of a sample of GPs toward part time practice. As part of a larger study, GPs in two divisions in metropolitan Melbourne were sent a questionnaire based survey. GPs were asked to rate statements about part time practice using a Likert scale. The response rate was 55% (n = 246). The majority of GPs disagreed with the statement 'part time GPs are not real GPs' but feelings were mixed about whether part timers covered the same range of clinical content as full timers. One fifth of respondents questioned the competence of part time GPs. Male GPs, those over 55 years and full timers were more likely to hold negative views toward part time general practice. Our results show a 'generational' pattern toward part time practice. With the increasing numbers of women entering general practice, these attitudes will need to change to accommodate the fact that more GPs will be choosing to work part time in the future.

Selected Findings from What's It Worth? The Economic Value of College Majors

Science.gov (United States)

Carnevale, Anthony P.; Strohl, Jeff; Melton, Michelle

2011-01-01

These Selected Findings are part of a larger report: "What's It Worth?: The Economic Value of College Majors." In the full report, readers can find detailed information about earnings, broken down by 171 different undergraduate majors and a variety of demographic factors. The study also analyzes the likelihood that students in specific majors…

Intercellular signaling pathways active during and after growth and differentiation of the lumbar vertebral growth plate.

Science.gov (United States)

Dahia, Chitra Lekha; Mahoney, Eric J; Durrani, Atiq A; Wylie, Christopher

2011-06-15

Vertebral growth plates at different postnatal ages were assessed for active intercellular signaling pathways. To generate a spatial and temporal map of the major signaling pathways active in the postnatal mouse lumbar vertebral growth plate. The growth of all long bones is known to occur by cartilaginous growth plates. The growth plate is composed of layers of chondrocyets that actively proliferate, differentiate, die and, are replaced by bone. The role of major cell signaling pathways has been suggested for regulation of the fetal long bones. But not much is known about the molecular or cellular signals that control the postnatal vertebral growth plate and hence postnatal vertebral bone growth. Understanding such molecular mechanisms will help design therapeutic treatments for vertebral growth disorders such as scoliosis. Antibodies against activated downstream intermediates were used to identify cells in the growth plate responding to BMP, TGFβ, and FGF in cryosections of lumbar vertebrae from different postnatal age mice to identify the zones that were responding to these signals. Reporter mice were used to identify the chondrocytes responding to hedgehog (Ihh), and Wnt signaling. We present a spatial/temporal map of these signaling pathways during growth, and differentiation of the mouse lumbar vertebral growth plate. During growth and differentiation of the vertebral growth plate, its different components respond at different times to different intercellular signaling ligands. Response to most of these signals is dramatically downregulated at the end of vertebral growth.

Deconstruction of archaeal genome depict strategic consensus in core pathways coding sequence assembly.

Directory of Open Access Journals (Sweden)

Ayon Pal

Full Text Available A comprehensive in silico analysis of 71 species representing the different taxonomic classes and physiological genre of the domain Archaea was performed. These organisms differed in their physiological attributes, particularly oxygen tolerance and energy metabolism. We explored the diversity and similarity in the codon usage pattern in the genes and genomes of these organisms, emphasizing on their core cellular pathways. Our thrust was to figure out whether there is any underlying similarity in the design of core pathways within these organisms. Analyses of codon utilization pattern, construction of hierarchical linear models of codon usage, expression pattern and codon pair preference pointed to the fact that, in the archaea there is a trend towards biased use of synonymous codons in the core cellular pathways and the Nc-plots appeared to display the physiological variations present within the different species. Our analyses revealed that aerobic species of archaea possessed a larger degree of freedom in regulating expression levels than could be accounted for by codon usage bias alone. This feature might be a consequence of their enhanced metabolic activities as a result of their adaptation to the relatively O2-rich environment. Species of archaea, which are related from the taxonomical viewpoint, were found to have striking similarities in their ORF structuring pattern. In the anaerobic species of archaea, codon bias was found to be a major determinant of gene expression. We have also detected a significant difference in the codon pair usage pattern between the whole genome and the genes related to vital cellular pathways, and it was not only species-specific but pathway specific too. This hints towards the structuring of ORFs with better decoding accuracy during translation. Finally, a codon-pathway interaction in shaping the codon design of pathways was observed where the transcription pathway exhibited a significantly different coding

Deconstruction of archaeal genome depict strategic consensus in core pathways coding sequence assembly.

Science.gov (United States)

Pal, Ayon; Banerjee, Rachana; Mondal, Uttam K; Mukhopadhyay, Subhasis; Bothra, Asim K

2015-01-01

A comprehensive in silico analysis of 71 species representing the different taxonomic classes and physiological genre of the domain Archaea was performed. These organisms differed in their physiological attributes, particularly oxygen tolerance and energy metabolism. We explored the diversity and similarity in the codon usage pattern in the genes and genomes of these organisms, emphasizing on their core cellular pathways. Our thrust was to figure out whether there is any underlying similarity in the design of core pathways within these organisms. Analyses of codon utilization pattern, construction of hierarchical linear models of codon usage, expression pattern and codon pair preference pointed to the fact that, in the archaea there is a trend towards biased use of synonymous codons in the core cellular pathways and the Nc-plots appeared to display the physiological variations present within the different species. Our analyses revealed that aerobic species of archaea possessed a larger degree of freedom in regulating expression levels than could be accounted for by codon usage bias alone. This feature might be a consequence of their enhanced metabolic activities as a result of their adaptation to the relatively O2-rich environment. Species of archaea, which are related from the taxonomical viewpoint, were found to have striking similarities in their ORF structuring pattern. In the anaerobic species of archaea, codon bias was found to be a major determinant of gene expression. We have also detected a significant difference in the codon pair usage pattern between the whole genome and the genes related to vital cellular pathways, and it was not only species-specific but pathway specific too. This hints towards the structuring of ORFs with better decoding accuracy during translation. Finally, a codon-pathway interaction in shaping the codon design of pathways was observed where the transcription pathway exhibited a significantly different coding frequency signature.

MENA is a transcriptional target of the Wnt/beta-catenin pathway.

Directory of Open Access Journals (Sweden)

Ayaz Najafov

Full Text Available Wnt/β-catenin signalling pathway plays important roles in embryonic development and carcinogenesis. Overactivation of the pathway is one of the most common driving forces in major cancers such as colorectal and breast cancers. The downstream effectors of the pathway and its regulation of carcinogenesis and metastasis are still not very well understood. In this study, which was based on two genome-wide transcriptomics screens, we identify MENA (ENAH, Mammalian enabled homologue as a novel transcriptional target of the Wnt/β-catenin signalling pathway. We show that the expression of MENA is upregulated upon overexpression of degradation-resistant β-catenin. Promoters of all mammalian MENA homologues contain putative binding sites for Tcf4 transcription factor--the primary effector of the Wnt/β-catenin pathway and we demonstrate functionality of these Tcf4-binding sites using luciferase reporter assays and overexpression of β-catenin, Tcf4 and dominant-negative Tcf4. In addition, lithium chloride-mediated inhibition of GSK3β also resulted in increase in MENA mRNA levels. Chromatin immunoprecipitation showed direct interaction between β-catenin and MENA promoter in Huh7 and HEK293 cells and also in mouse brain and liver tissues. Moreover, overexpression of Wnt1 and Wnt3a ligands increased MENA mRNA levels. Additionally, knock-down of MENA ortholog in D. melanogaster eyeful and sensitized eye cancer fly models resulted in increased tumor and metastasis formations. In summary, our study identifies MENA as novel nexus for the Wnt/β-catenin and the Notch signalling cascades.

Lymphatic drainage pathways from the cervix uteri: implications for radical hysterectomy?

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Kraima, A C; Derks, M; Smit, N N; Van Munsteren, J C; Van der Velden, J; Kenter, G G; DeRuiter, M C

2014-01-01

Radical hysterectomy with pelvic lymphadenectomy is the treatment of choice for early-stage cervical cancer. Wertheim's original technique has been often modified, mainly in the extent of parametrectomy. Okabayashi's technique is considered as the most radical variant regarding removal of the ventral parametrium and paracolpal tissues. Surgical outcome concerning recurrence and survival is good, but morbidity is high due to autonomic nerve damage. While the autonomic network has been studied extensively, the lymphatic system is less understood. This study describes the lymphatic drainage pathways of the cervix uteri and specifically the presence of lymphatics in the vesico-uterine ligament (VUL). A developmental series of 10 human female fetal pelves was studied. Paraffin embedded blocks were sliced in transverse sections of 8 or 10 μm. Analysis was performed by staining with antibodies against LYVE-1 (lymphatic endothelium), S100 (Schwann cells), alpha-Smooth Muscle Actin (smooth muscle cells) and CD68 (macrophages). The results were three-dimensionally represented. Two major pathways drained the cervix uteri: a supra-ureteral pathway, running in the cardinal ligament superior to the ureter, and a dorsal pathway, running in the utero-sacral ligament towards the rectal pillars. No lymph vessels draining the cervix uteri were detected in the VUL. In the paracolpal parametrium lymph vessels draining the upper vagina fused with those from the bladder. The VUL does not contain lymphatics from the cervix uteri. Hence, the favorable survival outcomes of the Okabayashi technique cannot be explained by radical removal of lymphatic pathways in the ventrocaudal parametrium. © 2013.

MENA is a transcriptional target of the Wnt/beta-catenin pathway.

Science.gov (United States)

Najafov, Ayaz; Seker, Tuncay; Even, Ipek; Hoxhaj, Gerta; Selvi, Osman; Ozel, Duygu Esen; Koman, Ahmet; Birgül-İyison, Necla

2012-01-01

Wnt/β-catenin signalling pathway plays important roles in embryonic development and carcinogenesis. Overactivation of the pathway is one of the most common driving forces in major cancers such as colorectal and breast cancers. The downstream effectors of the pathway and its regulation of carcinogenesis and metastasis are still not very well understood. In this study, which was based on two genome-wide transcriptomics screens, we identify MENA (ENAH, Mammalian enabled homologue) as a novel transcriptional target of the Wnt/β-catenin signalling pathway. We show that the expression of MENA is upregulated upon overexpression of degradation-resistant β-catenin. Promoters of all mammalian MENA homologues contain putative binding sites for Tcf4 transcription factor--the primary effector of the Wnt/β-catenin pathway and we demonstrate functionality of these Tcf4-binding sites using luciferase reporter assays and overexpression of β-catenin, Tcf4 and dominant-negative Tcf4. In addition, lithium chloride-mediated inhibition of GSK3β also resulted in increase in MENA mRNA levels. Chromatin immunoprecipitation showed direct interaction between β-catenin and MENA promoter in Huh7 and HEK293 cells and also in mouse brain and liver tissues. Moreover, overexpression of Wnt1 and Wnt3a ligands increased MENA mRNA levels. Additionally, knock-down of MENA ortholog in D. melanogaster eyeful and sensitized eye cancer fly models resulted in increased tumor and metastasis formations. In summary, our study identifies MENA as novel nexus for the Wnt/β-catenin and the Notch signalling cascades.

Gamabufotalin, a major derivative of bufadienolide, inhibits VEGF-induced angiogenesis by suppressing VEGFR-2 signaling pathway.

Science.gov (United States)

Tang, Ning; Shi, Lei; Yu, Zhenlong; Dong, Peipei; Wang, Chao; Huo, Xiaokui; Zhang, Baojing; Huang, Shanshan; Deng, Sa; Liu, Kexin; Ma, Tonghui; Wang, Xiaobo; Wu, Lijun; Ma, Xiao-Chi

2016-01-19

Gamabufotalin (CS-6), a main active compound isolated from Chinese medicine Chansu, has been shown to strongly inhibit cancer cell growth and inflammatory response. However, its effects on angiogenesis have not been known yet. Here, we sought to determine the biological effects of CS-6 on signaling mechanisms during angiogenesis. Our present results fully demonstrate that CS-6 could significantly inhibit VEGF triggered HUVECs proliferation, migration, invasion and tubulogenesis in vitro and blocked vascularization in Matrigel plugs impregnated in C57/BL6 mice as well as reduced vessel density in human lung tumor xenograft implanted in nude mice. Computer simulations revealed that CS-6 interacted with the ATP-binding sites of VEGFR-2 using molecular docking. Furthermore, western blot analysis indicated that CS-6 inhibited VEGF-induced phosphorylation of VEGFR-2 kinase and suppressed the activity of VEGFR-2-mediated signaling cascades. Therefore, our studies demonstrated that CS-6 inhibited angiogenesis by inhibiting the activation of VEGFR-2 signaling pathways and CS-6 could be a potential candidate in angiogenesis-related disease therapy.

Research advances in sorafenib-induced apoptotic signaling pathways in liver cancer cells

Directory of Open Access Journals (Sweden)

ZHANG Chaoya

2016-04-01

Full Text Available Currently, sorafenib is the multi-target inhibitor for the treatment of advanced primary liver cancer, and can effectively prolong the progression-free survival and overall survival in patients with advanced primary liver cancer. The application of sorafenib in the targeted therapy for liver cancer has become a hot topic. Major targets or signaling pathways include Raf/Mek/Erk, Jak/Stat, PI3K/Akt/mTOR, VEGFR and PDGFR, STAT, microRNA, Wnt/β-catenin, autolysosome, and tumor-related proteins, and sorafenib can regulate the proliferation, differentiation, metastasis, and apoptosis of liver cancer cells through these targets. This article reviews the current research on the action of sorafenib on these targets or signaling pathways to provide useful references for further clinical research on sorafenib.

Distinct Calcium Signaling Pathways Regulate Calmodulin Gene Expression in Tobacco1

Science.gov (United States)

van der Luit, Arnold H.; Olivari, Claudio; Haley, Ann; Knight, Marc R.; Trewavas, Anthony J.

1999-01-01

Cold shock and wind stimuli initiate Ca2+ transients in transgenic tobacco (Nicotiana plumbaginifolia) seedlings (named MAQ 2.4) containing cytoplasmic aequorin. To investigate whether these stimuli initiate Ca2+ pathways that are spatially distinct, stress-induced nuclear and cytoplasmic Ca2+ transients and the expression of a stress-induced calmodulin gene were compared. Tobacco seedlings were transformed with a construct that encodes a fusion protein between nucleoplasmin (a major oocyte nuclear protein) and aequorin. Immunocytochemical evidence indicated targeting of the fusion protein to the nucleus in these plants, which were named MAQ 7.11. Comparison between MAQ 7.11 and MAQ 2.4 seedlings confirmed that wind stimuli and cold shock invoke separate Ca2+ signaling pathways. Partial cDNAs encoding two tobacco calmodulin genes, NpCaM-1 and NpCaM-2, were identified and shown to have distinct nucleotide sequences that encode identical polypeptides. Expression of NpCaM-1, but not NpCaM-2, responded to wind and cold shock stimulation. Comparison of the Ca2+ dynamics with NpCaM-1 expression after stimulation suggested that wind-induced NpCaM-1 expression is regulated by a Ca2+ signaling pathway operational predominantly in the nucleus. In contrast, expression of NpCaM-1 in response to cold shock is regulated by a pathway operational predominantly in the cytoplasm. PMID:10557218

Robust de novo pathway enrichment with KeyPathwayMiner 5

DEFF Research Database (Denmark)

Alcaraz, Nicolas; List, Markus; Dissing-Hansen, Martin

2016-01-01

Identifying functional modules or novel active pathways, recently termed de novo pathway enrichment, is a computational systems biology challenge that has gained much attention during the last decade. Given a large biological interaction network, KeyPathwayMiner extracts connected subnetworks tha...

NutrimiRAging: Micromanaging Nutrient Sensing Pathways through Nutrition to Promote Healthy Aging.

Science.gov (United States)

Micó, Víctor; Berninches, Laura; Tapia, Javier; Daimiel, Lidia

2017-04-26

Current sociodemographic predictions point to a demographic shift in developed and developing countries that will result in an unprecedented increase of the elderly population. This will be accompanied by an increase in age-related conditions that will strongly impair human health and quality of life. For this reason, aging is a major concern worldwide. Healthy aging depends on a combination of individual genetic factors and external environmental factors. Diet has been proved to be a powerful tool to modulate aging and caloric restriction has emerged as a valuable intervention in this regard. However, many questions about how a controlled caloric restriction intervention affects aging-related processes are still unanswered. Nutrient sensing pathways become deregulated with age and lose effectiveness with age. These pathways are a link between diet and aging. Thus, fully understanding this link is a mandatory step before bringing caloric restriction into practice. MicroRNAs have emerged as important regulators of cellular functions and can be modified by diet. Some microRNAs target genes encoding proteins and enzymes belonging to the nutrient sensing pathways and, therefore, may play key roles in the modulation of the aging process. In this review, we aimed to show the relationship between diet, nutrient sensing pathways and microRNAs in the context of aging.

NutrimiRAging: Micromanaging Nutrient Sensing Pathways through Nutrition to Promote Healthy Aging

Directory of Open Access Journals (Sweden)

Víctor Micó

2017-04-01

Full Text Available Current sociodemographic predictions point to a demographic shift in developed and developing countries that will result in an unprecedented increase of the elderly population. This will be accompanied by an increase in age-related conditions that will strongly impair human health and quality of life. For this reason, aging is a major concern worldwide. Healthy aging depends on a combination of individual genetic factors and external environmental factors. Diet has been proved to be a powerful tool to modulate aging and caloric restriction has emerged as a valuable intervention in this regard. However, many questions about how a controlled caloric restriction intervention affects aging-related processes are still unanswered. Nutrient sensing pathways become deregulated with age and lose effectiveness with age. These pathways are a link between diet and aging. Thus, fully understanding this link is a mandatory step before bringing caloric restriction into practice. MicroRNAs have emerged as important regulators of cellular functions and can be modified by diet. Some microRNAs target genes encoding proteins and enzymes belonging to the nutrient sensing pathways and, therefore, may play key roles in the modulation of the aging process. In this review, we aimed to show the relationship between diet, nutrient sensing pathways and microRNAs in the context of aging.

Navigating career pathways--dental therapists in the workforce: a report of the career path subcommittee.

Science.gov (United States)

Yoder, Karen; DePaola, Dominick

2011-01-01

Creating career pathways to facilitate current dental and other healthcare providers becoming dental therapists can be an efficient means to expand the dental workforce and reduce barriers to access to oral health services. Career pathways are proposed to facilitate dental providers building on previously learned skills to broaden their scope of practice and become even more versatile and productive providers of oral health services. Creation of a unified and integrated curriculum will enable research to document the effectiveness of this new dental provider who will work as part of dental teams and with supervision by dentists. The goal of augmenting the current dental team and reducing barriers to access to dental services for underserved populations can be enhanced by offering alternative pathways to achieve the competencies required of dental therapists.

Selection of personalized patient therapy through the use of knowledge-based computational models that identify tumor-driving signal transduction pathways.

Science.gov (United States)

Verhaegh, Wim; van Ooijen, Henk; Inda, Márcia A; Hatzis, Pantelis; Versteeg, Rogier; Smid, Marcel; Martens, John; Foekens, John; van de Wiel, Paul; Clevers, Hans; van de Stolpe, Anja

2014-06-01

Increasing knowledge about signal transduction pathways as drivers of cancer growth has elicited the development of "targeted drugs," which inhibit aberrant signaling pathways. They require a companion diagnostic test that identifies the tumor-driving pathway; however, currently available tests like estrogen receptor (ER) protein expression for hormonal treatment of breast cancer do not reliably predict therapy response, at least in part because they do not adequately assess functional pathway activity. We describe a novel approach to predict signaling pathway activity based on knowledge-based Bayesian computational models, which interpret quantitative transcriptome data as the functional output of an active signaling pathway, by using expression levels of transcriptional target genes. Following calibration on only a small number of cell lines or cohorts of patient data, they provide a reliable assessment of signaling pathway activity in tumors of different tissue origin. As proof of principle, models for the canonical Wnt and ER pathways are presented, including initial clinical validation on independent datasets from various cancer types. ©2014 American Association for Cancer Research.

Pathways to Health Risk Exposure in Adult Film Performers

OpenAIRE

Grudzen, Corita R.; Ryan, Gery; Margold, William; Torres, Jacqueline; Gelberg, Lillian

2008-01-01

Despite being part of a large and legal industry in Los Angeles, little is known about adult film performers’ exposure to health risks and when and how these risks might occur. The objective was to identify exposure to physical, mental, and social health risks and the pathways to such risks among adult film performers and to determine how risks differ between different types of performers, such as men and women. Semi-structured in-depth interviews were conducted with 18 female and ten male pe...

Promoting Exercise as Part of a Physiotherapy-Led Falls Pathway Service for Adults with Intellectual Disabilities: A Service Evaluation

Science.gov (United States)

Crockett, Jennifer; Finlayson, Janet; Skelton, Dawn A.; Miller, Gillian

2015-01-01

Background: People with intellectual disabilities experience high rates of falls. Balance and gait problems are common in people with intellectual disabilities, increasing the likelihood of falls; thus, tailored exercise interventions to improve gait and balance are recommended. The present authors set up a physiotherapy-led falls pathway service…

Novel Augmentation Strategies in Major Depression

DEFF Research Database (Denmark)

Martiny, Klaus

2017-01-01

Hypothesis The hypotheses of all the four included studies share the common idea that it is possible to augment the effect of antidepressant drug treatment by applying different interventions and with each intervention attain a clinically meaningful better effect compared to a control condition......, and with minor side effects, thus improving the short- and medium-term outcome in major depression. Procedures Study design The basic study design has been the double blind randomised controlled trial (RCT). In the light therapy study, all patients were treated with sertraline for the whole of the study duration...... open psychiatric wards. Only a few patients were re-cruited through advertisements (in the PEMF and Chronos studies). Inclusion criteria Inclusion criteria were major depression according to the DSM-IV, including a depressive episode as part of a bipolar disorder. For the PEMF study, treatment...

Bayesian inference of the sites of perturbations in metabolic pathways via Markov chain Monte Carlo

NARCIS (Netherlands)

Jayawardhana, Bayu; Kell, Douglas B.; Rattray, Magnus

2008-01-01

Motivation: Genetic modifications or pharmaceutical interventions can influence multiple sites in metabolic pathways, and often these are ‘distant’ from the primary effect. In this regard, the ability to identify target and off-target effects of a specific compound or gene therapy is both a major

Efficient algorithms for extracting biological key pathways with global constraints

DEFF Research Database (Denmark)

Baumbach, Jan; Friedrich, T.; Kötzing, T.

2012-01-01

The integrated analysis of data of different types and with various interdependencies is one of the major challenges in computational biology. Recently, we developed KeyPathwayMiner, a method that combines biological networks modeled as graphs with disease-specific genetic expression data gained....... Here we present an alternative approach that avoids a certain bias towards hub nodes: We now aim for extracting all maximal connected sub-networks where all but at most K nodes are expressed in all cases but in total (!) at most L, i.e. accumulated over all cases and all nodes in a solution. We call...... this strategy GLONE (global node exceptions); the previous problem we call INES (individual node exceptions). Since finding GLONE-components is computationally hard, we developed an Ant Colony Optimization algorithm and implemented it with the KeyPathwayMiner Cytoscape framework as an alternative to the INES...

14 CFR 21.289 - Major repairs, rebuilding and alteration.

Science.gov (United States)

2010-01-01

... TRANSPORTATION AIRCRAFT CERTIFICATION PROCEDURES FOR PRODUCTS AND PARTS Delegation Option Authorization Procedures § 21.289 Major repairs, rebuilding and alteration. For types covered by a delegation option... any employee to execute and sign FAA Form 337 and make required log book entries if that employee— (1...

Increased neural response to social rejection in major depression

NARCIS (Netherlands)

Kumar, Poornima; Waiter, Gordon D.; Dubois, Magda; Milders, Maarten; Reid, Ian; Steele, J. Douglas

2017-01-01

Background: Being a part of community is critical for survival and individuals with major depressive disorder (MDD) have a greater sensitivity to interpersonal stress that makes them vulnerable to future episodes. Social rejection is a critical risk factor for depression and it is said to increase

Rules of thumb for assessing reductive dechlorination pathways of PCDDs in specific systems

International Nuclear Information System (INIS)

Lu Guining; Dang Zhi; Fennell, Donna E.; Huang Weilin; Li Zhong; Liu Congqiang

2010-01-01

This paper reports a theoretical validation and proposition of the reductive dechlorination pathways for polychlorinated dibenzo-p-dioxin (PCDD) congeners. Density functional theory (DFT) calculations were carried out at the B3LYP/6-31G(d) level for all PCDDs and Mulliken atomic charges on chlorine atoms were adopted as the probe of the dechlorination reaction activity. The experimentally substantiated dechlorination pathways of 1,2,3,4-tetrachlorodibenzo-p-dioxin (1,2,3,4-TCDD) and its daughter products in the presence of zero-valent zinc were validated and the complete pathway of dechlorination of octachlorodibenzo-p-dioxin (OCDD) was proposed. The proposed pathways were found to be consistent with anaerobic biotransformation of several PCDD congeners. Four rules of thumb arrived from this study include (1) the chlorine atoms in the longitudinal (1,4,6,9) positions are removed in preference to the chlorine atoms on lateral (2,3,7,8) positions; (2) the chlorine atom that has more neighboring chlorine atoms at ortho-, meta- and para-positions is to be eliminated; (3) reductive dechlorination prefers to take place on the benzene ring having more chlorine substitutions; and (4) a chlorine atom on the side of the longitudinal symmetry axis containing more chlorine atoms is preferentially eliminated. These rules of thumb can be conveniently used for rapidly predicting the major dechlorination pathway for a given PCDD in specific systems.

Evolution and Design Governing Signal Precision and Amplification in a Bacterial Chemosensory Pathway.

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Mathilde Guzzo

2015-08-01

Full Text Available Understanding the principles underlying the plasticity of signal transduction networks is fundamental to decipher the functioning of living cells. In Myxococcus xanthus, a particular chemosensory system (Frz coordinates the activity of two separate motility systems (the A- and S-motility systems, promoting multicellular development. This unusual structure asks how signal is transduced in a branched signal transduction pathway. Using combined evolution-guided and single cell approaches, we successfully uncoupled the regulations and showed that the A-motility regulation system branched-off an existing signaling system that initially only controlled S-motility. Pathway branching emerged in part following a gene duplication event and changes in the circuit structure increasing the signaling efficiency. In the evolved pathway, the Frz histidine kinase generates a steep biphasic response to increasing external stimulations, which is essential for signal partitioning to the motility systems. We further show that this behavior results from the action of two accessory response regulator proteins that act independently to filter and amplify signals from the upstream kinase. Thus, signal amplification loops may underlie the emergence of new connectivity in signal transduction pathways.

Relationships between the use of Embden Meyerhof pathway (EMP) or Phosphoketolase pathway (PKP) and lactate production capabilities of diverse Lactobacillus reuteri strains.

Science.gov (United States)

Burgé, Grégoire; Saulou-Bérion, Claire; Moussa, Marwen; Allais, Florent; Athes, Violaine; Spinnler, Henry-Eric

2015-10-01

The aims of this study is to compare the growth and glucose metabolism of three Lactobacillus reuteri strains (i.e. DSM 20016, DSM 17938, and ATCC 53608) which are lactic acid bacteria of interest used for diverse applications such as probiotics implying the production of biomass, or for the production of valuable chemicals (3-hydroxypropionaldehyde, 3-hydroxypropionic acid, 1,3-propanediol). However, the physiological diversity inside the species, even for basic metabolisms, like its capacity of acidification or glucose metabolism, has not been studied yet. In the present work, the growth and metabolism of three strains representative of the species diversity have been studied in batch mode. The strains were compared through characterization of growth kinetics and evaluation of acidification kinetics, substrate consumption and product formation. The results showed significant differences between the three strains which may be explained, at least in part, by variations in the distribution of carbon source between two glycolytic pathways during the bacterial growth: the phosphoketolase or heterolactic pathway (PKP) and the Embden-Meyerhof pathway (EMP). It was also shown that, in the context of obtaining a large amount of biomass, DSM 20016 and DSM 17938 strains were the most effective in terms of growth kinetics. The DSM 17938 strain, which shows the more significant metabolic shift from EMP to PKP when the pH decreases, is more effective for lactate production.

Turning over renal osteodystrophy dogma: direct actions of FGF23 on osteoblast β-catenin pathway.

Science.gov (United States)

Schiavi, Susan C; Moysés, Rosa M A

2016-07-01

Although recognized as a major complication of chronic kidney disease (CKD), the pathophysiology of the CKD-related mineral and bone disorder (CKD-MBD) is not completely understood. Recently, the inhibition of Wnt/β-catenin pathway in osteocytes by sclerostin has been shown to play a role in CKD-MBD. The study by Carrilo-Lopez et al. confirms this inhibition in an experimental model of CKD. Moreover, they describe direct actions of FGF23-Klotho on osteoblasts, increasing the expression of DKK1, another Wnt/β-catenin pathway inhibitor. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Crystallization Pathways in Biomineralization

Science.gov (United States)

Weiner, Steve; Addadi, Lia

2011-08-01

A crystallization pathway describes the movement of ions from their source to the final product. Cells are intimately involved in biological crystallization pathways. In many pathways the cells utilize a unique strategy: They temporarily concentrate ions in intracellular membrane-bound vesicles in the form of a highly disordered solid phase. This phase is then transported to the final mineralization site, where it is destabilized and crystallizes. We present four case studies, each of which demonstrates specific aspects of biological crystallization pathways: seawater uptake by foraminifera, calcite spicule formation by sea urchin larvae, goethite formation in the teeth of limpets, and guanine crystal formation in fish skin and spider cuticles. Three representative crystallization pathways are described, and aspects of the different stages of crystallization are discussed. An in-depth understanding of these complex processes can lead to new ideas for synthetic crystallization processes of interest to materials science.

Effect of Short-Circuit Pathways on Water Quality in Selected Confined Aquifers (Invited)

Science.gov (United States)

McMahon, P. B.

2010-12-01

Confined aquifers in the United States generally contain fewer anthropogenic contaminants than unconfined aquifers because confined aquifers often contain water recharged prior to substantial human development and redox conditions are more reducing, which favors degradation of common contaminants like nitrate and chlorinated solvents. Groundwater in a confined part of the High Plains aquifer near York, Nebraska had an adjusted radiocarbon age of about 2,000 years, and groundwater in a confined part of the Floridan aquifer near Tampa, Florida had apparent ages greater than 60 years on the basis of tritium measurements. Yet compounds introduced more recently into the environment (anthropogenic nitrate and volatile organic compounds) were detected in selected public-supply wells completed in both aquifers. Depth-dependent measurements of flow and chemistry in the pumping supply wells, groundwater age dating, numerical modeling of groundwater flow, and other monitoring data indicated that the confined aquifers sampled by the supply wells were connected to contaminated unconfined aquifers by short-circuit pathways. In the High Plains aquifer, the primary pathways appeared to be inactive irrigation wells screened in both the unconfined and confined aquifers. In the Floridan aquifer, the primary pathways were karst sinkholes and conduits. Heavy pumping in both confined systems exacerbated the problem by reducing the potentiometric surface and increasing groundwater velocities, thus enhancing downward gradients and reducing reaction times for processes like denitrification. From a broader perspective, several confined aquifers in the U.S. have experienced large declines in their potentiometric surfaces because of groundwater pumping and this could increase the potential for contamination in those aquifers, particularly where short-circuit pathways connect them to shallower, contaminated sources of water, such as was observed in York and Tampa.

Mutational Analysis of a Peripheral Pathway for Phospholipid Transport in ATP8A2

DEFF Research Database (Denmark)

Mogensen, Louise; Mikkelsen, Stine; Gantzel, Rasmus

2017-01-01

for conservation of classical transport elements from P2-ATPases. Moreover, T108 located at the exoplasmic end of M2 is critical to ATPase activity and lipid substrate affinity indicating that this residue could be part of an entry gate of the peripheral pathway. Overall, several findings in our study...

Parallel pathways of ethoxylated alcohol biodegradation under aerobic conditions

International Nuclear Information System (INIS)

Zembrzuska, Joanna; Budnik, Irena; Lukaszewski, Zenon

2016-01-01

Non-ionic surfactants (NS) are a major component of the surfactant flux discharged into surface water, and alcohol ethoxylates (AE) are the major component of this flux. Therefore, biodegradation pathways of AE deserve more thorough investigation. The aim of this work was to investigate the stages of biodegradation of homogeneous oxyethylated dodecanol C_1_2E_9 having 9 oxyethylene subunits, under aerobic conditions. Enterobacter strain Z3 bacteria were chosen as biodegrading organisms under conditions with C_1_2E_9 as the sole source of organic carbon. Bacterial consortia of river water were used in a parallel test as an inoculum for comparison. The LC-MS technique was used to identify the products of biodegradation. Liquid-liquid extraction with ethyl acetate was selected for the isolation of C_1_2E_9 and metabolites from the biodegradation broth. The LC-MS/MS technique operating in the multiple reaction monitoring (MRM) mode was used for quantitative determination of C_1_2E_9, C_1_2E_8, C_1_2E_7 and C_1_2E_6. Apart from the substrate, the homologues C_1_2E_8, C_1_2E_7 and C_1_2E_6, being metabolites of C_1_2E_9 biodegradation by shortening of the oxyethylene chain, as well as intermediate metabolites having a carboxyl end group in the oxyethylene chain (C_1_2E_8COOH, C_1_2E_7COOH, C_1_2E_6COOH and C_1_2E_5COOH), were identified. Poly(ethylene glycols) (E) having 9, 8 and 7 oxyethylene subunits were also identified, indicating parallel central fission of C_1_2E_9 and its metabolites. Similar results were obtained with river water as inoculum. It is concluded that AE, under aerobic conditions, are biodegraded via two parallel pathways: by central fission with the formation of PEG, and by Ω-oxidation of the oxyethylene chain with the formation of carboxylated AE and subsequent shortening of the oxyethylene chain by a single unit. - Highlights: • Two parallel biodegradation pathways of alcohol ethoxylates have been discovered. • Apart from central fission

Comparison of pathways associated with hepatitis B- and C-infected hepatocellular carcinoma using pathway-based class discrimination method.

Science.gov (United States)

Lee, Sun Young; Song, Kwang Hoon; Koo, Imhoi; Lee, Kee-Ho; Suh, Kyung-Suk; Kim, Bu-Yeo

2012-06-01

Molecular signatures causing hepatocellular carcinoma (HCC) from chronic infection of hepatitis B virus (HBV) or hepatitis C virus (HCV) are not clearly known. Using microarray datasets composed of HCV-positive HCC or HBV-positive HCC, pathways that could discriminate tumor tissue from adjacent non-tumor liver tissue were selected by implementing nearest shrunken centroid algorithm. Cancer-related signaling pathways and lipid metabolism-related pathways were predominantly enriched in HCV-positive HCC, whereas functionally diverse pathways including immune-related pathways, cell cycle pathways, and RNA metabolism pathways were mainly enriched in HBV-positive HCC. In addition to differentially involved pathways, signaling pathways such as TGF-β, MAPK, and p53 pathways were commonly significant in both HCCs, suggesting the presence of common hepatocarcinogenesis process. The pathway clustering also verified segregation of pathways into the functional subgroups in both HCCs. This study indicates the functional distinction and similarity on the pathways implicated in the development of HCV- and/or HBV-positive HCC. Copyright © 2012 Elsevier Inc. All rights reserved.