Caenorhabditis elegans ABCRNAi transporters interact genetically with rde-2 and mut-7.

PubMed

Sundaram, Prema; Han, Wang; Cohen, Nancy; Echalier, Benjamin; Albin, John; Timmons, Lisa

2008-02-01

RNA interference (RNAi) mechanisms are conserved and consist of an interrelated network of activities that not only respond to exogenous dsRNA, but also perform endogenous functions required in the fine tuning of gene expression and in maintaining genome integrity. Not surprisingly, RNAi functions have widespread influences on cellular function and organismal development. Previously, we observed a reduced capacity to mount an RNAi response in nine Caenorhabditis elegans mutants that are defective in ABC transporter genes (ABC(RNAi) mutants). Here, we report an exhaustive study of mutants, collectively defective in 49 different ABC transporter genes, that allowed for the categorization of one additional transporter into the ABC(RNAi) gene class. Genetic complementation tests reveal functions for ABC(RNAi) transporters in the mut-7/rde-2 branch of the RNAi pathway. These second-site noncomplementation interactions suggest that ABC(RNAi) proteins and MUT-7/RDE-2 function together in parallel pathways and/or as multiprotein complexes. Like mut-7 and rde-2, some ABC(RNAi) mutants display transposon silencing defects. Finally, our analyses reveal a genetic interaction network of ABC(RNAi) gene function with respect to this part of the RNAi pathway. From our results, we speculate that the coordinated activities of ABC(RNAi) transporters, through their effects on endogenous RNAi-related mechanisms, ultimately affect chromosome function and integrity.

Caenorhabditis elegans ABCRNAi Transporters Interact Genetically With rde-2 and mut-7

PubMed Central

Sundaram, Prema; Han, Wang; Cohen, Nancy; Echalier, Benjamin; Albin, John; Timmons, Lisa

2008-01-01

RNA interference (RNAi) mechanisms are conserved and consist of an interrelated network of activities that not only respond to exogenous dsRNA, but also perform endogenous functions required in the fine tuning of gene expression and in maintaining genome integrity. Not surprisingly, RNAi functions have widespread influences on cellular function and organismal development. Previously, we observed a reduced capacity to mount an RNAi response in nine Caenorhabditis elegans mutants that are defective in ABC transporter genes (ABCRNAi mutants). Here, we report an exhaustive study of mutants, collectively defective in 49 different ABC transporter genes, that allowed for the categorization of one additional transporter into the ABCRNAi gene class. Genetic complementation tests reveal functions for ABCRNAi transporters in the mut-7/rde-2 branch of the RNAi pathway. These second-site noncomplementation interactions suggest that ABCRNAi proteins and MUT-7/RDE-2 function together in parallel pathways and/or as multiprotein complexes. Like mut-7 and rde-2, some ABCRNAi mutants display transposon silencing defects. Finally, our analyses reveal a genetic interaction network of ABCRNAi gene function with respect to this part of the RNAi pathway. From our results, we speculate that the coordinated activities of ABCRNAi transporters, through their effects on endogenous RNAi-related mechanisms, ultimately affect chromosome function and integrity. PMID:18245353

Increasing scientific confidence in adverse outcome pathways: Application of tailored Bradford-Hill considerations for evaluating weight of evidence

EPA Science Inventory

Systematic consideration of scientific support is a critical element in developing and, ultimately, using adverse outcome pathways (AOPs) for various regulatory applications. Though weight of evidence (WoE) analysis has been proposed as a basis for assessment of the maturity and...

Integrating Mechanisms for Insulin Resistance: Common Threads and Missing Links

PubMed Central

Samuel, Varman T.; Shulman, Gerald I.

2012-01-01

Insulin resistance is a complex metabolic disorder that defies a single etiological pathway. Accumulation of ectopic lipid metabolites, activation of the unfolded protein response (UPR) pathway and innate immune pathways have all been implicated in the pathogenesis of insulin resistance. However, these pathways are also closely linked to changes in fatty acid uptake, lipogenesis, and energy expenditure that can impact ectopic lipid deposition. Ultimately, accumulation of specific lipid metabolites (diacylglycerols and/or ceramides) in liver and skeletal muscle, may be a common pathway leading to impaired insulin signaling and insulin resistance. PMID:22385956

Integration of oxygen signaling at the consensus HRE.

PubMed

Wenger, Roland H; Stiehl, Daniel P; Camenisch, Gieri

2005-10-18

The hypoxia-inducible factor 1 (HIF-1) was initially identified as a transcription factor that regulated erythropoietin gene expression in response to a decrease in oxygen availability in kidney tissue. Subsequently, a family of oxygen-dependent protein hydroxylases was found to regulate the abundance and activity of three oxygen-sensitive HIFalpha subunits, which, as part of the HIF heterodimer, regulated the transcription of at least 70 different effector genes. In addition to responding to a decrease in tissue oxygenation, HIF is proactively induced, even under normoxic conditions, in response to stimuli that lead to cell growth, ultimately leading to higher oxygen consumption. The growing cell thus profits from an anticipatory increase in HIF-dependent target gene expression. Growth stimuli-activated signaling pathways that influence the abundance and activity of HIFs include pathways in which kinases are activated and pathways in which reactive oxygen species are liberated. These pathways signal to the HIF protein hydroxylases, as well as to HIF itself, by means of covalent or redox modifications and protein-protein interactions. The final point of integration of all of these pathways is the hypoxia-response element (HRE) of effector genes. Here, we provide comprehensive compilations of the known growth stimuli that promote increases in HIF abundance, of protein-protein interactions involving HIF, and of the known HIF effector genes. The consensus HRE derived from a comparison of the HREs of these HIF effectors will be useful for identification of novel HIF target genes, design of oxygen-regulated gene therapy, and prediction of effects of future drugs targeting the HIF system.

Global biogeography of microbial nitrogen-cycling traits in soil

NASA Astrophysics Data System (ADS)

Nelson, M.; Martiny, A.; Martiny, J. B. H.

2016-12-01

Microorganisms drive much of the Earth's nitrogen (N) cycle. However, despite their importance, many ecosystem models do not explicitly consider microbial communities and their functions. One obstacle in doing this is that we lack a complete understanding of the role that microbes play in biogeochemical processes. To address this challenge we used metagenomics to assess various N cycling traits of soil microorganisms in samples from around the globe. As measurable characteristics of an organism, traits can be used to quantify the role of microbes in ecosystem processes. Using 365 publically available soil metagenomes, we characterized the biogeography of microbial N cycling traits, defined as the abundance and composition of eight N pathways. We found strong biogeographic patterns in the frequency of N pathway traits; however, our models explained much less variation in taxonomic composition across sites. Focusing on individual N pathways, we identified the prominent taxa harboring these pathways. In addition, we found an unexpectedly high frequency of Bacteria encoding the dissimilatory nitrate reduction to ammonium (DNRA) pathway, a little studied N cycle process in soils. Finally, across all N pathways, phylogenetic analysis revealed that some phyla seem to be N cycle generalists (i.e delta-Proteobacteria), with the potential to carry out many N transformations, whereas others seem to be specialists (i.e. Cyanobacteria). As the most comprehensive map to date of the global distribution of microbial N traits, this study provides a springboard for further investigation of the prominent players in N cycling in soils. Overall, biogeographic patterns of traits can provide a foundation for understanding how microbial diversity impacts ecosystem processes and ultimately predicting how this diversity may shift in the face of global change.

Can Perspective-Taking Reduce Crime? Examining a Pathway Through Empathic-Concern and Guilt-Proneness

PubMed Central

Martinez, Andres G.; Stuewig, Jeffrey; Tangney, June

2015-01-01

We describe and test a theoretical model in which individual differences in perspective-taking eventuate in crime reduction. Specifically, it is hypothesized that perspective-taking propensities influence the tendency to feel empathic-concern, thereby heightening proneness for guilt, which then ultimately inhibits criminal behavior (perspective-taking → empathic-concern → guilt-proneness → crime desistance). Data from two sources were analyzed: (1) a cross-sectional college sample and (2) a longitudinal sample of jail inmates. Overall, results lend credence to this model. Perspective-taking propensities ultimately “put the brakes” on criminal behavior via an affective pathway of empathic-concern and guilt-proneness. Discussion focuses on the nature of perspective-taking, its generative role in moral emotions, as well as potential applications for crime prevention. PMID:25324328

Central Brain Circuitry for Color-Vision-Modulated Behaviors.

PubMed

Longden, Kit D

2016-10-24

Color is famous for not existing in the external world: our brains create the perception of color from the spatial and temporal patterns of the wavelength and intensity of light. For an intangible quality, we have detailed knowledge of its origins and consequences. Much is known about the organization and evolution of the first phases of color processing, the filtering of light in the eye and processing in the retina, and about the final phases, the roles of color in behavior and natural selection. To understand how color processing in the central brain has evolved, we need well-defined pathways or circuitry where we can gauge how color contributes to the computations involved in specific behaviors. Examples of such pathways or circuitry that are dedicated to processing color cues are rare, despite the separation of color and luminance pathways early in the visual system of many species, and despite the traditional definition of color as being independent of luminance. This minireview presents examples in which color vision contributes to behaviors dominated by other visual modalities, examples that are not part of the canon of color vision circuitry. The pathways and circuitry process a range of chromatic properties of objects and their illumination, and are taken from a variety of species. By considering how color processing complements luminance processing, rather than being independent of it, we gain an additional way to account for the diversity of color coding in the central brain, its consequences for specific behaviors and ultimately the evolution of color vision. Copyright © 2016 Elsevier Ltd. All rights reserved.

Best (but oft-forgotten) practices: mediation analysis.

PubMed

Fairchild, Amanda J; McDaniel, Heather L

2017-06-01

This contribution in the "Best (but Oft-Forgotten) Practices" series considers mediation analysis. A mediator (sometimes referred to as an intermediate variable, surrogate endpoint, or intermediate endpoint) is a third variable that explains how or why ≥2 other variables relate in a putative causal pathway. The current article discusses mediation analysis with the ultimate intention of helping nutrition researchers to clarify the rationale for examining mediation, avoid common pitfalls when using the model, and conduct well-informed analyses that can contribute to improving causal inference in evaluations of underlying mechanisms of effects on nutrition-related behavioral and health outcomes. We give specific attention to underevaluated limitations inherent in common approaches to mediation. In addition, we discuss how to conduct a power analysis for mediation models and offer an applied example to demonstrate mediation analysis. Finally, we provide an example write-up of mediation analysis results as a model for applied researchers. © 2017 American Society for Nutrition.

Best (but oft-forgotten) practices: mediation analysis12

PubMed Central

McDaniel, Heather L

2017-01-01

This contribution in the “Best (but Oft-Forgotten) Practices” series considers mediation analysis. A mediator (sometimes referred to as an intermediate variable, surrogate endpoint, or intermediate endpoint) is a third variable that explains how or why ≥2 other variables relate in a putative causal pathway. The current article discusses mediation analysis with the ultimate intention of helping nutrition researchers to clarify the rationale for examining mediation, avoid common pitfalls when using the model, and conduct well-informed analyses that can contribute to improving causal inference in evaluations of underlying mechanisms of effects on nutrition-related behavioral and health outcomes. We give specific attention to underevaluated limitations inherent in common approaches to mediation. In addition, we discuss how to conduct a power analysis for mediation models and offer an applied example to demonstrate mediation analysis. Finally, we provide an example write-up of mediation analysis results as a model for applied researchers. PMID:28446497

NBIC: National Ballast Information Clearinghouse

Science.gov Websites

and characteristics of this important pathway of biological invasion. Ultimately, NBIC data will be combined with on-the-ground biological survey data that track rates of marine invasions to determine the

Socioeconomic status and the health of youth: a multilevel, multidomain approach to conceptualizing pathways.

PubMed

Schreier, Hannah M C; Chen, Edith

2013-05-01

Previous research has clearly established associations between low socioeconomic status (SES) and poor youth physical health outcomes. This article provides an overview of the main pathways through which low SES environments come to influence youth health. We focus on 2 prevalent chronic health problems in youth today, asthma and obesity. We review and propose a model that encompasses (a) multiple levels of influence, including the neighborhood, family and person level; (b) both social and physical domains in the environment; and finally (c) dynamic relationships between these factors. A synthesis of existing research and our proposed model draw attention to the notion of adverse physical and social exposures in youth's neighborhood environments altering family characteristics and youth psychosocial and behavioral profiles, thereby increasing youth's risk for health problems. We also note the importance of acknowledging reciprocal influences across levels and domains (e.g., between family and child) that create self-perpetuating patterns of influence that further accentuate the impact of these factors on youth health. Finally, we document that factors across levels can interact (e.g., environmental pollution levels with child stress) to create unique, synergistic effects on youth health. Our model stresses the importance of evaluating influences on youth's physical health not in isolation but in the context of the broader social and physical environments in which youth live. Understanding the complex relationships between the factors that link low SES to youth's long-term health trajectories is necessary for the creation and implementation of successful interventions and policies to ultimately reduce health disparities. PsycINFO Database Record (c) 2013 APA, all rights reserved.

Socioeconomic Status and the Health of Youth: A Multi-level, Multi-domain Approach to Conceptualizing Pathways

PubMed Central

Schreier, Hannah M. C.; Chen, Edith

2012-01-01

Previous research has clearly established associations between low socioeconomic status (SES) and poor youth physical health outcomes. This article provides an overview of the main pathways through which low SES environments come to influence youth health. We focus on two of the most prevalent chronic health problems in youth today, asthma and obesity. We review and propose a model that encompasses (1) multiple levels of influence, including the neighborhood, family and person level, (2) both social and physical domains in the environment, and finally (3) dynamic relationships between these factors. A synthesis of existing research and our proposed model draw attention to the notion of adverse physical and social exposures in youth’s neighborhood environments altering family characteristics and youth psychosocial and behavioral profiles, thereby increasing youth’s risk for health problems. We also note the importance of acknowledging reciprocal influences across levels and domains (e.g., between family and child) that create self-perpetuating patterns of influence that further accentuate the impact of these factors on youth health. Finally, we document that factors across levels can interact (e.g., environmental pollution levels with child stress) to create unique, synergistic effects on youth health. Our model stresses the importance of evaluating influences on youth’s physical health not in isolation but in the context of the broader social and physical environments in which youth live. Understanding the complex relationships between the factors that link low SES to youth’s long-term health trajectories is necessary for the creation and implementation of successful interventions and policies to ultimately reduce health disparities. PMID:22845752

Deciphering the Combinatorial Roles of Geometric, Mechanical, and Adhesion Cues in Regulation of Cell Spreading

PubMed Central

Harris, Greg M.; Shazly, Tarek; Jabbarzadeh, Ehsan

2013-01-01

Significant effort has gone towards parsing out the effects of surrounding microenvironment on macroscopic behavior of stem cells. Many of the microenvironmental cues, however, are intertwined, and thus, further studies are warranted to identify the intricate interplay among the conflicting downstream signaling pathways that ultimately guide a cell response. In this contribution, by patterning adhesive PEG (polyethylene glycol) hydrogels using Dip Pen Nanolithography (DPN), we demonstrate that substrate elasticity, subcellular elasticity, ligand density, and topography ultimately define mesenchymal stem cells (MSCs) spreading and shape. Physical characteristics are parsed individually with 7 kilopascal (kPa) hydrogel islands leading to smaller, spindle shaped cells and 105 kPa hydrogel islands leading to larger, polygonal cell shapes. In a parallel effort, a finite element model was constructed to characterize and confirm experimental findings and aid as a predictive tool in modeling cell microenvironments. Signaling pathway inhibition studies suggested that RhoA is a key regulator of cell response to the cooperative effect of the tunable substrate variables. These results are significant for the engineering of cell-extra cellular matrix interfaces and ultimately decoupling matrix bound cues presented to cells in a tissue microenvironment for regenerative medicine. PMID:24282570

A beta1-adrenergic receptor CaM kinase II-dependent pathway mediates cardiac myocyte fetal gene induction.

PubMed

Sucharov, Carmen C; Mariner, Peter D; Nunley, Karin R; Long, Carlin; Leinwand, Leslie; Bristow, Michael R

2006-09-01

Beta-adrenergic signaling plays an important role in the natural history of dilated cardiomyopathies. Chronic activation of beta-adrenergic receptors (beta1-AR and beta2-AR) during periods of cardiac stress ultimately harms the failing heart by mechanisms that include alterations in gene expression. Here, we show that stimulation of beta-ARs with isoproterenol in neonate rat ventricular myocytes causes a "fetal" response in the relative activities of the human cardiac fetal and/or adult gene promoters that includes repression of the human and rat alpha-myosin heavy chain (alpha-MyHC) promoters with simultaneous activation of the human atrial natriuretic peptide (ANP) and rat beta-MyHC promoters. We also show that the promoter changes correlate with changes in endogenous gene expression as measured by mRNA expression. Furthermore, we show that these changes are specifically mediated by the beta1-AR, but not the beta2-AR, and are independent of alpha1-AR stimulation. We also demonstrate that the fetal gene response is independent of cAMP and protein kinase A, whereas inhibition of Ca2+/calmodulin-dependent protein kinase (CaMK) pathway blocks isoproterenol-mediated fetal gene program induction. Finally, we show that induction of the fetal program is dependent on activation of the L-type Ca2+ channel. We conclude that in neonatal rat cardiac myocytes, agonist-occupied beta1-AR mobilizes Ca2+ stores to activate fetal gene induction through cAMP independent pathways that involve CaMK.

Integrated Science Assessment (ISA) for Sulfur Oxides – Health Criteria (Final Report, Sep 2008)

EPA Science Inventory

EPA announced the availability of the final report, Integrated Science Assessment (ISA) for Sulfur Oxides – Health Criteria final assessment. This report represents a concise synthesis and evaluation of the most policy-relevant science and will ultimately provide the scien...

Mapping the pathways of resistance to targeted therapies

PubMed Central

Wood, Kris C.

2015-01-01

Resistance substantially limits the depth and duration of clinical responses to targeted anticancer therapies. Through the use of complementary experimental approaches, investigators have revealed that cancer cells can achieve resistance through adaptation or selection driven by specific genetic, epigenetic, or microenvironmental alterations. Ultimately, these diverse alterations often lead to the activation of signaling pathways that, when co-opted, enable cancer cells to survive drug treatments. Recently developed methods enable the direct and scalable identification of the signaling pathways capable of driving resistance in specific contexts. Using these methods, novel pathways of resistance to clinically approved drugs have been identified and validated. By combining systematic resistance pathway mapping methods with studies revealing biomarkers of specific resistance pathways and pharmacological approaches to block these pathways, it may be possible to rationally construct drug combinations that yield more penetrant and lasting responses in patients. PMID:26392071

The canonical Wnt signaling pathway in autism.

PubMed

Zhang, Yinghua; Yuan, Xiangshan; Wang, Zhongping; Li, Ruixi

2014-01-01

Mounting attention is being focused on the canonical Wnt signaling pathway which has been implicated in the pathogenesis of autism in some our and other recent studies. The canonical Wnt pathway is involved in cell proliferation, differentiation and migration, especially during nervous system development. Given its various functions, dysfunction of the canonical Wnt pathway may exert adverse effects on neurodevelopment and therefore leads to the pathogenesis of autism. Here, we review human and animal studies that implicate the canonical Wnt signal transduction pathway in the pathogenesis of autism. We also describe the crosstalk between the canonical Wnt pathway and the Notch signaling pathway in several types of autism spectrum disorders, including Asperger syndrome and Fragile X. Further research on the crosstalk between the canonical Wnt signaling pathway and other signaling cascades in autism may be an efficient avenue to understand the etiology of autism and ultimately lead to alternative medications for autism-like phenotypes.

Nanomaterial disposal by incineration

EPA Science Inventory

As nanotechnology-based products enter into widespread use, nanomaterials will end up in disposal waste streams that are ultimately discharged to the environment. One possible end-of-life scenario is incineration. This review attempts to ascertain the potential pathways by which ...

Antiangiogenic Therapy for Glioblastoma: Current Status and Future Prospects

PubMed Central

Batchelor, Tracy T.; Reardon, David A.; de Groot, John F.; Wick, Wolfgang; Weller, Michael

2014-01-01

Glioblastoma is characterized by high expression levels of pro-angiogenic cytokines and microvascular proliferation, highlighting the potential value of treatments targeting angiogenesis. Antiangiogenic treatment likely achieves a beneficial impact through multiple mechanisms of action. Ultimately, however, alternative pro-angiogenic signal transduction pathways are activated leading to the development of resistance, even in tumors that initially respond. The identification of biomarkers or imaging parameters to predict response and to herald resistance is of high priority. Despite promising phase 2 clinical trial results and patient benefit in terms of clinical improvement and longer progression-free survival, an overall survival benefit has not been demonstrated in 4 randomized phase 3 trials of bevacizumab or cilengitide in newly diagnosed glioblastoma or cediranib or enzastaurin recurrent glioblastoma. However, future studies are warranted: predictive markers may allow appropriate patient enrichment, combination with chemotherapy may ultimately prove successful in improving overall survival, and novel agents targeting multiple pro-angiogenic pathways may prove effective. PMID:25398844

Can perspective-taking reduce crime? Examining a pathway through empathic-concern and guilt-proneness.

PubMed

Martinez, Andres G; Stuewig, Jeffrey; Tangney, June P

2014-12-01

We describe and appraise a theoretical model in which individual differences in perspective-taking eventuate in crime reduction. Specifically, it is hypothesized that perspective-taking propensities influence the tendency to feel empathic-concern, thereby heightening proneness for guilt, which ultimately inhibits criminal behavior (perspective-taking → empathic-concern → guilt-proneness → crime desistance). Data from two sources were analyzed: (a) a cross-sectional college sample and (b) a longitudinal sample of jail inmates. Overall, results lend credence to this theoretical model: Perspective-taking propensities ultimately "put the brakes" on criminal behavior-via an emotional pathway of empathic-concern and then guilt-proneness. Discussion focuses on the nature of perspective-taking, its generative role for moral emotion and behavior, as well as potential applications for crime reduction. © 2014 by the Society for Personality and Social Psychology, Inc.

Implant Surface Design Regulates Mesenchymal Stem Cell Differentiation and Maturation

PubMed Central

Boyan, B.D.; Cheng, A.; Olivares-Navarrete, R.; Schwartz, Z.

2016-01-01

Changes in dental implant materials, structural design, and surface properties can all affect biological response. While bulk properties are important for mechanical stability of the implant, surface design ultimately contributes to osseointegration. This article reviews the surface parameters of dental implant materials that contribute to improved cell response and osseointegration. In particular, we focus on how surface design affects mesenchymal cell response and differentiation into the osteoblast lineage. Surface roughness has been largely studied at the microscale, but recent studies have highlighted the importance of hierarchical micron/submicron/nanosurface roughness, as well as surface roughness in combination with surface wettability. Integrins are transmembrane receptors that recognize changes in the surface and mediate downstream signaling pathways. Specifically, the noncanonical Wnt5a pathway has been implicated in osteoblastic differentiation of cells on titanium implant surfaces. However, much remains to be elucidated. Only recently have studies been conducted on the differences in biological response to implants based on sex, age, and clinical factors; these all point toward differences that advocate for patient-specific implant design. Finally, challenges in implant surface characterization must be addressed to optimize and compare data across studies. An understanding of both the science and the biology of the materials is crucial for developing novel dental implant materials and surface modifications for improved osseointegration. PMID:26927483

The NOTCH Ligand JAG1 Regulates GDNF Expression in Sertoli Cells

PubMed Central

Garcia, Thomas X.; Parekh, Parag; Gandhi, Pooja; Sinha, Krishna

2017-01-01

In the seminiferous epithelium of the testis, Sertoli cells are key niche cells directing proliferation and differentiation of spermatogonial stem cells (SSCs) into spermatozoa. Sertoli cells produce glial cell line-derived neurotrophic factor (GDNF), which is essential for SSC self-renewal and progenitor expansion. While the role of GDNF in the testis stem cell niche is established, little is known about how this factor is regulated. Our previous studies on NOTCH activity in Sertoli cells demonstrated a role of this pathway in limiting stem/progenitor cell numbers, thus ultimately downregulating sperm cell output. In this study we demonstrate through a double-mutant mouse model that NOTCH signaling in Sertoli cells functions solely through the canonical pathway. Further, we demonstrate through Dual luciferase assay and chromatin immunoprecipitation quantitative polymerase chain reaction (ChIP-qPCR) analysis that the NOTCH targets HES1 and HEY1, which are transcriptional repressors, directly downregulate GDNF expression by binding to the Gdnf promoter, thus antagonizing the effects of FSH/cAMP. Finally, we demonstrate that testicular stem/progenitors cells are activating NOTCH signaling in Sertoli cells in vivo and in vitro through the NOTCH ligand JAG1 at their surface, indicating that these cells may ensure their own homeostasis through negative feedback regulation. PMID:28051360

77 FR 59892 - Carbon and Certain Alloy Steel Wire Rod From Mexico: Affirmative Final Determination of...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-10-01

... merchandise, the expectations of the ultimate users, the use of the merchandise, the channels of marketing... expectations of the ultimate users, the use of the merchandise, and the channels of marketing in any meaningful... Comment 7: Fourth Prong of the Minor Alteration Analysis--Channels of Trade and Advertising Comment 8...

Cell Signaling Pathways that Regulate Ag Presentation

PubMed Central

Brutkiewicz, Randy R.

2016-01-01

Cell signaling pathways regulate much in the life of a cell: from shuttling cargo through intracellular compartments and onto the cell surface, how it should respond to stress, protecting itself from harm (environmental insults or infections), to ultimately, death by apoptosis. These signaling pathways are important for various aspects of the immune response as well. However, not much is known in terms of the participation of cell signaling pathways in Ag presentation--a necessary first step in the activation of innate and adaptive T cells. In this brief review, I will discuss the known signaling molecules (and pathways) that regulate how Ags are presented to T cells and the mechanism(s) if identified. Studies in this area have important implications in vaccine development and new treatment paradigms against infectious diseases, autoimmunity and cancer. PMID:27824592

The micronutrient genomics project: a community-driven knowledge base for micronutrient research

USDA-ARS?s Scientific Manuscript database

Micronutrients influence multiple metabolic pathways including oxidative and inflammatory processes. Optimum micronutrient supply is important for the maintenance of homeostasis in metabolism and, ultimately, for maintaining good health. With advances in systems biology and genomics technologies, it...

EGF-like peptide-enhanced cell motility in Dictyostelium functions independently of the cAMP-mediated pathway and requires active Ca2+/calmodulin signaling.

PubMed

Huber, Robert; O'Day, Danton H

2011-04-01

Current knowledge suggests that cell movement in the eukaryotic slime mold Dictyostelium discoideum is mediated by different signaling pathways involving a number of redundant components. Our previous research has identified a specific motility-enhancing function for epidermal growth factor-like (EGFL) repeats in Dictyostelium, specifically for the EGFL repeats of cyrA, a matricellular, calmodulin (CaM)-binding protein in Dictyostelium. Using mutants of cAMP signaling (carA(-), carC(-), gpaB(-), gpbA(-)), the endogenous calcium (Ca(2+)) release inhibitor TMB-8, the CaM antagonist W-7, and a radial motility bioassay, we show that DdEGFL1, a synthetic peptide whose sequence is obtained from the first EGFL repeat of cyrA, functions independently of the cAMP-mediated signaling pathways to enhance cell motility through a mechanism involving Ca(2+) signaling, CaM, and RasG. We show that DdEGFL1 increases the amounts of polymeric myosin II heavy chain and actin in the cytoskeleton by 24.1±10.7% and 25.9±2.1% respectively and demonstrate a link between Ca(2+)/CaM signaling and cytoskeletal dynamics. Finally, our findings suggest that carA and carC mediate a brake mechanism during chemotaxis since DdEGFL1 enhanced the movement of carA(-)/carC(-) cells by 844±136% compared to only 106±6% for parental DH1 cells. Based on our data, this signaling pathway also appears to involve the G-protein β subunit, RasC, RasGEFA, and protein kinase B. Together, our research provides insight into the functionality of EGFL repeats in Dictyostelium and the signaling pathways regulating cell movement in this model organism. It also identifies several mechanistic components of DdEGFL1-enhanced cell movement, which may ultimately provide a model system for understanding EGFL repeat function in higher organisms. Copyright © 2010 Elsevier Inc. All rights reserved.

Crossroads of Wnt and Hippo in epithelial tissues.

PubMed

Bernascone, Ilenia; Martin-Belmonte, Fernando

2013-08-01

Epithelial tissues undergo constant growth and differentiation during embryonic development and to replace damaged tissue in adult organs. These processes are governed by different signaling pathways that ultimately control the expression of genes associated with cell proliferation, patterning, and death. One essential pathway is Wnt, which controls tubulogenesis in several epithelial organs. Recently, Wnt has been closely linked to other signaling pathways, such as Hippo, that orchestrate proliferation and apoptosis to control organ size. There is evidence that epithelial cell junctions may sequester the transcription factors that act downstream of these signaling pathways, which would represent an important aspect of their functional regulation and their influence on cell behavior. Here, we review the transcriptional control exerted by the Wnt and Hippo signaling pathways during epithelial growth, patterning, and differentiation and recent advances in understanding of the regulation and crosstalk of these pathways in epithelial tissues. Copyright © 2013 Elsevier Ltd. All rights reserved.

Light Robots: Bridging the Gap between Microrobotics and Photomechanics in Soft Materials.

PubMed

Zeng, Hao; Wasylczyk, Piotr; Wiersma, Diederik S; Priimagi, Arri

2018-06-01

For decades, roboticists have focused their efforts on rigid systems that enable programmable, automated action, and sophisticated control with maximal movement precision and speed. Meanwhile, material scientists have sought compounds and fabrication strategies to devise polymeric actuators that are small, soft, adaptive, and stimuli-responsive. Merging these two fields has given birth to a new class of devices-soft microrobots that, by combining concepts from microrobotics and stimuli-responsive materials research, provide several advantages in a miniature form: external, remotely controllable power supply, adaptive motion, and human-friendly interaction, with device design and action often inspired by biological systems. Herein, recent progress in soft microrobotics is highlighted based on light-responsive liquid-crystal elastomers and polymer networks, focusing on photomobile devices such as walkers, swimmers, and mechanical oscillators, which may ultimately lead to flying microrobots. Finally, self-regulated actuation is proposed as a new pathway toward fully autonomous, intelligent light robots of the future. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Iron-Induced Damage in Cardiomyopathy: Oxidative-Dependent and Independent Mechanisms

PubMed Central

Gammella, Elena; Recalcati, Stefania; Rybinska, Ilona; Buratti, Paolo; Cairo, Gaetano

2015-01-01

The high incidence of cardiomyopathy in patients with hemosiderosis, particularly in transfusional iron overload, strongly indicates that iron accumulation in the heart plays a major role in the process leading to heart failure. In this context, iron-mediated generation of noxious reactive oxygen species is believed to be the most important pathogenetic mechanism determining cardiomyocyte damage, the initiating event of a pathologic progression involving apoptosis, fibrosis, and ultimately cardiac dysfunction. However, recent findings suggest that additional mechanisms involving subcellular organelles and inflammatory mediators are important factors in the development of this disease. Moreover, excess iron can amplify the cardiotoxic effect of other agents or events. Finally, subcellular misdistribution of iron within cardiomyocytes may represent an additional pathway leading to cardiac injury. Recent advances in imaging techniques and chelators development remarkably improved cardiac iron overload detection and treatment, respectively. However, increased understanding of the pathogenic mechanisms of iron overload cardiomyopathy is needed to pave the way for the development of improved therapeutic strategies. PMID:25878762

Sequencing of the Cheese Microbiome and Its Relevance to Industry.

PubMed

Yeluri Jonnala, Bhagya R; McSweeney, Paul L H; Sheehan, Jeremiah J; Cotter, Paul D

2018-01-01

The microbiota of cheese plays a key role in determining its organoleptic and other physico-chemical properties. It is essential to understand the various contributions, positive or negative, of these microbial components in order to promote the growth of desirable taxa and, thus, characteristics. The recent application of high throughput DNA sequencing (HTS) facilitates an even more accurate identification of these microbes, and their functional properties, and has the potential to reveal those microbes, and associated pathways, responsible for favorable or unfavorable characteristics. This technology also facilitates a detailed analysis of the composition and functional potential of the microbiota of milk, curd, whey, mixed starters, processing environments, and how these contribute to the final cheese microbiota, and associated characteristics. Ultimately, this information can be harnessed by producers to optimize the quality, safety, and commercial value of their products. In this review we highlight a number of key studies in which HTS was employed to study the cheese microbiota, and pay particular attention to those of greatest relevance to industry.

Oxidation of trimethoprim by ferrate(VI): kinetics, products, and antibacterial activity.

PubMed

Anquandah, George A K; Sharma, Virender K; Knight, D Andrew; Batchu, Sudha Rani; Gardinali, Piero R

2011-12-15

Kinetics, stoichiometry, and products of the oxidation of trimethoprim (TMP), one of the most commonly detected antibacterial agents in surface waters and municipal wastewaters, by ferrate(VI) (Fe(VI)) were determined. The pH dependent second-order rate constants of the reactions of Fe(VI) with TMP were examined using acid-base properties of Fe(VI) and TMP. The kinetics of reactions of diaminopyrimidine (DAP) and trimethoxytoluene (TMT) with Fe(VI) were also determined to understand the reactivity of Fe(VI) with TMP. Oxidation products of the reactions of Fe(VI) with TMP and DAP were identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Reaction pathways of oxidation of TMP by Fe(VI) are proposed to demonstrate the cleavage of the TMP molecule to ultimately result in 3,4,5,-trimethoxybenzaldehyde and 2,4-dinitropyrimidine as among the final identified products. The oxidized products mixture exhibited no antibacterial activity against E. coli after complete consumption of TMP. Removal of TMP in the secondary effluent by Fe(VI) was achieved.

Role of bone morphogenetic protein-7 in renal fibrosis

PubMed Central

Li, Rui Xi; Yiu, Wai Han; Tang, Sydney C. W.

2015-01-01

Renal fibrosis is final common pathway of end stage renal disease. Irrespective of the primary cause, renal fibrogenesis is a dynamic process which involves a large network of cellular and molecular interaction, including pro-inflammatory cell infiltration and activation, matrix-producing cell accumulation and activation, and secretion of profibrogenic factors that modulate extracellular matrix (ECM) formation and cell-cell interaction. Bone morphogenetic protein-7 is a protein of the TGF-β super family and increasingly regarded as a counteracting molecule against TGF-β. A large variety of evidence shows an anti-fibrotic role of BMP-7 in chronic kidney disease, and this effect is largely mediated via counterbalancing the profibrotic effect of TGF-β. Besides, BMP-7 reduced ECM formation by inactivating matrix-producing cells and promoting mesenchymal-to-epithelial transition (MET). BMP-7 also increased ECM degradation. Despite these observations, the anti-fibrotic effect of BMP-7 is still controversial such that fine regulation of BMP-7 expression in vivo might be a great challenge for its ultimate clinical application. PMID:25954203

Integrated Science Assessment (ISA) for Lead (Final Report, Jul 2013)

EPA Science Inventory

EPA announced the availability of the final report, Integrated Science Assessment (ISA) for Lead (Pb). This document represents a concise synthesis and evaluation of the most policy-relevant science and will ultimately provide the scientific bases for EPA’s decision regard...

Renewable Fuel Pathways II Final Rule to Identify Additional Fuel Pathways under Renewable Fuel Standard Program

EPA Pesticide Factsheets

This final rule describes EPA’s evaluation of biofuels derived from biogas fuel pathways under the RFS program and other minor amendments related to survey requirements associated with ULSD program and misfueling mitigation regulations for E15.

Sunlight-driven Environmental Benign Production of Bioactive Natural Products with Focus on Diterpenoids and the Pathways Involved in their Formation.

PubMed

Luo, Dan; Møller, Birger Lindberg; Pateraki, Irini

2017-12-01

Diterpenoids are high value compounds characterized by high structural complexity. They constitute the largest class of specialized metabolites produced by plants. Diterpenoids are flexible molecules able to engage in specific binding to drug targets like receptors and transporters. In this review we provide an account on how the complex pathways for diterpenoids may be elucidated. Following plant pathway discovery, the compounds may be produced in heterologous hosts like yeasts and E. coli. Environmentally contained production in photosynthetic cells like cyanobacteria, green algae or mosses are envisioned as the ultimate future production system.

Kinetic modeling of plant metabolism and its predictive power: peppermint essential oil biosynthesis as an example.

PubMed

Lange, Bernd Markus; Rios-Estepa, Rigoberto

2014-01-01

The integration of mathematical modeling with analytical experimentation in an iterative fashion is a powerful approach to advance our understanding of the architecture and regulation of metabolic networks. Ultimately, such knowledge is highly valuable to support efforts aimed at modulating flux through target pathways by molecular breeding and/or metabolic engineering. In this article we describe a kinetic mathematical model of peppermint essential oil biosynthesis, a pathway that has been studied extensively for more than two decades. Modeling assumptions and approximations are described in detail. We provide step-by-step instructions on how to run simulations of dynamic changes in pathway metabolites concentrations.

Pollen Acceptance or Rejection: A Tale of Two Pathways.

PubMed

Doucet, Jennifer; Lee, Hyun Kyung; Goring, Daphne R

2016-12-01

While the molecular and cellular basis of self-incompatibility leading to self-pollen rejection in the Brassicaceae has been extensively studied, relatively little attention has been paid to compatible pollen recognition and the corresponding cellular responses in the stigmatic papillae. This is now changing because research has started to uncover steps in the Brassicaceae 'basal compatible pollen response pathway' in the stigma leading to pollen hydration and germination. Furthermore, recent studies suggest that self-incompatible pollen activates both the basal compatible pathway and the self-incompatibility pathway in the stigma, with the self-incompatibility response ultimately prevailing to reject self-pollen. We review here recent discoveries in both pathways and discuss how compatible pollen is accepted by the stigma versus the rejection of self-incompatible pollen. Copyright © 2016 Elsevier Ltd. All rights reserved.

Integrated Science Assessment (ISA) of Ozone and Related Photochemical Oxidants (Final Report, Feb 2013)

EPA Science Inventory

EPA announced the availability of the final report, Integrated Science Assessment of Ozone and Related Photochemical Oxidants. This document represents a concise synthesis and evaluation of the most policy-relevant science and will ultimately provide the scientific bases f...

Phthalate-induced toxicity: Identifying the vulnerable pathways during sexual differentiation in the male rat

EPA Science Inventory

Human exposures to phthalate ester plasticizer compounds are widespread. Studies in rodents have demonstrated that in utero exposure to various phthalates throughout sexual differentiation (GD14-18) results in decreased fetal testicular androgen production, and ultimately leads t...

Disruption of IGF-1R signaling increases TRAIL-induced apoptosis: A new potential therapy for the treatment of melanoma

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

Karasic, Thomas B.; Hei, Tom K.; Ivanov, Vladimir N., E-mail: vni3@columbia.edu

2010-07-15

Resistance of cancer cells to apoptosis is dependent on a balance of multiple genetic and epigenetic mechanisms, which up-regulate efficacy of the surviving growth factor-receptor signaling pathways and suppress death-receptor signaling pathways. The Insulin-like Growth Factor-1 Receptor (IGF-1R) signaling pathway is highly active in metastatic melanoma cells by mediating downstream activation of PI3K-AKT and MAPK pathways and controlling general cell survival and proliferation. In the present study, we used human melanoma lines with established genotypes that represented different phases of cancer development: radial-growth-phase WM35, vertical-growth-phase WM793, metastatic LU1205 and WM9 [1]. All these lines have normal NRAS. WM35, WM793, LU1205more » and WM9 cells have mutated BRAF (V600E). WM35 and WM9 cells express normal PTEN, while in WM793 cells PTEN expression is down-regulated; finally, in LU1205 cells PTEN is inactivated by mutation. Cyclolignan picropodophyllin (PPP), a specific inhibitor of IGF-1R kinase activity, strongly down-regulated the basal levels of AKT activity in WM9 and in WM793 cells, modestly does so in LU1205, but has no effect on AKT activity in the early stage WM35 cells that are deficient in IGF-1R. In addition, PPP partially down-regulated the basal levels of active ERK1/2 in all lines used, highlighting the role of an alternative, non-BRAF pathway in MAPK activation. The final result of PPP treatment was an induction of apoptosis in WM793, WM9 and LU1205 melanoma cells. On the other hand, dose-dependent inhibition of IGF-1R kinase activity by PPP at a relatively narrow dose range (near 500 nM) has different effects on melanoma cells versus normal cells, inducing apoptosis in cancer cells and G2/M arrest of fibroblasts. To further enhance the pro-apoptotic effects of PPP on melanoma cells, we used a combined treatment of TNF-Related Apoptosis-Inducing Ligand (TRAIL) and PPP. This combination substantially increased death by apoptosis for WM793 and WM9 cells, but did so only modestly for LU1205 cells with very high basal activity of AKT. The ultimate goal of this direction of research is the discovery of a new treatment method for highly resistant human metastatic melanomas. Our findings provide the rationale for further preclinical evaluation of this novel treatment.« less

Ubiquitin-Modifying Enzymes and Regulation of the Inflammasome.

PubMed

Kattah, Michael G; Malynn, Barbara A; Ma, Averil

2017-11-10

Ubiquitin and ubiquitin-modifying enzymes play critical roles in a wide variety of intracellular signaling pathways. Inflammatory signaling cascades downstream of TNF, TLR agonists, antigen receptor cross-linking, and cytokine receptors, all rely on ubiquitination events to direct subsequent immune responses. In the past several years, inflammasome activation and subsequent signal transduction have emerged as an excellent example of how ubiquitin signals control inflammatory responses. Inflammasomes are multiprotein signaling complexes that ultimately lead to caspase activation and release of the interleukin-1 (IL-1) family members, IL-1β and IL-18. Inflammasome activation is critical for the host's defense against pathogens, but dysregulation of inflammasomes may contribute to the pathogenesis of multiple diseases. Ultimately, understanding how various ubiquitin interacting proteins control inflammatory signaling cascades could provide new pathways for therapeutic intervention. Here we review specific ubiquitin-modifying enzymes and ubiquitination events that orchestrate inflammatory responses, with an emphasis on the NLRP3 inflammasome. Copyright © 2017 Elsevier Ltd. All rights reserved.

Theoretical evaluation of two plausible routes for bioactivation of S-(1,1-difluoro-2,2-dihaloethyl)-L-cysteine conjugates: thiirane vs thionoacyl fluoride pathway.

PubMed

Shim, J Y; Richard, A M

1997-01-01

The selective nephrotoxicity of halogenated alkenes has been attributed to a glutathione (GSH) S-conjugate pathway involving enzymatic hydrolysis to the cysteine S-conjugate and beta-lyase bioactivation to thiolates, which are presumed to give rise to the ultimate mutagenic or cytotoxic reactive species. Studies have shown that the brominated S-(2,2-dihalo-1,1-difluoroethyl)-L-cysteine conjugates are mutagenic in the Ames test, whereas the nonbrominated analogues are nonmutagenic. While careful experimentation has contributed much to current understanding, the ultimate reactive species responsible for the differing mutagenic effects remain unknown. Computational methods were applied to the investigation of two proposed metabolic pathways leading from the thiolate to either a thiirane or thionoacyl fluoride intermediate, both electrophilic species presumed capable of binding to proteins or DNA. Studied were six F-, Cl-, and Br-substituted 2,2-dihalo-1,1-difluoroethane-1-thiolates (2,2-dihalo-DFETs). Pathway preference was determined for each thiolate by comparison of reaction energy profiles and activation energies. At all but the lowest level of ab initio theory, a thionoacyl fluoride pathway was predicted for 2,2-difluoro-DFET, while a thiirane pathway was energetically preferred for the brominated 2,2-dihalo-DFETs. These results offer a clear mechanism-based rationale for distinguishing 2,2-difluoro-DFET from the brominated 2,2-dihalo-DFETs, while the results are less clear for the 2,2-dichloro and 2-chloro-2-fluoro-DFETs, which at the highest level of ab initio treatment had a relatively small energy preference (2.4 kcal/mol) for the thiirane pathway. The predicted clear preference for a thiirane pathway for the brominated 2,2-dihalo-DFETs is not consistent with a recently proposed pathway involving alpha-thiolactone formation through a thionoacyl fluoride intermediate [Finkelstein, M. B., et al. (1995) J. Am. Chem. Soc. 117, 9590-9591], but is supported by results of a recent study providing experimental evidence for thiirane formation from the brominated 2,2-dihalo-DFETs [Finkelstein, M. B., et al. (1996) Chem. Res. Toxicol. 9, 227-231].

Molecular mechanism of TGF-β signaling pathway in colon carcinogenesis and status of curcumin as chemopreventive strategy.

PubMed

Ramamoorthi, Ganesan; Sivalingam, Nageswaran

2014-08-01

Colon cancer is one of the third most common cancer in man, the second most common cancer in women worldwide, and the second leading cause of mortality in the USA. There are a number of molecular pathways that have been implicated in colon carcinogenesis, including TGF-β/Smad signaling pathway. TGF-β (transforming growth factor-beta) signaling pathway has the potential to regulate various biological processes including cell growth, differentiation, apoptosis, extracellular matrix modeling, and immune response. TGF-β signaling pathway acts as a tumor suppressor, but alterations in TGF-β signaling pathway promotes colon cancer cell growth, migration, invasion, angiogenesis, and metastasis. Here we review the role of TGF-β signaling cascade in colon carcinogenesis and multiple molecular targets of curcumin in colon carcinogenesis. Elucidation of the molecular mechanism of curcumin on TGF-β signaling pathway-induced colon carcinogenesis may ultimately lead to novel and more effective treatments for colon cancer.

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

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

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

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

Ultimate justification: Wittgenstein and medical ethics.

PubMed

Hughes, J

1995-02-01

Decisions must be justified. In medical ethics various grounds are given to justify decisions, but ultimate justification seems illusory and little considered. The philosopher Wittgenstein discusses the problem of ultimate justification in the context of general philosophy. His comments, nevertheless, are pertinent to ethics. From a discussion of Wittgensteinian notions, such as 'bedrock', the idea that 'ultimate' justification is grounded in human nature as such is derived. This discussion is relevant to medical ethics in at least five ways: it shows generally what type of certainty there is in practical ethics; it seems to imply some objective foundation to our ethical judgements; it squares with our experience of making ethical decisions; it shows something of the nature of moral arguments; and, finally, it has implications for teaching medicine and ethics.

Revisiting perceptions of quality of hospice care: managing for the ultimate referral.

PubMed

Churchman, Richard; York, Grady S; Woodard, Beth; Wainright, Charles; Rau-Foster, Mary

2014-08-01

Hospice services provided in the final months of life are delivered through complex interpersonal relationships between caregivers, patients, and families. Often, service value and quality are defined by these interpersonal interactions. This understanding provides hospice leaders with an enormous opportunity to create processes that provide the optimal level of care during the last months of life. The authors argue that the ultimate referral is attained when a family member observes the care of a loved one, and the family member conveys a desire to receive the same quality of services their loved one received at that facility. The point of this article is to provide evidence that supports the methods to ultimately enhance the patient's and family's experience and increase the potential for the ultimate referral. © The Author(s) 2013.

Ultimate justification: Wittgenstein and medical ethics.

PubMed Central

Hughes, J

1995-01-01

Decisions must be justified. In medical ethics various grounds are given to justify decisions, but ultimate justification seems illusory and little considered. The philosopher Wittgenstein discusses the problem of ultimate justification in the context of general philosophy. His comments, nevertheless, are pertinent to ethics. From a discussion of Wittgensteinian notions, such as 'bedrock', the idea that 'ultimate' justification is grounded in human nature as such is derived. This discussion is relevant to medical ethics in at least five ways: it shows generally what type of certainty there is in practical ethics; it seems to imply some objective foundation to our ethical judgements; it squares with our experience of making ethical decisions; it shows something of the nature of moral arguments; and, finally, it has implications for teaching medicine and ethics. PMID:7776343

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

PubMed

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.

Integrated Science Assessment (ISA) for Oxides of Nitrogen and Sulfur - Ecological Criteria (Final Report, Dec 2008)

EPA Science Inventory

EPA announced the availability of the final report, Integrated Science Assessment (ISA) for Oxides of Nitrogen and Sulfur - Ecological Criteria. This document represents a concise synthesis and evaluation of the most policy-relevant science and will ultimately provide the ...

Berberine inhibits the chemotherapy-induced repopulation by suppressing the arachidonic acid metabolic pathway and phosphorylation of FAK in ovarian cancer.

PubMed

Zhao, Yawei; Cui, Lianzhi; Pan, Yue; Shao, Dan; Zheng, Xiao; Zhang, Fan; Zhang, Hansi; He, Kan; Chen, Li

2017-12-01

Cytotoxic chemotherapy is an effective and traditional treatment of ovarian cancer. However, chemotherapy-induced apoptosis may also trigger and ultimately accelerate the repopulation of the small number of adjacent surviving cells. This study mainly focused on the tumour cell repopulation caused by chemotherapy in ovarian cancer and the adjunctive/synergistic effect of Berberine on the prevention of tumour repopulation. The transwell system was used to mimic the co-culture of surviving ovarian cancer cells in the microenvironment of cytotoxic chemotherapy-treated dying cells. Tumour cell proliferation was observed by crystal violet staining. AA and PGE 2 levels were measured by ELISA, and changes of protein expression were analysed by Western blot. Chemotherapy drug VP16 treatment triggered AA pathway, leading to the elevated PGE 2 level, and ultimately enhanced the repopulation of ovarian cancer cells. Berberine can block the caspase 3-iPLA 2 -AA-COX-2-PGE 2 pathway by inhibiting the expression of iPLA 2 and COX-2. Berberine can also reverse the increased phosphorylation of FAK caused by abnormal PGE 2 level and thus reverse the repopulation of ovarian cancer cells after VP16 treatment. Our observation suggested that Berberine could inhibit the chemotherapy-induced repopulation of ovarian cancer cells by suppressing the AA pathway and phosphorylation of FAK. And these findings implicated a novel combined use of Berberine and chemotherapeutics, which might prevent ovarian cancer recurrence by abrogating early tumour repopulation. © 2017 John Wiley & Sons Ltd.

Rapid Identification of Chemoresistance Mechanisms Using Yeast DNA Mismatch Repair Mutants

PubMed Central

Ojini, Irene; Gammie, Alison

2015-01-01

Resistance to cancer therapy is a major obstacle in the long-term treatment of cancer. A greater understanding of drug resistance mechanisms will ultimately lead to the development of effective therapeutic strategies to prevent resistance from occurring. Here, we exploit the mutator phenotype of mismatch repair defective yeast cells combined with whole genome sequencing to identify drug resistance mutations in key pathways involved in the development of chemoresistance. The utility of this approach was demonstrated via the identification of the known CAN1 and TOP1 resistance targets for two compounds, canavanine and camptothecin, respectively. We have also experimentally validated the plasma membrane transporter HNM1 as the primary drug resistance target of mechlorethamine. Furthermore, the sequencing of mitoxantrone-resistant strains identified inactivating mutations within IPT1, a gene encoding inositolphosphotransferase, an enzyme involved in sphingolipid biosynthesis. In the case of bactobolin, a promising anticancer drug, the endocytosis pathway was identified as the drug resistance target responsible for conferring resistance. Finally, we show that that rapamycin, an mTOR inhibitor previously shown to alter the fitness of the ipt1 mutant, can effectively prevent the formation of mitoxantrone resistance. The rapid and robust nature of these techniques, using Saccharomyces cerevisiae as a model organism, should accelerate the identification of drug resistance targets and guide the development of novel therapeutic combination strategies to prevent the development of chemoresistance in various cancers. PMID:26199284

Mercury in Arctic Marine Ecosystems: Sources, Pathways, and Exposure

PubMed Central

Kirk, Jane L.; Lehnherr, Igor; Andersson, Maria; Braune, Birgit M.; Chan, Laurie; Dastoor, Ashu P.; Durnford, Dorothy; Gleason, Amber L.; Loseto, Lisa L.; Steffen, Alexandra; St. Louis, Vincent L.

2014-01-01

Mercury in the Arctic is an important environmental and human health issue. The reliance of Northern Peoples on traditional foods, such as marine mammals, for subsistence means that they are particularly at risk from mercury exposure. The cycling of mercury in Arctic marine systems is reviewed here, with emphasis placed on the key sources, pathways and processes which regulate mercury levels in marine food webs and ultimately the exposure of human populations to this contaminant. While many knowledge gaps exist limiting our ability to make strong conclusions, it appears that the long range transport of mercury from Asian emissions is an important source of atmospheric Hg to the Arctic and that mercury methylation resulting in monomethylmercury production (an organic form of mercury which is both toxic and bioaccumulated) in Arctic marine waters is the principal source of mercury incorporated into food webs. Mercury concentrations in biological organisms have increased since the onset of the industrial age and are controlled by a combination of abiotic factors (e.g., monomethylmercury supply), food web dynamics and structure, and animal behavior (e.g., habitat selection and feeding behavior). Finally, although some Northern Peoples have high mercury concentrations of mercury in their blood and hair, harvesting and consuming traditional foods has many nutritional, social, cultural and physical health benefits which must be considered in risk management and communication. PMID:23102902

Modeling a molecular initiating event to population effects: A case study of aromatase inhibition in fathead minnows

EPA Science Inventory

An adverse outcome pathway (AOP) conceptually links a molecular initiating event with measureable key events at higher levels of biological organization that ultimately result in an adverse outcome. Development of an AOP requires experimental data and scientific expertise to ide...

Investigation of the Factors That Influence Undergraduate Student Chemistry Course Selection

ERIC Educational Resources Information Center

Hinds, Elsa M.; Shultz, Ginger V.

2018-01-01

The introductory chemistry sequence is a common pathway for undergraduates pursuing science, technology, engineering, and math (STEM) and prehealth careers. Student's academic decision-making has far-reaching consequences for their trajectory, including persistence in the major and ultimate career choice. This phenomenon was studied using a survey…

The Vilification and Vindication of Colonel Kuklinski

DTIC Science & Technology

2000-01-01

Brzezinski , �Kuklinski�s informa tion permitted us to make counterplans to disrupt com mand-and-control facilities rather than only relying on a massive...final verdict �~3 This buck-pass ing would continue for another five years. Dr. Brzezinski was Kuklinski�s earli est and ultimately his most...return to Poland, � Brzezinski was Kuklinski�s earliest and ultimately his most effective champion. 9~ despite his legal problems, to com memorate the

Identification of JAK/STAT pathway regulators—Insights from RNAi screens

PubMed Central

Müller, Patrick; Boutros, Michael; Zeidler, Martin P.

2008-01-01

While many core JAK/STAT pathway components have been discovered in Drosophila via classical genetic approaches, the identification of pathway regulators has been more challenging. Recently two cell-based RNAi screens for JAK/STAT pathway regulators have been undertaken using libraries of double-stranded RNAs targeting a large proportion of the predicted Drosophila transcriptome. While both screens identified multiple regulators, only relatively few loci are common to both data sets. Here we compare the two screens and discuss these differences. Although many factors are likely to be contributory, differences in the assay design are of key importance. Low levels of stimulation favouring the identification of negative pathway regulators and high levels of stimulation favouring the identification of positively acting factors. Ultimately, the results from both screens are likely to be largely complementary and have identified a range of novel candidate regulators of JAK/STAT pathway activity as a starting point for new research directions in the future. PMID:18586112

Disruption of the Fanconi anemia-BRCA pathway in cisplatin-sensitive ovarian tumors.

PubMed

Taniguchi, Toshiyasu; Tischkowitz, Marc; Ameziane, Najim; Hodgson, Shirley V; Mathew, Christopher G; Joenje, Hans; Mok, Samuel C; D'Andrea, Alan D

2003-05-01

Ovarian tumor cells are often genomically unstable and hypersensitive to cisplatin. To understand the molecular basis for this phenotype, we examined the integrity of the Fanconi anemia-BRCA (FANC-BRCA) pathway in those cells. This pathway regulates cisplatin sensitivity and is governed by the coordinate activity of six genes associated with Fanconi anemia (FANCA, FANCC, FANCD2, FANCE, FANCF and FANCG) as well as BRCA1 and BRCA2 (FANCD1). Here we show that the FANC-BRCA pathway is disrupted in a subset of ovarian tumor lines. Mono-ubiquitination of FANCD2, a measure of the function of this pathway, and cisplatin resistance were restored by functional complementation with FANCF, a gene that is upstream in this pathway. FANCF inactivation in ovarian tumors resulted from methylation of its CpG island, and acquired cisplatin resistance correlated with demethylation of FANCF. We propose a model for ovarian tumor progression in which the initial methylation of FANCF is followed by FANCF demethylation and ultimately results in cisplatin resistance.

Complex two-component signaling regulates the general stress response in Alphaproteobacteria.

PubMed

Kaczmarczyk, Andreas; Hochstrasser, Ramon; Vorholt, Julia A; Francez-Charlot, Anne

2014-12-02

The general stress response (GSR) in Alphaproteobacteria was recently shown to be controlled by a partner-switching mechanism that is triggered by phosphorylation of the response regulator PhyR. Activation of PhyR ultimately results in release of the alternative extracytoplasmic function sigma factor σ(EcfG), which redirects transcription toward the GSR. Little is known about the signal transduction pathway(s) controlling PhyR phosphorylation. Here, we identified the single-domain response regulator (SDRR) SdrG and seven histidine kinases, PakA to PakG, belonging to the HWE/HisKA2 family as positive modulators of the GSR in Sphingomonas melonis Fr1. Phenotypic analyses, epistasis experiments, and in vitro phosphorylation assays indicate that Paks directly phosphorylate PhyR and SdrG, and that SdrG acts upstream of or in concert with PhyR, modulating its activity in a nonlinear pathway. Furthermore, we found that additional SDRRs negatively affect the GSR in a way that strictly requires PhyR and SdrG. Finally, analysis of GSR activation by thermal, osmotic, and oxidative stress indicates that Paks display different degrees of redundancy and that a specific kinase can sense multiple stresses, suggesting that the GSR senses a particular condition as a combination of, rather than individual, molecular cues. This study thus establishes the alphaproteobacterial GSR as a complex and interlinked network of two-component systems, in which multiple histidine kinases converge to PhyR, the phosphorylation of which is, in addition, subject to regulation by several SDRRs. Our finding that most HWE/HisKA2 kinases contribute to the GSR in S. melonis Fr1 opens the possibility that this notion might also be true for other Alphaproteobacteria.

Direct covalent modification as a strategy to inhibit nuclear factor-kappa B.

PubMed

Pande, Vineet; Sousa, Sérgio F; Ramos, Maria João

2009-01-01

Nuclear Factor-KkappaB (NF-kappaB) is a transcription factor whose inappropriate activation may result in the development of a number of diseases including cancer, inflammation, neurodegeneration and AIDS. Recent studies on NF-kappaB mediated pathologies, made therapeutic interventions leading to its inhibition an emerging theme in pharmaceutical research. NF-kappaB resides in the cytoplasm and is activated by several time-dependent factors, leading to proteasome-dependent degradation of its inhibitory protein (IkappaB), resulting in free NF-kappaB (p50 and p65 subunits, involved in disease states), which binds to target DNA sites, further resulting in enhanced transcription of several disease associated proteins. The complex pathway of NF-kappaB, finally leading to its DNA binding, has attracted several approaches interfering with this pathway. One such approach is that of a direct covalent modification of NF-kappaB. In this article, we present a critical review on the pharmacological agents that have been studied as inhibitors of NF-kappaB by covalently modifying redox-regulated cysteine residues in its subunits, ultimately resulting in the inhibition of kappaB DNA recognition and binding. Beginning with a general overview of NF-kappaB pathway and several possibilities of chemical interventions, the significance of redox-regulation in NF-kappaB activation and DNA binding is presented. Further, protein S-thiolation, S-nitrosylation and irreversible covalent modification are described as regular biochemical events in the cell, having provided a guideline for the development of NF-kappaB inhibitors discussed further. Although just a handful of inhibitors, with most of them being alkylating agents have been studied in the present context, this approach presents potential for the development of a new class of NF-kappaB-inhibitors.

State feedback control design for Boolean networks.

PubMed

Liu, Rongjie; Qian, Chunjiang; Liu, Shuqian; Jin, Yu-Fang

2016-08-26

Driving Boolean networks to desired states is of paramount significance toward our ultimate goal of controlling the progression of biological pathways and regulatory networks. Despite recent computational development of controllability of general complex networks and structural controllability of Boolean networks, there is still a lack of bridging the mathematical condition on controllability to real boolean operations in a network. Further, no realtime control strategy has been proposed to drive a Boolean network. In this study, we applied semi-tensor product to represent boolean functions in a network and explored controllability of a boolean network based on the transition matrix and time transition diagram. We determined the necessary and sufficient condition for a controllable Boolean network and mapped this requirement in transition matrix to real boolean functions and structure property of a network. An efficient tool is offered to assess controllability of an arbitrary Boolean network and to determine all reachable and non-reachable states. We found six simplest forms of controllable 2-node Boolean networks and explored the consistency of transition matrices while extending these six forms to controllable networks with more nodes. Importantly, we proposed the first state feedback control strategy to drive the network based on the status of all nodes in the network. Finally, we applied our reachability condition to the major switch of P53 pathway to predict the progression of the pathway and validate the prediction with published experimental results. This control strategy allowed us to apply realtime control to drive Boolean networks, which could not be achieved by the current control strategy for Boolean networks. Our results enabled a more comprehensive understanding of the evolution of Boolean networks and might be extended to output feedback control design.

Understanding the cancer cell phenotype beyond the limitations of current omics analyses.

PubMed

Moreno-Sánchez, Rafael; Saavedra, Emma; Gallardo-Pérez, Juan Carlos; Rumjanek, Franklin D; Rodríguez-Enríquez, Sara

2016-01-01

Efforts to understand the mechanistic principles driving cancer metabolism and proliferation have been lately governed by genomic, transcriptomic and proteomic studies. This paper analyzes the caveats of these approaches. As molecular biology's central dogma proposes a unidirectional flux of information from genes to mRNA to proteins, it has frequently been assumed that monitoring the changes in the gene sequences and in mRNA and protein contents is sufficient to explain complex cellular processes. Such a stance commonly disregards that post-translational modifications can alter the protein function/activity and also that regulatory mechanisms enter into action, to coordinate the protein activities of pathways/cellular processes, in order to keep the cellular homeostasis. Hence, the actual protein activities (as enzymes/transporters/receptors) and their regulatory mechanisms ultimately dictate the final outcomes of a pathway/cellular process. In this regard, it is here documented that the mRNA levels of many metabolic enzymes and transcriptional factors have no correlation with the respective protein contents and activities. The validity of current clinical mRNA-based tests and proposed metabolite biomarkers for cancer detection/prognosis is also discussed. Therefore, it is proposed that, to achieve a thorough understanding of the modifications undergone by proliferating cancer cells, it is mandatory to experimentally analyze the cellular processes at the functional level. This could be achieved (a) locally, by examining the actual protein activities in the cell and their kinetic properties (or at least kinetically characterize the most controlling steps of the pathway/cellular process); (b) systemically, by analyzing the main fluxes of the pathway/cellular process, and how they are modulated by metabolites, all which should contribute to comprehending the regulatory mechanisms that have been altered in cancer cells. By adopting a more holistic approach it may become possible to improve the design of therapeutic strategies that would target cancer cells more specifically. © 2015 FEBS.

Converging Pathways in Lifespan Regulation

PubMed Central

Narasimhan, Sri Devi; Yen, Kelvin; Tissenbaum, Heidi A.

2011-01-01

The processes that determine an organism’s lifespan are complex and poorly understood. Yet single gene manipulations and environmental interventions can substantially delay age-related morbidity. In this review, we focus on the two most potent modulators of longevity: insulin/insulin-like growth factor 1 (IGF-1) signaling and dietary restriction. The remarkable molecular conservation of the components associated with insulin/IGF-1 signaling and dietary restriction allow us to understand longevity from a multi-species perspective. We summarize the most recent findings on insulin/IGF-1 signaling and examine the proteins and pathways that reveal a more genetic basis for dietary restriction. Although insulin/IGF-1 signaling and dietary restriction pathways are currently viewed as being independent, we suggest that these two pathways are more intricately connected than previously appreciated. We highlight that numerous interactions between these two pathways can occur at multiple levels. Ultimately, both the insulin/IGF-1 pathway and the pathway that mediates the effects of dietary restriction have evolved to respond to the nutritional status of an organism, which in turn affects its lifespan. PMID:19674551

Hippo Pathway: An Emerging Regulator of Craniofacial and Dental Development.

PubMed

Wang, J; Martin, J F

2017-10-01

The evolutionarily conserved Hippo signaling pathway is a vital regulator of organ size that fine-tunes cell proliferation, apoptosis, and differentiation. A number of important studies have revealed critical roles of Hippo signaling and its effectors Yap (Yes-associated protein) and Taz (transcriptional coactivator with PDZ binding motif) in tissue development, homeostasis, and regeneration, as well as in tumorigenesis. In addition, recent studies have shown evidence of crosstalk between the Hippo pathway and other key signaling pathways, such as Wnt signaling, that not only regulates developmental processes but also contributes to disease pathogenesis. In this review, we summarize the major discoveries in the field of Hippo signaling and what has been learned about its regulation and crosstalk with other signaling pathways, with a particular focus on recent findings involving the Hippo-Yap pathway in craniofacial and tooth development. New and exciting studies of the Hippo pathway are anticipated that will significantly improve our understanding of the molecular mechanisms of human craniofacial and tooth development and disease and will ultimately lead to the development of new therapies.

Using a Microbial Physiologic and Genetic Approach to Investigate How Bacteria Sense Physical Stimuli

ERIC Educational Resources Information Center

Mussi, María Alejandra; Actis, Luis A.; de Mendoza, Diego; Cybulski, Larisa E.

2014-01-01

A laboratory exercise was designed to illustrate how physical stimuli such as temperature and light are sensed and processed by bacteria to elaborate adaptive responses. In particular, we use the well-characterized Des pathway of "Bacillus subtilis" to show that temperature modulates gene expression, resulting ultimately in modification…

Identifying Functionally Linked Gene Modules Within Biological Pathways Assessed by ToxCast In Vitro Assays

EPA Science Inventory

The US EPA ToxCast program is using in vitro high-throughput screening assays to profile the bioactivity of environmental chemicals, with the ultimate goal of predicting in vivo toxicity. We hypothesize that in modeling toxicity it will be more constructive to understand the pert...

Examining the Role of Corporate Sponsorship in the Public School System: Appropriate Pathways

ERIC Educational Resources Information Center

Potter, Maria

2012-01-01

To compensate for declining public school budgets, an increasing number of local public education organizations are soliciting and accepting financial support from U.S. corporations. There is considerable debate as to whether corporate involvement ultimately aids or hampers students' academic achievement, and there are many conflicting opinions as…

Optimization and Prediction of Ultimate Tensile Strength in Metal Active Gas Welding.

PubMed

Ampaiboon, Anusit; Lasunon, On-Uma; Bubphachot, Bopit

2015-01-01

We investigated the effect of welding parameters on ultimate tensile strength of structural steel, ST37-2, welded by Metal Active Gas welding. A fractional factorial design was used for determining the significance of six parameters: wire feed rate, welding voltage, welding speed, travel angle, tip-to-work distance, and shielded gas flow rate. A regression model to predict ultimate tensile strength was developed. Finally, we verified optimization of the process parameters experimentally. We achieved an optimum tensile strength (558 MPa) and wire feed rate, 19 m/min, had the greatest effect, followed by tip-to-work distance, 7 mm, welding speed, 200 mm/min, welding voltage, 30 V, and travel angle, 60°. Shield gas flow rate, 10 L/min, was slightly better but had little effect in the 10-20 L/min range. Tests showed that our regression model was able to predict the ultimate tensile strength within 4%.

Bilateral crosstalk of rho- and extracellular-signal-regulated-kinase (ERK) pathways is confined to an unidirectional mode in spinal muscular atrophy (SMA).

PubMed

Hensel, Niko; Stockbrügger, Inga; Rademacher, Sebastian; Broughton, Natasha; Brinkmann, Hella; Grothe, Claudia; Claus, Peter

2014-03-01

Rho-kinase (ROCK) as well as extracellular signal regulated kinase (ERK) control actin cytoskeletal organization thereby regulating dynamic changes of cellular morphology. In neurons, motility processes such as axonal guidance and neurite outgrowth demand a fine regulation of upstream pathways. Here we demonstrate a bilateral ROCK-ERK information flow in neurons. This process is shifted towards an unidirectional crosstalk in a model of the neurodegenerative disease Spinal Muscular Atrophy (SMA), ultimately leading to neurite outgrowth dysregulations. As both pathways are of therapeutic relevance for SMA, our results argue for a combinatorial ROCK/ERK-targeting as a future treatment strategy. Copyright © 2013 Elsevier Inc. All rights reserved.

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

PubMed

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

2017-08-16

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

Advances in the Understanding and Treatment of Mitochondrial Fatty Acid Oxidation Disorders.

PubMed

Goetzman, Eric S

2017-09-01

This review focuses on advances made in the past three years with regards to understanding the mitochondrial fatty acid oxidation (FAO) pathway, the pathophysiological ramifications of genetic lesions in FAO enzymes, and emerging therapies for FAO disorders. FAO has now been recognized to play a key energetic role in pulmonary surfactant synthesis, T-cell differentiation and memory, and the response of the proximal tubule to kidney injury. Patients with FAO disorders may face defects in these cellular systems as they age. Aspirin, statins, and nutritional supplements modulate the rate of FAO under normal conditions and could be risk factors for triggering symptoms in patients with FAO disorders. Patients have been identified with mutations in the ACAD9 and ECHS1 genes, which may represent new FAO disorders. New interventions for long-chain FAODs are in clinical trials. Finally, post-translational modifications that regulate fatty acid oxidation protein activities have been characterized that represent important new therapeutic targets. Recent research has led to a deeper understanding of FAO. New therapeutic avenues are being pursued that may ultimately cause a paradigm shift for patient care.

Angiotensin receptors and norepinephrine neuromodulation: implications of functional coupling.

PubMed

Gelband, C H; Sumners, C; Lu, D; Raizada, M K

1997-10-31

The objective of this review is to examine the role of neuronal angiotensin II (Ang II) receptors in vitro. Two types of G protein-coupled Ang II receptors have been identified in cardiovascularly relevant areas of the brain: the AT1 and the AT2. We have utilized neurons in culture to study the signaling mechanisms of AT1 and AT2 receptors. Neuronal AT1 receptors are involved in norepinephrine (NE) neuromodulation. NE neuromodulation can be either evoked or enhanced. Evoked NE neuromodulation involves AT1 receptor-mediated, losartan-dependent, rapid NE release, inhibition of K+ channels and stimulation of Ca2+ channels. AT1 receptor-mediated enhanced NE neuromodulation involves the Ras-Raf-MAP kinase cascade and ultimately leads to an increase in NE transporter, tyrosine hydroxylase and dopamine beta-hydroxylase mRNA transcription. Neuronal AT2 receptors signal via a Gi protein and are coupled to activation of PP2A and PLA2 and stimulation of K+ channels. Finally, putative cross-talk pathways between AT1 and AT2 receptors will be discussed.

Angiotensin receptors and norepinephrine neuromodulation: implications of functional coupling.

PubMed

Gelband, C H; Sumners, C; Lu, D; Raizada, M K

1998-02-27

The objective of this review is to examine the role of neuronal angiotensin II (Ang II) receptors in vitro. Two types of G protein-coupled Ang II receptors have been identified in cardiovascularly relevant areas of the brain: the AT1 and the AT2. We have utilized neurons in culture to study the signaling mechanisms of AT1 and AT2 receptors. Neuronal AT1 receptors are involved in norepinephrine (NE) neuromodulation. NE neuromodulation can be either evoked or enhanced. Evoked NE neuromodulation involves AT1 receptor-mediated, losartan-dependent, rapid NE release, inhibition of K+ channels and stimulation of Ca2+ channels. AT1 receptor-mediated enhanced NE neuromodulation involves the Ras-Raf-MAP kinase cascade and ultimately leads to an increase in NE transporter, tyrosine hydroxylase and dopamine beta-hydroxylase mRNA transcription. Neuronal AT2 receptors signal via a Gi protein and are coupled to activation of PP2A and PLA2 and stimulation of K+ channels. Finally, putative cross-talk pathways between AT1 and AT2 receptors will be discussed.

Health-and-environment indicators in the context of sustainable development.

PubMed

von Schirnding, Yasmin E

2002-01-01

This paper gives a broad overview of issues relevant to the development and use of health-and-environment indicators in the broader context of sustainable development. Criteria for the construction of indicators are given, and their key characteristics are highlighted. Selected international indicator initiatives are discussed, as well as the concept and use of core indicators in policy and planning. Finally, an organizational framework for the consideration of health-environment-development linkages is presented, which can be used in the development of health-and-environment indicators in various contexts. This framework is the Driving forces-Pressures-State-Exposures-Health Effects-Actions framework (DPSEEA) of the World Health Organization (WHO). It is a descriptive representation of the way in which various driving forces generate pressures which affect the state of the environment, and ultimately human health through the various exposure pathways by which people come into contact with the environment. Throughout the paper, emphasis is placed on work done within the UN system, in particular that of the WHO, and examples of suites of indicators developed and in use are provided.

Beyond cause to consequence: The road from possible to core self-revision

PubMed Central

Carroll, Patrick J.; Agler, Robert A.; Newhart, Daniel W.

2015-01-01

Two studies addressed the ultimate consequences and pathways running from repeated possible self-revisions to gradual revisions in core selves over time. As hypothesized, greater prior experiences of downward possible self-revision ultimately predicted greater subsequent declines in core self-integrity (e.g., greater self-doubt, lower self-esteem). However, also as hypothesized, this effect was mediated by the relative use of defensive vs. remedial attributions for past downward self-revision experiences. In closing, we unpack how the present work extends prior work by situating possible selves and motivated self-attributions as complementary systems that can slowly undermine as well as expand the integrity of core selves over time. PMID:26635509

Disruptive technologies and transportation : final report.

DOT National Transportation Integrated Search

2016-06-01

Disruptive technologies refer to innovations that, at first, may be considered unproven, lacking refinement, relatively unknown, or even impractical, but ultimately they supplant existing technologies and/or applications. In general, disruptive techn...

No hormone to rule them all: Interactions of plant hormones during the responses of plants to pathogens.

PubMed

Shigenaga, Alexandra M; Argueso, Cristiana T

2016-08-01

Plant hormones are essential regulators of plant growth and immunity. In the last few decades, a vast amount of information has been obtained detailing the role of different plant hormones in immunity, and how they work together to ultimately shape the outcomes of plant pathogen interactions. Here we provide an overview on the roles of the main classes of plant hormones in the regulation of plant immunity, highlighting their metabolic and signaling pathways and how plants and pathogens utilize these pathways to activate or suppress defence. Copyright © 2016 Elsevier Ltd. All rights reserved.

Molecular Phenotyping Combines Molecular Information, Biological Relevance, and Patient Data to Improve Productivity of Early Drug Discovery.

PubMed

Drawnel, Faye Marie; Zhang, Jitao David; Küng, Erich; Aoyama, Natsuyo; Benmansour, Fethallah; Araujo Del Rosario, Andrea; Jensen Zoffmann, Sannah; Delobel, Frédéric; Prummer, Michael; Weibel, Franziska; Carlson, Coby; Anson, Blake; Iacone, Roberto; Certa, Ulrich; Singer, Thomas; Ebeling, Martin; Prunotto, Marco

2017-05-18

Today, novel therapeutics are identified in an environment which is intrinsically different from the clinical context in which they are ultimately evaluated. Using molecular phenotyping and an in vitro model of diabetic cardiomyopathy, we show that by quantifying pathway reporter gene expression, molecular phenotyping can cluster compounds based on pathway profiles and dissect associations between pathway activities and disease phenotypes simultaneously. Molecular phenotyping was applicable to compounds with a range of binding specificities and triaged false positives derived from high-content screening assays. The technique identified a class of calcium-signaling modulators that can reverse disease-regulated pathways and phenotypes, which was validated by structurally distinct compounds of relevant classes. Our results advocate for application of molecular phenotyping in early drug discovery, promoting biological relevance as a key selection criterion early in the drug development cascade. Copyright © 2017 Elsevier Ltd. All rights reserved.

How does patient-provider communication influence adherence to asthma medications?

PubMed

Young, Henry N; Len-Rios, Maria E; Brown, Roger; Moreno, Megan M; Cox, Elizabeth

2017-04-01

To assess hypothesized pathways through which patient-provider communication impacts asthma medication adherence. A national sample of 452 adults with asthma reported assessments of patient-provider communication, proximal outcomes (understanding of asthma self-management, patient-provider agreement, trust in the clinician, involvement in care, motivation), and adherence to asthma medications. Structural equation modeling was used to examine hypothesized pathways. Significantly positive direct pathways were found between patient-provider communication and all proximal outcomes. Only positive indirect pathways, operating through trust and motivation, were found between patient-provider communication and medication adherence. Patient-provider communication influences many desirable proximal outcomes, but only influences adherence through trust and motivation. To promote better adherence to asthma medication regimens and, ultimately positive asthma outcomes, healthcare providers can focus on implementing communication strategies that strengthen patients' trust and increase patient motivation to use asthma medications. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Ketone body metabolism and cardiovascular disease

PubMed Central

Cotter, David G.; Schugar, Rebecca C.

2013-01-01

Ketone bodies are metabolized through evolutionarily conserved pathways that support bioenergetic homeostasis, particularly in brain, heart, and skeletal muscle when carbohydrates are in short supply. The metabolism of ketone bodies interfaces with the tricarboxylic acid cycle, β-oxidation of fatty acids, de novo lipogenesis, sterol biosynthesis, glucose metabolism, the mitochondrial electron transport chain, hormonal signaling, intracellular signal transduction pathways, and the microbiome. Here we review the mechanisms through which ketone bodies are metabolized and how their signals are transmitted. We focus on the roles this metabolic pathway may play in cardiovascular disease states, the bioenergetic benefits of myocardial ketone body oxidation, and prospective interactions among ketone body metabolism, obesity, metabolic syndrome, and atherosclerosis. Ketone body metabolism is noninvasively quantifiable in humans and is responsive to nutritional interventions. Therefore, further investigation of this pathway in disease models and in humans may ultimately yield tailored diagnostic strategies and therapies for specific pathological states. PMID:23396451

Mitochondrial pathways governing stress resistance, life, and death in the fungal aging model Podospora anserina.

PubMed

Osiewacz, Heinz D; Brust, Diana; Hamann, Andrea; Kunstmann, Birgit; Luce, Karin; Müller-Ohldach, Mathis; Scheckhuber, Christian Q; Servos, Jörg; Strobel, Ingmar

2010-06-01

Work from more than 50 years of research has unraveled a number of molecular pathways that are involved in controlling aging of the fungal model system Podospora anserina. Early research revealed that wild-type strain aging is linked to gross reorganization of the mitochondrial DNA. Later it was shown that aging of P. anserina does also take place, although at a slower pace, when the wild-type specific mitochondrial DNA rearrangements do not occur. Now it is clear that a network of different pathways is involved in the control of aging. Branches of these pathways appear to be connected and constitute a hierarchical system of responses. Although cross talk between the individual pathways seems to be fundamental in the coordination of the overall system, the precise underlying interactions remain to be unraveled. Such a systematic approach aims at a holistic understanding of the process of biological aging, the ultimate goal of modern systems biology.

A Small RNA-Catalytic Argonaute Pathway Tunes Germline Transcript Levels to Ensure Embryonic Divisions

PubMed Central

Gerson-Gurwitz, Adina; Wang, Shaohe; Sathe, Shashank; Green, Rebecca; Yeo, Gene W.; Oegema, Karen; Desai, Arshad

2016-01-01

SUMMARY Multiple division cycles without growth are a characteristic feature of early embryogenesis. The female germline loads proteins and RNAs into oocytes to support these divisions, which lack many quality control mechanisms operating in somatic cells undergoing growth. Here we describe a small RNA-Argonaute pathway that ensures early embryonic divisions in C. elegans by employing catalytic slicing activity to broadly tune, instead of silence, germline gene expression. Misregulation of one target, a kinesin-13 microtubule depolymerase, underlies a major phenotype associated with pathway loss. Tuning of target transcript levels is guided by density of homologous small RNAs, whose generation must ultimately be related to target sequence. Thus, the tuning action of a small RNA-catalytic Argonaute pathway generates oocytes capable of supporting embryogenesis. We speculate that the specialized nature of germline chromatin led to emergence of small RNA-catalytic Argonaute pathways in the female germline as a post-transcriptional control layer to optimize oocyte composition. PMID:27020753

Establishing Final Cleanup Decisions for the Hanford Site River Corridor

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

Lerch, J.A.; Sands, J.P.

2007-07-01

A major challenge in the River Corridor Closure Contract is establishing final cleanup decisions for the source operable units in the Hanford Site river corridor. Cleanup actions in the river corridor began in 1994 and have been performed in accordance with a 'bias for action' approach adopted by the Tri-Parties - the U.S. Department of Energy, U.S. Environmental Protection Agency, and Washington State Department of Ecology. This approach enabled early application of cleanup dollars on actual remediation of contaminated waste sites. Consequently, the regulatory framework authorizing cleanup actions at source operable units in the river corridor consists largely of interimmore » action records of decision, which were supported by qualitative risk assessments. Obtaining final cleanup decisions for the source operable units is necessary to determine whether past cleanup actions in the river corridor are protective of human health and the environment and to identify any course corrections that may be needed to ensure that ongoing and future cleanup actions are protective. Because the cleanup actions are ongoing, it is desirable to establish the final cleanup decisions as early as possible to minimize the impacts of any identified course corrections to the present cleanup approach. Development of a strategy to obtain final cleanup decisions for the source operable units in a manner that is responsive to desires for an integrated approach with the groundwater and Columbia River components while maintaining the ability to evaluate each component on its own merit represents a significant challenge. There are many different options for grouping final cleanup decisions, and each involved party or stakeholder brings slightly different interests that shape the approach. Regardless of the selected approach, there are several specific challenges and issues to be addressed before making final cleanup decisions. A multi-agency and contractor working group has been established to address these issues and develop an endorsed strategy. Ultimately, it is anticipated that the Tri-Parties will establish a set of milestones to document pathway selection and define schedule requirements. (authors)« less

Biosynthesis, Trafficking and Secretion of Pro-opiomelanocortin-derived peptides

PubMed Central

Cawley, Niamh X.; Li, Zhaojin; Loh, Y. Peng

2016-01-01

Pro-opiomelanocortin (POMC) is a prohormone that encodes multiple smaller peptide hormones within its structure. These peptide hormones can be generated by cleavage of POMC at basic-residue cleavage sites by prohormone converting enzymes in the regulated secretory pathway of POMC synthesizing endocrine cells and neurons. The peptides are stored inside the cells in dense core secretory granules until released in a stimulus dependent manner. The complexity of the regulation of the biosynthesis, trafficking and secretion of POMC and its peptides reflect an impressive level of control over many factors involved in the ultimate role of POMC expressing cells, i.e. to produce a range of different biologically active peptide hormones ready for action when signaled by the body. From the discovery of POMC as the precursor to ACTH and β-Lipotropin in the late 1970s to our current knowledge, the understanding of POMC physiology remains a monumental body of work that has provided insight into many aspects of molecular endocrinology. In this chapter, we describe the intracellular trafficking of POMC in endocrine cells, its sorting into dense core secretory granules and transport of these granules to the regulated secretory pathway. Additionally, we review the enzymes involved in the maturation of POMC to its various peptides and the mechanisms involved in the differential processing of POMC in different cell types. Finally, we highlight studies pertaining to the regulation of ACTH secretion in the anterior and intermediate pituitary and POMC neurons of the hypothalamus. PMID:26880796

In vivo imaging of the dynamics of different variants of EGFR in glioblastomas.

PubMed

Shah, Khalid

2011-01-01

A number of altered pathways in cancer cells depend on growth factor receptors. The amplification/alteration of the epidermal growth factor receptor (EGFR) has been shown to play a significant role in enhancing tumor burden in a number of tumors, including malignant glioblastomas (GBM). To dissect the role of EGFR expression in tumor progression in mouse models of cancer and ultimately evaluate targeted therapies, it is necessary to visualize the dynamics of EGFR in real time in vivo. Non-invasive imaging based on quantitative and qualitative changes in light emission by fluorescent and bioluminescent markers offers a huge potential to facilitate drug development. Multiple approaches could be used to follow a molecular target or pathway with the fusion of a bioluminescent-fluorescent marker. This unit describes a protocol for simultaneously imaging EGFR activity and progression of GBM in a mouse model. Human glioma cells transduced with lentiviral vectors bearing different combinations of fluorescent and bioluminescent proteins either fused to EGFR or expressed alone can be grown as monolayers and maintained over several passages. The unit begins with a method for transducing glioma cells with lentiviral vectors for stable expression of these fluorescent and bioluminescent markers in vitro, followed by transplantation of engineered glioma cells in mice, and, finally, sequential bioluminescent imaging of EGFR expression and GBM progression in mice. The protocol details characterization of engineered glioma cells in culture, surgical preparation, craniotomy, cell implantation, animal recovery, and imaging procedures to study kinetics of EGFR expression and GBM progression.

Drug development against sleeping sickness: old wine in new bottles?

PubMed

Stein, J; Mogk, S; Mudogo, C N; Sommer, B P; Scholze, M; Meiwes, A; Huber, M; Gray, A; Duszenko, M

2014-01-01

Atoxyl, the first medicinal drug against human African trypanosomiasis (HAT), also known as sleeping sickness, was applied more than 100 years ago. Ever since, the search for more effective, more specific and less toxic drugs continued, leading to a set of compounds currently in use against this devastating disease. Unfortunately, none of these medicines fulfill modern pharmaceutical requirements and may be considered as therapeutic ultima ratio due to the many, often severe side effects. Starting with a historic overview on drug development against HAT, we present a selection of trypanosome specific pathways and enzymes considered as highly potent druggable targets. In addition, we describe cellular mechanisms the parasite uses for differentiation and cell density regulation and present our considerations how interference with these steps, elementary for life cycle progression and infection, may lead to new aspects of drug development. Finally we refer to our recent work about CNS infection that offers novel insights in how trypanosomes hide in an immune privileged area to establish a chronic state of the disease, thereby considering new ways for drug application. Depressingly, HAT specific drug development has failed over the last 30 years to produce better suited medicine. However, unraveling of parasite-specific pathways and cellular behavior together with the ability to produce high resolution structures of essential parasite proteins by X-ray crystallography, leads us to the optimistic view that development of an ultimate drug to eradicate sleeping sickness from the globe might just be around the corner.

The Assessment of the Ultimate Hull Girder Strength of RO-RO Ship after Damages

NASA Astrophysics Data System (ADS)

Zubair Muis Alie, Muhammad; Sitepu, Ganding; Izaak Latumahin, Samuel

2018-03-01

Many accidents of Ro-Ro ships happen in Indonesia such as collision and grounding. When the collision or grounding takes place on the Ro-Ro ship, the ultimate strength of hull structure after damage becomes decrease. Car and passenger decks are critical location since collision and/or grounding occur. In the present study, the assessment of the ultimate hull girder strength is conducted. The cross section of Ro-Ro ship is taken to be analyzed. The collision and grounding damages are assumed to be palced on the side and bottom area, respectively. The damages are created by removing the element from the side shell and bottom part. Finally, the result obtained is compared with one another.

Aedes aegypti juvenile hormone acid methyl transferase, the ultimate enzyme in the biosynthetic pathway of juvenile hormone III, exhibits substrate control

USDA-ARS?s Scientific Manuscript database

We report on the cloning, sequencing, characterization, 3D modeling and docking of Aedes aegypti juvenile hormone acid methyl transferase (AeaJHAMT), the enzyme that converts juvenile hormone acid (JHA) into juvenile hormone (JH). Purified recombinant AeaJHAMT was extensively characterized for enzym...

T-cell costimulatory pathways in allograft rejection and tolerance.

PubMed

Rothstein, David M; Sayegh, Mohamed H

2003-12-01

The destiny of activated T cells is critical to the ultimate fate of immune response. After encountering antigen, naïve T cells receive signal 1 through the T-cell receptor (TCR)-major histocompatibility complex (MHC) plus antigenic peptide complex and signal 2 through "positive" costimulatory molecules leading to full activation. "Negative" T-cell costimulatory pathways, on the other hand, function to downregulate immune responses. The purpose of this article is to review the current state of knowledge and recent advances in our understanding of the functions of the positive and negative T-cell costimulatory pathways in alloimmune responses. Specifically, we discuss the functions of the CD28:B7 and the tumor necrosis factor receptor (TNFR):tumor necrosis factor (TNF) family of molecules in allograft rejection and tolerance. We address the following important questions: are T-cell costimulatory pathways merely redundant or do they provide distinct and unique functions? What are the important and unique interactions between the various pathways? And, what are the effects and mechanisms of targeting of these pathways in different types and patterns of allograft rejection and tolerance models?

Assimilation of NAD(+) precursors in Candida glabrata.

PubMed

Ma, Biao; Pan, Shih-Jung; Zupancic, Margaret L; Cormack, Brendan P

2007-10-01

The yeast pathogen Candida glabrata is a nicotinamide adenine dinucleotide (NAD(+)) auxotroph and its growth depends on the environmental supply of vitamin precursors of NAD(+). C. glabrata salvage pathways defined in this article allow NAD(+) to be synthesized from three compounds - nicotinic acid (NA), nicotinamide (NAM) and nicotinamide riboside (NR). NA is salvaged through a functional Preiss-Handler pathway. NAM is first converted to NA by nicotinamidase and then salvaged by the Preiss-Handler pathway. Salvage of NR in C. glabrata occurs via two routes. The first, in which NR is phosphorylated by the NR kinase Nrk1, is independent of the Preiss-Handler pathway. The second is a novel pathway in which NR is degraded by the nucleosidases Pnp1 and Urh1, with a minor role for Meu1, and ultimately converted to NAD(+) via the nicotinamidase Pnc1 and the Preiss-Handler pathway. Using C. glabrata mutants whose growth depends exclusively on the external NA or NR supply, we also show that C. glabrata utilizes NR and to a lesser extent NA as NAD(+) sources during disseminated infection.

Final analysis of cost, value, and risk.

DOT National Transportation Integrated Search

2009-03-05

USDOT understands that access to emergency services provided by 9-1-1 in todays world of evolving : technology will ultimately occur within a broader array of interconnected networks comprehensively : supporting emergency servicesfrom public ac...

Ionotropic GABA receptor antagonism-induced adverse outcome pathways for potential neurotoxicity biomarkers.

PubMed

Gong, Ping; Hong, Huixiao; Perkins, Edward J

2015-01-01

Antagonism of ionotropic GABA receptors (iGABARs) can occur at three distinct types of receptor binding sites causing chemically induced epileptic seizures. Here we review three adverse outcome pathways, each characterized by a specific molecular initiating event where an antagonist competitively binds to active sites, negatively modulates allosteric sites or noncompetitively blocks ion channel on the iGABAR. This leads to decreased chloride conductance, followed by depolarization of affected neurons, epilepsy-related death and ultimately decreased population. Supporting evidence for causal linkages from the molecular to population levels is presented and differential sensitivity to iGABAR antagonists in different GABA receptors and organisms discussed. Adverse outcome pathways are poised to become important tools for linking mechanism-based biomarkers to regulated outcomes in next-generation risk assessment.

Dynamic change of SGK expression and its role in neuron apoptosis after traumatic brain injury.

PubMed

Wu, Xinmin; Mao, Hui; Liu, Jiao; Xu, Jian; Cao, Jianhua; Gu, Xingxing; Cui, Gang

2013-01-01

Activation of specific signaling pathways in response to mechanical trauma causes delayed neuronal apoptosis; GSK-3β/β-catenin signaling plays a critical role in the apoptosis of neurons in CNS diseases, SGK was discovered as a regulator of GSK-3β/β-catenin pathway, The goal of this study was to determine if the mechanism of cell death or survival mediated by the SGK/GSK-3β/β-catenin pathway is involved in a rat model of TBI. Here, an acute traumatic brain injury model was applied to investigate the expression change and possible roles of SGK, Expression of SGK, and total-GSK-3β, phospho-GSK3β on ser-9, beta-catenin, and caspase-3 were examined by immunohistochemistry and Western blot analysis. Double immunofluorescent staining was used to observe the SGK localizations. Si-RNA was performed to identify whether SGK regulates neuron apoptosis via GSK-3β/β-catenin pathway, ultimately inhibit caspase-3 activation. Temporally, SGK expression showed an increase pattern after TBI and reached a peak at day 3. Spatially, SGK was widely expressed in the neuron, rarely in astrocytes and oligodendrocytes; in addition, the expression patterns of active caspase-3 and phospho-GSK3β were parallel with that of SGK, at the same time, the expression of β-catenin shows similarity with SGK. In vitro, to further investigate the function of SGK, a neuronal cell line PC12 was employed to establish an apoptosis model. We analyzed the association of SGK with apoptosis on PC12 cells by western blot, immunofluorescent labeling and siRNA. the results implied that SGK plays an important role in neuron apoptosis via the regulation of GSK3β/β-catenin signaling pathway; ultimately inhibit caspase-3 activation. Taken together, we inferred traumatic brain injury induced an upregulation of SGK in the central nervous system, which show a protective role in neuron apoptosis.

Alcohol-related hot-spot analysis and prediction : final report.

DOT National Transportation Integrated Search

2017-05-01

This project developed methods to more accurately identify alcohol-related crash hot spots, ultimately allowing for more effective and efficient enforcement and safety campaigns. Advancements in accuracy came from improving the calculation of spatial...

Utah DOT weather responsive traveler information system.

DOT National Transportation Integrated Search

1996-06-01

The Final Performance and Benefits Summary describes our understanding of the connection between the National ITS Architecture, its technical performance characteristics, and its likely benefits for ITS users and suppliers. Ultimately, the goal of th...

Acidic Ca2+ stores in neurodegeneration

PubMed Central

Lloyd-Evans, Emyr

2017-01-01

Lysosomes have emerged in the last decade as an immensely important intracellular site of Ca2+ storage and signalling. More recently there has been an increase in the number of new ion channels found to be functional on lysosomes and the potential roles that these signalling pathways might play in fundamental cellular processes are being uncovered. Defects in lysosomal function have been shown to result in changes in lysosomal Ca2+ homeostasis and ultimately can result in cell death. Several neurodegenerative diseases, from rare lysosomal storage diseases through to more common diseases of ageing, have recently been identified as having alterations in lysosomal Ca2+ homeostasis that may play an important role in neuronal excitotoxicity and ultimately cell death. This review will critically summarise these recent findings. PMID:28593104

Mechanistic aspects of fluorescent gold nanocluster internalization by live HeLa cells

NASA Astrophysics Data System (ADS)

Yang, Linxiao; Shang, Li; Nienhaus, G. Ulrich

2013-01-01

We have studied cellular uptake of ultrasmall fluorescent gold nanoclusters (AuNCs) by HeLa cells by confocal fluorescence microscopy in combination with quantitative image analysis. Water solubilized, lipoic acid-protected AuNCs, which had an overall hydrodynamic diameter of 3.3 nm and emitted fluorescence in the near-infrared region at ~700 nm, were observed to accumulate on the cell membrane prior to internalization. The internalization mechanisms were analyzed using inhibitors known to interfere with specific pathways. Cellular uptake of AuNCs is energy-dependent and involves multiple mechanisms: clathrin-mediated endocytosis and macropinocytosis appear to play a significant role, whereas the caveolin-mediated pathway contributes only to a lesser extent. Co-labeling of different cell organelles showed that intracellular trafficking of AuNCs mainly follows through endosomal pathways. The AuNCs were ultimately transferred to lysosomes; they were completely excluded from the nucleus even after 24 h.We have studied cellular uptake of ultrasmall fluorescent gold nanoclusters (AuNCs) by HeLa cells by confocal fluorescence microscopy in combination with quantitative image analysis. Water solubilized, lipoic acid-protected AuNCs, which had an overall hydrodynamic diameter of 3.3 nm and emitted fluorescence in the near-infrared region at ~700 nm, were observed to accumulate on the cell membrane prior to internalization. The internalization mechanisms were analyzed using inhibitors known to interfere with specific pathways. Cellular uptake of AuNCs is energy-dependent and involves multiple mechanisms: clathrin-mediated endocytosis and macropinocytosis appear to play a significant role, whereas the caveolin-mediated pathway contributes only to a lesser extent. Co-labeling of different cell organelles showed that intracellular trafficking of AuNCs mainly follows through endosomal pathways. The AuNCs were ultimately transferred to lysosomes; they were completely excluded from the nucleus even after 24 h. Electronic supplementary information (ESI) available: Effect of serum on the AuNC uptake by HeLa cells and colocalization result of AuNCs with the cell nucleus for 2-24 h. See DOI: 10.1039/c2nr33147k

State Strategies to Scale Quality Work-Based Learning. NGA Paper

ERIC Educational Resources Information Center

Hauge, Kimberly; Parton, Brent

2016-01-01

Industries in every state are struggling to find qualified applicants for jobs, while job seekers too often find they lack the skills needed to enter or move along a career pathway to a good job. Preparing a workforce that is poised to meet the needs of businesses and ultimately to make the state more economically competitive is a top priority for…

Aerobic biodegradation of amphoteric amine-oxide-based surfactants: Effect of molecular structure, initial surfactant concentration and pH.

PubMed

Ríos, Francisco; Lechuga, Manuela; Fernández-Serrano, Mercedes; Fernández-Arteaga, Alejandro

2017-03-01

The present study was designed to provide information regarding the effect of the molecular structure of amphoteric amine-oxide-based surfactants and the initial surfactant concentration on their ultimate biodegradation. Moreover, given this parameter's pH-dependence, the effect of pH was also investigated. Three amine-oxide-based surfactants with structural differences in their hydrophobic alkyl chain were tested: Lauramine oxide (AO-R 12 ), Myristamine oxide (AO-R 14 ) and Cocamidopropylamine oxide (AO-Cocoamido). We studied the ultimate biodegradation using the Modified OECD Screening Test at initial surfactant concentrations ranged from 5 to 75 mg L -1 and at pH levels from 5 to 7.4. The results demonstrate that at pH 7.4, amine-oxide-based surfactants are readily biodegradable. In this study, we concluded that ω-oxidation can be assumed to be the main biodegradation pathway of amine-oxides and that differences in the biodegradability between them can be explained by the presence of an amide group in the alkyl chain of AO-Cocoamido; the CN fission of the amide group slows down their mineralization process. In addition, the increase in the concentration of the surfactant from 5 to 75 mg L -1 resulted in an increase in the final biodegradation of AO-R 12 and AO-R 14 . However, in the case of AO-Cocoamido, a clear relationship between the concentration and biodegradation cannot be stated. Conversely, the biodegradability of AO-R 12 and AO-R 14 was considerably lower in an acid condition than at a pH of 7.4, whereas AO-Cocoamido reached similar percentages in acid conditions and at a neutral pH. However, microorganisms required more time to acclimate. Copyright © 2016 Elsevier Ltd. All rights reserved.

Innate Immunity and Biomaterials at the Nexus: Friends or Foes.

PubMed

Christo, Susan N; Diener, Kerrilyn R; Bachhuka, Akash; Vasilev, Krasimir; Hayball, John D

2015-01-01

Biomaterial implants are an established part of medical practice, encompassing a broad range of devices that widely differ in function and structural composition. However, one common property amongst biomaterials is the induction of the foreign body response: an acute sterile inflammatory reaction which overlaps with tissue vascularisation and remodelling and ultimately fibrotic encapsulation of the biomaterial to prevent further interaction with host tissue. Severity and clinical manifestation of the biomaterial-induced foreign body response are different for each biomaterial, with cases of incompatibility often associated with loss of function. However, unravelling the mechanisms that progress to the formation of the fibrotic capsule highlights the tightly intertwined nature of immunological responses to a seemingly noncanonical "antigen." In this review, we detail the pathways associated with the foreign body response and describe possible mechanisms of immune involvement that can be targeted. We also discuss methods of modulating the immune response by altering the physiochemical surface properties of the biomaterial prior to implantation. Developments in these areas are reliant on reproducible and effective animal models and may allow a "combined" immunomodulatory approach of adapting surface properties of biomaterials, as well as treating key immune pathways to ultimately reduce the negative consequences of biomaterial implantation.

Diatoms to human uses: linking nitrogen deposition, aquatic eutrophication, and ecosystem services

DOE PAGES

Rhodes, Charles; Bingham, Andrew; Heard, Andrea M.; ...

2017-07-24

Nitrogen (N) loading to aquatic ecosystems can lead to eutrophication, changing the ecosystem within a waterbody, including primary productivity, water clarity, and food web dynamics. Nutrient loading often first affects the primary productivity of aquatic systems through shifts in phytoplankton communities. However, ecologically important changes in phytoplankton are often not relatable to the general public—whose behavior would need to change to alter patterns of nutrient loading. Therefore, we use the STressor–Ecological Production function–final ecosystem Services Framework to develop 154 chains that link changes in biological indicators of aquatic eutrophication (a shift in phytoplankton community) to final ecosystem services that peoplemore » use or appreciate. We identify 13 ecological production functions (EPF) within three different ecosystems (alpine lakes, lakes, and estuaries) that connect changes in phytoplankton and algae to ecological endpoints that the general public and policy makers can appreciate. Using the Final Ecosystem Goods and Services Classification System, we identify 18 classes of human beneficiaries that potentially will be impacted by a change in one of these endpoints. We further assign strength-of-science scores to each link within the EPFs for the 154 chains according to how well each link is supported by current peer-reviewed literature. By identifying many pathways through which excess N loading in U.S. surface waters can affect ecosystems and ultimately the beneficiaries of ecosystem services, this work intends to draw attention to gaps in empirical ecological literature that constrain understanding of the magnitude of effects that excess N loading can have on human well-being. Here, results highlight the importance of intersections between the natural and social sciences when managers and policy makers evaluate impacts from ecological stressors. A balance between knowledgeable specialists proved key to applying this approach and will continue to remain important.« less

Diatoms to human uses: linking nitrogen deposition, aquatic eutrophication, and ecosystem services

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

Rhodes, Charles; Bingham, Andrew; Heard, Andrea M.

Nitrogen (N) loading to aquatic ecosystems can lead to eutrophication, changing the ecosystem within a waterbody, including primary productivity, water clarity, and food web dynamics. Nutrient loading often first affects the primary productivity of aquatic systems through shifts in phytoplankton communities. However, ecologically important changes in phytoplankton are often not relatable to the general public—whose behavior would need to change to alter patterns of nutrient loading. Therefore, we use the STressor–Ecological Production function–final ecosystem Services Framework to develop 154 chains that link changes in biological indicators of aquatic eutrophication (a shift in phytoplankton community) to final ecosystem services that peoplemore » use or appreciate. We identify 13 ecological production functions (EPF) within three different ecosystems (alpine lakes, lakes, and estuaries) that connect changes in phytoplankton and algae to ecological endpoints that the general public and policy makers can appreciate. Using the Final Ecosystem Goods and Services Classification System, we identify 18 classes of human beneficiaries that potentially will be impacted by a change in one of these endpoints. We further assign strength-of-science scores to each link within the EPFs for the 154 chains according to how well each link is supported by current peer-reviewed literature. By identifying many pathways through which excess N loading in U.S. surface waters can affect ecosystems and ultimately the beneficiaries of ecosystem services, this work intends to draw attention to gaps in empirical ecological literature that constrain understanding of the magnitude of effects that excess N loading can have on human well-being. Here, results highlight the importance of intersections between the natural and social sciences when managers and policy makers evaluate impacts from ecological stressors. A balance between knowledgeable specialists proved key to applying this approach and will continue to remain important.« less

Developing regulatory strategy for microbicides.

PubMed

Nardi, Ronald; Arterburn, Linda; Carlton, Lisa

2014-01-01

Ever since the discovery that a virus was responsible for AIDS, prevention of HIV infection has been a drug/vaccine development target in therapeutic research. Microbicide products are a viable, globally applicable option; however, to date, no product has been approved anywhere in the world. Development of such a product will need to account for the changing disease landscape and will need to leverage available regulatory pathways to gain approvals in the developed world and emerging markets. In countries where the regulatory pathway is not clear which is the case in several emerging markets, sponsors will need to employ a flexible approach to gather and meet local regulatory requirements and ultimately gain product approvals.

Cancer cachexia: mediators, signaling, and metabolic pathways.

PubMed

Fearon, Kenneth C H; Glass, David J; Guttridge, Denis C

2012-08-08

Cancer cachexia is characterized by a significant reduction in body weight resulting predominantly from loss of adipose tissue and skeletal muscle. Cachexia causes reduced cancer treatment tolerance and reduced quality and length of life, and remains an unmet medical need. Therapeutic progress has been impeded, in part, by the marked heterogeneity of mediators, signaling, and metabolic pathways both within and between model systems and the clinical syndrome. Recent progress in understanding conserved, molecular mechanisms of skeletal muscle atrophy/hypertrophy has provided a downstream platform for circumventing the variations and redundancy in upstream mediators and may ultimately translate into new targeted therapies. Copyright © 2012 Elsevier Inc. All rights reserved.

Molecular mechanism of Danshensu on platelet antiaggregation

NASA Astrophysics Data System (ADS)

Yu, Chen; Geng, Feng; Fan, Hua-Ying; Luan, Hai-Yun; Liu, Yue; Ji, Kai; Fu, Feng-Hua

2018-04-01

In this study, we detected the effect of Danshensu on PARs-PLCβsignaling pathway to elucidate molecular mechanism of Danshensu on platelet anti-aggregation. Our results demonstrate that Danshensu is able to decrease the levels of IP3, Ca2+ and AA secretion, which indicate that Danshensu may involve in PARs-PLCβ signaling pathways. Molecular docking study shows that Danshesu has similar polar interactions with PAR1 receptors as BMS200261 at the same position. The findings from our study enable a better understanding of Danshensu biological properties, which could ultimately lead to the development of multi-target antiplatelet natural medicine for the treatment and/or prevention of some thrombotic diseases.

76 FR 59533 - Mandatory Reporting of Greenhouse Gases: Petroleum and Natural Gas Systems: Revisions to Best...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-09-27

... final rule, but which might not necessarily be ``extreme'' in practice. The Miriam Webster dictionary...'', ``ultimate'', ``outermost.'' According to the Miriam Webster dictionary, the term ``unique'' can refer to...

Crystallization Pathways in Biomineralization

NASA Astrophysics Data System (ADS)

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.

Investigation of Voltage-Activated BAW Devices and Filters

DTIC Science & Technology

2016-09-04

strontium titanate (STO) and barium-strontium titanate (BST), with the ultimate objective of creating high- performance, reconfigurable filters and...Distribution Unlimited UU UU UU UU 04-09-2016 1-Sep-2010 31-Aug-2014 Final Report: Investigation of Voltage-Activated BAW Devices and Filters The views...2016 Investigation of Voltage-Activated BAW Devices and Filters Final Report Award Information: Contract Number: W911NF1010286 Period of Work

Cytosolic thioredoxin reductase 1 is required for correct disulfide formation in the ER.

PubMed

Poet, Greg J; Oka, Ojore Bv; van Lith, Marcel; Cao, Zhenbo; Robinson, Philip J; Pringle, Marie Anne; Arnér, Elias Sj; Bulleid, Neil J

2017-03-01

Folding of proteins entering the secretory pathway in mammalian cells frequently requires the insertion of disulfide bonds. Disulfide insertion can result in covalent linkages found in the native structure as well as those that are not, so-called non-native disulfides. The pathways for disulfide formation are well characterized, but our understanding of how non-native disulfides are reduced so that the correct or native disulfides can form is poor. Here, we use a novel assay to demonstrate that the reduction in non-native disulfides requires NADPH as the ultimate electron donor, and a robust cytosolic thioredoxin system, driven by thioredoxin reductase 1 (TrxR1 or TXNRD1). Inhibition of this reductive pathway prevents the correct folding and secretion of proteins that are known to form non-native disulfides during their folding. Hence, we have shown for the first time that mammalian cells have a pathway for transferring reducing equivalents from the cytosol to the ER, which is required to ensure correct disulfide formation in proteins entering the secretory pathway. © 2017 The Authors. Published under the terms of the CC BY 4.0 license.

Activation of the Protein Kinase C1 Pathway upon Continuous Heat Stress in Saccharomyces cerevisiae Is Triggered by an Intracellular Increase in Osmolarity due to Trehalose Accumulation

PubMed Central

Mensonides, Femke I. C.; Brul, Stanley; Klis, Frans M.; Hellingwerf, Klaas J.; Teixeira de Mattos, M. Joost

2005-01-01

This paper reports on physiological and molecular responses of Saccharomyces cerevisiae to heat stress conditions. We observed that within a very narrow range of culture temperatures, a shift from exponential growth to growth arrest and ultimately to cell death occurred. A detailed analysis was carried out of the accumulation of trehalose and the activation of the protein kinase C1 (PKC1) (cell integrity) pathway in both glucose- and ethanol-grown cells upon temperature upshifts within this narrow range of growth temperatures. It was observed that the PKC1 pathway was hardly activated in a tps1 mutant that is unable to accumulate any trehalose. Furthermore, it was observed that an increase of the extracellular osmolarity during a continuous heat stress prevented the activation of the pathway. The results of these analyses support our hypothesis that under heat stress conditions the activation of the PKC1 pathway is triggered by an increase in intracellular osmolarity, due to the accumulation of trehalose, rather than by the increase in temperature as such. PMID:16085846

Protection of reinforced concrete bridge substructures using submerged bulk anodes : final report, January 25, 2009.

DOT National Transportation Integrated Search

2010-01-01

Reinforced concrete bridge substructures in Florida coastal waters have historically experienced deterioration as a consequence of embedded steel corrosion and resultant concrete cracking and spalling. Ultimately, this deterioration leads to added ma...

Theorizing a model information pathway to mitigate the menstrual taboo.

PubMed

Yagnik, Arpan

2017-12-13

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

Control of Organ Growth by Patterning and Hippo Signaling in Drosophila

PubMed Central

Irvine, Kenneth D.; Harvey, Kieran F.

2015-01-01

Control of organ size is of fundamental importance and is controlled by genetic, environmental, and mechanical factors. Studies in many species have pointed to the existence of both organ-extrinsic and -intrinsic size-control mechanisms, which ultimately must coordinate to regulate organ size. Here, we discuss organ size control by organ patterning and the Hippo pathway, which both act in an organ-intrinsic fashion. The influence of morphogens and other patterning molecules couples growth and patterning, whereas emerging evidence suggests that the Hippo pathway controls growth in response to mechanical stimuli and signals emanating from cell–cell interactions. Several points of cross talk have been reported between signaling pathways that control organ patterning and the Hippo pathway, both at the level of membrane receptors and transcriptional regulators. However, despite substantial progress in the past decade, key questions in the growth-control field remain, including precisely how and when organ patterning and the Hippo pathway communicate to control size, and whether these communication mechanisms are organ specific or general. In addition, elucidating mechanisms by which organ-intrinsic cues, such as patterning factors and the Hippo pathway, interface with extrinsic cues, such as hormones to control organ size, remain unresolved. PMID:26032720

Overlapping gene expression profiles indicative of antigen processing and the interferon pathway characterize inflammatory fibrotic skin diseases.

PubMed

Limpers, Annelies; van Royen-Kerkhof, Annet; van Roon, Joel A G; Radstake, Timothy R D J; Broen, Jasper C A

2014-02-01

Inflammatory fibrotic disorders have been of high interest both for dermatologists and rheumatologists. Although the phenotypic end stage of this group of diseases is ultimately the same, namely fibrosis, patients present with different clinical features and are often treated with distinct therapeutic modalities. This review addresses whether there is evidence for different underlying molecular pathways in the various inflammatory fibrotic diseases such as localized scleroderma, pediatric lichen sclerosus, adult lichen sclerosus, eosinophilic fasciitis and systemic sclerosis. To investigate this, a large number of gene expression microarray studies performed on skin or fibroblasts from patients with these aforementioned diseases were described, (re-)analysed, and compared. As suspected by the heterogeneous phenotype, most diseases showed unique gene expression features. Intriguingly, a clear overlap was observed between adult and pediatric lichen sclerosus and localized scleroderma, in antigen processing and the interferon pathway. Delineating the cause and consequence of these pathways may generate novel tools to better characterize and more effectively treat these patients.

Ultimate fate of constrained voters

NASA Astrophysics Data System (ADS)

Vazquez, F.; Redner, S.

2004-09-01

We examine the ultimate fate of individual opinions in a socially interacting population of leftists, centrists and rightists. In an elemental interaction between agents, a centrist and a leftist can both become centrists or both become leftists with equal rates (and similarly for a centrist and a rightist). However leftists and rightists do not interact. This interaction step between pairs of agents is applied repeatedly until the system can no longer evolve. In the mean-field limit, we determine the exact probability that the system reaches consensus (either leftist, rightist or centrist) or a frozen mixture of leftists and rightists as a function of the initial composition of the population. We also determine the mean time until the final state is reached. Some implications of our results for the ultimate fate in a limit of the Axelrod model are discussed.

Mechanical performance and parameter sensitivity analysis of 3D braided composites joints.

PubMed

Wu, Yue; Nan, Bo; Chen, Liang

2014-01-01

3D braided composite joints are the important components in CFRP truss, which have significant influence on the reliability and lightweight of structures. To investigate the mechanical performance of 3D braided composite joints, a numerical method based on the microscopic mechanics is put forward, the modeling technologies, including the material constants selection, element type, grid size, and the boundary conditions, are discussed in detail. Secondly, a method for determination of ultimate bearing capacity is established, which can consider the strength failure. Finally, the effect of load parameters, geometric parameters, and process parameters on the ultimate bearing capacity of joints is analyzed by the global sensitivity analysis method. The results show that the main pipe diameter thickness ratio γ, the main pipe diameter D, and the braided angle α are sensitive to the ultimate bearing capacity N.

Effectiveness of Telerehabilitation for OIF/OEF returnees with Combat Related Trauma

DTIC Science & Technology

2018-04-01

validated health outcome instruments that capture physical function, cognition, mental health status and integration into society. We have enrolled a total...community integration over time. 2) The presence of comorbid Post Traumatic Stress Disorders was a significant predictor in reported patient health 3...Individualized treatment pathways may be needed for rehabilitation and ultimate integration into society and 4) Veterans have expressed appreciation for

The School-Community Integrated Learning Pathway: Exploring a New Way to Prepare and Induct Final-Year Preservice Teachers

ERIC Educational Resources Information Center

Hudson, Suzanne; Hudson, Peter; Adie, Lenore

2015-01-01

Universities and teacher employment bodies seek new, cost-effective ways for graduating classroom-ready teachers. This study involved 32 final-year preservice teachers in an innovative school--university partnership teacher education programme titled, the School-Community Integrated Learning (SCIL) pathway. Data were collected using a five-part…

A Model Study to Unravel the Complexity of Bio-Oil from Organic Wastes.

PubMed

Croce, Annamaria; Battistel, Ezio; Chiaberge, Stefano; Spera, Silvia; De Angelis, Francesco; Reale, Samantha

2017-01-10

Binary and ternary mixtures of cellulose, bovine serum albumin (BSA) and tripalmitin, as biomass reference compounds for carbohydrates, proteins and triglycerides, respectively, were treated under hydrothermal liquefaction (HTL) conditions to describe the main reaction pathways involved in the process of bio-oil production from municipal organic wastes. Several analytical techniques (elemental analysis, GC-MS, atmospheric-pressure photo-ionisation high-resolution Fourier transform ion cyclotron resonance mass spectrometry, and 13 C cross-polarisation magic-angle spinning NMR spectroscopy) were used for the molecular-level characterisation of the resulting aqueous phase, solid residue and bio-oil, in particular. The main reaction pathways led to free fatty acids, fatty acid amides, 2,5-diketopiperazines and Maillard-type compounds as the main components of the bio-oil. The relationship of such compounds to the original components of the biomass was thus determined, which highlights the fate of the heteroatom-containing molecules in particular. Finally, the molecular composition of the bio-oils from our reference compounds was matched with that of the bio-oil from municipal organic waste biomass by comparing their high-resolution Fourier transform ion cyclotron resonance mass spectra, and we obtained a surprisingly high similarity. Hence, the ternary mixture acts as a reliable biomass model and is a powerful tool to clarify the degradation mechanisms that occur in the biomass under HTL treatment, with the ultimate goal to improve the HTL process itself by modulating the input of the organic starting matter and then the upgrading steps to bio-fuels. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

ZEAXANTHIN EPOXIDASE Activity Potentiates Carotenoid Degradation in Maturing Seed1[OPEN

PubMed Central

Magallanes-Lundback, Maria; Lipka, Alexander E.; Angelovici, Ruthie; DellaPenna, Dean

2016-01-01

Elucidation of the carotenoid biosynthetic pathway has enabled altering the composition and content of carotenoids in various plants, but to achieve desired nutritional impacts, the genetic components regulating carotenoid homeostasis in seed, the plant organ consumed in greatest abundance, must be elucidated. We used a combination of linkage mapping, genome-wide association studies (GWAS), and pathway-level analysis to identify nine loci that impact the natural variation of seed carotenoids in Arabidopsis (Arabidopsis thaliana). ZEAXANTHIN EPOXIDASE (ZEP) was the major contributor to carotenoid composition, with mutants lacking ZEP activity showing a remarkable 6-fold increase in total seed carotenoids relative to the wild type. Natural variation in ZEP gene expression during seed development was identified as the underlying mechanism for fine-tuning carotenoid composition, stability, and ultimately content in Arabidopsis seed. We previously showed that two CAROTENOID CLEAVAGE DIOXYGENASE enzymes, CCD1 and CCD4, are the primary mediators of seed carotenoid degradation, and here we demonstrate that ZEP acts as an upstream control point of carotenoid homeostasis, with ZEP-mediated epoxidation targeting carotenoids for degradation by CCD enzymes. Finally, four of the nine loci/enzymatic activities identified as underlying natural variation in Arabidopsis seed carotenoids also were identified in a recent GWAS of maize (Zea mays) kernel carotenoid variation. This first comparison of the natural variation in seed carotenoids in monocots and dicots suggests a surprising overlap in the genetic architecture of these traits between the two lineages and provides a list of likely candidates to target for selecting seed carotenoid variation in other species. PMID:27208224

FANCD2 re-expression is associated with glioma grade and chemical inhibition of the Fanconi Anaemia pathway sensitises gliomas to chemotherapeutic agents.

PubMed

Patil, Abhijit A; Sayal, Parag; Depondt, Marie-Lise; Beveridge, Ryan D; Roylance, Anthony; Kriplani, Deepti H; Myers, Katie N; Cox, Angela; Jellinek, David; Fernando, Malee; Carroll, Thomas A; Collis, Spencer J

2014-08-15

Brain tumours kill more children and adults under 40 than any other cancer. Around half of primary brain tumours are glioblastoma multiforme (GBMs) where treatment remains a significant challenge, where survival rates have improved little over the last 40 years, thus highlighting an unmet need for the identification/development of novel therapeutic targets and agents to improve GBM treatment. Using archived and fresh glioma tissue, we show that in contrast to normal brain or benign schwannomas GBMs exhibit re-expression of FANCD2, a key protein of the Fanconi Anaemia (FA) DNA repair pathway, and possess an active FA pathway. Importantly, FANCD2 expression levels are strongly associated with tumour grade, revealing a potential exploitable therapeutic window to allow inhibition of the FA pathway in tumour cells, whilst sparing normal brain tissue. Using several small molecule inhibitors of the FA pathway in combination with isogenic FA-proficient/deficient glioma cell lines as well as primary GBM cultures, we demonstrate that inhibition of the FA pathway sensitises gliomas to the chemotherapeutic agents Temozolomide and Carmustine. Our findings therefore provide a strong rationale for the development of novel and potent inhibitors of the FA pathway to improve the treatment of GBMs, which may ultimately impact on patient outcome.

FANCD2 re-expression is associated with glioma grade and chemical inhibition of the Fanconi Anaemia pathway sensitises gliomas to chemotherapeutic agents

PubMed Central

Patil, Abhijit A.; Sayal, Parag; Depondt, Marie-Lise; Beveridge, Ryan D.; Roylance, Anthony; Kriplani, Deepti H.; Myers, Katie N.; Cox, Angela; Jellinek, David; Fernando, Malee; Carroll, Thomas A.; Collis, Spencer J.

2014-01-01

Brain tumours kill more children and adults under 40 than any other cancer. Around half of primary brain tumours are glioblastoma multiforme (GBMs) where treatment remains a significant challenge. GBM survival rates have improved little over the last 40 years, thus highlighting an unmet need for the identification/development of novel therapeutic targets and agents to improve GBM treatment. Using archived and fresh glioma tissue, we show that in contrast to normal brain or benign schwannomas GBMs exhibit re-expression of FANCD2, a key protein of the Fanconi Anaemia (FA) DNA repair pathway, and possess an active FA pathway. Importantly, FANCD2 expression levels are strongly associated with tumour grade, revealing a potential exploitable therapeutic window to allow inhibition of the FA pathway in tumour cells, whilst sparing normal brain tissue. Using several small molecule inhibitors of the FA pathway in combination with isogenic FA-proficient/deficient glioma cell lines as well as primary GBM cultures, we demonstrate that inhibition of the FA pathway sensitises gliomas to the chemotherapeutic agents Temozolomide and Carmustine. Our findings therefore provide a strong rationale for the development of novel and potent inhibitors of the FA pathway to improve the treatment of GBMs, which may ultimately impact on patient outcome. PMID:25071006

Bardoxolone brings Nrf2-based therapies to light.

PubMed

Zhang, Donna D

2013-08-10

The targeted activation of nuclear factor erythroid-derived-2-like 2 (Nrf2) to alleviate symptoms of chronic kidney disease has recently garnered much attention. Unfortunately, the greatest clinical success to date, bardoxolone, failed in phase III clinical trial for unspecified safety reasons. The present letter to the editor discusses the clinical development of bardoxolone and explores potential reasons for the ultimate withdrawal from clinical trials. In particular, was the correct clinical indication pursued and would improved specificity have mitigated the safety concerns? Ultimately, it is concluded that the right clinical indication and heightened specificity will lead to successful Nrf2-based therapies. Therefore, the bardoxolone clinical results do not dampen enthusiasm for Nrf2-based therapies; rather it illuminates the clinical potential of the Nrf2 pathway as a drug target.

Engineering Ultimate Self-Protection in Autonomic Agents for Space Exploration Missions

NASA Technical Reports Server (NTRS)

Sterritt, Roy; Hinchey, Mike

2005-01-01

NASA's Exploration Initiative (EI) will push space exploration missions to the limit. Future missions will be required to be self-managing as well as self-directed, in order to meet the challenges of human and robotic space exploration. We discuss security and self protection in autonomic agent based-systems, and propose the ultimate self-protection mechanism for such systems-self-destruction. Like other metaphors in Autonomic Computing, this is inspired by biological systems, and is the analog of biological apoptosis. Finally, we discus the role it might play in future NASA space exploration missions.

Cysteine-Conjugated Metabolites of Ginger Components, Shogaols, Induce Apoptosis through Oxidative Stress-Mediated p53 Pathway in Human Colon Cancer Cells

PubMed Central

2015-01-01

Shogaols, the major constituents of thermally processed ginger, have been proven to be highly effective anticancer agents. Our group has identified cysteine-conjugated shogaols (M2, M2′, and M2″) as the major metabolites of [6]-, [8]-, and [10]-shogaol in human and found that M2 is a carrier of its parent molecule [6]-shogaol in cancer cells and in mice, while being less toxic to normal colon fibroblast cells. The objectives of this study are to determine whether M2′ and M2″ behave in a similar manner to M2, in both metabolism and efficacy as anticancer agents, and to further explore the biological pro-apoptotic mechanisms of the cysteine-conjugated shogaols against human colon cancer cells HCT-116 and HT-29. Our results show that [8]- and [10]-shogaol have similar metabolic profiles to [6]-shogaol and exhibit similar toxicity toward human colon cancer cells. M2′ and M2″ both show low toxicity against normal colon cells but retain potency against colon cancer cells, suggesting that they have similar activity to M2. We further demonstrate that the cysteine-conjugated shogaols can cause cancer cell death through the activation of the mitochondrial apoptotic pathway. Our results show that oxidative stress activates a p53 pathway that ultimately leads to p53 up-regulated modulator of apoptosis (PUMA) induction and down-regulation of B-cell lymphoma 2 (Bcl-2), followed by cytochrome c release, perturbation of inhibitory interactions of X-linked inhibitor of apoptosis protein (XIAP) with caspases, and finally caspase 9 and 3 activation and cleavage. A brief screen of the markers attenuated by the proapoptotic activity of M2 revealed similar results for [8]- and [10]-shogaol and their respective cysteine-conjugated metabolites M2′ and M2″. This study highlights the cysteine-conjugated metabolites of shogaols as novel dietary colon cancer preventive agents. PMID:24786146

Mechanisms of Bond Cleavage during Manganese Oxide and UV Degradation of Glyphosate: Results from Phosphate Oxygen Isotopes and Molecular Simulations.

PubMed

Jaisi, Deb P; Li, Hui; Wallace, Adam F; Paudel, Prajwal; Sun, Mingjing; Balakrishna, Avula; Lerch, Robert N

2016-11-16

Degradation of glyphosate in the presence of manganese oxide and UV light was analyzed using phosphate oxygen isotope ratios and density function theory (DFT). The preference of C-P or C-N bond cleavage was found to vary with changing glyphosate/manganese oxide ratios, indicating the potential role of sorption-induced conformational changes on the composition of intermediate degradation products. Isotope data confirmed that one oxygen atom derived solely from water was incorporated into the released phosphate during glyphosate degradation, and this might suggest similar nucleophilic substitution at P centers and C-P bond cleavage both in manganese oxide- and UV light-mediated degradation. The DFT results reveal that the C-P bond could be cleaved by water, OH - or • OH, with the energy barrier opposing bond dissociation being lowest in the presence of the radical species, and that C-N bond cleavage is favored by the formation of both nitrogen- and carbon-centered radicals. Overall, these results highlight the factors controlling the dominance of C-P or C-N bond cleavage that determines the composition of intermediate/final products and ultimately the degradation pathway.

Synthetic Biology: Putting Synthesis into Biology

PubMed Central

Liang, Jing; Luo, Yunzi; Zhao, Huimin

2010-01-01

The ability to manipulate living organisms is at the heart of a range of emerging technologies that serve to address important and current problems in environment, energy, and health. However, with all its complexity and interconnectivity, biology has for many years been recalcitrant to engineering manipulations. The recent advances in synthesis, analysis, and modeling methods have finally provided the tools necessary to manipulate living systems in meaningful ways, and have led to the coining of a field named synthetic biology. The scope of synthetic biology is as complicated as life itself – encompassing many branches of science, and across many scales of application. New DNA synthesis and assembly techniques have made routine the customization of very large DNA molecules. This in turn has allowed the incorporation of multiple genes and pathways. By coupling these with techniques that allow for the modeling and design of protein functions, scientists have now gained the tools to create completely novel biological machineries. Even the ultimate biological machinery – a self-replicating organism – is being pursued at this moment. It is the purpose of this review to dissect and organize these various components of synthetic biology into a coherent picture. PMID:21064036

Muscle Atrophy Induced by Mechanical Unloading: Mechanisms and Potential Countermeasures

PubMed Central

Gao, Yunfang; Arfat, Yasir; Wang, Huiping; Goswami, Nandu

2018-01-01

Prolonged periods of skeletal muscle inactivity or mechanical unloading (bed rest, hindlimb unloading, immobilization, spaceflight and reduced step) can result in a significant loss of musculoskeletal mass, size and strength which ultimately lead to muscle atrophy. With advancement in understanding of the molecular and cellular mechanisms involved in disuse skeletal muscle atrophy, several different signaling pathways have been studied to understand their regulatory role in this process. However, substantial gaps exist in our understanding of the regulatory mechanisms involved, as well as their functional significance. This review aims to update the current state of knowledge and the underlying cellular mechanisms related to skeletal muscle loss during a variety of unloading conditions, both in humans and animals. Recent advancements in understanding of cellular and molecular mechanisms, including IGF1-Akt-mTOR, MuRF1/MAFbx, FOXO, and potential triggers of disuse atrophy, such as calcium overload and ROS overproduction, as well as their role in skeletal muscle protein adaptation to disuse is emphasized. We have also elaborated potential therapeutic countermeasures that have shown promising results in preventing and restoring disuse-induced muscle loss. Finally, identified are the key challenges in this field as well as some future prospectives. PMID:29615929

Research on the degradation mechanism of dimethyl phthalate in drinking water by strong ionization discharge

NASA Astrophysics Data System (ADS)

Hong, ZHAO; Chengwu, YI; Rongjie, YI; Huijuan, WANG; Lanlan, YIN; I, N. MUHAMMAD; Zhongfei, MA

2018-03-01

The degradation mechanism of dimethyl phthalate (DMP) in the drinking water was investigated using strong ionization discharge technology in this study. Under the optimized condition, the degradation efficiency of DMP in drinking water was up to 93% in 60 min. A series of analytical techniques including high-performance liquid chromatography, liquid chromatography mass spectrometry, total organic carbon analyzer and ultraviolet-visible spectroscopy were used in the study. It was found that a high concentration of ozone (O3) produced by dielectric barrier discharge reactor was up to 74.4 mg l-1 within 60 min. Tert-butanol, isopropyl alcohol, carbonate ions ({{{{CO}}}3}2-) and bicarbonate ions ({{{{HCO}}}3}-) was added to the sample solution to indirectly prove the presence and effect of hydroxyl radicals (·OH). These analytical findings indicate that mono-methyl phthalate, phthalic acid (PA) and methyl ester PA were detected as the major intermediates in the process of DMP degradation. Finally, DMP and all products were mineralized into carbon dioxide (CO2) and water (H2O) ultimately. Based on these analysis results, the degradation pathway of DMP by strong ionization discharge technology were proposed.

Single-Molecule Imaging of Cellular Signaling

NASA Astrophysics Data System (ADS)

De Keijzer, Sandra; Snaar-Jagalska, B. Ewa; Spaink, Herman P.; Schmidt, Thomas

Single-molecule microscopy is an emerging technique to understand the function of a protein in the context of its natural environment. In our laboratory this technique has been used to study the dynamics of signal transduction in vivo. A multitude of signal transduction cascades are initiated by interactions between proteins in the plasma membrane. These cascades start by binding a ligand to its receptor, thereby activating downstream signaling pathways which finally result in complex cellular responses. To fully understand these processes it is important to study the initial steps of the signaling cascades. Standard biological assays mostly call for overexpression of the proteins and high concentrations of ligand. This sets severe limits to the interpretation of, for instance, the time-course of the observations, given the large temporal spread caused by the diffusion-limited binding processes. Methods and limitations of single-molecule microscopy for the study of cell signaling are discussed on the example of the chemotactic signaling of the slime-mold Dictyostelium discoideum. Single-molecule studies, as reviewed in this chapter, appear to be one of the essential methodologies for the full spatiotemporal clarification of cellular signaling, one of the ultimate goals in cell biology.

Aging and the genetic road towards the positivity effect in memory.

PubMed

Mammarella, Nicola; Di Domenico, Alberto; Fairfield, Beth

2016-09-01

Better memory for positive information compared to negative and neutral information has been repeatedly associated with successful aging. The main psychological explanations for this so-called "positivity effect" in memory principally rely on emotional, motivational, and cognitive mechanisms that make older adults' cognition highly sensitive to positive information according to ultimate goals of well-being. However, emerging evidence also delineates a genetic profile for positivity effects in memory, which may render some older adults more prone than others to encoding and remembering positive memories. First, we present a brief overview of behavioral and neuroimaging studies about the positivity effect in aging. Subsequently, we report studies on candidate genes associated with positive memories. In particular, we review work to date on several candidate genes that are sensitive to stimulus valence such as ADRA2B, COMT, and 5HTTLPR. Finally, we propose that the future approach to the study of genetic correlates of positivity effects in memory should also include mitochondrial functioning (TOMM40). Altogether, the study of genetics and cell biology of positivity effects in memory can help us to reveal the underlying bottom-up pathways to positive affect in healthy aging. Copyright © 2016 Elsevier Inc. All rights reserved.

Academic Provenance: Mapping Geoscience Students' Academic Pathways to their Career Trajectories

NASA Astrophysics Data System (ADS)

Houlton, H. R.; Gonzales, L. M.; Keane, C. M.

2011-12-01

Targeted recruitment and retention efforts for the geosciences have become increasingly important with the growing concerns about program visibility on campuses, and given that geoscience degree production remains low relative to the demand for new geoscience graduates. Furthermore, understanding the career trajectories of geoscience degree recipients is essential for proper occupational placement. A theoretical framework was developed by Houlton (2010) to focus recruitment and retention efforts. This "pathway model" explicitly maps undergraduate students' geoscience career trajectories, which can be used to refine existing methods for recruiting students into particular occupations. Houlton's (2010) framework identified three main student population groups: Natives, Immigrants or Refugees. Each student followed a unique pathway, which consisted of six pathway steps. Each pathway step was comprised of critical incidents that influenced students' overall career trajectories. An aggregate analysis of students' pathways (Academic Provenance Analysis) showed that different populations' pathways exhibited a deviation in career direction: Natives indicated intentions to pursue industry or government sectors, while Immigrants intended to pursue academic or research-based careers. We expanded on Houlton's (2010) research by conducting a follow-up study to determine if the original participants followed the career trajectories they initially indicated in the 2010 study. A voluntary, 5-question, short-answer survey was administered via email. We investigated students' current pathway steps, pathway deviations, students' goals for the near future and their ultimate career ambitions. This information may help refine Houlton's (2010) "pathway model" and may aid geoscience employers in recruiting the new generation of professionals for their respective sectors.

Cellular Response to Ionizing Radiation: A MicroRNA Story

PubMed Central

Halimi, Mohammad; Asghari, S. Mohsen; Sariri, Reyhaneh; Moslemi, Dariush; Parsian, Hadi

2012-01-01

MicroRNAs (miRNAs) represent a class of small non-coding RNA molecules that regulate gene expression at the post-transcriptional level. They play a crucial role in diverse cellular pathways. Ionizing radiation (IR) is one of the most important treatment protocols for patients that suffer from cancer and affects directly or indirectly cellular integration. Recently it has been discovered that microRNA-mediated gene regulation interferes with radio-related pathways in ionizing radiation. Here, we review the recent discoveries about miRNAs in cellular response to IR. Thoroughly understanding the mechanism of miRNAs in radiation response, it will be possible to design new strategies for improving radiotherapy efficiency and ultimately cancer treatment. PMID:24551775

A genetic platform to model sarcomagenesis from primary adult mesenchymal stem cells

PubMed Central

Guarnerio, Jlenia; Riccardi, Luisa; Taulli, Riccardo; Maeda, Takahiro; Wang, Guocan; Hobbs, Robin M.; Song, Min Sup; Sportoletti, Paolo; Bernardi, Rosa; Bronson, Roderick T.; Castillo-Martin, Mireia; Cordon-Cardo, Carlos; Lunardi, Andrea; Pandolfi, Pier Paolo

2015-01-01

The regulatory factors governing adult mesenchymal stem cells (MSCs) physiology and their tumorigenic potential are still largely unknown, which substantially delays the identification of effective therapeutic approaches for the treatment of aggressive and lethal form of MSC-derived mesenchymal tumors, such as undifferentiated sarcomas. Here we have developed a novel platform to screen and quickly identify genes and pathways responsible for adult MSCs transformation, modeled undifferentiated sarcoma in vivo, and, ultimately, tested the efficacy of targeting the identified oncopathways. Importantly, by taking advantage of this new platform, we demonstrate the key role of an aberrant LRF-DLK1-SOX9 pathway in the pathogenesis of undifferentiated sarcoma with important therapeutic implications. PMID:25614485

Reaction pathways in atomistic models of thin film growth

NASA Astrophysics Data System (ADS)

Lloyd, Adam L.; Zhou, Ying; Yu, Miao; Scott, Chris; Smith, Roger; Kenny, Steven D.

2017-10-01

The atomistic processes that form the basis of thin film growth often involve complex multi-atom movements of atoms or groups of atoms on or close to the surface of a substrate. These transitions and their pathways are often difficult to predict in advance. By using an adaptive kinetic Monte Carlo (AKMC) approach, many complex mechanisms can be identified so that the growth processes can be understood and ultimately controlled. Here the AKMC technique is briefly described along with some special adaptions that can speed up the simulations when, for example, the transition barriers are small. Examples are given of such complex processes that occur in different material systems especially for the growth of metals and metallic oxides.

Depletion of juvenile hormone esterase extends larval growth in Bombyx mori.

PubMed

Zhang, Zhongjie; Liu, Xiaojing; Shiotsuki, Takahiro; Wang, Zhisheng; Xu, Xia; Huang, Yongping; Li, Muwang; Li, Kai; Tan, Anjiang

2017-02-01

Two major hormones, juvenile hormone (JH) and 20-hydroxyecdysone (20E), regulate insect growth and development according to their precisely coordinated titres, which are controlled by both biosynthesis and degradation pathways. Juvenile hormone esterase (JHE) is the primary JH-specific degradation enzyme that plays a key role in regulating JH titers, along with JH epoxide hydrolase (JHEH) and JH diol kinase (JHDK). In the current study, a loss-of-function analysis of JHE in the silkworm, Bombyx mori, was performed by targeted gene disruption using the transgenic CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/RNA-guided Cas9 nucleases) system. Depletion of B. mori JHE (BmJHE) resulted in the extension of larval stages, especially the penultimate and ultimate larval stages, without deleterious effects to silkworm physiology. The expression of JHEH and JHDK was upregulated in mutant animals, indicating the existence of complementary routes in the JH metabolism pathway in which inactivation of one enzyme will activate other enzymes. RNA-Seq analysis of mutant animals revealed that genes involved in protein processing in the endoplasmic reticulum and in amino acid metabolism were affected by BmJHE depletion. Depletion of JHE and subsequent delayed JH metabolism activated genes in the TOR pathway, which are ultimately responsible for extending larval growth. The transgenic Cas9 system used in the current study provides a promising approach for analysing the actions of JH, especially in nondrosophilid insects. Furthermore, prolonging larval stages produced larger larvae and cocoons, which is greatly beneficial to silk production. Copyright © 2017 Elsevier Ltd. All rights reserved.

Personalized diagnostics and biosensors: a review of the biology and technology needed for personalized medicine.

PubMed

Ahmed, Minhaz Uddin; Saaem, Ishtiaq; Wu, Pae C; Brown, April S

2014-06-01

Exploiting the burgeoning fields of genomics, proteomics and metabolomics improves understanding of human physiology and, critically, the mutations that signal disease susceptibility. Through these emerging fields, rational design approaches to diagnosis, drug development and ultimately personalized medicine are possible. Personalized medicine and point-of-care testing techniques must fulfill a host of constraints for real-world applicability. Point-of-care devices (POCDs) must ultimately provide a cost-effective alternative to expensive and time-consuming laboratory tests in order to assist health care personnel with disease diagnosis and treatment decisions. Sensor technologies are also expanding beyond the more traditional classes of biomarkers--nucleic acids and proteins--to metabolites and direct detection of pathogens, ultimately increasing the palette of available techniques for the use of personalized medicine. The technologies needed to perform such diagnostics have also been rapidly evolving, with each generation being increasingly sensitive and selective while being more resource conscious. Ultimately, the final hurdle for all such technologies is to be able to drive consumer adoption and achieve a meaningful medical outcome for the patient.

Clinical Pathways and the Patient Perspective in the Pursuit of Value-Based Oncology Care.

PubMed

Ersek, Jennifer L; Nadler, Eric; Freeman-Daily, Janet; Mazharuddin, Samir; Kim, Edward S

2017-01-01

The art of practicing oncology has evolved substantially in the past 5 years. As more and more diagnostic tests, biomarker-directed therapies, and immunotherapies make their way to the oncology marketplace, oncologists will find it increasingly difficult to keep up with the many therapeutic options. Additionally, the cost of cancer care seems to be increasing. Clinical pathways are a systematic way to organize and display detailed, evidence-based treatment options and assist the practitioner with best practice. When selecting which treatment regimens to include on a clinical pathway, considerations must include the efficacy and safety, as well as costs, of the therapy. Pathway treatment regimens must be continually assessed and modified to ensure that the most up-to-date, high-quality options are incorporated. Value-based models, such as the ASCO Value Framework, can assist providers in presenting economic evaluations of clinical pathway treatment options to patients, thus allowing the patient to decide the overall value of each treatment regimen. Although oncologists and pathway developers can decide which treatment regimens to include on a clinical pathway based on the efficacy of the treatment, assessment of the value of that treatment regimen ultimately lies with the patient. Patient definitions of value will be an important component to enhancing current value-based oncology care models and incorporating new, high-quality, value-based therapeutics into oncology clinical pathways.

AIP Career Pathways

NASA Astrophysics Data System (ADS)

Palchak, Amanda

2012-02-01

American Institute of Physics (AIP) Career Pathways is a new project funded by the National Science Foundation. One of the goals of AIP Career Pathways is to prepare students to compete for Science, Technology, Engineering, and Mathematics (STEM) careers with a bachelor's degree in physics. In order to do so, I reviewed and compiled useful resources on finding a STEM career with a bachelor's degree in physics. These resources not only supply the job seeker with job postings in STEM careers but also provide them with information on resumes, interviewing skills, and networking. Recently at the 2011 Industrial Physics Forum, I interviewed companies in the private sector to obtain a unique perspective on what types of skills potential employers expect an applicant to posses with a bachelor's degree in physics. Ultimately, these components will be used as supplements at student career workshops held at annual Society of Physics Students Zone Meetings.

Locate the Lesion: A Project-Based Learning Case that Stimulates Comprehension and Application of Neuroanatomy

PubMed Central

Lemons, Michele L.

2017-01-01

A fictitious patient, Mr. Challenge, is admitted to the emergency room and displays symptoms consistent with damage to the central nervous system. In this problem-based learning case, students are challenged to determine the location of a lesion that is consistent with Mr. Challenge’s symptoms. Students discover details about Mr. Challenge’s symptoms while exploring three anatomical pathways: corticospinal tract, spinothalamic tract and medial lemniscal pathway. Students make predictions as to which of these pathways may be damaged in Mr. Challenge and defend their predictions based on their research of the function and anatomical location of these tracts. This ultimately leads the student to identifying a single lesion site that can account for Mr. Challenge’s symptoms. This case is executed in an undergraduate neuroscience course and would be useful in anatomy and physiology course, as well as other courses that serve students interested in health science related careers. PMID:28690440

Stability limits and transformation pathways of α-quartz under high pressure

NASA Astrophysics Data System (ADS)

Hu, Q. Y.; Shu, J.-F.; Yang, W. G.; Park, C.; Chen, M. W.; Fujita, T.; Mao, H.-K.; Sheng, H. W.

2017-03-01

Ubiquitous on Earth, α-quartz plays an important role in modern science and technology. However, despite extensive research in the past, the mechanism of the polymorphic transitions of α-quartz at high pressures remains poorly understood. Here, combining in situ single-crystal x-ray diffraction experiment and advanced ab initio modeling, we report two stability limits and competing transition pathways of α-quartz under high pressure. Under near-equilibrium compression conditions at room temperature, α-quartz transits to a new P 2 /c silica phase via a structural intermediate. If the thermally activated transition is kinetically suppressed, the ultimate stability of α-quartz is controlled by its phonon instability and α-quartz collapses into a different crystalline phase. Our studies reveal that pressure-induced solid-state transformation of α-quartz undergoes a succession of structural stability limits, due to thermodynamic and mechanical catastrophes, and exhibits a hierarchy of transition pathways contingent upon kinetic conditions.

Parkin and PINK1 function in a vesicular trafficking pathway regulating mitochondrial quality control

PubMed Central

McLelland, Gian-Luca; Soubannier, Vincent; Chen, Carol X; McBride, Heidi M; Fon, Edward A

2014-01-01

Mitochondrial dysfunction has long been associated with Parkinson's disease (PD). Parkin and PINK1, two genes associated with familial PD, have been implicated in the degradation of depolarized mitochondria via autophagy (mitophagy). Here, we describe the involvement of parkin and PINK1 in a vesicular pathway regulating mitochondrial quality control. This pathway is distinct from canonical mitophagy and is triggered by the generation of oxidative stress from within mitochondria. Wild-type but not PD-linked mutant parkin supports the biogenesis of a population of mitochondria-derived vesicles (MDVs), which bud off mitochondria and contain a specific repertoire of cargo proteins. These MDVs require PINK1 expression and ultimately target to lysosomes for degradation. We hypothesize that loss of this parkin- and PINK1-dependent trafficking mechanism impairs the ability of mitochondria to selectively degrade oxidized and damaged proteins leading, over time, to the mitochondrial dysfunction noted in PD. PMID:24446486

Locate the Lesion: A Project-Based Learning Case that Stimulates Comprehension and Application of Neuroanatomy.

PubMed

Lemons, Michele L

2017-01-01

A fictitious patient, Mr. Challenge, is admitted to the emergency room and displays symptoms consistent with damage to the central nervous system. In this problem-based learning case, students are challenged to determine the location of a lesion that is consistent with Mr. Challenge's symptoms. Students discover details about Mr. Challenge's symptoms while exploring three anatomical pathways: corticospinal tract, spinothalamic tract and medial lemniscal pathway. Students make predictions as to which of these pathways may be damaged in Mr. Challenge and defend their predictions based on their research of the function and anatomical location of these tracts. This ultimately leads the student to identifying a single lesion site that can account for Mr. Challenge's symptoms. This case is executed in an undergraduate neuroscience course and would be useful in anatomy and physiology course, as well as other courses that serve students interested in health science related careers.

Symbolic Martyrdom: The Ultimate Apology.

ERIC Educational Resources Information Center

Burkholder, Thomas R.

1991-01-01

Examines the claim that "scaffold speeches" (speeches by individuals awaiting execution) form a discrete genre. Argues that they constitute a subgenre within the larger genre of apologia. Illustrates the subgenre through analysis of John Brown's final speech at his trial following the Harper's Ferry raid. (SR)

Use of eQTL Analysis for the Discovery of Target Genes Identified by GWAS

DTIC Science & Technology

2013-04-01

the biologic pathways affected by these inherited factors, and ultimately to identify targets for disease prediction, risk stratification and...quality using an Agilent chip technology. Cases having a RIN number of 7.0 or greater were considered good quality. Once completed, the optimum set of...AD_________________ Award Number: W81XWH-11-1-0261 TITLE: Use of eQTL Analysis for the Discovery of

Literary Festivals, Library Style: Libraries Can Use Literary Festivals to Secure Their Role as the Ultimate Connection among Readers, Authors, and Books

ERIC Educational Resources Information Center

Dempsey, Beth

2005-01-01

Literary festivals offer a unique proposition to libraries: host one, bring the reading public up-close and personal with writers of all kinds, and they will bask in the glory of that connection. Indeed, festivals can be the pathway for libraries to "own" the literary niche in their community. Bob Cannon, executive director of the Broward County…

Synergistic Action of FOXP3 and TSC1 Pathways During Tumor Progression

DTIC Science & Technology

2015-10-01

invasive carcinoma and, ultimately, metastatic disease [1-3]. Mouse models of PIN (mPIN) generated by a single- mutant gene in prostate do not progress...downstream target) is sufficient to significantly reduce the initiation of prostate cancer in the Pten conditional knockout mouse model [19-21...the possibility that these two genetic hits cooperate to promote tumor progression, and mouse models show that this cooperation accelerates

Fractional Analysis of Escherichia coli O157:H7 by Mass Spectrometry-Based Proteomics

DTIC Science & Technology

2012-10-01

column with the Dionex UltiMate 3000 (Thermo Scientific Dionex , Sunnyvale, CA). The resolved peptides were electrosprayed into a linear ion trap MS... chromatography -tandem mass spectrometry, followed by biochemical pathway mapping using the Kyoto Encyclopedia of Genes and Genomes. The fimbriae-specific subset...15. SUBJECT TERMS 3T3 murine fibroblasts Cell toxicity Liquid chromatography Mass spectrometry LC-MS Ricin Ricinus communis

Chemical Suppression of the Reactivated Androgen Signaling Pathway in Androgen-Independent Prostate Cancer

DTIC Science & Technology

2012-07-01

13. SUPPLEMENTARY NOTES 14. ABSTRACT The project studies the role of Hedgehog /Gli signaling in generating the androgen growth-independent...behavior of castration resistant prostate cancer and will test the ability of drugs that target Hedgehog or Gli as a means to suppress this behavior...advanced prostate cancer. The ultimate goal of the project is to define the mechanisms by which Hedgehog signaling molecules support aggressive

Mechanisms of load dependency of myocardial ischemia reperfusion injury

PubMed Central

Mozaffari, Mahmood S; Liu, Jun Yao; Abebe, Worku; Baban, Babak

2013-01-01

Coronary artery disease and associated ischemic heart disease are prevalent disorders worldwide. Further, systemic hypertension is common and markedly increases the risk for heart disease. A common denominator of systemic hypertension of various etiologies is increased myocardial load/mechanical stress. Thus, it is likely that high pressure/mechanical stress attenuates the contribution of cardioprotective but accentuates the contribution of cardiotoxic pathways thereby exacerbating the outcome of an ischemia reperfusion insult to the heart. Critical events which contribute to cardiomyocyte injury in the ischemic-reperfused heart include cellular calcium overload and generation of reactive oxygen/nitrogen species which, in turn, promote the opening of the mitochondrial permeability transition pore, an important event in cell death. Increasing evidence also indicates that the myocardium is capable of mounting a robust inflammatory response which contributes importantly to tissue injury. On the other hand, cardioprotective maneuvers of ischemic preconditioning and postconditioning have led to identification of complex web of signaling pathways (e.g., reperfusion injury salvage kinase) which ultimately converge on the mitochondria to exert cytoprotection. The present review is intended to briefly describe mechanisms of cardiac ischemia reperfusion injury followed by a discussion of our work focused on how pressure/mechanical stress modulates endogenous cardiotoxic and cardioprotective mechanisms to ultimately exacerbate ischemia reperfusion injury. PMID:24224132

Innate Immunity and Biomaterials at the Nexus: Friends or Foes

PubMed Central

Christo, Susan N.; Diener, Kerrilyn R.; Bachhuka, Akash; Vasilev, Krasimir; Hayball, John D.

2015-01-01

Biomaterial implants are an established part of medical practice, encompassing a broad range of devices that widely differ in function and structural composition. However, one common property amongst biomaterials is the induction of the foreign body response: an acute sterile inflammatory reaction which overlaps with tissue vascularisation and remodelling and ultimately fibrotic encapsulation of the biomaterial to prevent further interaction with host tissue. Severity and clinical manifestation of the biomaterial-induced foreign body response are different for each biomaterial, with cases of incompatibility often associated with loss of function. However, unravelling the mechanisms that progress to the formation of the fibrotic capsule highlights the tightly intertwined nature of immunological responses to a seemingly noncanonical “antigen.” In this review, we detail the pathways associated with the foreign body response and describe possible mechanisms of immune involvement that can be targeted. We also discuss methods of modulating the immune response by altering the physiochemical surface properties of the biomaterial prior to implantation. Developments in these areas are reliant on reproducible and effective animal models and may allow a “combined” immunomodulatory approach of adapting surface properties of biomaterials, as well as treating key immune pathways to ultimately reduce the negative consequences of biomaterial implantation. PMID:26247017

Channeling Polyolefin Molecular Structure - Bulk Property Correlation Strategies for Industrial Applicability

NASA Astrophysics Data System (ADS)

Hule, Rohan; Thurman, Derek; Doufas, Antonios

Polyolefins occupy a significant volume of the polymer products portfolio in commodity and high value applications. Quantifying and optimizing structure-property relationships enables growth in new markets. It is well recognized that coupling lab-based, comprehensive methodologies with bulk properties of interest to industrial environments offer the greatest potential of technology advancement, ultimately leading to commercial success. It is imperative to recognize the existing gap of knowledge translation between lab measurements and industrial-scale operability. This study highlights experimental HDPEs synthesized from dual, single-site, co-supported catalysts that exhibit enhanced solid-state properties such as stiffness, impact and ESCR surpassing conventional trends. Commercial resins across distinct sub-families were included as well. Commonality amongst these resins is bimodality and broad MW distribution with well-defined splits and spreads. Investigations on commercially relevant parameters such as melt strength, melt elasticity and shear thinning established excellent performance for experimental bimodals, corroborating potential benefits compared to commercial HDPEs. To summarize, the effort highlights well-recognized pathways such as improvements in mechanical and melt properties that can be attributed to apposite tuning of polymer chain architecture and MW distribution with implications across myriad markets. Ultimately, this may serve as a pathway for producing innovative products that deliver business success and growth.

A Computational Model of Torque Generation: Neural, Contractile, Metabolic and Musculoskeletal Components

PubMed Central

Callahan, Damien M.; Umberger, Brian R.; Kent-Braun, Jane A.

2013-01-01

The pathway of voluntary joint torque production includes motor neuron recruitment and rate-coding, sarcolemmal depolarization and calcium release by the sarcoplasmic reticulum, force generation by motor proteins within skeletal muscle, and force transmission by tendon across the joint. The direct source of energetic support for this process is ATP hydrolysis. It is possible to examine portions of this physiologic pathway using various in vivo and in vitro techniques, but an integrated view of the multiple processes that ultimately impact joint torque remains elusive. To address this gap, we present a comprehensive computational model of the combined neuromuscular and musculoskeletal systems that includes novel components related to intracellular bioenergetics function. Components representing excitatory drive, muscle activation, force generation, metabolic perturbations, and torque production during voluntary human ankle dorsiflexion were constructed, using a combination of experimentally-derived data and literature values. Simulation results were validated by comparison with torque and metabolic data obtained in vivo. The model successfully predicted peak and submaximal voluntary and electrically-elicited torque output, and accurately simulated the metabolic perturbations associated with voluntary contractions. This novel, comprehensive model could be used to better understand impact of global effectors such as age and disease on various components of the neuromuscular system, and ultimately, voluntary torque output. PMID:23405245

Recovering metabolic pathways via optimization.

PubMed

Beasley, John E; Planes, Francisco J

2007-01-01

A metabolic pathway is a coherent set of enzyme catalysed biochemical reactions by which a living organism transforms an initial (source) compound into a final (target) compound. Some of the different metabolic pathways adopted within organisms have been experimentally determined. In this paper, we show that a number of experimentally determined metabolic pathways can be recovered by a mathematical optimization model.

Behavior of standard hook anchorage with corrosion resistant reinforcement : final report, June 2008.

DOT National Transportation Integrated Search

2008-06-01

The objective of this study was to evaluate the behavior of standard books that are made using corrosion resistant reinforcement, which typically have higher yield and ultimate strengths than that of ASTM A615 Grade 60 reinforcement. Two steel types ...

Can violations of Bell's inequalities be considered as a final proof of quantum physics?

NASA Astrophysics Data System (ADS)

Hénault, François

2013-10-01

Nowadays, it is commonly admitted that the experimental violation of Bell's inequalities that was successfully demonstrated in the last decades by many experimenters, are indeed the ultimate proof of quantum physics and of its ability to describe the whole microscopic world and beyond. But the historical and scientific story may not be envisioned so clearly: it starts with the original paper of Einstein, Podolsky and Rosen (EPR) aiming at demonstrating that the formalism of quantum theory is incomplete. It then goes through the works of D. Bohm, to finally proceed to the famous John Bell's relationships providing an experimental setup to solve the EPR paradox. In this communication is proposed an alternative reading of this history, showing that modern experiments based on correlations between light polarizations significantly deviate from the original spirit of the EPR paper. It is concluded that current experimental violations of Bell's inequalities cannot be considered as an ultimate proof of the completeness of quantum physics models.

A brief history of botulism in South Africa.

PubMed

Cameron, C M

2009-03-01

When looking back into the history of botulism and contemplating the final understanding of the syndrome and the ultimate solutions, there are four facets that stand out clearly. The first is that much of the solution was guided by astute observations, curious travellers, committed veterinarians and particularly farmers themselves who were able to relate the occurrence of the condition to climatic and grazing conditions. Secondly, there was the identification of the osteophagia and pica syndrome which led to the feeding of bone-meal as a successful mitigating measure as well as the establishment that botulism was not due to a plant poisoning. Thirdly, the solution of the problem depended on the integration of experience and knowledge from diverse disciplines such as soil science, animal behaviour and husbandry, nutrition, botany and ultimately advanced bacteriology and the science of immunology. Finally it required the technical advancement to produce toxoids in large quantities and formulate effective aluminium hydroxide precipitated and oil emulsion vaccines.

Bardoxolone Brings Nrf2-Based Therapies to Light

PubMed Central

2013-01-01

Abstract The targeted activation of nuclear factor erythroid-derived-2-like 2 (Nrf2) to alleviate symptoms of chronic kidney disease has recently garnered much attention. Unfortunately, the greatest clinical success to date, bardoxolone, failed in phase III clinical trial for unspecified safety reasons. The present letter to the editor discusses the clinical development of bardoxolone and explores potential reasons for the ultimate withdrawal from clinical trials. In particular, was the correct clinical indication pursued and would improved specificity have mitigated the safety concerns? Ultimately, it is concluded that the right clinical indication and heightened specificity will lead to successful Nrf2-based therapies. Therefore, the bardoxolone clinical results do not dampen enthusiasm for Nrf2-based therapies; rather it illuminates the clinical potential of the Nrf2 pathway as a drug target. Antioxid. Redox Signal. 19, 517–518. PMID:23227819

Optimum swimming pathways of fish spawning migrations in rivers

USGS Publications Warehouse

McElroy, Brandon; DeLonay, Aaron; Jacobson, Robert

2012-01-01

Fishes that swim upstream in rivers to spawn must navigate complex fluvial velocity fields to arrive at their ultimate locations. One hypothesis with substantial implications is that fish traverse pathways that minimize their energy expenditure during migration. Here we present the methodological and theoretical developments necessary to test this and similar hypotheses. First, a cost function is derived for upstream migration that relates work done by a fish to swimming drag. The energetic cost scales with the cube of a fish's relative velocity integrated along its path. By normalizing to the energy requirements of holding a position in the slowest waters at the path's origin, a cost function is derived that depends only on the physical environment and not on specifics of individual fish. Then, as an example, we demonstrate the analysis of a migration pathway of a telemetrically tracked pallid sturgeon (Scaphirhynchus albus) in the Missouri River (USA). The actual pathway cost is lower than 105 random paths through the surveyed reach and is consistent with the optimization hypothesis. The implication—subject to more extensive validation—is that reproductive success in managed rivers could be increased through manipulation of reservoir releases or channel morphology to increase abundance of lower-cost migration pathways.

Virtual Institute of Microbial Stress and Survival: Deduction of Stress Response Pathways in Metal and Radionuclide Reducing Microorganisms

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

None

2004-04-17

The projects application goals are to: (1) To understand bacterial stress-response to the unique stressors in metal/radionuclide contamination sites; (2) To turn this understanding into a quantitative, data-driven model for exploring policies for natural and biostimulatory bioremediation; (3) To implement proposed policies in the field and compare results to model predictions; and (4) Close the experimental/computation cycle by using discrepancies between models and predictions to drive new measurements and construction of new models. The projects science goals are to: (1) Compare physiological and molecular response of three target microorganisms to environmental perturbation; (2) Deduce the underlying regulatory pathways that controlmore » these responses through analysis of phenotype, functional genomic, and molecular interaction data; (3) Use differences in the cellular responses among the target organisms to understand niche specific adaptations of the stress and metal reduction pathways; (4) From this analysis derive an understanding of the mechanisms of pathway evolution in the environment; and (5) Ultimately, derive dynamical models for the control of these pathways to predict how natural stimulation can optimize growth and metal reduction efficiency at field sites.« less

Clinically Applicable Inhibitors Impacting Genome Stability.

PubMed

Prakash, Anu; Garcia-Moreno, Juan F; Brown, James A L; Bourke, Emer

2018-05-13

Advances in technology have facilitated the molecular profiling (genomic and transcriptomic) of tumours, and has led to improved stratification of patients and the individualisation of treatment regimes. To fully realize the potential of truly personalised treatment options, we need targeted therapies that precisely disrupt the compensatory pathways identified by profiling which allow tumours to survive or gain resistance to treatments. Here, we discuss recent advances in novel therapies that impact the genome (chromosomes and chromatin), pathways targeted and the stage of the pathways targeted. The current state of research will be discussed, with a focus on compounds that have advanced into trials (clinical and pre-clinical). We will discuss inhibitors of specific DNA damage responses and other genome stability pathways, including those in development, which are likely to synergistically combine with current therapeutic options. Tumour profiling data, combined with the knowledge of new treatments that affect the regulation of essential tumour signalling pathways, is revealing fundamental insights into cancer progression and resistance mechanisms. This is the forefront of the next evolution of advanced oncology medicine that will ultimately lead to improved survival and may, one day, result in many cancers becoming chronic conditions, rather than fatal diseases.

[Development and implementation of an integrated care pathway at the POLIKUM health centers using the example of anemia].

PubMed

Bierbaum, M; Grad, M O; Wulff, H; Kewenig, S; Schöffski, O

2014-04-01

Integrated treatment pathways are an appropriate means for increasing the quality of treatment and outcome via process optimization. Taking the POLIKUM Health Centers as an example, we intend to demonstrate how the implementation can be effected for the indication of anemia. The development and implementation were executed by an interdisciplinary workgroup in several workshops. In addition, the diagnoses and hemoglobin values of all patients with requests for hemograms were obtained and analyzed at two locations. Developing the pathway required significantly greater efforts than initially planned. The biggest challenge was to adequately map the complexity of the different forms of anemia and, concomitantly, to design a pathway that can actually be realized in everyday life. Moreover, evaluation of the patient data demonstrated that there are a large number of cases where existing anemias are not reflected in the respective diagnoses. While the ultimate effects of the new pathway cannot yet be assessed conclusively, it was possible to obtain valuable findings for practical use even at this point. Despite the limitations of the sample, the surprisingly high number of undetected anemias should give physicians cause for taking diagnostic measures even in patients with mild anemia.

Binding Mode Analysis of Zerumbone to Key Signal Proteins in the Tumor Necrosis Factor Pathway

PubMed Central

Fatima, Ayesha; Abdul, Ahmad Bustamam Hj.; Abdullah, Rasedee; Karjiban, Roghayeh Abedi; Lee, Vannajan Sanghiran

2015-01-01

Breast cancer is the second most common cancer among women worldwide. Several signaling pathways have been implicated as causative and progression agents. The tumor necrosis factor (TNF) α protein plays a dual role in promoting and inhibiting cancer depending largely on the pathway initiated by the binding of the protein to its receptor. Zerumbone, an active constituent of Zingiber zerumbet, Smith, is known to act on the tumor necrosis factor pathway upregulating tumour necrosis factor related apoptosis inducing ligand (TRAIL) death receptors and inducing apoptosis in cancer cells. Zerumbone is a sesquiterpene that is able to penetrate into the hydrophobic pockets of proteins to exert its inhibiting activity with several proteins. We found a good binding with the tumor necrosis factor, kinase κB (IKKβ) and the Nuclear factor κB (NF-κB) component proteins along the TNF pathway. Our results suggest that zerumbone can exert its apoptotic activities by inhibiting the cytoplasmic proteins. It inhibits the IKKβ kinase that activates the NF-κB and also binds to the NF-κB complex in the TNF pathway. Blocking both proteins can lead to inhibition of cell proliferating proteins to be downregulated and possibly ultimate induction of apoptosis. PMID:25629232

Federal Employees Health Benefits Program and Federal Employees Dental and Vision Insurance Program: eligibility for Pathway Programs participants. Interim final rule with request for comments.

PubMed

2014-01-06

The U.S. Office of Personnel Management (OPM) is issuing an interim final regulation to update the Federal Employees Health Benefits Program (FEHBP) and the Federal Employees Dental and Vision Insurance Program (FEDVIP) regulations to reflect updated election opportunities for participants in the Pathways Programs. The Pathways Programs were created by Executive Order (E.O.) 13562, signed by the President on December 27, 2010, and are designed to enable the Federal Government to compete effectively for students and recent graduates by improving its recruitment efforts through internships and similar programs with Federal agencies. This interim final rule furthers these recruitment and retention efforts by providing health insurance, as well as dental and vision benefits, to eligible program participants and their families.

Complement in autoimmune diseases.

PubMed

Vignesh, Pandiarajan; Rawat, Amit; Sharma, Madhubala; Singh, Surjit

2017-02-01

The complement system is an ancient and evolutionary conserved element of the innate immune mechanism. It comprises of more than 20 serum proteins most of which are synthesized in the liver. These proteins are synthesized as inactive precursor proteins which are activated by appropriate stimuli. The activated forms of these proteins act as proteases and cleave other components successively in amplification pathways leading to exponential generation of final effectors. Three major pathways of complement pathways have been described, namely the classical, alternative and lectin pathways which are activated by different stimuli. However, all the 3 pathways converge on Complement C3. Cleavage of C3 and C5 successively leads to the production of the membrane attack complex which is final common effector. Excessive and uncontrolled activation of the complement has been implicated in the host of autoimmune diseases. But the complement has also been bemusedly described as the proverbial "double edged sword". On one hand, complement is the final effector of tissue injury in autoimmune diseases and on the other, deficiencies of some components of the complement can result in autoimmune diseases. Currently available tools such as enzyme based immunoassays for functional assessment of complement pathways, flow cytometry, next generation sequencing and proteomics-based approaches provide an exciting opportunity to study this ancient yet mysterious element of innate immunity. Copyright © 2017 Elsevier B.V. All rights reserved.

Bilateral avascular necrosis of the femoral head due to the use of heroin: A case report.

PubMed

Ozkunt, Okan; Sarıyılmaz, Kerim; Sungur, Mustafa; Ilen, Ferhat; Dikici, Fatih

2015-01-01

Femoral head avascular necrosis is caused by disruption of the blood supply of the femoral head, which finally results in hip dysfunction. Non traumatic osteonecrosis may related with corticosteroid use, alcohol abuse, SLE, hemoglobinopathies or exposure to cytotoxic agents. But avascular necrosis of the femoral head (ANFH) due to heroin use is a rare condition. We report a patient with bilateral ANFH due to heroin use treated by simultaneous bilateral hip arthroplasty. 37 year-old male patient presented with bilateral hip pain that had been occurring for four years. The patient had no history of smoking, excessive drinking, using corticosteroid and the other drugs or trauma but used heroin for 10 years. In clinic and radiologic examination indicated advanced degenerative changes on both hip due to femoral head avascular necrosis. The patient was treated with simultaneous bilateral total hip arthroplasty. After 6 months postoperatively the active hip range of motion was painless. Avascular femoral head necrosis caused by the using of heroin is rare. Ultimately, osteonecrosis of the femoral head occurs through one final common pathway, which is decreased blood flow to the femoral head that leads bone ischemia and death. But it is still unknown that heroin's systemic effects. Intravenous drug use more as a serious problem for today. There is a need for comprehensive studies to demonstrate effects of heroin on bone and vascularity metabolism. Heroin use will be important problem for population. That's why is crucial to understand the effect of heroin. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Identification of degradation routes of metamitron in soil microcosms using 13C-isotope labeling.

PubMed

Wang, Shizong; Miltner, Anja; Nowak, Karolina M

2017-01-01

Metamitron is one of the most commonly used herbicide in sugar beet and flower bulb cultures. Numerous laboratory and field studies on sorption and degradation of metamitron were performed. Detailed biodegradation studies in soil using 13 C-isotope labeling are still missing. Therefore, we aimed at providing a detailed turnover mass balance of 13 C 6 -metamitron in soil microcosms over 80 days. In the biotic system, metamitron mineralized rapidly, and 13 CO 2 finally constituted 60% of the initial 13 C 6 -metamitron equivalents. In abiotic control experiments CO 2 rose to only 7.4% of the initial 13 C 6 -metamitron equivalents. The 13 C label from 13 C 6 -metamitron was incorporated into microbial amino acids that were ultimately stabilized in the soil organic matter forming presumably harmless biogenic residues. Finally, 13 C label from 13 C 6 -metamitron was distributed between the 13 CO 2 and the 13 C-biogenic residues indicating nearly complete biodegradation. The parallel increase of 13 C-alanine, 13 C-glutamate and 13 CO 2 indicates that metamitron was initially biodegraded via the desamino-metamitron route suggesting its relevance in the growth metabolism. In later phases of biodegradation, the "Rhodococcus route" was indicated by the low 13 CO 2 evolution and the high relevance of the pyruvate pathway, which aims at biomolecule synthesis and seems to be related to starvation. This is a first report on the detailed degradation route of metamitron in soil. Copyright © 2016 Elsevier Ltd. All rights reserved.

Programs of Study as a State Policy Mandate: A Longitudinal Study of the South Carolina Personal Pathways to Success Initiative. Final Technical Report: Major Findings and Implications

ERIC Educational Resources Information Center

Hammond, Cathy; Drew, Sam F.; Withington, Cairen; Griffith, Cathy; Swiger, Caroline M.; Mobley, Catherine; Sharp, Julia L.; Stringfield, Samuel C.; Stipanovic, Natalie; Daugherty, Lindsay

2013-01-01

This is the final technical report from the National Research Center for Career and Technical Education's (NRCCTE's) five-year longitudinal study of South Carolina's Personal Pathway to Success initiative, which was authorized by the state's Education and Economic Development Act (EEDA) in 2005. NRCCTE-affiliated researchers at the National…

Bacterial superantigens bypass Lck-dependent T cell receptor signaling by activating a Galpha11-dependent, PLC-beta-mediated pathway.

PubMed

Bueno, Clara; Lemke, Caitlin D; Criado, Gabriel; Baroja, Miren L; Ferguson, Stephen S G; Rahman, A K M Nur-Ur; Tsoukas, Constantine D; McCormick, John K; Madrenas, Joaquin

2006-07-01

The paradigm to explain antigen-dependent T cell receptor (TCR) signaling is based on the activation of the CD4 or CD8 coreceptor-associated kinase Lck. It is widely assumed that this paradigm is also applicable to signaling by bacterial superantigens. However, these bacterial toxins can activate human T cells lacking Lck, suggesting the existence of an additional pathway of TCR signaling. Here we showed that this alternative pathway operates in the absence of Lck-dependent tyrosine-phosphorylation events and was initiated by the TCR-dependent activation of raft-enriched heterotrimeric Galpha11 proteins. This event, in turn, activated a phospholipase C-beta and protein kinase C-mediated cascade that turned on the mitogen-activated protein kinases ERK-1 and ERK-2, triggered Ca(2+) influx, and translocated the transcription factors NF-AT and NF-kappaB to the nucleus, ultimately inducing the production of interleukin-2 in Lck-deficient T cells. The triggering of this alternative pathway by superantigens suggests that these toxins use a G protein-coupled receptor as a coreceptor on T cells.

Mechanistic pathways of recognition of a solvent-inaccessible cavity of protein by a ligand

NASA Astrophysics Data System (ADS)

Mondal, Jagannath; Pandit, Subhendu; Dandekar, Bhupendra; Vallurupalli, Pramodh

One of the puzzling questions in the realm of protein-ligand recognition is how a solvent-inaccessible hydrophobic cavity of a protein gets recognized by a ligand. We address the topic by simulating, for the first time, the complete binding process of benzene from aqueous media to the well-known buried cavity of L99A T4 Lysozyme at an atomistic resolution. Our multiple unbiased microsecond-long trajectories, which were completely blind to the location of target binding site, are able to unequivocally identify the kinetic pathways along which benzene molecule meanders across the solvent and protein and ultimately spontaneously recognizes the deeply buried cavity of L99A T4 Lysozyme at an accurate precision. Our simulation, combined with analysis based on markov state model and free energy calculation, reveals that there are more than one distinct ligand binding pathways. Intriguingly, each of the identified pathways involves the transient opening of a channel of the protein prior to ligand binding. The work will also decipher rich mechanistic details on unbinding kinetics of the ligand as obtained from enhanced sampling techniques.

You have an idea, now what?

PubMed

Gertner, Michael

2006-11-01

The innovation process is often more important than the original idea, particularly when the ultimate goal is to improve patient care through technologically advanced products. Many physicians have great ideas; unfortunately, many of these great ideas are never translated to patient care improvements because of a misunderstanding of "the next step." In many cases, the next step is a step backward to understand the real clinical problem: "the clinical need." With the clinical need in hand, the most efficient path to a product for improved patient care can then be derived. Often, the most efficient pathway involves an appreciation of many issues, including intellectual property, regulatory pathways, finance, and clinical trial strategies. The integration of these issues underlies innovation in biomedical technology.

Ubiquitination in the antiviral immune response.

PubMed

Davis, Meredith E; Gack, Michaela U

2015-05-01

Ubiquitination has long been known to regulate fundamental cellular processes through the induction of proteasomal degradation of target proteins. More recently, 'atypical' non-degradative types of polyubiquitin chains have been appreciated as important regulatory moieties by modulating the activity or subcellular localization of key signaling proteins. Intriguingly, many of these non-degradative types of ubiquitination regulate the innate sensing pathways initiated by pattern recognition receptors (PRRs), ultimately coordinating an effective antiviral immune response. Here we discuss recent advances in understanding the functional roles of degradative and atypical types of ubiquitination in innate immunity to viral infections, with a specific focus on the signaling pathways triggered by RIG-I-like receptors, Toll-like receptors, and the intracellular viral DNA sensor cGAS. Copyright © 2015 Elsevier Inc. All rights reserved.

Medulloblastoma initiation and spread: Where neurodevelopment, microenvironment and cancer cross pathways.

PubMed

Martirosian, Vahan; Chen, Thomas C; Lin, Michelle; Neman, Josh

2016-12-01

Medulloblastomas are the most common malignant pediatric brain tumors. Over the past several decades, a wide range of tumor-centric studies have identified genes and their regulators within signaling pathways that promote medulloblastoma growth. This review aims to raise awareness that transdisciplinary research between developmental neurobiology and cancer foundations can advance our current understanding of how the nervous system contributes to medulloblastomas. By leveraging current advances in neurodevelopment, microenvironment (including secreted neuropeptides), neurotransmitters, and axon guidance cues, we can uncover novel mechanisms used by the nervous system to promote medulloblastoma growth and spread. This will ultimately result in development of improved strategies for cancer prevention and treatment of pediatric patients with this devastating disease. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Mechanism for Si–Si Bond Rupture in Single Molecule Junctions

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

Li, Haixing; Kim, Nathaniel T.; Su, Timothy A.

The stability of chemical bonds can be studied experimentally by rupturing single molecule junctions under applied voltage. Here, we compare voltage-induced bond rupture in two Si–Si backbones: one has no alternate conductive pathway whereas the other contains an additional naphthyl pathway in parallel to the Si–Si bond. We show that in contrast to the first system, the second can conduct through the naphthyl group when the Si–Si bond is ruptured using an applied voltage. We investigate this voltage induced Si–Si bond rupture by ab initio density functional theory calculations and molecular dynamics simulations that ultimately demonstrate that the excitation ofmore » molecular vibrational modes by tunneling electrons leads to homolytic Si–Si bond rupture.« less

Mechanism for Si-Si Bond Rupture in Single Molecule Junctions.

PubMed

Li, Haixing; Kim, Nathaniel T; Su, Timothy A; Steigerwald, Michael L; Nuckolls, Colin; Darancet, Pierre; Leighton, James L; Venkataraman, Latha

2016-12-14

The stability of chemical bonds can be studied experimentally by rupturing single molecule junctions under applied voltage. Here, we compare voltage-induced bond rupture in two Si-Si backbones: one has no alternate conductive pathway whereas the other contains an additional naphthyl pathway in parallel to the Si-Si bond. We show that in contrast to the first system, the second can conduct through the naphthyl group when the Si-Si bond is ruptured using an applied voltage. We investigate this voltage induced Si-Si bond rupture by ab initio density functional theory calculations and molecular dynamics simulations that ultimately demonstrate that the excitation of molecular vibrational modes by tunneling electrons leads to homolytic Si-Si bond rupture.

Pathologic and Therapeutic Implications for the Cell Biology of Parkin

PubMed Central

Charan, Rakshita A.; LaVoie, Matthew J.

2015-01-01

Mutations in the E3 ligase parkin are the most common cause of autosomal recessive Parkinson's disease (PD), but it is believed that parkin dysfunction may also contribute to idiopathic PD. Since its discovery, parkin has been implicated in supporting multiple neuroprotective pathways, many revolving around the maintenance of mitochondrial health quality control and governance of cell survival. Recent advances across the structure, biochemistry, and cell biology of parkin have provided great insights into the etiology of parkin-linked and idiopathic PD and may ultimately generate novel therapeutic strategies to slow or halt disease progression. This review describes the various pathways in which parkin acts and the mechanisms by which parkin may be targeted for therapeutic intervention. PMID:25697646

Drug resistance to targeted therapies: déjà vu all over again.

PubMed

Groenendijk, Floris H; Bernards, René

2014-09-12

A major limitation of targeted anticancer therapies is intrinsic or acquired resistance. This review emphasizes similarities in the mechanisms of resistance to endocrine therapies in breast cancer and those seen with the new generation of targeted cancer therapeutics. Resistance to single-agent cancer therapeutics is frequently the result of reactivation of the signaling pathway, indicating that a major limitation of targeted agents lies in their inability to fully block the cancer-relevant signaling pathway. The development of mechanism-based combinations of targeted therapies together with non-invasive molecular disease monitoring is a logical way forward to delay and ultimately overcome drug resistance development. Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

A Genetic and Pharmacological Analysis of Isoprenoid Pathway by LC-MS/MS in Fission Yeast

PubMed Central

Takami, Tomonori; Fang, Yue; Zhou, Xin; Jaiseng, Wurentuya; Ma, Yan; Kuno, Takayoshi

2012-01-01

Currently, statins are the only drugs acting on the mammalian isoprenoid pathway. The mammalian genes in this pathway are not easily amenable to genetic manipulation. Thus, it is difficult to study the effects of the inhibition of various enzymes on the intermediate and final products in the isoprenoid pathway. In fission yeast, antifungal compounds such as azoles and terbinafine are available as inhibitors of the pathway in addition to statins, and various isoprenoid pathway mutants are also available. Here in these mutants, treated with statins or antifungals, we quantified the final and intermediate products of the fission yeast isoprenoid pathway using liquid chromatography-mass spectrometry/mass spectrometry. In hmg1-1, a mutant of the gene encoding 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR), ergosterol (a final sterol product), and squalene (an intermediate pathway product), were decreased to approximately 80% and 10%, respectively, compared with that of wild-type cells. Consistently in wild-type cells, pravastatin, an HMGR inhibitor decreased ergosterol and squalene, and the effect was more pronounced on squalene. In hmg1-1 mutant and in wild-type cells treated with pravastatin, the decrease in the levels of farnesyl pyrophosphate and geranylgeranyl pyrophosphate respectively was larger than that of ergosterol but was smaller than that of squalene. In Δerg6 or Δsts1 cells, mutants of the genes involved in the last step of the pathway, ergosterol was not detected, and the changes of intermediate product levels were distinct from that of hmg1-1 mutant. Notably, in wild-type cells miconazole and terbinafine only slightly decreased ergosterol level. Altogether, these studies suggest that the pleiotropic phenotypes caused by the hmg1-1 mutation and pravastatin might be due to decreased levels of isoprenoid pyrophosphates or other isoprenoid pathway intermediate products rather than due to a decreased ergosterol level. PMID:23145048

A unified approach for determining the ultimate strength of RC members subjected to combined axial force, bending, shear and torsion

PubMed Central

Huang, Zhen

2017-01-01

This paper uses experimental investigation and theoretical derivation to study the unified failure mechanism and ultimate capacity model of reinforced concrete (RC) members under combined axial, bending, shear and torsion loading. Fifteen RC members are tested under different combinations of compressive axial force, bending, shear and torsion using experimental equipment designed by the authors. The failure mechanism and ultimate strength data for the four groups of tested RC members under different combined loading conditions are investigated and discussed in detail. The experimental research seeks to determine how the ultimate strength of RC members changes with changing combined loads. According to the experimental research, a unified theoretical model is established by determining the shape of the warped failure surface, assuming an appropriate stress distribution on the failure surface, and considering the equilibrium conditions. This unified failure model can be reasonably and systematically changed into well-known failure theories of concrete members under single or combined loading. The unified calculation model could be easily used in design applications with some assumptions and simplifications. Finally, the accuracy of this theoretical unified model is verified by comparisons with experimental results. PMID:28414777

Four-miRNA signature as a prognostic tool for lung adenocarcinoma.

PubMed

Lin, Yan; Lv, Yufeng; Liang, Rong; Yuan, Chunling; Zhang, Jinyan; He, Dan; Zheng, Xiaowen; Zhang, Jianfeng

2018-01-01

The aim of this study was to generate a novel miRNA expression signature to accurately predict prognosis for patients with lung adenocarcinoma (LUAD). Using expression profiles downloaded from The Cancer Genome Atlas database, we identified multiple miRNAs with differential expression between LUAD and paired healthy tissues. We then evaluated the prognostic values of the differentially expressed miRNAs using univariate/multivariate Cox regression analysis. This analysis was ultimately used to construct a four-miRNA signature that effectively predicted patient survival. Finally, we analyzed potential functional roles of the target genes for these four miRNAs using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. Based on our cutoff criteria ( P <0.05 and |log2FC| >1.0), we identified a total of 187 differentially expressed miRNAs, including 148 that were upregulated in LUAD tissues and 39 that were downregulated. Four miRNAs (miR-148a-5p, miR-31-5p, miR-548v, and miR-550a-5p) were independently associated with survival based on Kaplan-Meier analysis. We generated a signature index based on the expression of these four miRNAs and stratified patients into low- and high-risk groups. Patients in the high-risk group had significantly shorter survival times than those in the low-risk group ( P =0.002). A functional enrichment analysis suggested that the target genes of these four miRNAs were involved in protein phosphorylation and the Hippo and sphingolipid signaling pathways. Taken together, our results suggest that our four-miRNA signature can be used as a prognostic tool for patients with LUAD.

miR-125a induces apoptosis, metabolism disorder and migration impairment in pancreatic cancer cells by targeting Mfn2-related mitochondrial fission

PubMed Central

Pan, Lichao; Zhou, Lin; Yin, Weijia; Bai, Jia; Liu, Rong

2018-01-01

Mitochondrial fission is important for the development and progression of pancreatic cancer (PC). However, little is known regarding its role in pancreatic cancer apoptosis, metabolism and migration. In the current study, the mechanism by which mitochondrial fission modifies the biological characteristics of PC was explored. MicroRNA-125a (miR-125a) had the ability to inhibit mitochondrial fission and contributed to cellular survival. Suppressed mitochondrial fission led to a reduction in mitochondrial debris, preserved the mitochondrial membrane potential, inhibited mitochondrial permeability transition pore opening, ablated cytochrome c leakage into the cytoplasm and reduced the pro-apoptotic protein contents, finally blocking mitochondria related apoptosis pathways. Furthermore, defective mitochondrial fission induced by miR-125a enhanced mitochondria-dependent energy metabolism by promoting activity of electron transport chain complexes. Furthermore, suppressed mitochondrial fission also contributed to PANC-1 cell migration by preserving the F-actin balance. Furthermore, mitofusin 2 (Mfn2), the key defender of mitochondrial fission, is involved in inhibition of miR125a-mediated mitochondrial fission. Low contents of miR-125a upregulated Mfn2 transcription and expression, leading to inactivation of mitochondrial fission. Ultimately, the current study determined that miR-125a and Mfn2 are regulated by hypoxia-inducible factor 1 (HIF1). Knockdown of HIF1 reversed miR-125a expression, and therefore, inhibited Mfn2 expression, leading to activation of mitochondrial fission. Collectively, the present study demonstrated mitochondrial fission as a tumor suppression process that is regulated by the HIF/miR-125a/Mfn2 pathways, acting to restrict PANC-1 cell survival, energy metabolism and migration, with potential implications for novel approaches for PC therapy. PMID:29749475

Molecular Dynamics Simulations of Amyloid β-Peptide (1-42): Tetramer Formation and Membrane Interactions.

PubMed

Brown, Anne M; Bevan, David R

2016-09-06

The aggregation cascade and peptide-membrane interactions of the amyloid β-peptide (Aβ) have been implicated as toxic events in the development and progression of Alzheimer's disease. Aβ42 forms oligomers and ultimately plaques, and it has been hypothesized that these oligomeric species are the main toxic species contributing to neuronal cell death. To better understand oligomerization events and subsequent oligomer-membrane interactions of Aβ42, we performed atomistic molecular-dynamics (MD) simulations to characterize both interpeptide interactions and perturbation of model membranes by the peptides. MD simulations were utilized to first show the formation of a tetramer unit by four separate Aβ42 peptides. Aβ42 tetramers adopted an oblate ellipsoid shape and showed a significant increase in β-strand formation in the final tetramer unit relative to the monomers, indicative of on-pathway events for fibril formation. The Aβ42 tetramer unit that formed in the initial simulations was used in subsequent MD simulations in the presence of a pure POPC or cholesterol-rich raft model membrane. Tetramer-membrane simulations resulted in elongation of the tetramer in the presence of both model membranes, with tetramer-raft interactions giving rise to the rearrangement of key hydrophobic regions in the tetramer and the formation of a more rod-like structure indicative of a fibril-seeding aggregate. Membrane perturbation by the tetramer was manifested in the form of more ordered, rigid membranes, with the pure POPC being affected to a greater extent than the raft membrane. These results provide critical atomistic insight into the aggregation pathway of Aβ42 and a putative toxic mechanism in the pathogenesis of Alzheimer's disease. Copyright © 2016 Biophysical Society. Published by Elsevier Inc. All rights reserved.

miR-125a induces apoptosis, metabolism disorder and migrationimpairment in pancreatic cancer cells by targeting Mfn2-related mitochondrial fission.

PubMed

Pan, Lichao; Zhou, Lin; Yin, Weijia; Bai, Jia; Liu, Rong

2018-07-01

Mitochondrial fission is important for the development and progression of pancreatic cancer (PC). However, little is known regarding its role in pancreatic cancer apoptosis, metabolism and migration. In the current study, the mechanism by which mitochondrial fission modifies the biological characteristics of PC was explored. MicroRNA‑125a (miR‑125a) had the ability to inhibit mitochondrial fission and contributed to cellular survival. Suppressed mitochondrial fission led to a reduction in mitochondrial debris, preserved the mitochondrial membrane potential, inhibited mitochondrial permeability transition pore opening, ablated cytochrome c leakage into the cytoplasm and reduced the pro‑apoptotic protein contents, finally blocking mitochondria related apoptosis pathways. Furthermore, defective mitochondrial fission induced by miR‑125a enhanced mitochondria‑dependent energy metabolism by promoting activity of electron transport chain complexes. Furthermore, suppressed mitochondrial fission also contributed to PANC‑1 cell migration by preserving the F‑actin balance. Furthermore, mitofusin 2 (Mfn2), the key defender of mitochondrial fission, is involved in inhibition of miR125a‑mediated mitochondrial fission. Low contents of miR‑125a upregulated Mfn2 transcription and expression, leading to inactivation of mitochondrial fission. Ultimately, the current study determined that miR‑125a and Mfn2 are regulated by hypoxia‑inducible factor 1 (HIF1). Knockdown of HIF1 reversed miR‑125a expression, and therefore, inhibited Mfn2 expression, leading to activation of mitochondrial fission. Collectively, the present study demonstrated mitochondrial fission as a tumor suppression process that is regulated by the HIF/miR‑125a/Mfn2 pathways, acting to restrict PANC‑1 cell survival, energy metabolism and migration, with potential implications for novel approaches for PC therapy.

Exploring the intricate regulatory network controlling the thiazide-sensitive NaCl cotransporter (NCC).

PubMed

Dimke, Henrik

2011-12-01

The thiazide-sensitive NaCl cotransporter (NCC) plays key roles in renal electrolyte transport and blood pressure maintenance. Regulation of this cotransporter has received increased attention recently, prompted by the discovery that mutations in the with-no-lysine (WNK) kinases are the molecular explanation for pseudohypoaldosteronism type II (PHAII). Studies suggest that WNK4 regulates NCC via two distinct pathways, depending on its state of activation. Furthermore, an intact STE20-related proline-alanine-rich kinase (SPAK)/oxidative stress response 1 kinase (OSR1) pathway was found to be necessary for a WNK4 PHAII mutation to increase NCC phosphorylation and blood pressure in mice. The mouse protein 25α is a novel regulator of the SPAK/OSR1 kinase family, which greatly increases their activity. The phosphorylation status of NCC and the WNK is regulated by the serum- and glucocorticoid-inducible kinase 1, suggesting novel mechanisms whereby aldosterone modulates NCC activity. Dephosphorylation of NCC by protein phosphatase 4 strongly influences the activity of the cotransporter, confirming an important role for NCC phosphorylation. Finally, γ-adducin increases NCC activity. This stimulatory effect is dependent on the phosphorylation status of the cotransporter. γ-Adducin only binds the dephosphorylated cotransporter, suggesting that phosphorylation of NCC causes the dissociation of γ-adducin. Since γ-adducin is not a kinase, it is tempting to speculate that the protein exerts its function by acting as a scaffold between the dephosphorylated cotransporter and the regulatory kinase. As more molecular regulators of NCC are identified, the system-controlling NCC activity is becoming increasingly complex. This intricacy confers an ability to integrate a variety of stimuli, thereby regulating NCC transport activity and ultimately blood pressure.

Hypertrophic cardiomyopathy mutation R58Q in the myosin regulatory light chain perturbs thick filament-based regulation in cardiac muscle.

PubMed

Kampourakis, Thomas; Ponnam, Saraswathi; Irving, Malcolm

2018-04-01

Hypertrophic cardiomyopathy (HCM) is frequently linked to mutations in the protein components of the myosin-containing thick filaments leading to contractile dysfunction and ultimately heart failure. However, the molecular structure-function relationships that underlie these pathological effects remain largely obscure. Here we chose an example mutation (R58Q) in the myosin regulatory light chain (RLC) that is associated with a severe HCM phenotype and combined the results from a wide range of in vitro and in situ structural and functional studies on isolated protein components, myofibrils and ventricular trabeculae to create an extensive map of structure-function relationships. The results can be understood in terms of a unifying hypothesis that illuminates both the effects of the mutation and physiological signaling pathways. R58Q promotes an OFF state of the thick filaments that reduces the number of myosin head domains that are available for actin interaction and ATP utilization. Moreover this mutation uncouples two aspects of length-dependent activation (LDA), the cellular basis of the Frank-Starling relation that couples cardiac output to venous return; R58Q reduces maximum calcium-activated force with no significant effect on myofilament calcium sensitivity. Finally, phosphorylation of R58Q-RLC to levels that may be relevant both physiologically and pathologically restores the regulatory state of the thick filament and the effect of sarcomere length on maximum calcium-activated force and thick filament structure, as well as increasing calcium sensitivity. We conclude that perturbation of thick filament-based regulation may be a common mechanism in the etiology of missense mutation-associated HCM, and that this signaling pathway offers a promising target for the development of novel therapeutics. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Distinct Roles for CdtA and CdtC during Intoxication by Cytolethal Distending Toxins

PubMed Central

Tamilselvam, Batcha; Spiegelman, Lindsey M.; Son, Sophia B.; Eshraghi, Aria; Blanke, Steven R.; Bradley, Kenneth A.

2015-01-01

Cytolethal distending toxins (CDTs) are heterotrimeric protein exotoxins produced by a diverse array of Gram-negative pathogens. The enzymatic subunit, CdtB, possesses DNase and phosphatidylinositol 3-4-5 trisphosphate phosphatase activities that induce host cell cycle arrest, cellular distension and apoptosis. To exert cyclomodulatory and cytotoxic effects CDTs must be taken up from the host cell surface and transported intracellularly in a manner that ultimately results in localization of CdtB to the nucleus. However, the molecular details and mechanism by which CDTs bind to host cells and exploit existing uptake and transport pathways to gain access to the nucleus are poorly understood. Here, we report that CdtA and CdtC subunits of CDTs derived from Haemophilus ducreyi (Hd-CDT) and enteropathogenic E. coli (Ec-CDT) are independently sufficient to support intoxication by their respective CdtB subunits. CdtA supported CdtB-mediated killing of T-cells and epithelial cells that was nearly as efficient as that observed with holotoxin. In contrast, the efficiency by which CdtC supported intoxication was dependent on the source of the toxin as well as the target cell type. Further, CdtC was found to alter the subcellular trafficking of Ec-CDT as determined by sensitivity to EGA, an inhibitor of endosomal trafficking, colocalization with markers of early and late endosomes, and the kinetics of DNA damage response. Finally, host cellular cholesterol was found to influence sensitivity to intoxication mediated by Ec-CdtA, revealing a role for cholesterol or cholesterol-rich membrane domains in intoxication mediated by this subunit. In summary, data presented here support a model in which CdtA and CdtC each bind distinct receptors on host cell surfaces that direct alternate intracellular uptake and/or trafficking pathways. PMID:26618479

Integrated Science Assessment for Oxides of Nitrogen – Health Criteria (Final Report, Jul 2008)

EPA Science Inventory

The Integrated Science Assessment (ISA) for Oxides of Nitrogen – Health Criteria document represents a concise synthesis and evaluation of the most policy-relevant science and will ultimately provide the scientific bases for EPA’s decision regarding whether the current standard f...

A combined report for freight information real-time system for transport (FIRST). Part A, final evaluation. Part B, detailed test plans

DOT National Transportation Integrated Search

2002-05-30

The ultimate goal of this evaluation is to identify any benefits in operational efficiency, air quality, and customer satisfaction with the implementation of the FIRST information technology system for the intermodal freight industry at the Port of N...

Unemployment Benefit Exhaustion: Incentive Effects on Job-Finding Rates

ERIC Educational Resources Information Center

Filges, Trine; Geerdsen, Lars Pico; Knudsen, Anne-Sofie Due; Jørgensen, Anne-Marie Klint

2015-01-01

Purpose: This systematic review studied the impact of exhaustion of unemployment benefits on the exit rate out of unemployment and into employment prior to benefit exhaustion or shortly thereafter. Method: We followed Campbell Collaboration guidelines to prepare this review, and ultimately located 12 studies for final analysis and interpretation.…

Collapsing permafrost coasts in the Arctic

NASA Astrophysics Data System (ADS)

Fritz, Michael; Lantuit, Hugues

2017-04-01

Arctic warming is exposing permafrost coastlines, which account for 34% of the Earth's coasts, to rapid thaw and erosion. Coastal erosion rates as high as 25 m yr-1 together with the large amount of organic matter frozen in permafrost are resulting in an annual release of 14.0 Tg (1012 gram) particulate organic carbon into the nearshore zone. The nearshore zone is the primary recipient of higher fluxes of carbon and nutrients from thawing permafrost. We highlight the crucial role the nearshore zone plays in Arctic biogeochemical cycling, as here the fate of the released material is determined to: (1) degrade into greenhouse gases, (2) fuel marine primary production, (3) be buried in nearshore sediments or (4) be transported offshore. With Arctic warming, coastal erosion fluxes have the potential to increase by an order of magnitude until 2100. Such increases would result in drastic impacts on global carbon fluxes and their climate feedbacks, on nearshore food webs and on local communities, whose survival still relies on marine biological resources. Quantifying the potential impacts of increasing erosion on coastal ecosystems is crucial for food security of northern residents living in Arctic coastal communities. We need to know how the traditional hunting and fishing grounds might be impacted by high loads of sediment and nutrients released from eroding coasts, and to what extent coastal retreat will lead to a loss of natural habitat. Quantifying fluxes of organic carbon and nutrients is required, both in nearshore deposits and in the water column by sediment coring and systematic oceanographic monitoring. Ultimately, this will allow us to assess the transport and degradation pathways of sediment and organic matter derived from erosion. We need to follow the complete pathway, which is multi-directional including atmospheric release, lateral transport, transitional retention in the food web, and ultimate burial in seafloor sediments. We present numbers of multi-year dissolved organic matter (DOM) fluxes from coastal erosion into the nearshore zone of the southern Canadian Beaufort Sea. We further explore removal and degradation patterns of DOM based on oceanographic monitoring of coastal waters. Ultimately, we present accumulation rates and biogeochemical properties of marine sediment sequences drilled off the Yukon coast to track the pathways of the eroded material.

Ultimately short ballistic vertical graphene Josephson junctions

PubMed Central

Lee, Gil-Ho; Kim, Sol; Jhi, Seung-Hoon; Lee, Hu-Jong

2015-01-01

Much efforts have been made for the realization of hybrid Josephson junctions incorporating various materials for the fundamental studies of exotic physical phenomena as well as the applications to superconducting quantum devices. Nonetheless, the efforts have been hindered by the diffusive nature of the conducting channels and interfaces. To overcome the obstacles, we vertically sandwiched a cleaved graphene monoatomic layer as the normal-conducting spacer between superconducting electrodes. The atomically thin single-crystalline graphene layer serves as an ultimately short conducting channel, with highly transparent interfaces with superconductors. In particular, we show the strong Josephson coupling reaching the theoretical limit, the convex-shaped temperature dependence of the Josephson critical current and the exceptionally skewed phase dependence of the Josephson current; all demonstrate the bona fide short and ballistic Josephson nature. This vertical stacking scheme for extremely thin transparent spacers would open a new pathway for exploring the exotic coherence phenomena occurring on an atomic scale. PMID:25635386

Ribose in the heart.

PubMed

Herrick, James; St Cyr, John

2008-01-01

Every cell needs energy, i.e., adenosine triphosphate (ATP), to carry out its function. Decreased oxygen levels, decreased blood flow, and other stressful conditions can drastically effect the intracellular concentrations of these energy compounds. Skeletal muscle, unlike the heart, can address this drop in ATP by employing the myokinase reaction, ultimately producing ATP with a subsequent elevation in adenosine monophosphate (AMP). Ribose, a naturally occurring 5-carbon monosaccharide, is a key component of RNA, DNA (which has deoxyribose), acetyl coenzyme A, and ATP. Each cell produces its own ribose, involved in the pentose phosphate pathway (PPP), to aid in ATP production. States of ischemia and/or hypoxia can severely lower levels of cellular energy compounds in the heart, with an associated compromise in cellular processes, ultimately reflected in altered function. Ribose appears to provide a solution to the problem in replenishing the depressed ATP levels and improving functional status of patients afflicted with cardiovascular diseases.

The ultimate legs of Chilopoda (Myriapoda): a review on their morphological disparity and functional variability

PubMed Central

Kenning, Matthes; Müller, Carsten H.G.

2017-01-01

The arthropodium is the key innovation of arthropods. Its various modifications are the outcome of multiple evolutionary transformations, and the foundation of nearly endless functional possibilities. In contrast to hexapods, crustaceans, and even chelicerates, the spectrum of evolutionary transformations of myriapod arthropodia is insufficiently documented and rarely scrutinized. Among Myriapoda, Chilopoda (centipedes) are characterized by their venomous forcipules—evolutionarily transformed walking legs of the first trunk segment. In addition, the posterior end of the centipedes’ body, in particular the ultimate legs, exhibits a remarkable morphological heterogeneity. Not participating in locomotion, they hold a vast functional diversity. In many centipede species, elongation and annulation in combination with an augmentation of sensory structures indicates a functional shift towards a sensory appendage. In other species, thickening, widening and reinforcement with a multitude of cuticular protuberances and glandular systems suggests a role in both attack and defense. Moreover, sexual dimorphic characteristics indicate that centipede ultimate legs play a pivotal role in intraspecific communication, mate finding and courtship behavior. We address ambiguous identifications and designations of podomeres in order to point out controversial aspects of homology and homonymy. We provide a broad summary of descriptions, illustrations, ideas and observations published in past 160 years, and propose that studying centipede ultimate legs is not only essential in itself for filling gaps of knowledge in descriptive morphology, but also provides an opportunity to explore diverse pathways of leg transformations within Myriapoda. PMID:29158971

Biomass for thermochemical conversion: targets and challenges

PubMed Central

Tanger, Paul; Field, John L.; Jahn, Courtney E.; DeFoort, Morgan W.; Leach, Jan E.

2013-01-01

Bioenergy will be one component of a suite of alternatives to fossil fuels. Effective conversion of biomass to energy will require the careful pairing of advanced conversion technologies with biomass feedstocks optimized for the purpose. Lignocellulosic biomass can be converted to useful energy products via two distinct pathways: enzymatic or thermochemical conversion. The thermochemical pathways are reviewed and potential biotechnology or breeding targets to improve feedstocks for pyrolysis, gasification, and combustion are identified. Biomass traits influencing the effectiveness of the thermochemical process (cell wall composition, mineral and moisture content) differ from those important for enzymatic conversion and so properties are discussed in the language of biologists (biochemical analysis) as well as that of engineers (proximate and ultimate analysis). We discuss the genetic control, potential environmental influence, and consequences of modification of these traits. Improving feedstocks for thermochemical conversion can be accomplished by the optimization of lignin levels, and the reduction of ash and moisture content. We suggest that ultimate analysis and associated properties such as H:C, O:C, and heating value might be more amenable than traditional biochemical analysis to the high-throughput necessary for the phenotyping of large plant populations. Expanding our knowledge of these biomass traits will play a critical role in the utilization of biomass for energy production globally, and add to our understanding of how plants tailor their composition with their environment. PMID:23847629

The Cardiopulmonary Effects of Ambient Air Pollution and Mechanistic Pathways: A Comparative Hierarchical Pathway Analysis

PubMed Central

Thomas, Duncan C.; Zhang, Junfeng; Kipen, Howard M.; Rich, David Q.; Zhu, Tong; Huang, Wei; Hu, Min; Wang, Guangfa; Wang, Yuedan; Zhu, Ping; Lu, Shou-En; Ohman-Strickland, Pamela; Diehl, Scott R.; Eckel, Sandrah P.

2014-01-01

Previous studies have investigated the associations between exposure to ambient air pollution and biomarkers of physiological pathways, yet little has been done on the comparison across biomarkers of different pathways to establish the temporal pattern of biological response. In the current study, we aim to compare the relative temporal patterns in responses of candidate pathways to different pollutants. Four biomarkers of pulmonary inflammation and oxidative stress, five biomarkers of systemic inflammation and oxidative stress, ten parameters of autonomic function, and three biomarkers of hemostasis were repeatedly measured in 125 young adults, along with daily concentrations of ambient CO, PM2.5, NO2, SO2, EC, OC, and sulfate, before, during, and after the Beijing Olympics. We used a two-stage modeling approach, including Stage I models to estimate the association between each biomarker and pollutant over each of 7 lags, and Stage II mixed-effect models to describe temporal patterns in the associations when grouping the biomarkers into the four physiological pathways. Our results show that candidate pathway groupings of biomarkers explained a significant amount of variation in the associations for each pollutant, and the temporal patterns of the biomarker-pollutant-lag associations varied across candidate pathways (p<0.0001) and were not linear (from lag 0 to lag 3: p = 0.0629, from lag 3 to lag 6: p = 0.0005). These findings suggest that, among this healthy young adult population, the pulmonary inflammation and oxidative stress pathway is the first to respond to ambient air pollution exposure (within 24 hours) and the hemostasis pathway responds gradually over a 2–3 day period. The initial pulmonary response may contribute to the more gradual systemic changes that likely ultimately involve the cardiovascular system. PMID:25502951

Advancing a multivalent ‘Pan-anthelmintic’ vaccine against soil-transmitted nematode infections

PubMed Central

Zhan, Bin; Beaumier, Coreen M; Briggs, Neima; Jones, Kathryn M; Keegan, Brian P; Bottazzi, Maria Elena; Hotez, Peter J

2014-01-01

Ascaris lumbricoides The Sabin Vaccine Institute Product Development Partnership is developing a Pan-anthelmintic vaccine that simultaneously targets the major soil-transmitted nematode infections, in other words, ascariasis, trichuriasis and hookworm infection. The approach builds off the current bivalent Human Hookworm Vaccine now in clinical development and would ultimately add both a larval Ascaris lumbricoides antigen and an adult-stage Trichuris trichiura antigen from the parasite stichosome. Each selected antigen would partially reproduce the protective immunity afforded by UV-attenuated Ascaris eggs and Trichuris stichosome extracts, respectively. Final antigen selection will apply a ranking system that includes the evaluation of expression yields and solubility, feasibility of process development and the absence of circulating antigen-specific IgE among populations living in helminth-endemic regions. Here we describe a five year roadmap for the antigen discovery, feasibility and antigen selection, which will ultimately lead to the scale-up expression, process development, manufacture, good laboratory practices toxicology and preclinical evaluation, ultimately leading to Phase 1 clinical testing. PMID:24392641

Neo-Darwinists and Neo-Aristotelians: how to talk about natural purpose.

PubMed

Woodford, Peter

2016-12-01

This paper examines the points of disagreement between Neo-Darwinian and recent Neo-Aristotelian discussions of the status of purposive language in biology. I discuss recent Neo-Darwinian "evolutionary" treatments and distinguish three ways to deal with the philosophical status of teleological language of purpose: teleological error theory, methodological teleology, and Darwinian teleological realism. I then show how "non-evolutionary" Neo-Aristotelian approaches in the work of Michael Thompson and Philippa Foot differ from these by offering a view of purposiveness grounded in life-cycle patterns, rather than in long-term evolutionary processes or natural selection. Finally, I argue that the crucial difference between Neo-Darwinian and Neo-Aristotelian approaches regards the question of whether or not reproduction deserves the status of an "ultimate" aim of organisms. I offer reasons to reject the concept of an "ultimate" aim in evolutionary biology and to reject the notion that reproduction serves a purpose. I argue that evolutionary biology is not in the position to determine what the "ultimate" explanation of natural purpose is.

Patents for Toll-like receptor ligands as radiation countermeasures for acute radiation syndrome.

PubMed

Singh, Vijay K; Pollard, Harvey B

2015-01-01

Acute radiation exposure induces apoptosis of tissues in the hematopoietic, digestive, cutaneous, cardiovascular and nervous systems; extensive apoptosis of these tissues ultimately leads to acute radiation syndrome. A novel strategy for developing radiation countermeasures has been to imitate the genetic mechanisms acquired by radiation-resistant tumors. Two mechanisms that underlie this ability of tumor cells are the p53 and NF-κB pathways. The loss of p53 function results in the inactivation of pro-apoptotic control mechanisms, while constitutive activation of NF-κB results in the up-regulation of anti-apoptotic genes. Various Toll-like receptor ligands are capable of up regulating the NF-κB pathway, which increases radio-resistance and reduces radiation-induced apoptosis in various tissues. Several Toll-like receptor ligands have been patented and are currently under development as radiation countermeasures for acute radiation syndrome. Ongoing studies suggest that a few of these attractive agents are progressing well along the US FDA approval pathway to become radiation countermeasures.

The causative role and therapeutic potential of the kynurenine pathway in neurodegenerative disease.

PubMed

Amaral, Marta; Outeiro, Tiago F; Scrutton, Nigel S; Giorgini, Flaviano

2013-06-01

Metabolites of the kynurenine pathway (KP), which arise from the degradation of tryptophan, have been studied in detail for over a century and garnered the interest of the neuroscience community in the late 1970s and early 1980s with work uncovering the neuromodulatory potential of this pathway. Much research in the following decades has found that perturbations in the levels of KP metabolites likely contribute to the pathogenesis of several neurodegenerative diseases. More recently, it has become apparent that targeting KP enzymes, in particular kynurenine 3-monooxygenase (KMO), may hold substantial therapeutic potential for these disorders. Here we provide an overview of the KP, the neuroactive properties of KP metabolites and their role in neurodegeneration. We also discuss KMO as a therapeutic target for these disorders, and our recent resolution of the crystallographic structure of KMO, which will permit the development of new and improved KMO inhibitors which may ultimately expedite clinical application of these compounds.

Patents for Toll-like receptor ligands as radiation countermeasures for acute radiation syndrome

PubMed Central

Singh, Vijay K; Pollard, Harvey B

2015-01-01

Acute radiation exposure induces apoptosis of tissues in the hematopoietic, digestive, cutaneous, cardiovascular and nervous systems; extensive apoptosis of these tissues ultimately leads to acute radiation syndrome. A novel strategy for developing radiation countermeasures has been to imitate the genetic mechanisms acquired by radiation-resistant tumors. Two mechanisms that underlie this ability of tumor cells are the p53 and NF-κB pathways. The loss of p53 function results in the inactivation of pro-apoptotic control mechanisms, while constitutive activation of NF-κB results in the up-regulation of anti-apoptotic genes. Various Toll-like receptor ligands are capable of up regulating the NF-κB pathway, which increases radio-resistance and reduces radiation-induced apoptosis in various tissues. Several Toll-like receptor ligands have been patented and are currently under development as radiation countermeasures for acute radiation syndrome. Ongoing studies suggest that a few of these attractive agents are progressing well along the US FDA approval pathway to become radiation countermeasures. PMID:26135043

Autophagy: not good OR bad, but good AND bad.

PubMed

Altman, Brian J; Rathmell, Jeffrey C

2009-05-01

Autophagy is a well-established mechanism to degrade intracellular components and provide a nutrient source to promote survival of cells in metabolic distress. Such stress can be caused by a lack of available nutrients or by insufficient rates of nutrient uptake. Indeed, growth factor deprivation leads to internalization and degradation of nutrient transporters, leaving cells with limited means to access extracellular nutrients even when plentiful.This loss of growth factor signaling and extracellular nutrients ultimately leads to apoptosis, but also activates autophagy, which may degrade intracellular components and provide fuel for mitochondrial bioenergetics. The precise metabolic role of autophagy and how it intersects with the apoptotic pathways in growth factor withdrawal, however, has been uncertain. Our recent findings ingrowth factor-deprived hematopoietic cells show that autophagy can simultaneously contribute to cell metabolism and initiate a pathway to sensitize cells to apoptotic death. This pathway may promote tissue homeostasis by ensuring that only cells with high resistance to apoptosis may utilize autophagy as a survival mechanism when growth factors are limiting and nutrient uptake decreases.

Convergence of isoprene and polyketide biosynthetic machinery: isoprenyl-S-carrier proteins in the pksX pathway of Bacillus subtilis.

PubMed

Calderone, Christopher T; Kowtoniuk, Walter E; Kelleher, Neil L; Walsh, Christopher T; Dorrestein, Pieter C

2006-06-13

The pksX gene cluster from Bacillus subtilis is predicted to encode the biosynthesis of an as yet uncharacterized hybrid nonribosomal peptide/polyketide secondary metabolite. We used a combination of biochemical and mass spectrometric techniques to assign functional roles to the proteins AcpK, PksC, PksL, PksF, PksG, PksH, and PksI, and we conclude that they act to incorporate an acetate-derived beta-methyl branch on an acetoacetyl-S-carrier protein and ultimately generate a Delta(2)-isoprenyl-S-carrier protein. This work highlights the power of mass spectrometry to elucidate the functions of orphan biosynthetic enzymes, and it details a mechanism by which single-carbon beta-branches can be inserted into polyketide-like structures. This pathway represents a noncanonical route to the construction of prenyl units and serves as a prototype for the intersection of isoprenoid and polyketide biosynthetic manifolds in other natural product biosynthetic pathways.

Analysis of EAWAG-BBD pathway prediction system for the identification of malathion degrading microbes

PubMed Central

Sivakumar, Subramaniam; Anitha, Palanivel; Ramesh, Balsubramanian; Suresh, Gopal

2017-01-01

Insecticides are the toxic substances that are used to kill insects. The use of insecticides is believed to be one of the major factors behind the increase in agricultural productivity in the 20th century. The organophosphates are now the largest and most versatile class of insecticide used and Malathion is the predominant type utilized. The accumulation of Malathion in environment is the biggest threat to the environment because of its toxicity. Malathion is lethal to beneficial insects, snails, micro crustaceans, fish, birds, amphibians, and soil microorganisms. Chronic exposure of non-diabetic farmers to organophosphorus Malathion pesticides may induce insulin resistance, which might ultimately results in diabetes mellitus. Given the potential carcinogenic risk from the pesticides there is serious need to develop remediation processes to eliminate or minimize contamination in the environment. Biodegradation could be a reliable and cost effective technique for pesticide abatement. Since today as there were no metabolic pathway predicted for the degradation of organophosphates pesticide Malathion in KEGG database or in any of the other pathway databases. Thus in the present study, an attempt has been made to predict the microbial biodegradation pathway of Malathion using bioinformatics tools. The present study predicted the degradation pathway for Malathion. The present study also identifies, Streptomyces sp. and E.coli are capable of degrading Malathion through pathway prediction system. PMID:28584447

Analysis of EAWAG-BBD pathway prediction system for the identification of malathion degrading microbes.

PubMed

Sivakumar, Subramaniam; Anitha, Palanivel; Ramesh, Balsubramanian; Suresh, Gopal

2017-01-01

Insecticides are the toxic substances that are used to kill insects. The use of insecticides is believed to be one of the major factors behind the increase in agricultural productivity in the 20th century. The organophosphates are now the largest and most versatile class of insecticide used and Malathion is the predominant type utilized. The accumulation of Malathion in environment is the biggest threat to the environment because of its toxicity. Malathion is lethal to beneficial insects, snails, micro crustaceans, fish, birds, amphibians, and soil microorganisms. Chronic exposure of non-diabetic farmers to organophosphorus Malathion pesticides may induce insulin resistance, which might ultimately results in diabetes mellitus. Given the potential carcinogenic risk from the pesticides there is serious need to develop remediation processes to eliminate or minimize contamination in the environment. Biodegradation could be a reliable and cost effective technique for pesticide abatement. Since today as there were no metabolic pathway predicted for the degradation of organophosphates pesticide Malathion in KEGG database or in any of the other pathway databases. Thus in the present study, an attempt has been made to predict the microbial biodegradation pathway of Malathion using bioinformatics tools. The present study predicted the degradation pathway for Malathion. The present study also identifies, Streptomyces sp. and E.coli are capable of degrading Malathion through pathway prediction system.

Dynamic changes in global microRNAome and transcriptome reveal complex miRNA-mRNA regulated host response to Japanese Encephalitis Virus in microglial cells

PubMed Central

Kumari, Bharti; Jain, Pratistha; Das, Shaoli; Ghosal, Suman; Hazra, Bibhabasu; Trivedi, Ashish Chandra; Basu, Anirban; Chakrabarti, Jayprokas; Vrati, Sudhanshu; Banerjee, Arup

2016-01-01

Microglia cells in the brain play essential role during Japanese Encephalitis Virus (JEV) infection and may lead to change in microRNA (miRNA) and mRNA profile. These changes may together control disease outcome. Using Affymetrix microarray platform, we profiled cellular miRNA and mRNA expression at multiple time points during viral infection in human microglial (CHME3) cells. In silico analysis of microarray data revealed a phased pattern of miRNAs expression, associated with JEV replication and provided unique signatures of infection. Target prediction and pathway enrichment analysis identified anti correlation between differentially expressed miRNA and the gene expression at multiple time point which ultimately affected diverse signaling pathways including Notch signaling pathways in microglia. Activation of Notch pathway during JEV infection was demonstrated in vitro and in vivo. The expression of a subset of miRNAs that target multiple genes in Notch signaling pathways were suppressed and their overexpression could affect JEV induced immune response. Further analysis provided evidence for the possible presence of cellular competing endogenous RNA (ceRNA) associated with innate immune response. Collectively, our data provide a uniquely comprehensive view of the changes in the host miRNAs induced by JEV during cellular infection and identify Notch pathway in modulating microglia mediated inflammation. PMID:26838068

Dynamic changes in global microRNAome and transcriptome reveal complex miRNA-mRNA regulated host response to Japanese Encephalitis Virus in microglial cells.

PubMed

Kumari, Bharti; Jain, Pratistha; Das, Shaoli; Ghosal, Suman; Hazra, Bibhabasu; Trivedi, Ashish Chandra; Basu, Anirban; Chakrabarti, Jayprokas; Vrati, Sudhanshu; Banerjee, Arup

2016-02-03

Microglia cells in the brain play essential role during Japanese Encephalitis Virus (JEV) infection and may lead to change in microRNA (miRNA) and mRNA profile. These changes may together control disease outcome. Using Affymetrix microarray platform, we profiled cellular miRNA and mRNA expression at multiple time points during viral infection in human microglial (CHME3) cells. In silico analysis of microarray data revealed a phased pattern of miRNAs expression, associated with JEV replication and provided unique signatures of infection. Target prediction and pathway enrichment analysis identified anti correlation between differentially expressed miRNA and the gene expression at multiple time point which ultimately affected diverse signaling pathways including Notch signaling pathways in microglia. Activation of Notch pathway during JEV infection was demonstrated in vitro and in vivo. The expression of a subset of miRNAs that target multiple genes in Notch signaling pathways were suppressed and their overexpression could affect JEV induced immune response. Further analysis provided evidence for the possible presence of cellular competing endogenous RNA (ceRNA) associated with innate immune response. Collectively, our data provide a uniquely comprehensive view of the changes in the host miRNAs induced by JEV during cellular infection and identify Notch pathway in modulating microglia mediated inflammation.

[Association of Inorganics Accumulation with the Activation of NF-κB Signaling Pathway and the iNOS Expression of Lung Tissue in Xuanwei Lung Cancer Patients].

PubMed

Yang, Jiapeng; Li, Guangjian; Huang, Yunchao; Ye, Lianhua; Zhou, Yongchun; Zhao, Guangqiang; Lei, Yujie; Chen, Xiaobo; Wang, Kun; Chen, Ying; Dai, Chun; Zhang, Yanjun

2016-01-01

Indoor air pollution induces asthma, leads to chronic obstructive pulmonary disease, and may promote lung cancer. Our previous studies found that the accumulation of inorganic particulate matter that is due to indoor air pollution can lead to damage to alveolar cells and activation of signaling pathway, and ultimately provoke tumorigenesis. The aim of this study is to explore the accumulation of inorganics and activation of nuclear factor κB (NF-κB)-inducible nitric oxide synthase (iNOS) signaling pathway of lung tissue in Xuanwei lung cancer patients. From December 2013 to November 2014, 48 cases Xuanwei patients with lung cancer who underwent surgical treatment from the Third Affiliated Hospital of Kunming Medical University were enrolled in this study and compared with lung cancer patients from other regions. The ultrastructure of postoperative specimens was observed by transmission electron microscopy (TEM) to explore the occurrence of inorganic particles. Serum cytokines were analyzed. Then, the expression levels of NF-κB-p65 protein and iNOS protein in postoperative specimens was explored by immunohistochemistry and Western blot. Finally, 8-OHdG accumulation in lung cancer tissues and urine was measured. A large number of nanoscale inorganics were observed in alveolar type II cells and macrophages located in adjacent tissues of lung cancer with Xuanwei patients. Silicon (Si) content was found in inorganic elemental analysis. The serum interleukin (IL)-1β levels (31.50 ± 19.16) pg/mL of Xuanwei lung-cancer patients were remarkably higher than those from other regions (11.33 ± 6.94) pg/mL (P<0.01), with statistically significant difference. The pathological tissues of Xuanwei lung-cancer patients express NF-κB-p65, and iNOS expression were significantly higher than those of patients from non-Xuanwei regions. No significant difference was found between cancerous and normal adjacent tissues. Xuanwei lung-cancer tissues and urine 8-OHdG level (40.124 ± 8.597) ng/mgCr were significantly higher than those of patients from other regions (25.673 ± 7.986) ng/mg Cr (P<0.05), with statistically significant difference. The accumulation of inorganics and the activation of NF-κB-iNOS signaling pathway may contribute to Xuanwei lung cancer.
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GeLC-MS-based proteomics of Chromobacterium violaceum: comparison of proteome changes elicited by hydrogen peroxide

PubMed Central

Lima, D. C.; Duarte, F. T.; Medeiros, V. K. S.; Carvalho, P. C.; Nogueira, F. C. S.; Araujo, G. D. T.; Domont, G. B.; Batistuzzo de Medeiros, S. R.

2016-01-01

Chromobacterium violaceum is a free-living bacillus with several genes that enables it survival under different harsh environments such as oxidative and temperature stresses. Here we performed a label-free quantitative proteomic study to unravel the molecular mechanisms that enable C. violaceum to survive oxidative stress. To achieve this, total proteins extracted from control and C. violaceum cultures exposed during two hours with 8 mM hydrogen peroxide were analyzed using GeLC-MS proteomics. Analysis revealed that under the stress condition, the bacterium expressed proteins that protected it from the damage caused by reactive oxygen condition and decreasing the abundance of proteins responsible for bacterial growth and catabolism. GeLC-MS proteomics analysis provided an overview of the metabolic pathways involved in the response of C. violaceum to oxidative stress ultimately aggregating knowledge of the response of this organism to environmental stress. This study identified approximately 1500 proteins, generating the largest proteomic coverage of C. violaceum so far. We also detected proteins with unknown function that we hypothesize to be part of new mechanisms related to oxidative stress defense. Finally, we identified the mechanism of clustered regularly interspaced short palindromic repeats (CRISPR), which has not yet been reported for this organism. PMID:27321545

GeLC-MS-based proteomics of Chromobacterium violaceum: comparison of proteome changes elicited by hydrogen peroxide.

PubMed

Lima, D C; Duarte, F T; Medeiros, V K S; Carvalho, P C; Nogueira, F C S; Araujo, G D T; Domont, G B; Batistuzzo de Medeiros, S R

2016-06-20

Chromobacterium violaceum is a free-living bacillus with several genes that enables it survival under different harsh environments such as oxidative and temperature stresses. Here we performed a label-free quantitative proteomic study to unravel the molecular mechanisms that enable C. violaceum to survive oxidative stress. To achieve this, total proteins extracted from control and C. violaceum cultures exposed during two hours with 8 mM hydrogen peroxide were analyzed using GeLC-MS proteomics. Analysis revealed that under the stress condition, the bacterium expressed proteins that protected it from the damage caused by reactive oxygen condition and decreasing the abundance of proteins responsible for bacterial growth and catabolism. GeLC-MS proteomics analysis provided an overview of the metabolic pathways involved in the response of C. violaceum to oxidative stress ultimately aggregating knowledge of the response of this organism to environmental stress. This study identified approximately 1500 proteins, generating the largest proteomic coverage of C. violaceum so far. We also detected proteins with unknown function that we hypothesize to be part of new mechanisms related to oxidative stress defense. Finally, we identified the mechanism of clustered regularly interspaced short palindromic repeats (CRISPR), which has not yet been reported for this organism.

Multi-Scale Microstructural Thermoelectric Materials: Transport Behavior, Non-Equilibrium Preparation, and Applications.

PubMed

Su, Xianli; Wei, Ping; Li, Han; Liu, Wei; Yan, Yonggao; Li, Peng; Su, Chuqi; Xie, Changjun; Zhao, Wenyu; Zhai, Pengcheng; Zhang, Qingjie; Tang, Xinfeng; Uher, Ctirad

2017-05-01

Considering only about one third of the world's energy consumption is effectively utilized for functional uses, and the remaining is dissipated as waste heat, thermoelectric (TE) materials, which offer a direct and clean thermal-to-electric conversion pathway, have generated a tremendous worldwide interest. The last two decades have witnessed a remarkable development in TE materials. This Review summarizes the efforts devoted to the study of non-equilibrium synthesis of TE materials with multi-scale structures, their transport behavior, and areas of applications. Studies that work towards the ultimate goal of developing highly efficient TE materials possessing multi-scale architectures are highlighted, encompassing the optimization of TE performance via engineering the structures with different dimensional aspects spanning from the atomic and molecular scales, to nanometer sizes, and to the mesoscale. In consideration of the practical applications of high-performance TE materials, the non-equilibrium approaches offer a fast and controllable fabrication of multi-scale microstructures, and their scale up to industrial-size manufacturing is emphasized here. Finally, the design of two integrated power generating TE systems are described-a solar thermoelectric-photovoltaic hybrid system and a vehicle waste heat harvesting system-that represent perhaps the most important applications of thermoelectricity in the energy conversion area. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Pathway to Support the Sustainable National Health Information System

NASA Astrophysics Data System (ADS)

Sahavechaphan, Naiyana; Phengsuwan, Jedsada; U-Ruekolan, Suriya; Aroonrua, Kamron; Ponhan, Jukrapong; Harnsamut, Nattapon; Vannarat, Sornthep

Heath information across geographically distributed healthcare centers has been recognized as an essential resource that drives an efficient national health-care plan. There is thus a need for the National Health Information System (NHIS) that provides the transparent and secure access to health information from different healthcare centers both on demand and in a time efficient manner. As healthiness is the ultimate goal of people and nation, we believe that the NHIS should be sustainable by taking the healthcare center and information consumer perspectives into account. Several issues in particular must be resolved altogether: (i) the diversity of health information structures among healthcare centers; (ii) the availability of health information sharing from healthcare centers; (iii) the efficient information access to various healthcare centers; and (iv) the privacy and privilege of heath information. To achieve the sustainable NHIS, this paper details our work which is divided into 3 main phases. Essentially, the first phase focuses on the application of metadata standard to enable the interoperability and usability of health information across healthcare centers. The second phase moves forward to make information sharing possible and to provide an efficient information access to a large number of healthcare centers. Finally, in the third phase, the privacy and privilege of health information is promoted with respect to access rights of information consumers.

Post-GWAS in Psychiatric Genetics: A Developmental Perspective on the "Other" Next Steps.

PubMed

Dick, Danielle M; Barr, Peter B; Cho, Seung Bin; Cooke, Megan E; Kuo, Sally I-Chun; Lewis, Tenesha J; Neale, Zoe; Salvatore, Jessica E; Savage, Jeanne; Su, Jinni

2018-03-01

As psychiatric genetics enters an era where gene identification is finally yielding robust, replicable genetic associations and polygenic risk scores, it is important to consider next steps and delineate how that knowledge will be applied to ultimately ameliorate suffering associated with substance use and psychiatric disorders. Much of the post-genome-wide association study discussion has focused on the potential of genetic information to elucidate the underlying biology and use this information for the development of more effective pharmaceutical treatments. In this review we focus on additional areas of research that should follow gene identification. By taking genetic findings into longitudinal, developmental studies, we can map the pathways by which genetic risk manifests across development, elucidating the early behavioral manifestations of risk, and studying how various environments and interventions moderate that risk across developmental stages. The delineation of risk across development will advance our understanding of mechanism, sex differences and risk and resilience processes in different racial/ethnic groups. Here, we review how the extant twin study literature can be used to guide these efforts. Together, these new lines of research will enable us to develop more informed, tailored prevention and intervention efforts. © 2017 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

Calcium Influx and Male Fertility in the Context of the Sperm Proteome: An Update

PubMed Central

Rahman, Md Saidur; Kwon, Woo-Sung; Pang, Myung-Geol

2014-01-01

Freshly ejaculated spermatozoa are incapable or poorly capable of fertilizing an oocyte. The fertilization aptness of spermatozoa depends on the appropriate and time-dependent acquisition of hyperactivation, chemotaxis, capacitation, and the acrosome reaction, where calcium (Ca2+) is extensively involved in almost every step. A literature review showed that several ion channel proteins are likely responsible for regulation of the Ca2+ uptake in spermatozoa. Therefore, manipulation of the functions of channel proteins is closely related to Ca2+ influx, ultimately affecting male fertility. Recently, it has been shown that, together with different physiological stimuli, protein-protein interaction also modifies the Ca2+ influx mechanism in spermatozoa. Modern proteomic analyses have identified several sperm proteins, and, therefore, these findings might provide further insight into understanding the Ca2+ influx, protein functions, and regulation of fertility. The objective of this review was to synthesize the published findings on the Ca2+ influx mechanism in mammalian spermatozoa and its implications for the regulation of male fertility in the context of sperm proteins. Finally, Pathway Studio (9.0) was used to catalog the sperm proteins that regulate the Ca2+ influx signaling by using the information available from the PubMed database following a MedScan Reader (5.0) search. PMID:24877140

Cardiac Conduction through Engineered Tissue

PubMed Central

Choi, Yeong-Hoon; Stamm, Christof; Hammer, Peter E.; Kwaku, Kevin F.; Marler, Jennifer J.; Friehs, Ingeborg; Jones, Mara; Rader, Christine M.; Roy, Nathalie; Eddy, Mau-Thek; Triedman, John K.; Walsh, Edward P.; McGowan, Francis X.; del Nido, Pedro J.; Cowan, Douglas B.

2006-01-01

In children, interruption of cardiac atrioventricular (AV) electrical conduction can result from congenital defects, surgical interventions, and maternal autoimmune diseases during pregnancy. Complete AV conduction block is typically treated by implanting an electronic pacemaker device, although long-term pacing therapy in pediatric patients has significant complications. As a first step toward developing a substitute treatment, we implanted engineered tissue constructs in rat hearts to create an alternative AV conduction pathway. We found that skeletal muscle-derived cells in the constructs exhibited sustained electrical coupling through persistent expression and function of gap junction proteins. Using fluorescence in situ hybridization and polymerase chain reaction analyses, myogenic cells in the constructs were shown to survive in the AV groove of implanted hearts for the duration of the animal’s natural life. Perfusion of hearts with fluorescently labeled lectin demonstrated that implanted tissues became vascularized and immunostaining verified the presence of proteins important in electromechanical integration of myogenic cells with surrounding recipient rat cardiomyocytes. Finally, using optical mapping and electrophysiological analyses, we provide evidence of permanent AV conduction through the implant in one-third of recipient animals. Our experiments provide a proof-of-principle that engineered tissue constructs can function as an electrical conduit and, ultimately, may offer a substitute treatment to conventional pacing therapy. PMID:16816362

Towards computer-assisted surgery in shoulder joint replacement

NASA Astrophysics Data System (ADS)

Valstar, Edward R.; Botha, Charl P.; van der Glas, Marjolein; Rozing, Piet M.; van der Helm, Frans C. T.; Post, Frits H.; Vossepoel, Albert M.

A research programme that aims to improve the state of the art in shoulder joint replacement surgery has been initiated at the Delft University of Technology. Development of improved endoprostheses for the upper extremities (DIPEX), as this effort is called, is a clinically driven multidisciplinary programme consisting of many contributory aspects. A part of this research programme focuses on the pre-operative planning and per-operative guidance issues. The ultimate goal of this part of the DIPEX project is to create a surgical support infrastructure that can be used to predict the optimal surgical protocol and can assist with the selection of the most suitable endoprosthesis for a particular patient. In the pre-operative planning phase, advanced biomechanical models of the endoprosthesis fixation and the musculo-skeletal system of the shoulder will be incorporated, which are adjusted to the individual's morphology. Subsequently, the support infrastructure must assist the surgeon during the operation in executing his surgical plan. In the per-operative phase, the chosen optimal position of the endoprosthesis can be realised using camera-assisted tools or mechanical guidance tools. In this article, the pathway towards the desired surgical support infrastructure is described. Furthermore, we discuss the pre-operative planning phase and the per-operative guidance phase, the initial work performed, and finally, possible approaches for improving prosthesis placement.

Carbon isotope variations in a solar pond microbial mat: Role of environmental gradients as steering variables

NASA Astrophysics Data System (ADS)

Schidlowski, Manfred; Gorzawski, Hendrik; Dor, Inka

1994-05-01

A biogeochemical traverse is presented for a juvenile benthic mat covering the depth profile of an artificially stratified and eutrophicated hypersaline heliothermal pond with known gradients of temperature, salinity, pH, and light transmission. It can be shown that visual mat development depends primarily on temperature and salinity as main environmental steering variables whose increase with depth goes along with the attenuation and final disappearance of a visible microbial film in the pond's hypolimnic compartment. Recorded biogeochemical parameters (C org content, cell numbers, chlorophyll-a content) evidently reflect, as either biomass- or productivity-related index functions, the visually perceptible growth gradient of the microbial ecosystem along the pond slope. The observed coincidence of maxima in these index functions with maxima in δ13Corg clearly identifies high rates of primary productivity as the agent ultimately responsible for the generation of isotopically heavy ( 13C-enriched) biomass in these and related environments. Extreme demands placed on the local feeder pool of dissolved inorganic carbon by high rates of primary productivity entertained by the mat-forming microbenthos obviously give rise to severe CO 2 limitation, enforcing the operation of a diffusion-(supply-)limited assimilatory pathway with an isotopically indiscriminate metabolization of the available CO 2 resources.

Hypertrophic scar contracture is mediated by the TRPC3 mechanical force transducer via NFkB activation

PubMed Central

Ishise, Hisako; Larson, Barrett; Hirata, Yutaka; Fujiwara, Toshihiro; Nishimoto, Soh; Kubo, Tateki; Matsuda, Ken; Kanazawa, Shigeyuki; Sotsuka, Yohei; Fujita, Kazutoshi; Kakibuchi, Masao; Kawai, Kenichiro

2015-01-01

Wound healing process is a complex and highly orchestrated process that ultimately results in the formation of scar tissue. Hypertrophic scar contracture is considered to be a pathologic and exaggerated wound healing response that is known to be triggered by repetitive mechanical forces. We now show that Transient Receptor Potential (TRP) C3 regulates the expression of fibronectin, a key regulatory molecule involved in the wound healing process, in response to mechanical strain via the NFkB pathway. TRPC3 is highly expressed in human hypertrophic scar tissue and mechanical stimuli are known to upregulate TRPC3 expression in human skin fibroblasts in vitro. TRPC3 overexpressing fibroblasts subjected to repetitive stretching forces showed robust expression levels of fibronectin. Furthermore, mechanical stretching of TRPC3 overexpressing fibroblasts induced the activation of nuclear factor-kappa B (NFκB), a regulator fibronectin expression, which was able to be attenuated by pharmacologic blockade of either TRPC3 or NFκB. Finally, transplantation of TRPC3 overexpressing fibroblasts into mice promoted wound contraction and increased fibronectin levels in vivo. These observations demonstrate that mechanical stretching drives fibronectin expression via the TRPC3-NFkB axis, leading to intractable wound contracture. This model explains how mechanical strain on cutaneous wounds might contribute to pathologic scarring. PMID:26108359

The Emergence of Physiology and Form: Natural Selection Revisited

PubMed Central

Torday, John S.

2016-01-01

Natural Selection describes how species have evolved differentially, but it is descriptive, non-mechanistic. What mechanisms does Nature use to accomplish this feat? One known way in which ancient natural forces affect development, phylogeny and physiology is through gravitational effects that have evolved as mechanotransduction, seen in the lung, kidney and bone, linking as molecular homologies to skin and brain. Tracing the ontogenetic and phylogenetic changes that have facilitated mechanotransduction identifies specific homologous cell-types and functional molecular markers for lung homeostasis that reveal how and why complex physiologic traits have evolved from the unicellular to the multicellular state. Such data are reinforced by their reverse-evolutionary patterns in chronic degenerative diseases. The physiologic responses of model organisms like Dictyostelium and yeast to gravity provide deep comparative molecular phenotypic homologies, revealing mammalian Target of Rapamycin (mTOR) as the final common pathway for vertical integration of vertebrate physiologic evolution; mTOR integrates calcium/lipid epistatic balance as both the proximate and ultimate positive selection pressure for vertebrate physiologic evolution. The commonality of all vertebrate structure-function relationships can be reduced to calcium/lipid homeostatic regulation as the fractal unit of vertebrate physiology, demonstrating the primacy of the unicellular state as the fundament of physiologic evolution. PMID:27534726

"The Evolution of Photosynthesis and the Transition from an Anaerobic to an Aerobic World"

NASA Technical Reports Server (NTRS)

Blankenship, Robert E.

2005-01-01

This project was focused on elucidating the evolution of photosynthesis, in particular the evolutionary developments that preceded and accompanied the transition from anoxygenic to oxygenic photosynthesis. Development of this process has clearly been of central importance to evolution of life on Earth. Photosynthesis is the mechanism that ultimately provides for the energy needs of most surface-dwelling organisms. Eukaryotic organisms are absolutely dependent on the molecular oxygen that has been produced by oxygenic photosynthesis. In this project we have employed a multidisciplinary approach to understand some of the processes that took place during the evolution of photosynthesis. In this project, we made excellent progress in the overall area of understanding the origin and evolution of photosynthesis. Particular progress has been made on several more specific research questions, including the molecular evolutionary analysis of photosynthetic components and biosynthetic pathways (2,3, 5, 7, 10), as well as biochemical characterization of electron transfer proteins related to photosynthesis and active oxygen protection (4,6,9). Finally, several review and commentary papers have been published (1, 8, 1 1). A total of twelve publications arose out of this grant, references to which are given below. Some specific areas of progress are highlighted and discussed in more detail.

Biological pathways, candidate genes and molecular markers associated with quality-of-life domains: an update

PubMed Central

Sprangers, Mirjam A.G.; Thong, Melissa S.Y.; Bartels, Meike; Barsevick, Andrea; Ordoñana, Juan; Shi, Qiuling; Wang, Xin Shelley; Klepstad, Pål; Wierenga, Eddy A.; Singh, Jasvinder A.; Sloan, Jeff A.

2014-01-01

Background There is compelling evidence of a genetic foundation of patient-reported QOL. Given the rapid development of substantial scientific advances in this area of research, the current paper updates and extends reviews published in 2010. Objectives The objective is to provide an updated overview of the biological pathways, candidate genes and molecular markers involved in fatigue, pain, negative (depressed mood) and positive (well-being/happiness) emotional functioning, social functioning, and overall QOL. Methods We followed a purposeful search algorithm of existing literature to capture empirical papers investigating the relationship between biological pathways and molecular markers and the identified QOL domains. Results Multiple major pathways are involved in each QOL domain. The inflammatory pathway has the strongest evidence as a controlling mechanism underlying fatigue. Inflammation and neurotransmission are key processes involved in pain perception and the COMT gene is associated with multiple sorts of pain. The neurotransmitter and neuroplasticity theories have the strongest evidence for their relationship with depression. Oxytocin-related genes and genes involved in the serotonergic and dopaminergic pathways play a role in social functioning. Inflammatory pathways, via cytokines, also play an important role in overall QOL. Conclusions Whereas the current findings need future experiments and replication efforts, they will provide researchers supportive background information when embarking on studies relating candidate genes and/or molecular markers to QOL domains. The ultimate goal of this area of research is to enhance patients’ QOL. PMID:24604075

Biological pathways, candidate genes, and molecular markers associated with quality-of-life domains: an update.

PubMed

Sprangers, Mirjam A G; Thong, Melissa S Y; Bartels, Meike; Barsevick, Andrea; Ordoñana, Juan; Shi, Qiuling; Wang, Xin Shelley; Klepstad, Pål; Wierenga, Eddy A; Singh, Jasvinder A; Sloan, Jeff A

2014-09-01

There is compelling evidence of a genetic foundation of patient-reported quality of life (QOL). Given the rapid development of substantial scientific advances in this area of research, the current paper updates and extends reviews published in 2010. The objective was to provide an updated overview of the biological pathways, candidate genes, and molecular markers involved in fatigue, pain, negative (depressed mood) and positive (well-being/happiness) emotional functioning, social functioning, and overall QOL. We followed a purposeful search algorithm of existing literature to capture empirical papers investigating the relationship between biological pathways and molecular markers and the identified QOL domains. Multiple major pathways are involved in each QOL domain. The inflammatory pathway has the strongest evidence as a controlling mechanism underlying fatigue. Inflammation and neurotransmission are key processes involved in pain perception, and the catechol-O-methyltransferase (COMT) gene is associated with multiple sorts of pain. The neurotransmitter and neuroplasticity theories have the strongest evidence for their relationship with depression. Oxytocin-related genes and genes involved in the serotonergic and dopaminergic pathways play a role in social functioning. Inflammatory pathways, via cytokines, also play an important role in overall QOL. Whereas the current findings need future experiments and replication efforts, they will provide researchers supportive background information when embarking on studies relating candidate genes and/or molecular markers to QOL domains. The ultimate goal of this area of research is to enhance patients' QOL.

Kinase Pathway Dependence in Primary Human Leukemias Determined by Rapid Inhibitor Screening

PubMed Central

Tyner, Jeffrey W.; Yang, Wayne F.; Bankhead, Armand; Fan, Guang; Fletcher, Luke B.; Bryant, Jade; Glover, Jason M.; Chang, Bill H.; Spurgeon, Stephen E.; Fleming, William H.; Kovacsovics, Tibor; Gotlib, Jason R.; Oh, Stephen T.; Deininger, Michael W.; Zwaan, C. Michel; Den Boer, Monique L.; van den Heuvel-Eibrink, Marry M.; O’Hare, Thomas; Druker, Brian J.; Loriaux, Marc M.

2012-01-01

Kinases are dysregulated in most cancer but the frequency of specific kinase mutations is low, indicating a complex etiology in kinase dysregulation. Here we report a strategy to rapidly identify functionally important kinase targets, irrespective of the etiology of kinase pathway dysregulation, ultimately enabling a correlation of patient genetic profiles to clinically effective kinase inhibitors. Our methodology assessed the sensitivity of primary leukemia patient samples to a panel of 66 small-molecule kinase inhibitors over 3 days. Screening of 151 leukemia patient samples revealed a wide diversity of drug sensitivities, with 70% of the clinical specimens exhibiting hypersensitivity to one or more drugs. From this data set, we developed an algorithm to predict kinase pathway dependence based on analysis of inhibitor sensitivity patterns. Applying this algorithm correctly identified pathway dependence in proof-of-principle specimens with known oncogenes, including a rare FLT3 mutation outside regions covered by standard molecular diagnostic tests. Interrogation of all 151 patient specimens with this algorithm identified a diversity of gene targets and signaling pathways that could aid prioritization of deep sequencing data sets, permitting a cumulative analysis to understand kinase pathway dependence within leukemia subsets. In a proof-of-principle case, we showed that in vitro drug sensitivity could predict both a clinical response and the development of drug resistance. Taken together, our results suggested that drug target scores derived from a comprehensive kinase inhibitor panel could predict pathway dependence in cancer cells while simultaneously identifying potential therapeutic options. PMID:23087056

Protopine, a novel microtubule-stabilizing agent, causes mitotic arrest and apoptotic cell death in human hormone-refractory prostate cancer cell lines.

PubMed

Chen, Chun-Han; Liao, Cho-Hwa; Chang, Ya-Ling; Guh, Jih-Hwa; Pan, Shiow-Lin; Teng, Che-Ming

2012-02-01

In this study, we investigated the anticancer effect of protopine on human hormone-refractory prostate cancer (HRPC) cells. Protopine exhibited an anti-proliferative effect by induction of tubulin polymerization and mitotic arrest, which ultimately led to apoptotic cell death. The data suggest that protopine increased the activity of cyclin-dependent kinase 1 (Cdk1)/cyclin B1 complex and that contributed to cell apoptosis by modulating mitochondria-mediated signaling pathways, such as Bcl-2 phosphorylation and Mcl-1 down-regulation. In conclusion, the data suggest that protopine is a novel microtubule stabilizer with anticancer activity in HRPC cells through apoptotic pathway by modulating Cdk1 activity and Bcl-2 family of proteins. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Brief Strategic Family Therapy for Young People in Treatment for Drug Use

ERIC Educational Resources Information Center

Lindstrøm, Maia; Filges, Trine; Jørgensen, Anne-Marie Klint

2015-01-01

Purpose: This review evaluates the evidence on the effects of brief strategic family therapy (BSFT) on drug use reduction for young people in treatment for nonopioid drug use. Method: We followed Campbell Collaboration guidelines to prepare this review and ultimately located three studies for final analysis and interpretation. Results: The results…

Early Childhood Technology Integrated Instructional System (EC-TIIS) Phase 1: A Final Report

ERIC Educational Resources Information Center

Hutinger, Patricia; Robinson, Linda; Schneider, Carol

2004-01-01

The Early Childhood Technology Integrated Instructional System (EC-TIIS), a Steppingstones of Technology Innovation Phase 1--Development project, was developed by the Center for Best Practices in Early Childhood (the Center) at Western Illinois University as an online instructional system. EC-TIIS' ultimate goal was to improve technology services…

Biodegradation of nonionic and anionic surfactants in domestic wastewater under simulated sewer conditions.

PubMed

Menzies, Jennifer Z; McDonough, Kathleen; McAvoy, Drew; Federle, Thomas W

2017-02-01

The ultimate disposition of chemicals discarded down the drain can be substantially impacted by their fate in the sewer, but to date limited data have been published on the biodegradability of chemicals in sewer systems. The recently established OECD 314 guideline (Simulation tests to assess the biodegradability of chemicals discharged in wastewater, 2008) contains a simulation method (314A) for evaluating the biodegradation of chemicals in sewage under simulated sewer conditions. This research used the OECD 314A method to evaluate the rates and pathways of primary and ultimate biodegradation of a suite of 14 C-labeled homologues representing four classes of high volume surfactants including nonionic alkyl ethoxylates (AE), and anionic alkyl ethoxysulfates (AES), alkyl sulfate (AS) and linear alkyl benzene sulfonate (LAS). All the tested homologues exhibited >97 % loss of parent, formation of metabolites, and some level (16-94 %) of CO 2 production after being incubated 96-100 h in raw domestic wastewater. Comparison of C 12 E 3 , C 14 E 3 , and C 16 E 3 showed that the first order biodegradation rate was affected by alkyl chain length with rates ranging from 6.8 h -1 for C 12 E 3 to 0.49 h -1 for C 16 E 3 . Conversely, comparison of C 14 E 1 , C 14 E 3 , and C 14 E 9 showed that the number of ethoxy units did not impact the biodegradation rate. AES and AS degraded quickly with first order kinetic rates of 1.9-3.7 and 41 h -1 respectively. LAS did not exhibit first order decay kinetics and primary degradation was slow. Biodegradation pathways were also determined. This work shows that biodegradation in the sewer has a substantial impact on levels of surfactants and surfactant metabolites that ultimately reach wastewater treatment plants.

Strategic larval decision-making in a bivoltine butterfly.

PubMed

Friberg, Magne; Dahlerus, Josefin; Wiklund, Christer

2012-07-01

In temperate areas, insect larvae must decide between entering winter diapause or developing directly and reproducing in the same season. Long daylength and high temperature promote direct development, which is generally associated with a higher growth rate. In this work, we investigated whether the larval pathway decision precedes the adjustment of growth rate (state-independent), or whether the pathway decision is conditional on the individual's growth rate (state-dependent), in the butterfly Pieris napi. This species typically makes the pathway decision in the penultimate instar. We measured growth rate throughout larval development under two daylengths: slightly shorter and slightly longer than the critical daylength. Results indicate that the pathway decision can be both state-independent and state-dependent; under the shorter daylength condition, most larvae entered diapause, and direct development was chosen exclusively by a small subset of larvae showing the highest growth rates already in the early instars; under the longer daylength condition, most larvae developed directly, and the diapause pathway was chosen exclusively by a small subset of slow-growing individuals. Among the remainder, the choice of pathway was independent of the early growth rate; larvae entering diapause under the short daylength grew as fast as or faster than the direct developers under the longer daylength in the early instars, whereas the direct developers grew faster than the diapausers only in the ultimate instar. Hence, the pathway decision was state-dependent in a subset with a very high or very low growth rate, whereas the decision was state-independent in the majority of the larvae, which made the growth rate adjustment downstream from the pathway decision.

Best strategies to implement clinical pathways in an emergency department setting: study protocol for a cluster randomized controlled trial.

PubMed

Jabbour, Mona; Curran, Janet; Scott, Shannon D; Guttman, Astrid; Rotter, Thomas; Ducharme, Francine M; Lougheed, M Diane; McNaughton-Filion, M Louise; Newton, Amanda; Shafir, Mark; Paprica, Alison; Klassen, Terry; Taljaard, Monica; Grimshaw, Jeremy; Johnson, David W

2013-05-22

The clinical pathway is a tool that operationalizes best evidence recommendations and clinical practice guidelines in an accessible format for 'point of care' management by multidisciplinary health teams in hospital settings. While high-quality, expert-developed clinical pathways have many potential benefits, their impact has been limited by variable implementation strategies and suboptimal research designs. Best strategies for implementing pathways into hospital settings remain unknown. This study will seek to develop and comprehensively evaluate best strategies for effective local implementation of externally developed expert clinical pathways. We will develop a theory-based and knowledge user-informed intervention strategy to implement two pediatric clinical pathways: asthma and gastroenteritis. Using a balanced incomplete block design, we will randomize 16 community emergency departments to receive the intervention for one clinical pathway and serve as control for the alternate clinical pathway, thus conducting two cluster randomized controlled trials to evaluate this implementation intervention. A minimization procedure will be used to randomize sites. Intervention sites will receive a tailored strategy to support full clinical pathway implementation. We will evaluate implementation strategy effectiveness through measurement of relevant process and clinical outcomes. The primary process outcome will be the presence of an appropriately completed clinical pathway on the chart for relevant patients. Primary clinical outcomes for each clinical pathway include the following: Asthma--the proportion of asthmatic patients treated appropriately with corticosteroids in the emergency department and at discharge; and Gastroenteritis--the proportion of relevant patients appropriately treated with oral rehydration therapy. Data sources include chart audits, administrative databases, environmental scans, and qualitative interviews. We will also conduct an overall process evaluation to assess the implementation strategy and an economic analysis to evaluate implementation costs and benefits. This study will contribute to the body of evidence supporting effective strategies for clinical pathway implementation, and ultimately reducing the research to practice gaps by operationalizing best evidence care recommendations through effective use of clinical pathways. ClinicalTrials.gov: NCT01815710.

Engineering dynamic pathway regulation using stress-response promoters.

PubMed

Dahl, Robert H; Zhang, Fuzhong; Alonso-Gutierrez, Jorge; Baidoo, Edward; Batth, Tanveer S; Redding-Johanson, Alyssa M; Petzold, Christopher J; Mukhopadhyay, Aindrila; Lee, Taek Soon; Adams, Paul D; Keasling, Jay D

2013-11-01

Heterologous pathways used in metabolic engineering may produce intermediates toxic to the cell. Dynamic control of pathway enzymes could prevent the accumulation of these metabolites, but such a strategy requires sensors, which are largely unknown, that can detect and respond to the metabolite. Here we applied whole-genome transcript arrays to identify promoters that respond to the accumulation of toxic intermediates, and then used these promoters to control accumulation of the intermediate and improve the final titers of a desired product. We apply this approach to regulate farnesyl pyrophosphate (FPP) production in the isoprenoid biosynthetic pathway in Escherichia coli. This strategy improved production of amorphadiene, the final product, by twofold over that from inducible or constitutive promoters, eliminated the need for expensive inducers, reduced acetate accumulation and improved growth. We extended this approach to another toxic intermediate to demonstrate the broad utility of identifying novel sensor-regulator systems for dynamic regulation.

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

NASA Technical Reports Server (NTRS)

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.

Chicken meat quality: genetic variability and relationship with growth and muscle characteristics

PubMed Central

Le Bihan-Duval, Elisabeth; Debut, Martine; Berri, Cécile M; Sellier, Nadine; Santé-Lhoutellier, Véronique; Jégo, Yves; Beaumont, Catherine

2008-01-01

Background The qualitative properties of the meat are of major importance for poultry breeding, since meat is now widely consumed as cuts or as processed products. The aim of this study was to evaluate the genetic parameters of several breast meat quality traits and their genetic relationships with muscle characteristics in a heavy commercial line of broilers. Results Significant levels of heritability (averaging 0.3) were obtained for breast meat quality traits such as pH at 15 min post-slaughter, ultimate pH (pHu), color assessed by lightness L*, redness a* and yellowness b*, drip loss, thawing-cooking loss and shear-force. The rate of decrease in pH early post-mortem and the final pH of the meat were shown to be key factors of chicken meat quality. In particular, a decrease in the final pH led to paler, more exudative and tougher breast meat. The level of glycogen stored in breast muscle estimated by the Glycolytic Potential (GP) at slaughter time was shown to be highly heritable (h2 0.43). There was a very strong negative genetic correlation (rg) with ultimate meat pH (rg -0.97), suggesting a common genetic control for GP and pHu. While breast muscle weight was genetically positively correlated with fiber size (rg 0.76), it was negatively correlated with the level of glycogen stored in the muscle (rg -0.58), and as a consequence it was positively correlated with the final pH of the meat (rg 0.84). Conclusion This genetic study confirmed that selection should be useful to improve meat characteristics of meat-type chickens without impairing profitability because no genetic conflict was detected between meat quality and meat quantity. Moreover, the results suggested relevant selection criteria such as ultimate pH, which is strongly related to color, water-holding capacity and texture of the meat in this heavy chicken line. PMID:18706119

History and future of the scientific consensus on anthropogenic global warming

NASA Astrophysics Data System (ADS)

Reusswig, Fritz

2013-09-01

The article by Cook et al offers an interesting new methodological approach to the debate about (supposedly lacking) scientific consensus on global warming, showing that contrarian claims that there was no such consensus are clearly misleading. But once the attribution issue can be regarded as settled, new questions and controversies arise. They ultimately result from the different technological and organizational pathways towards a new global society model that takes its adverse climate change effects into account and seeks for new, but also risky solutions.

Interaction of Microbial and Abiotic Processes in Soil Leading to the (Bio)Conversion and Ultimate Attenuation of New Insensitive Munitions Compounds

DTIC Science & Technology

2016-12-30

Toxicity is expressed as percentage of toxicant- free activity 125 Figure 4.12-1. Panel A: (Bio)transformation pathways of DNAN in anaerobic incubations...O-demethylation of the methoxy group was confirmed by formation of formaldehye. Cell free extracts of the Bacillus culture yielded formation of 2...periodically until the production of methane became constant in the toxicant- free controls. The maximum specific methanogenic activity of the

A novel mechanism of RNase L inhibition: Theiler's virus L* protein prevents 2-5A from binding to RNase L

PubMed Central

Drappier, Melissa; Elliott, Ruth; Zhang, Rong; Weiss, Susan R.; Silverman, Robert H.

2018-01-01

The OAS/RNase L pathway is one of the best-characterized effector pathways of the IFN antiviral response. It inhibits the replication of many viruses and ultimately promotes apoptosis of infected cells, contributing to the control of virus spread. However, viruses have evolved a range of escape strategies that act against different steps in the pathway. Here we unraveled a novel escape strategy involving Theiler’s murine encephalomyelitis virus (TMEV) L* protein. Previously we found that L* was the first viral protein binding directly RNase L. Our current data show that L* binds the ankyrin repeats R1 and R2 of RNase L and inhibits 2’-5’ oligoadenylates (2-5A) binding to RNase L. Thereby, L* prevents dimerization and oligomerization of RNase L in response to 2-5A. Using chimeric mouse hepatitis virus (MHV) expressing TMEV L*, we showed that L* efficiently inhibits RNase L in vivo. Interestingly, those data show that L* can functionally substitute for the MHV-encoded phosphodiesterase ns2, which acts upstream of L* in the OAS/RNase L pathway, by degrading 2-5A. PMID:29652922

Mechanical properties of Ti-6Al-4V specimens produced by shaped metal deposition

PubMed Central

Baufeld, Bernd; van der Biest, Omer

2009-01-01

Shaped metal deposition is a novel technique to build near net-shape components layer by layer by tungsten inert gas welding. Especially for complex shapes and small quantities, this technique can significantly lower the production cost of components by reducing the buy-to-fly ratio and lead time for production, diminishing final machining and preventing scrap. Tensile testing of Ti-6Al-4V components fabricated by shaped metal deposition shows that the mechanical properties are competitive to material fabricated by conventional techniques. The ultimate tensile strength is between 936 and 1014 MPa, depending on the orientation and location. Tensile testing vertical to the deposition layers reveals ductility between 14 and 21%, whereas testing parallel to the layers gives a ductility between 6 and 11%. Ultimate tensile strength and ductility are inversely related. Heat treatment within the α+β phase field does not change the mechanical properties, but heat treatment within the β phase field increases the ultimate tensile strength and decreases the ductility. The differences in ultimate tensile strength and ductility can be related to the α lath size and orientation of the elongated, prior β grains. The micro-hardness and Young’s modulus are similar to conventional Ti-6Al-4V with low oxygen content. PMID:27877271

Impact of High-Temperature, High-Pressure Synthesis Conditions on the Formation of the Grain Structure and Strength Properties of Intermetallic Ni3Al

NASA Astrophysics Data System (ADS)

Ovcharenko, V. E.; Ivanov, K. V.; Boyangin, E. N.; Krylova, T. A.; Pshenichnikov, A. P.

2018-01-01

The impact of the preliminary load on 3Ni+Al powder mixture and the impact of the duration of the delay in application of compacting pressure to synthesis product under the conditions of continuous heating of the mixture up to its self-ignition on the grain size and strength properties of the synthesized Ni3Al intermetallide material have been studied. The grain structure of the intermetallide synthesized under pressure was studied by means of metallography, transmission electron microscopy and EBSD analysis, with the dependence of ultimate tensile strength on the grain size in the synthesized intermetallide having been investigated at room temperature and at temperatures up to 1000°C. It is shown that an increase in the pressure preliminarily applied to the initial mixture compact results in reduced grain size of the final intermetallide, whereas an increase in pre-compaction time makes the grain size increased. A decrease in the grain size increases the ultimate tensile strength of the intermetallide. The maximum value of the ultimate tensile strength in the observed anomalous temperature dependence of this strength exhibits a shift by 200°C toward higher temperatures, and the ultimate strength of the synthesized intermetallide at 1000°C increases roughly two-fold.

Development of genetically engineered bacteria for production of selected aromatic compounds

DOEpatents

Ward, Thomas E.; Watkins, Carolyn S.; Bulmer, Deborah K.; Johnson, Bruce F.; Amaratunga, Mohan

2001-01-01

The cloning and expression of genes in the common aromatic pathway of E. coli are described. A compound for which chorismate, the final product of the common aromatic pathway, is an anabolic intermediate can be produced by cloning and expressing selected genes of the common aromatic pathway and the genes coding for enzymes necessary to convert chorismate to the selected compound. Plasmids carrying selected genes of the common aromatic pathway are also described.

The Relationship between Vocational Interests, Self-Efficacy, and Achievement in the Prediction of Educational Pathways

ERIC Educational Resources Information Center

Patrick, Lyn; Care, Esther; Ainley, Mary

2011-01-01

The influence of vocational interest, self-efficacy beliefs, and academic achievement on choice of educational pathway is described for a cohort of Australian students. Participants were 189 students aged 14-15 years, who were considering either academic or applied learning pathways and subject choices for the final 3 years of secondary school.…

Addressing the Common Pathway Underlying Hypertension and Diabetes in People Who Are Obese by Maximizing Health: The Ultimate Knowledge Translation Gap

PubMed Central

Dean, Elizabeth; Lomi, Constantina; Bruno, Selma; Awad, Hamzeh; O'Donoghue, Grainne

2011-01-01

In accordance with the WHO definition of health, this article examines the alarming discord between the epidemiology of hypertension, type 2 diabetes mellitus (T2DM), and obesity and the low profile of noninvasive (nondrug) compared with invasive (drug) interventions with respect to their prevention, reversal and management. Herein lies the ultimate knowledge translation gap and challenge in 21st century health care. Although lifestyle modification has long appeared in guidelines for medically managing these conditions, this evidence-based strategy is seldom implemented as rigorously as drug prescription. Biomedicine focuses largely on reducing signs and symptoms; the effects of the problem rather than the problem. This article highlights the evidence-based rationale supporting prioritizing the underlying causes and contributing factors for hypertension and T2DM, and, in turn, obesity. We argue that a primary focus on maximizing health could eliminate all three conditions, at best, or, at worst, minimize their severity, complications, and medication needs. To enable such knowledge translation and maximizing health outcome, the health care community needs to practice as an integrated team, and address barriers to effecting maximal health in all patients. Addressing the ultimate knowledge translation gap, by aligning the health care paradigm to 21st century needs, would constitute a major advance. PMID:21423684

Study of Adaptive Mathematical Models for Deriving Automated Pilot Performance Measurement Techniques. Volume II. Appendices. Final Report.

ERIC Educational Resources Information Center

Connelly, E. M.; And Others

A new approach to deriving human performance measures and criteria for use in automatically evaluating trainee performance is described. Ultimately, this approach will allow automatic measurement of pilot performance in a flight simulator or from recorded in-flight data. An efficient method of representing performance data within a computer is…

Minimal Brain Dysfunction in Childhood: 1. Outcome in Late Adolescence and Early Adult Years. Final Version.

ERIC Educational Resources Information Center

Milman, Doris H.

Seventy-three patients, diagnosed in childhood as having either maturational lag or organic brain syndrome, were followed for an average of 12 years into late adolescence and early adult life for the purpose of discovering the outcome with respect to ultimate psychiatric status, educational attainment, social adjustment, and global adjustment. At…

Development of USPS Laboratory and pilot-scale testing protocols

Treesearch

Carl Houtman; Nancy Ross Sutherland; David Bormett; Donald Donermeyer

2000-01-01

The ultimate goal of the US Postal Service (USPS) Environmentally Benign Stamp Program is to develop stamp adhesives that can be removed by unit operations found in recycling mills. The maintenance of final product quality specifications for a recycling mill while loading the feedstock with a significant quantity of adhesive is the criterion for success of this program...

A Tale of Two Courses: Challenging Millennials to Experience Culture through Film

ERIC Educational Resources Information Center

Kirakosian, Katie; McLaurin, Virginia; Speck, Cary

2017-01-01

In this article, we discuss how adding a final film project to a revised "Culture through Film" course led to deeper student learning and higher rates of student success, as well as increased student satisfaction. Ultimately, we urge social science educators to include experiential projects in their courses that connect to all learning…

Essential Competencies for Interdisciplinary Graduate Training in IGERT: Final Report. GS-10F-0086K

ERIC Educational Resources Information Center

Gamse, Beth C.; Espinosa, Lorelle L.; Roy, Radha

2013-01-01

The Integrative Graduate Education and Research Traineeship (IGERT) program represents a substantial investment by the National Science Foundation (NSF) to improve the quality of graduate education, and ultimately, to increase the number of graduates better prepared to address the nation's 21st century scientific and technological needs. The…

Air Force Reserve Officer Training Corps Indicators of Leadership Development in Undergraduate Military Education

ERIC Educational Resources Information Center

Shannon, Christopher C.

2013-01-01

The selection and retention assessment process is dynamic. Dipboye, Smith, and Howell (1994) argued that the most influential portion of the final hiring process is the result of the interviewer's impression of the applicants. The Air Force Reserve Officer Training Corps program is responsible for selecting, retaining and ultimately hiring…

NCLB's Ultimate Restructuring Alternatives: Do They Improve the Quality of Education?

ERIC Educational Resources Information Center

Mathis, William J.

2009-01-01

Across the nation, the final stage of school restructuring is being reached by an inexorably increasing number of schools. Under the No Child Left Behind law, if a school does not make its adequate yearly progress targets after four previous years of being "in need of improvement," it must implement a fundamental restructuring plan. The…

Case Study of a College that Closed: Saint Mary's College

ERIC Educational Resources Information Center

Brown, Alice W.

2011-01-01

Few colleges choose to close. One that did was Saint Mary's College in Raleigh, North Carolina. Although trustees resisted for a decade, they ultimately made the decision before an anticipated denial of accreditation, allowing the college to control its final days in ways not possible for those who wait until an outside agency forces closure. This…

Final Rule to Identify Additional Fuel Pathways under the Renewable Fuel Standard Program

EPA Pesticide Factsheets

This final rule describes EPA’s evaluation of biofuels produced from camelina oil and energy cane, as well as renewable gasoline and renewable gasoline blendstock made from certain qualifying feedstocks.

A cardiac pathway of cyclic GMP-independent signaling of guanylyl cyclase A, the receptor for atrial natriuretic peptide

PubMed Central

Klaiber, Michael; Dankworth, Beatrice; Kruse, Martin; Hartmann, Michael; Nikolaev, Viacheslav O.; Yang, Ruey-Bing; Völker, Katharina; Gaßner, Birgit; Oberwinkler, Heike; Feil, Robert; Freichel, Marc; Groschner, Klaus; Skryabin, Boris V.; Frantz, Stefan; Birnbaumer, Lutz; Pongs, Olaf; Kuhn, Michaela

2011-01-01

Cardiac atrial natriuretic peptide (ANP) regulates arterial blood pressure, moderates cardiomyocyte growth, and stimulates angiogenesis and metabolism. ANP binds to the transmembrane guanylyl cyclase (GC) receptor, GC-A, to exert its diverse functions. This process involves a cGMP-dependent signaling pathway preventing pathological [Ca2+]i increases in myocytes. In chronic cardiac hypertrophy, however, ANP levels are markedly increased and GC-A/cGMP responses to ANP are blunted due to receptor desensitization. Here we show that, in this situation, ANP binding to GC-A stimulates a unique cGMP-independent signaling pathway in cardiac myocytes, resulting in pathologically elevated intracellular Ca2+ levels. This pathway involves the activation of Ca2+‐permeable transient receptor potential canonical 3/6 (TRPC3/C6) cation channels by GC-A, which forms a stable complex with TRPC3/C6 channels. Our results indicate that the resulting cation influx activates voltage-dependent L-type Ca2+ channels and ultimately increases myocyte Ca2+i levels. These observations reveal a dual role of the ANP/GC-A–signaling pathway in the regulation of cardiac myocyte Ca2+i homeostasis. Under physiological conditions, activation of a cGMP-dependent pathway moderates the Ca2+i-enhancing action of hypertrophic factors such as angiotensin II. By contrast, a cGMP-independent pathway predominates under pathophysiological conditions when GC-A is desensitized by high ANP levels. The concomitant rise in [Ca2+]i might increase the propensity to cardiac hypertrophy and arrhythmias. PMID:22027011

Genomic variants in the ASS1 gene, involved in the nitric oxide biosynthesis and signaling pathway, predict hydroxyurea treatment efficacy in compound sickle cell disease/β-thalassemia patients.

PubMed

Chalikiopoulou, Constantina; Tavianatou, Anastasia-Gerasimoula; Sgourou, Argyro; Kourakli, Alexandra; Kelepouri, Dimitra; Chrysanthakopoulou, Maria; Kanelaki, Vasiliki-Kaliopi; Mourdoukoutas, Evangelos; Siamoglou, Stavroula; John, Anne; Symeonidis, Argyris; Ali, Bassam R; Katsila, Theodora; Papachatzopoulou, Adamantia; Patrinos, George P

2016-03-01

Hemoglobinopathies exhibit a remarkable phenotypic diversity that restricts any safe association between molecular pathology and clinical outcomes. Herein, we explored the role of genes involved in the nitric oxide biosynthesis and signaling pathway, implicated in the increase of fetal hemoglobin levels and response to hydroxyurea treatment, in 119 Hellenic patients with β-type hemoglobinopathies. We show that two ASS1 genomic variants (namely, rs10901080 and rs10793902) can serve as pharmacogenomic biomarkers to predict hydroxyurea treatment efficacy in sickle cell disease/β-thalassemia compound heterozygous patients. These markers may exert their effect by inducing nitric oxide biosynthesis, either via altering splicing and/or miRNA binding, as predicted by in silico analysis, and ultimately, increase γ-globin levels, via guanylyl cyclase targeting.

Molecular basis of physiological heart growth: fundamental concepts and new players

PubMed Central

Maillet, Marjorie; van Berlo, Jop H.; Molkentin, Jeffery D.

2015-01-01

The heart hypertrophies in response to developmental signals as well as increased workload. Although adult-onset hypertrophy can ultimately lead to disease, cardiac hypertrophy is not necessarily maladaptive and can even be beneficial. Progress has been made in our understanding of the structural and molecular characteristics of physiological cardiac hypertrophy, as well as of the endocrine effectors and associated signalling pathways that regulate it. Physiological hypertrophy is initiated by finite signals, which include growth hormones (such as thyroid hormone, insulin, insulin-like growth factor 1 and vascular endothelial growth factor) and mechanical forces that converge on a limited number of intracellular signalling pathways (such as PI3K, AKT, AMP-activated protein kinase and mTOR) to affect gene transcription, protein translation and metabolism. Harnessing adaptive signalling mediators to reinvigorate the diseased heart could have important medical ramifications. PMID:23258295

Porphyromonas gingivalis outer membrane vesicles enter human epithelial cells via an endocytic pathway and are sorted to lysosomal compartments.

PubMed

Furuta, Nobumichi; Tsuda, Kayoko; Omori, Hiroko; Yoshimori, Tamotsu; Yoshimura, Fuminobu; Amano, Atsuo

2009-10-01

Porphyromonas gingivalis, a periodontal pathogen, secretes outer membrane vesicles (MVs) that contain major virulence factors, including major fimbriae and proteases termed gingipains, although it is not confirmed whether MVs enter host cells. In this study, we analyzed the mechanisms involved in the interactions of P. gingivalis MVs with human epithelial cells. Our results showed that MVs swiftly adhered to HeLa and immortalized human gingival epithelial cells in a fimbria-dependent manner and then entered via a lipid raft-dependent endocytic pathway. The intracellular MVs were subsequently routed to early endosome antigen 1-associated compartments and then were sorted to lysosomal compartments within 90 min, suggesting that intracellular MVs were ultimately degraded by the cellular digestive machinery. However, P. gingivalis MVs remained there for over 24 h and significantly induced acidified compartment formation after being taken up by the cellular digestive machinery. In addition, MV entry was shown to be mediated by a novel pathway for transmission of bacterial products into host cells, a Rac1-regulated pinocytic pathway that is independent of caveolin, dynamin, and clathrin. Our findings indicate that P. gingivalis MVs efficiently enter host cells via an endocytic pathway and survive within the endocyte organelles for an extended period, which provides better understanding of the role of MVs in the etiology of periodontitis.

Porphyromonas gingivalis Outer Membrane Vesicles Enter Human Epithelial Cells via an Endocytic Pathway and Are Sorted to Lysosomal Compartments ▿

PubMed Central

Furuta, Nobumichi; Tsuda, Kayoko; Omori, Hiroko; Yoshimori, Tamotsu; Yoshimura, Fuminobu; Amano, Atsuo

2009-01-01

Porphyromonas gingivalis, a periodontal pathogen, secretes outer membrane vesicles (MVs) that contain major virulence factors, including major fimbriae and proteases termed gingipains, although it is not confirmed whether MVs enter host cells. In this study, we analyzed the mechanisms involved in the interactions of P. gingivalis MVs with human epithelial cells. Our results showed that MVs swiftly adhered to HeLa and immortalized human gingival epithelial cells in a fimbria-dependent manner and then entered via a lipid raft-dependent endocytic pathway. The intracellular MVs were subsequently routed to early endosome antigen 1-associated compartments and then were sorted to lysosomal compartments within 90 min, suggesting that intracellular MVs were ultimately degraded by the cellular digestive machinery. However, P. gingivalis MVs remained there for over 24 h and significantly induced acidified compartment formation after being taken up by the cellular digestive machinery. In addition, MV entry was shown to be mediated by a novel pathway for transmission of bacterial products into host cells, a Rac1-regulated pinocytic pathway that is independent of caveolin, dynamin, and clathrin. Our findings indicate that P. gingivalis MVs efficiently enter host cells via an endocytic pathway and survive within the endocyte organelles for an extended period, which provides better understanding of the role of MVs in the etiology of periodontitis. PMID:19651865

C/EBPβ and Nuclear Factor of Activated T Cells Differentially Regulate Adamts-1 Induction by Stimuli Associated with Vascular Remodeling

PubMed Central

Oller, Jorge; Alfranca, Arántzazu; Méndez-Barbero, Nerea; Villahoz, Silvia; Lozano-Vidal, Noelia; Martín-Alonso, Mara; Arroyo, Alicia G.; Escolano, Amelia; Armesilla, Angel Luis

2015-01-01

Emerging evidence indicates that the metalloproteinase Adamts-1 plays a significant role in the pathophysiology of vessel remodeling, but little is known about the signaling pathways that control Adamts-1 expression. We show that vascular endothelial growth factor (VEGF), angiotensin-II, interleukin-1β, and tumor necrosis factor α, stimuli implicated in pathological vascular remodeling, increase Adamts-1 expression in endothelial and vascular smooth muscle cells. Analysis of the intracellular signaling pathways implicated in this process revealed that VEGF and angiotensin-II upregulate Adamts-1 expression via activation of differential signaling pathways that ultimately promote functional binding of the NFAT or C/EBPβ transcription factors, respectively, to the Adamts-1 promoter. Infusion of mice with angiotensin-II triggered phosphorylation and nuclear translocation of C/EBPβ proteins in aortic cells concomitantly with an increase in the expression of Adamts-1, further underscoring the importance of C/EBPβ signaling in angiotensin-II-induced upregulation of Adamts-1. Similarly, VEGF promoted NFAT activation and subsequent Adamts-1 induction in aortic wall in a calcineurin-dependent manner. Our results demonstrate that Adamts-1 upregulation by inducers of pathological vascular remodeling is mediated by specific signal transduction pathways involving NFAT or C/EBPβ transcription factors. Targeting of these pathways may prove useful in the treatment of vascular disease. PMID:26217013

The ever-evolving role of mTOR in translation.

PubMed

Fonseca, Bruno D; Smith, Ewan M; Yelle, Nicolas; Alain, Tommy; Bushell, Martin; Pause, Arnim

2014-12-01

Control of translation allows for the production of stoichiometric levels of each protein in the cell. Attaining such a level of fine-tuned regulation of protein production requires the coordinated temporal and spatial control of numerous cellular signalling cascades impinging on the various components of the translational machinery. Foremost among these is the mTOR signalling pathway. The mTOR pathway regulates both the initiation and elongation steps of protein synthesis through the phosphorylation of numerous translation factors, while simultaneously ensuring adequate folding of nascent polypeptides through co-translational degradation of misfolded proteins. Perhaps most remarkably, mTOR is also a key regulator of the synthesis of ribosomal proteins and translation factors themselves. Two seminal studies have recently shown in translatome analysis that the mTOR pathway preferentially regulates the translation of mRNAs encoding ribosomal proteins and translation factors. Therefore, the role of the mTOR pathway in the control of protein synthesis extends far beyond immediate translational control. By controlling ribosome production (and ultimately ribosome availability), mTOR is a master long-term controller of protein synthesis. Herein, we review the literature spanning the early discoveries of mTOR on translation to the latest advances in our understanding of how the mTOR pathway controls the synthesis of ribosomal proteins. Crown Copyright © 2014. Published by Elsevier Ltd. All rights reserved.

Sensitivity analysis of gene ranking methods in phenotype prediction.

PubMed

deAndrés-Galiana, Enrique J; Fernández-Martínez, Juan L; Sonis, Stephen T

2016-12-01

It has become clear that noise generated during the assay and analytical processes has the ability to disrupt accurate interpretation of genomic studies. Not only does such noise impact the scientific validity and costs of studies, but when assessed in the context of clinically translatable indications such as phenotype prediction, it can lead to inaccurate conclusions that could ultimately impact patients. We applied a sequence of ranking methods to damp noise associated with microarray outputs, and then tested the utility of the approach in three disease indications using publically available datasets. This study was performed in three phases. We first theoretically analyzed the effect of noise in phenotype prediction problems showing that it can be expressed as a modeling error that partially falsifies the pathways. Secondly, via synthetic modeling, we performed the sensitivity analysis for the main gene ranking methods to different types of noise. Finally, we studied the predictive accuracy of the gene lists provided by these ranking methods in synthetic data and in three different datasets related to cancer, rare and neurodegenerative diseases to better understand the translational aspects of our findings. In the case of synthetic modeling, we showed that Fisher's Ratio (FR) was the most robust gene ranking method in terms of precision for all the types of noise at different levels. Significance Analysis of Microarrays (SAM) provided slightly lower performance and the rest of the methods (fold change, entropy and maximum percentile distance) were much less precise and accurate. The predictive accuracy of the smallest set of high discriminatory probes was similar for all the methods in the case of Gaussian and Log-Gaussian noise. In the case of class assignment noise, the predictive accuracy of SAM and FR is higher. Finally, for real datasets (Chronic Lymphocytic Leukemia, Inclusion Body Myositis and Amyotrophic Lateral Sclerosis) we found that FR and SAM provided the highest predictive accuracies with the smallest number of genes. Biological pathways were found with an expanded list of genes whose discriminatory power has been established via FR. We have shown that noise in expression data and class assignment partially falsifies the sets of discriminatory probes in phenotype prediction problems. FR and SAM better exploit the principle of parsimony and are able to find subsets with less number of high discriminatory genes. The predictive accuracy and the precision are two different metrics to select the important genes, since in the presence of noise the most predictive genes do not completely coincide with those that are related to the phenotype. Based on the synthetic results, FR and SAM are recommended to unravel the biological pathways that are involved in the disease development. Copyright © 2016 Elsevier Inc. All rights reserved.

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

Ronold, K.O.; Nielsen, N.J.R.; Tura, F.

This paper demonstrates how a structural reliability method can be applied as a rational means to analyze free spans of submarine pipelines with respect to failure in ultimate loading, and to establish partial safety factors for design of such free spans against this failure mode. It is important to note that the described procedure shall be considered as an illustration of a structural reliability methodology, and that the results do not represent a set of final design recommendations. A scope of design cases, consisting of a number of available site-specific pipeline spans, is established and is assumed representative for themore » future occurrence of submarine pipeline spans. Probabilistic models for the wave and current loading and its transfer to stresses in the pipe wall of a pipeline span is established together with a stochastic representation of the material resistance. The event of failure in ultimate loading is considered as based on a limit state which is reached when the maximum stress over the design life of the pipeline exceeds the yield strength of the pipe material. The yielding limit state is considered an ultimate limit state (ULS).« less

Effects of Fe and Mn deficiencies on the protein profiles of tomato (Solanum lycopersicum) xylem sap as revealed by shotgun analyses.

PubMed

Ceballos-Laita, Laura; Gutierrez-Carbonell, Elain; Takahashi, Daisuke; Abadía, Anunciación; Uemura, Matsuo; Abadía, Javier; López-Millán, Ana Flor

2018-01-06

The aim of this work was to study the effects of Fe and Mn deficiencies on the xylem sap proteome of tomato using a shotgun proteomic approach, with the final goal of elucidating plant response mechanisms to these stresses. This approach yielded 643 proteins reliably identified and quantified with 70% of them predicted as secretory. Iron and Mn deficiencies caused statistically significant and biologically relevant abundance changes in 119 and 118 xylem sap proteins, respectively. In both deficiencies, metabolic pathways most affected were protein metabolism, stress/oxidoreductases and cell wall modifications. First, results suggest that Fe deficiency elicited more stress responses than Mn deficiency, based on the changes in oxidative and proteolytic enzymes. Second, both nutrient deficiencies affect the secondary cell wall metabolism, with changes in Fe deficiency occurring via peroxidase activity, and in Mn deficiency involving peroxidase, Cu-oxidase and fasciclin-like arabinogalactan proteins. Third, the primary cell wall metabolism was affected by both nutrient deficiencies, with changes following opposite directions as judged from the abundances of several glycoside-hydrolases with endo-glycolytic activities and pectin esterases. Fourth, signaling pathways via xylem involving CLE and/or lipids as well as changes in phosphorylation and N-glycosylation also play a role in the responses to these stresses. Biological significance In spite of being essential for the delivery of nutrients to the shoots, our knowledge of xylem responses to nutrient deficiencies is very limited. The present work applies a shotgun proteomic approach to unravel the effects of Fe and Mn deficiencies on the xylem sap proteome. Overall, Fe deficiency seems to elicit more stress in the xylem sap proteome than Mn deficiency, based on the changes measured in proteolytic and oxido-reductase proteins, whereas both nutrients exert modifications in the composition of the primary and secondary cell wall. Cell wall modifications could affect the mechanical and permeability properties of the xylem sap vessels, and therefore ultimately affect solute transport and distribution to the leaves. Results also suggest that signaling cascades involving lipid and peptides might play a role in nutrient stress signaling and pinpoint interesting candidates for future studies. Finally, both nutrient deficiencies seem to affect phosphorylation and glycosylation processes, again following an opposite pattern. Copyright © 2017 Elsevier B.V. All rights reserved.

Understanding and preventing contrast-induced acute kidney injury.

PubMed

Fähling, Michael; Seeliger, Erdmann; Patzak, Andreas; Persson, Pontus B

2017-03-01

Contrast-induced acute kidney injury (CIAKI) occurs in up to 30% of patients who receive iodinated contrast media and is generally considered to be the third most common cause of hospital-acquired AKI. Accurate assessment of the incidence of CIAKI is obscured, however, by the use of various definitions for diagnosis, the different populations studied and the prophylactic measures put in place. A deeper understanding of the mechanisms that underlie CIAKI is required to enable reliable risk assessment for individual patients, as their medical histories will determine the specific pathways by which contrast media administration might lead to kidney damage. Here, we highlight common triggers that prompt the development of CIAKI and the subsequent mechanisms that ultimately cause kidney damage. We also discuss effective protective measures, such as rapidly acting oral hydration schemes and loop diuretics, in the context of CIAKI pathophysiology. Understanding of how CIAKI arises in different patient groups could enable a marked reduction in incidence and improved outcomes. The ultimate goal is to shape CIAKI prevention strategies for individual patients.

Bronchiolitis Obliterans Syndrome: The Achilles’ Heel of Lung Transplantation

PubMed Central

Weigt, S. Samuel; DerHovanessian, Ariss; Wallace, W. Dean; Lynch, Joseph P.; Belperio, John A.

2016-01-01

Lung transplantation is a therapeutic option for patients with end-stage pulmonary disorders. Unfortunately, chronic lung allograft dysfunction (CLAD), most commonly manifest as bronchiolitis obliterans syndrome (BOS), continues to be highly prevalent and is the major limitation to long-term survival. The pathogenesis of BOS is complex and involves alloimmune and nonalloimmune pathways. Clinically, BOS manifests as airway obstruction and dyspnea that are classically progressive and ultimately fatal; however, the course is highly variable, and distinguishable phenotypes may exist. There are few controlled studies assessing treatment efficacy, but only a minority of patients respond to current treatment modalities. Ultimately, preventive strategies may prove more effective at prolonging survival after lung transplantation, but their remains considerable debate and little data regarding the best strategies to prevent BOS. A better understanding of the risk factors and their relationship to the pathological mechanisms of chronic lung allograft rejection should lead to better pharmacological targets to prevent or treat this syndrome. PMID:23821508

Integrated Immunomodulatory Mechanisms through which Long-Chain n-3 Polyunsaturated Fatty Acids Attenuate Obese Adipose Tissue Dysfunction

PubMed Central

Liddle, Danyelle M.; Wellings, Hannah R.; Power, Krista A.; Robinson, Lindsay E.; Monk, Jennifer M.

2017-01-01

Obesity is a global health concern with rising prevalence that increases the risk of developing other chronic diseases. A causal link connecting overnutrition, the development of obesity and obesity-associated co-morbidities is visceral adipose tissue (AT) dysfunction, characterized by changes in the cellularity of various immune cell populations, altered production of inflammatory adipokines that sustain a chronic state of low-grade inflammation and, ultimately, dysregulated AT metabolic function. Therefore, dietary intervention strategies aimed to halt the progression of obese AT dysfunction through any of the aforementioned processes represent an important active area of research. In this connection, fish oil-derived dietary long-chain n-3 polyunsaturated fatty acids (PUFA) in the form of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been demonstrated to attenuate obese AT dysfunction through multiple mechanisms, ultimately affecting AT immune cellularity and function, adipokine production, and metabolic signaling pathways, all of which will be discussed herein. PMID:29186929

Tortuous pathways: Fundamental characterisation of the anisotropic permeability through clay-rich shales from macro- to nano-scale.

NASA Astrophysics Data System (ADS)

Mitchell, T. M.; Backeberg, N. R.; Iacoviello, F.; Rittner, M.; Jones, A. P.; Wheeler, J.; Day, R.; Vermeesch, P.; Shearing, P. R.; Striolo, A.

2017-12-01

The permeability of shales is important, because it controls where oil and gas resources can migrate to and where in the Earth hydrocarbons are ultimately stored. Shales have a well-known anisotropic directional permeability that is inherited from the depositional layering of sedimentary laminations, where the highest permeability is measured parallel to laminations and the lowest permeability is perpendicular to laminations. We combine state of the art laboratory permeability experiments with high-resolution X-ray computed tomography and for the first time can quantify the three-dimensional interconnected pathways through a rock that define the anisotropic behaviour of shales. Experiments record a physical anisotropy in permeability of one to two orders of magnitude. Two- and three-dimensional analyses of micro- and nano-scale X-ray computed tomography illuminate that the directional anisotropy is fundamentally controlled by the bulk rock mineral geometry, which determines the finite length (or tortuosity) of the interconnected pathways through the porous/permeable phases in shales. Understanding the mineral-scale control on permeability will allow for better estimations of the extent of recoverable reserves in shale gas plays globally.

Understanding disease mechanisms with models of signaling pathway activities.

PubMed

Sebastian-Leon, Patricia; Vidal, Enrique; Minguez, Pablo; Conesa, Ana; Tarazona, Sonia; Amadoz, Alicia; Armero, Carmen; Salavert, Francisco; Vidal-Puig, Antonio; Montaner, David; Dopazo, Joaquín

2014-10-25

Understanding the aspects of the cell functionality that account for disease or drug action mechanisms is one of the main challenges in the analysis of genomic data and is on the basis of the future implementation of precision medicine. Here we propose a simple probabilistic model in which signaling pathways are separated into elementary sub-pathways or signal transmission circuits (which ultimately trigger cell functions) and then transforms gene expression measurements into probabilities of activation of such signal transmission circuits. Using this model, differential activation of such circuits between biological conditions can be estimated. Thus, circuit activation statuses can be interpreted as biomarkers that discriminate among the compared conditions. This type of mechanism-based biomarkers accounts for cell functional activities and can easily be associated to disease or drug action mechanisms. The accuracy of the proposed model is demonstrated with simulations and real datasets. The proposed model provides detailed information that enables the interpretation disease mechanisms as a consequence of the complex combinations of altered gene expression values. Moreover, it offers a framework for suggesting possible ways of therapeutic intervention in a pathologically perturbed system.

Food reward, hyperphagia, and obesity

PubMed Central

Lenard, Natalie R.; Shin, Andrew C.

2011-01-01

Given the unabated obesity problem, there is increasing appreciation of expressions like “my eyes are bigger than my stomach,” and recent studies in rodents and humans suggest that dysregulated brain reward pathways may be contributing not only to drug addiction but also to increased intake of palatable foods and ultimately obesity. After describing recent progress in revealing the neural pathways and mechanisms underlying food reward and the attribution of incentive salience by internal state signals, we analyze the potentially circular relationship between palatable food intake, hyperphagia, and obesity. Are there preexisting individual differences in reward functions at an early age, and could they be responsible for development of obesity later in life? Does repeated exposure to palatable foods set off a cascade of sensitization as in drug and alcohol addiction? Are reward functions altered by secondary effects of the obese state, such as increased signaling through inflammatory, oxidative, and mitochondrial stress pathways? Answering these questions will significantly impact prevention and treatment of obesity and its ensuing comorbidities as well as eating disorders and drug and alcohol addiction. PMID:21411768

Unraveling Biochemical Pathways Affected by Mitochondrial Dysfunctions Using Metabolomic Approaches

PubMed Central

Demine, Stéphane; Reddy, Nagabushana; Renard, Patricia; Raes, Martine; Arnould, Thierry

2014-01-01

Mitochondrial dysfunction(s) (MDs) can be defined as alterations in the mitochondria, including mitochondrial uncoupling, mitochondrial depolarization, inhibition of the mitochondrial respiratory chain, mitochondrial network fragmentation, mitochondrial or nuclear DNA mutations and the mitochondrial accumulation of protein aggregates. All these MDs are known to alter the capacity of ATP production and are observed in several pathological states/diseases, including cancer, obesity, muscle and neurological disorders. The induction of MDs can also alter the secretion of several metabolites, reactive oxygen species production and modify several cell-signalling pathways to resolve the mitochondrial dysfunction or ultimately trigger cell death. Many metabolites, such as fatty acids and derived compounds, could be secreted into the blood stream by cells suffering from mitochondrial alterations. In this review, we summarize how a mitochondrial uncoupling can modify metabolites, the signalling pathways and transcription factors involved in this process. We describe how to identify the causes or consequences of mitochondrial dysfunction using metabolomics (liquid and gas chromatography associated with mass spectrometry analysis, NMR spectroscopy) in the obesity and insulin resistance thematic. PMID:25257998

Cytochrome P450 CYP1A1: wider roles in cancer progression and prevention

PubMed Central

2009-01-01

CYP1A1 is one of the main cytochrome P450 enzymes, examined extensively for its capacity to activate compounds with carcinogenic properties. Continuous exposure to inhalation chemicals and environmental carcinogens is thought to increase the level of CYP1A1 expression in extrahepatic tissues, through the aryl hydrocarbon receptor (AhR). Although the latter has long been recognized as a ligand-induced transcription factor, which is responsible for the xenobiotic activating pathway of several phase I and phase II metabolizing enzymes, recent evidence suggests that the AhR is involved in various cell signaling pathways critical to cell cycle regulation and normal homeostasis. Disregulation of these pathways is implicated in tumor progression. In addition, it is becoming increasingly evident that CYP1A1 plays an important role in the detoxication of environmental carcinogens, as well as in the metabolic activation of dietary compounds with cancer preventative activity. Ultimately the contribution of CYP1A1 to cancer progression or prevention may depend on the balance of procarcinogen activation/detoxication and dietary natural product extrahepatic metabolism. PMID:19531241

Modular Activating Receptors in Innate and Adaptive Immunity.

PubMed

Berry, Richard; Call, Matthew E

2017-03-14

Triggering of cell-mediated immunity is largely dependent on the recognition of foreign or abnormal molecules by a myriad of cell surface-bound receptors. Many activating immune receptors do not possess any intrinsic signaling capacity but instead form noncovalent complexes with one or more dimeric signaling modules that communicate with a common set of kinases to initiate intracellular information-transfer pathways. This modular architecture, where the ligand binding and signaling functions are detached from one another, is a common theme that is widely employed throughout the innate and adaptive arms of immune systems. The evolutionary advantages of this highly adaptable platform for molecular recognition are visible in the variety of ligand-receptor interactions that can be linked to common signaling pathways, the diversification of receptor modules in response to pathogen challenges, and the amplification of cellular responses through incorporation of multiple signaling motifs. Here we provide an overview of the major classes of modular activating immune receptors and outline the current state of knowledge regarding how these receptors assemble, recognize their ligands, and ultimately trigger intracellular signal transduction pathways that activate immune cell effector functions.

Neuroplasticity in the auditory system.

PubMed

Gil-Loyzaga, P

2005-01-01

An increasing interest on neuroplasticity and nerve regeneration within the auditory receptor and pathway has developed in recent years. The receptor and the auditory pathway are controlled by highly complex circuits that appear during embryonic development. During this early maturation process of the auditory sensory elements, we observe the development of two types of nerve fibers: permanent fibers that will remain to reach full-term maturity and other transient fibers that will ultimately disappear. Both stable and transitory fibers however, as well as developing sensory cells, express, and probably release, their respective neuro-transmitters that could be involved in neuroplasticity. Cell culture experiments have added significant information; the in vitro administration of glutamate or GABA to isolated spiral ganglion neurons clearly modified neural development. Neuroplasticity has been also found in the adult. Nerve regeneration and neuroplasticity have been demonstrated in the adult auditory receptors as well as throughout the auditory pathway. Neuroplasticity studies could prove interesting in the elaboration of current or future therapy strategies (e.g.: cochlear implants or stem cells), but also to really understand the pathogenesis of auditory or language diseases (e.g.: deafness, tinnitus, dyslexia, etc.).

My 65 years in protein chemistry.

PubMed

Scheraga, Harold A

2015-05-01

This is a tour of a physical chemist through 65 years of protein chemistry from the time when emphasis was placed on the determination of the size and shape of the protein molecule as a colloidal particle, with an early breakthrough by James Sumner, followed by Linus Pauling and Fred Sanger, that a protein was a real molecule, albeit a macromolecule. It deals with the recognition of the nature and importance of hydrogen bonds and hydrophobic interactions in determining the structure, properties, and biological function of proteins until the present acquisition of an understanding of the structure, thermodynamics, and folding pathways from a linear array of amino acids to a biological entity. Along the way, with a combination of experiment and theoretical interpretation, a mechanism was elucidated for the thrombin-induced conversion of fibrinogen to a fibrin blood clot and for the oxidative-folding pathways of ribonuclease A. Before the atomic structure of a protein molecule was determined by x-ray diffraction or nuclear magnetic resonance spectroscopy, experimental studies of the fundamental interactions underlying protein structure led to several distance constraints which motivated the theoretical approach to determine protein structure, and culminated in the Empirical Conformational Energy Program for Peptides (ECEPP), an all-atom force field, with which the structures of fibrous collagen-like proteins and the 46-residue globular staphylococcal protein A were determined. To undertake the study of larger globular proteins, a physics-based coarse-grained UNited-RESidue (UNRES) force field was developed, and applied to the protein-folding problem in terms of structure, thermodynamics, dynamics, and folding pathways. Initially, single-chain and, ultimately, multiple-chain proteins were examined, and the methodology was extended to protein-protein interactions and to nucleic acids and to protein-nucleic acid interactions. The ultimate results led to an understanding of a variety of biological processes underlying natural and disease phenomena.

Crystallization Conditions at Cascade and Other Arc Volcanoes: The Role of Recharge, and Ultimate, Proximal and Immediate Causes of Eruption

NASA Astrophysics Data System (ADS)

Putirka, K. D.

2016-12-01

A number of hypotheses have been offered to explain why volcanoes erupt. These include magma mixing, mafic recharge, or partial crystallization, any of which can drive parts or all of a system to vapor saturation, and so add to a magma's buoyancy. Age dates indicate long pre-eruption storage times for felsic magmas erupted at arcs, indicating that mafic recharge magmas, which can reinvigorate such systems, is a possible eruption trigger. However, plutonic systems reveal numerous recharge events that have no obvious ties to eruption (Coint et al. 2013; Putirka et al. 2014). And crystallization conditions at some arc systems support the implicit view, that recharge might be a necessary, but not a sufficient condition for eruption. At several Cascade volcanoes, Cpx and Amp crystals record coolings of 100-300oC. The Cpx grains derive exclusively from mafic enclaves, while Amp grains derive from both host and enclave materials. These considerable coolings call for a time lag following recharge, and indicate that vapor saturation is a proximal, although not necessarily an immediate cause of eruption. But we cannot discount recharge altogether. At the Cascades and at other arcs, Cpx crystalizes throughout the middle and upper crust, mostly from the surface down to 15 km. And high Fo olivine grains provide evidence for very hot magmas that intrude the upper mantle and lower crust, and possibly the middle crust, if hydrous. Volcanic pathways thus clearly extend into the middle crust, and at times, well below the Moho. It is unclear to what extent these deep pathways are hydraulically connected to the surface, or the role of deep-seated processes in initiating or sustaining eruptions. Progress in understanding these pathways, and triggering mechanisms, requires our differentiating "ultimate", "proximal" and "immediate" causes, and determining which of various magmatic processes provide necessary or sufficient conditions for eruption.

My 65 years in protein chemistry

PubMed Central

Scheraga, Harold A.

2015-01-01

This is a tour of a physical chemist through 65 years of protein chemistry from the time when emphasis was placed on the determination of the size and shape of the protein molecule as a colloidal particle, with an early breakthrough by James Sumner, followed by Linus Pauling and Fred Sanger, that a protein was a real molecule, albeit a macromolecule. It deals with the recognition of the nature and importance of hydrogen bonds and hydrophobic interactions in determining the structure, properties, and biological function of proteins until the present acquisition of an understanding of the structure, thermodynamics, and folding pathways from a linear array of amino acids to a biological entity. Along the way, with a combination of experiment and theoretical interpretation, a mechanism was elucidated for the thrombin-induced conversion of fibrinogen to a fibrin blood clot and for the oxidative-folding pathways of ribonuclease A. Before the atomic structure of a protein molecule was determined by x-ray diffraction or nuclear magnetic resonance spectroscopy, experimental studies of the fundamental interactions underlying protein structure led to several distance constraints which motivated the theoretical approach to determine protein structure, and culminated in the Empirical Conformational Energy Program for Peptides (ECEPP), an all-atom force field, with which the structures of fibrous collagen-like proteins and the 46-residue globular staphylococcal protein A were determined. To undertake the study of larger globular proteins, a physics-based coarse-grained UNited-RESidue (UNRES) force field was developed, and applied to the protein-folding problem in terms of structure, thermodynamics, dynamics, and folding pathways. Initially, single-chain and, ultimately, multiple-chain proteins were examined, and the methodology was extended to protein–protein interactions and to nucleic acids and to protein–nucleic acid interactions. The ultimate results led to an understanding of a variety of biological processes underlying natural and disease phenomena. PMID:25850343

Trypanosoma cruzi Exploits Wnt Signaling Pathway to Promote Its Intracellular Replication in Macrophages.

PubMed

Volpini, Ximena; Ambrosio, Laura F; Fozzatti, Laura; Insfran, Constanza; Stempin, Cinthia C; Cervi, Laura; Motran, Claudia Cristina

2018-01-01

During the acute phase of Trypanosoma cruzi infection, macrophages can act as host cells for the parasites as well as effector cells in the early anti-parasitic immune response. Thus, the targeting of specific signaling pathways could modulate macrophages response to restrict parasite replication and instruct an appropriate adaptive response. Recently, it has become evident that Wnt signaling has immunomodulatory functions during inflammation and infection. Here, we tested the hypothesis that during T. cruzi infection, the activation of Wnt signaling pathway in macrophages plays a role in modulating the inflammatory/tolerogenic response and therefore regulating the control of parasite replication. In this report, we show that early after T. cruzi infection of bone marrow-derived macrophages (BMM), β-catenin was activated and Wnt3a, Wnt5a, and some Frizzled receptors as well as Wnt/β-catenin pathway's target genes were upregulated, with Wnt proteins signaling sustaining the activation of Wnt/β-catenin pathway and then activating the Wnt/Ca +2 pathway. Wnt signaling pathway activation was critical to sustain the parasite's replication in BMM; since the treatments with specific inhibitors of β-catenin transcriptional activation or Wnt proteins secretion limited the parasite replication. Mechanistically, inhibition of Wnt signaling pathway armed BMM to fight against T. cruzi by inducing the production of pro-inflammatory cytokines and indoleamine 2,3-dioxygenase activity and by downregulating arginase activity. Likewise, in vivo pharmacological inhibition of the Wnts' interaction with its receptors controlled the parasite replication and improved the survival of lethally infected mice. It is well established that T. cruzi infection activates a plethora of signaling pathways that ultimately regulate immune mediators to determine the modulation of a defined set of effector functions in macrophages. In this study, we have revealed a new signaling pathway that is activated by the interaction between protozoan parasites and host innate immunity, establishing a new conceptual framework for the development of new therapies.

Programs of Study as a State Policy Mandate: A Longitudinal Study of the South Carolina Personal Pathways to Success Initiative. Executive Summary

ERIC Educational Resources Information Center

Hammond, Cathy; Drew, Sam F.; Withington, Cairen; Griffith, Cathy; Swiger, Caroline M.; Mobley, Catherine; Sharp, Julia L.; Stringfield, Samuel C.; Stipanovic, Natalie; Daugherty, Lindsay

2013-01-01

This executive summary outlines key findings from the final technical report of a five-year study of South Carolina's Personal Pathways to Success Initiative, which was authorized by the state's Education and Economic Development Act (EEDA) in 2005. The Personal Pathways initiative is a K-16, career-focused school reform model intended to improve…

Hitler's parkinsonism.

PubMed

Boettcher, Lillian B; Bonney, Phillip A; Smitherman, Adam D; Sughrue, Michael E

2015-07-01

Of the multitude of medical and psychiatric conditions ascribed to Hitler both in his lifetime and since his suicide in April 1945, few are more substantiated than parkinsonism. While the timeline of the development of this condition, as well as its etiology, are debated, there is clear evidence for classic manifestations of the disease, most prominently a resting tremor but also stooped posture, bradykinesia, micrographia, and masked facial expressions, with progression steadily seen over his final years. Though ultimately speculation, some have suggested that Hitler suffered from progressive cognitive and mood disturbances, possibly due to parkinsonism, that affected the course of events in the war. Here, the authors discuss Hitler's parkinsonism in the context of the Third Reich and its eventual destruction, maintaining that ultimately his disease had little effect on the end result.

Robust adaptive relative position and attitude control for spacecraft autonomous proximity.

PubMed

Sun, Liang; Huo, Wei; Jiao, Zongxia

2016-07-01

This paper provides new results of the dynamical modeling and controller designing for autonomous close proximity phase during rendezvous and docking in the presence of kinematic couplings and model uncertainties. A globally defined relative motion mechanical model for close proximity operations is introduced firstly. Then, in spite of the kinematic couplings and thrust misalignment between relative rotation and relative translation, robust adaptive relative position and relative attitude controllers are designed successively. Finally, stability of the overall system is proved that the relative position and relative attitude are uniformly ultimately bounded, and the size of the ultimate bound can be regulated small enough by control system parameters. Performance of the controlled overall system is demonstrated via a representative numerical example. Copyright © 2016 ISA. Published by Elsevier Ltd. All rights reserved.

Best strategies to implement clinical pathways in an emergency department setting: study protocol for a cluster randomized controlled trial

PubMed Central

2013-01-01

Background The clinical pathway is a tool that operationalizes best evidence recommendations and clinical practice guidelines in an accessible format for ‘point of care’ management by multidisciplinary health teams in hospital settings. While high-quality, expert-developed clinical pathways have many potential benefits, their impact has been limited by variable implementation strategies and suboptimal research designs. Best strategies for implementing pathways into hospital settings remain unknown. This study will seek to develop and comprehensively evaluate best strategies for effective local implementation of externally developed expert clinical pathways. Design/methods We will develop a theory-based and knowledge user-informed intervention strategy to implement two pediatric clinical pathways: asthma and gastroenteritis. Using a balanced incomplete block design, we will randomize 16 community emergency departments to receive the intervention for one clinical pathway and serve as control for the alternate clinical pathway, thus conducting two cluster randomized controlled trials to evaluate this implementation intervention. A minimization procedure will be used to randomize sites. Intervention sites will receive a tailored strategy to support full clinical pathway implementation. We will evaluate implementation strategy effectiveness through measurement of relevant process and clinical outcomes. The primary process outcome will be the presence of an appropriately completed clinical pathway on the chart for relevant patients. Primary clinical outcomes for each clinical pathway include the following: Asthma—the proportion of asthmatic patients treated appropriately with corticosteroids in the emergency department and at discharge; and Gastroenteritis—the proportion of relevant patients appropriately treated with oral rehydration therapy. Data sources include chart audits, administrative databases, environmental scans, and qualitative interviews. We will also conduct an overall process evaluation to assess the implementation strategy and an economic analysis to evaluate implementation costs and benefits. Discussion This study will contribute to the body of evidence supporting effective strategies for clinical pathway implementation, and ultimately reducing the research to practice gaps by operationalizing best evidence care recommendations through effective use of clinical pathways. Trial registration ClinicalTrials.gov: NCT01815710 PMID:23692634

Cellular and molecular specificity of pituitary gland physiology.

PubMed

Perez-Castro, Carolina; Renner, Ulrich; Haedo, Mariana R; Stalla, Gunter K; Arzt, Eduardo

2012-01-01

The anterior pituitary gland has the ability to respond to complex signals derived from central and peripheral systems. Perception of these signals and their integration are mediated by cell interactions and cross-talk of multiple signaling transduction pathways and transcriptional regulatory networks that cooperate for hormone secretion, cell plasticity, and ultimately specific pituitary responses that are essential for an appropriate physiological response. We discuss the physiopathological and molecular mechanisms related to this integrative regulatory system of the anterior pituitary gland and how it contributes to modulate the gland functions and impacts on body homeostasis.

Roadmap and standard operating procedures for biobanking and discovery of neurochemical markers in ALS.

PubMed

Otto, Markus; Bowser, Robert; Turner, Martin; Berry, James; Brettschneider, Johannes; Connor, James; Costa, Júlia; Cudkowicz, Merit; Glass, Jonathan; Jahn, Olaf; Lehnert, Stefan; Malaspina, Andrea; Parnetti, Lucilla; Petzold, Axel; Shaw, Pamela; Sherman, Alexander; Steinacker, Petra; Süssmuth, Sigurd; Teunissen, Charlotte; Tumani, Hayrettin; Wuolikainen, Anna; Ludolph, Albert

2012-01-01

Despite major advances in deciphering the neuropathological hallmarks of amyotrophic lateral sclerosis (ALS), validated neurochemical biomarkers for monitoring disease activity, earlier diagnosis, defining prognosis and unlocking key pathophysiological pathways are lacking. Although several candidate biomarkers exist, translation into clinical application is hindered by small sample numbers, especially longitudinal, for independent verification. This review considers the potential routes to the discovery of neurochemical markers in ALS, and provides a consensus statement on standard operating procedures that will facilitate multicenter collaboration, validation and ultimately clinical translation.

Deficiency in methionine, tryptophan, isoleucine, or choline induces apoptosis in cultured cells.

PubMed

Yen, Chi-Liang E; Mar, Mei-Heng; Craciunescu, Corneliu N; Edwards, Lloyd J; Zeisel, Steven H

2002-07-01

Cells in culture die by apoptosis when deprived of the essential nutrient choline. We now report that cells (both proliferating PC12 cells and postmitotic neurons isolated from fetal rat brains) undergo apoptosis when deprived of other individual essential nutrients (methionine, tryptophan or isoleucine). In PC12 cells, deficiencies of each nutrient independently led to ceramide accumulation and to caspase activation, both recognized signals of several apoptotic pathways. A similar profile of caspases was activated in PC12 cells deprived of choline, methionine, tryptophan or isoleucine. More than one caspase was involved and these caspases appeared to transmit parallel signals for apoptosis induction because only broad-spectrum caspase inhibitors, but not inhibitors for specific individual caspases inhibited apoptosis in choline- or methionine-deprived cells. The induction of these caspase-dependent apoptosis pathways likely did not involve the same upstream signals. Choline deficiency perturbed choline metabolism but did not affect protein synthesis, whereas amino acid deficiencies inhibited protein synthesis but did not perturb choline metabolism. In addition, a subclone of PC12 cells that was resistant to choline deficiency-induced apoptosis was not resistant to tryptophan deficiency-induced apoptosis. These observations suggest that deficiency of each studied nutrient activates different pathways for signaling apoptosis that ultimately converge on a common execution pathway.

Accelerating cancer therapy development: the importance of combination strategies and collaboration. Summary of an Institute of Medicine workshop.

PubMed

LoRusso, Patricia M; Canetta, Renzo; Wagner, John A; Balogh, Erin P; Nass, Sharyl J; Boerner, Scott A; Hohneker, John

2012-11-15

Cancer cells contain multiple genetic changes in cell signaling pathways that drive abnormal cell survival, proliferation, invasion, and metastasis. Unfortunately, patients treated with single agents inhibiting only one of these pathways--even if showing an initial response--often develop resistance with subsequent relapse or progression of their cancer, typically via the activation of an alternative uninhibited pathway. Combination therapies offer the potential for inhibiting multiple targets and pathways simultaneously to more effectively kill cancer cells and prevent or delay the emergence of drug resistance. However, there are many unique challenges to developing combination therapies, including devising and applying appropriate preclinical tests and clinical trial designs, prioritizing which combination therapies to test, avoiding overlapping toxicity of multiple agents, and overcoming legal, cultural, and regulatory barriers that impede collaboration among multiple companies, organizations, and/or institutions. More effective strategies to efficiently develop combination cancer therapies are urgently needed. Thus, the Institute of Medicine's National Cancer Policy Forum recently convened a workshop with the goal of identifying barriers that may be impeding the development of combination investigational cancer therapies, as well as potential solutions to overcome those barriers, improve collaboration, and ultimately accelerate the development of promising combinations of investigational cancer therapies. ©2012 AACR.

The Molecular Ecophysiology of Programmed Cell Death in Marine Phytoplankton

NASA Astrophysics Data System (ADS)

Bidle, Kay D.

2015-01-01

Planktonic, prokaryotic, and eukaryotic photoautotrophs (phytoplankton) share a diverse and ancient evolutionary history, during which time they have played key roles in regulating marine food webs, biogeochemical cycles, and Earth's climate. Because phytoplankton represent the basis of marine ecosystems, the manner in which they die critically determines the flow and fate of photosynthetically fixed organic matter (and associated elements), ultimately constraining upper-ocean biogeochemistry. Programmed cell death (PCD) and associated pathway genes, which are triggered by a variety of nutrient stressors and are employed by parasitic viruses, play an integral role in determining the cell fate of diverse photoautotrophs in the modern ocean. Indeed, these multifaceted death pathways continue to shape the success and evolutionary trajectory of diverse phytoplankton lineages at sea. Research over the past two decades has employed physiological, biochemical, and genetic techniques to provide a novel, comprehensive, mechanistic understanding of the factors controlling this key process. Here, I discuss the current understanding of the genetics, activation, and regulation of PCD pathways in marine model systems; how PCD evolved in unicellular photoautotrophs; how it mechanistically interfaces with viral infection pathways; how stress signals are sensed and transduced into cellular responses; and how novel molecular and biochemical tools are revealing the impact of PCD genes on the fate of natural phytoplankton assemblages.

Integrated care pathways for airway diseases (AIRWAYS-ICPs).

PubMed

Bousquet, J; Addis, A; Adcock, I; Agache, I; Agusti, A; Alonso, A; Annesi-Maesano, I; Anto, J M; Bachert, C; Baena-Cagnani, C E; Bai, C; Baigenzhin, A; Barbara, C; Barnes, P J; Bateman, E D; Beck, L; Bedbrook, A; Bel, E H; Benezet, O; Bennoor, K S; Benson, M; Bernabeu-Wittel, M; Bewick, M; Bindslev-Jensen, C; Blain, H; Blasi, F; Bonini, M; Bonini, S; Boulet, L P; Bourdin, A; Bourret, R; Bousquet, P J; Brightling, C E; Briggs, A; Brozek, J; Buhl, R; Bush, A; Caimmi, D; Calderon, M; Calverley, P; Camargos, P A; Camuzat, T; Canonica, G W; Carlsen, K H; Casale, T B; Cazzola, M; Cepeda Sarabia, A M; Cesario, A; Chen, Y Z; Chkhartishvili, E; Chavannes, N H; Chiron, R; Chuchalin, A; Chung, K F; Cox, L; Crooks, G; Crooks, M G; Cruz, A A; Custovic, A; Dahl, R; Dahlen, S E; De Blay, F; Dedeu, T; Deleanu, D; Demoly, P; Devillier, P; Didier, A; Dinh-Xuan, A T; Djukanovic, R; Dokic, D; Douagui, H; Dubakiene, R; Eglin, S; Elliot, F; Emuzyte, R; Fabbri, L; Fink Wagner, A; Fletcher, M; Fokkens, W J; Fonseca, J; Franco, A; Frith, P; Furber, A; Gaga, M; Garcés, J; Garcia-Aymerich, J; Gamkrelidze, A; Gonzales-Diaz, S; Gouzi, F; Guzmán, M A; Haahtela, T; Harrison, D; Hayot, M; Heaney, L G; Heinrich, J; Hellings, P W; Hooper, J; Humbert, M; Hyland, M; Iaccarino, G; Jakovenko, D; Jardim, J R; Jeandel, C; Jenkins, C; Johnston, S L; Jonquet, O; Joos, G; Jung, K S; Kalayci, O; Karunanithi, S; Keil, T; Khaltaev, N; Kolek, V; Kowalski, M L; Kull, I; Kuna, P; Kvedariene, V; Le, L T; Lodrup Carlsen, K C; Louis, R; MacNee, W; Mair, A; Majer, I; Manning, P; de Manuel Keenoy, E; Masjedi, M R; Melen, E; Melo-Gomes, E; Menzies-Gow, A; Mercier, G; Mercier, J; Michel, J P; Miculinic, N; Mihaltan, F; Milenkovic, B; Molimard, M; Momas, I; Montilla-Santana, A; Morais-Almeida, M; Morgan, M; N'Diaye, M; Nafti, S; Nekam, K; Neou, A; Nicod, L; O'Hehir, R; Ohta, K; Paggiaro, P; Palkonen, S; Palmer, S; Papadopoulos, N G; Papi, A; Passalacqua, G; Pavord, I; Pigearias, B; Plavec, D; Postma, D S; Price, D; Rabe, K F; Radier Pontal, F; Redon, J; Rennard, S; Roberts, J; Robine, J M; Roca, J; Roche, N; Rodenas, F; Roggeri, A; Rolland, C; Rosado-Pinto, J; Ryan, D; Samolinski, B; Sanchez-Borges, M; Schünemann, H J; Sheikh, A; Shields, M; Siafakas, N; Sibille, Y; Similowski, T; Small, I; Sola-Morales, O; Sooronbaev, T; Stelmach, R; Sterk, P J; Stiris, T; Sud, P; Tellier, V; To, T; Todo-Bom, A; Triggiani, M; Valenta, R; Valero, A L; Valiulis, A; Valovirta, E; Van Ganse, E; Vandenplas, O; Vasankari, T; Vestbo, J; Vezzani, G; Viegi, G; Visier, L; Vogelmeier, C; Vontetsianos, T; Wagstaff, R; Wahn, U; Wallaert, B; Whalley, B; Wickman, M; Williams, D M; Wilson, N; Yawn, B P; Yiallouros, P K; Yorgancioglu, A; Yusuf, O M; Zar, H J; Zhong, N; Zidarn, M; Zuberbier, T

2014-08-01

The objective of Integrated Care Pathways for Airway Diseases (AIRWAYS-ICPs) is to launch a collaboration to develop multi-sectoral care pathways for chronic respiratory diseases in European countries and regions. AIRWAYS-ICPs has strategic relevance to the European Union Health Strategy and will add value to existing public health knowledge by: 1) proposing a common framework of care pathways for chronic respiratory diseases, which will facilitate comparability and trans-national initiatives; 2) informing cost-effective policy development, strengthening in particular those on smoking and environmental exposure; 3) aiding risk stratification in chronic disease patients, using a common strategy; 4) having a significant impact on the health of citizens in the short term (reduction of morbidity, improvement of education in children and of work in adults) and in the long-term (healthy ageing); 5) proposing a common simulation tool to assist physicians; and 6) ultimately reducing the healthcare burden (emergency visits, avoidable hospitalisations, disability and costs) while improving quality of life. In the longer term, the incidence of disease may be reduced by innovative prevention strategies. AIRWAYSICPs was initiated by Area 5 of the Action Plan B3 of the European Innovation Partnership on Active and Healthy Ageing. All stakeholders are involved (health and social care, patients, and policy makers).

How Stuttering Develops: The Multifactorial Dynamic Pathways Theory

PubMed Central

Weber, Christine

2017-01-01

Purpose We advanced a multifactorial, dynamic account of the complex, nonlinear interactions of motor, linguistic, and emotional factors contributing to the development of stuttering. Our purpose here is to update our account as the multifactorial dynamic pathways theory. Method We review evidence related to how stuttering develops, including genetic/epigenetic factors; motor, linguistic, and emotional features; and advances in neuroimaging studies. We update evidence for our earlier claim: Although stuttering ultimately reflects impairment in speech sensorimotor processes, its course over the life span is strongly conditioned by linguistic and emotional factors. Results Our current account places primary emphasis on the dynamic developmental context in which stuttering emerges and follows its course during the preschool years. Rapid changes in many neurobehavioral systems are ongoing, and critical interactions among these systems likely play a major role in determining persistence of or recovery from stuttering. Conclusion Stuttering, or childhood onset fluency disorder (Diagnostic and Statistical Manual of Mental Disorders, 5th edition; American Psychiatric Association [APA], 2013), is a neurodevelopmental disorder that begins when neural networks supporting speech, language, and emotional functions are rapidly developing. The multifactorial dynamic pathways theory motivates experimental and clinical work to determine the specific factors that contribute to each child's pathway to the diagnosis of stuttering and those most likely to promote recovery. PMID:28837728

THE PATHOPHYSIOLOGY OF GEOGRAPHIC ATROPHY SECONDARY TO AGE-RELATED MACULAR DEGENERATION AND THE COMPLEMENT PATHWAY AS A THERAPEUTIC TARGET

PubMed Central

Schmidt-Erfurth, Ursula; van Lookeren Campagne, Menno; Henry, Erin C.; Brittain, Christopher

2017-01-01

Purpose: Geographic atrophy (GA) is an advanced, vision-threatening form of age-related macular degeneration (AMD) affecting approximately five million individuals worldwide. To date, there are no approved therapeutics for GA treatment; however, several are in clinical trials. This review focuses on the pathophysiology of GA, particularly the role of complement cascade dysregulation and emerging therapies targeting the complement cascade. Methods: Primary literature search on PubMed for GA, complement cascade in age-related macular degeneration. ClinicalTrials.gov was searched for natural history studies in GA and clinical trials of drugs targeting the complement cascade for GA. Results: Cumulative damage to the retina by aging, environmental stress, and other factors triggers inflammation via multiple pathways, including the complement cascade. When regulatory components in these pathways are compromised, as with several GA-linked genetic risk factors in the complement cascade, chronic inflammation can ultimately lead to the retinal cell death characteristic of GA. Complement inhibition has been identified as a key candidate for therapeutic intervention, and drugs targeting the complement pathway are currently in clinical trials. Conclusion: The complement cascade is a strategic target for GA therapy. Further research, including on natural history and genetics, is crucial to expand the understanding of GA pathophysiology and identify effective therapeutic targets. PMID:27902638

How Stuttering Develops: The Multifactorial Dynamic Pathways Theory.

PubMed

Smith, Anne; Weber, Christine

2017-09-18

We advanced a multifactorial, dynamic account of the complex, nonlinear interactions of motor, linguistic, and emotional factors contributing to the development of stuttering. Our purpose here is to update our account as the multifactorial dynamic pathways theory. We review evidence related to how stuttering develops, including genetic/epigenetic factors; motor, linguistic, and emotional features; and advances in neuroimaging studies. We update evidence for our earlier claim: Although stuttering ultimately reflects impairment in speech sensorimotor processes, its course over the life span is strongly conditioned by linguistic and emotional factors. Our current account places primary emphasis on the dynamic developmental context in which stuttering emerges and follows its course during the preschool years. Rapid changes in many neurobehavioral systems are ongoing, and critical interactions among these systems likely play a major role in determining persistence of or recovery from stuttering. Stuttering, or childhood onset fluency disorder (Diagnostic and Statistical Manual of Mental Disorders, 5th edition; American Psychiatric Association [APA], 2013), is a neurodevelopmental disorder that begins when neural networks supporting speech, language, and emotional functions are rapidly developing. The multifactorial dynamic pathways theory motivates experimental and clinical work to determine the specific factors that contribute to each child's pathway to the diagnosis of stuttering and those most likely to promote recovery.

RNA-Binding Protein FXR1 Regulates p21 and TERC RNA to Bypass p53-Mediated Cellular Senescence in OSCC

PubMed Central

Majumder, Mrinmoyee; House, Reniqua; Palanisamy, Nallasivam; Qie, Shuo; Day, Terrence A.; Neskey, David; Diehl, J. Alan

2016-01-01

RNA-binding proteins (RBP) regulate numerous aspects of co- and post-transcriptional gene expression in cancer cells. Here, we demonstrate that RBP, fragile X-related protein 1 (FXR1), plays an essential role in cellular senescence by utilizing mRNA turnover pathway. We report that overexpressed FXR1 in head and neck squamous cell carcinoma targets (G-quadruplex (G4) RNA structure within) both mRNA encoding p21 (Cyclin-Dependent Kinase Inhibitor 1A (CDKN1A, Cip1) and the non-coding RNA Telomerase RNA Component (TERC), and regulates their turnover to avoid senescence. Silencing of FXR1 in cancer cells triggers the activation of Cyclin-Dependent Kinase Inhibitors, p53, increases DNA damage, and ultimately, cellular senescence. Overexpressed FXR1 binds and destabilizes p21 mRNA, subsequently reduces p21 protein expression in oral cancer cells. In addition, FXR1 also binds and stabilizes TERC RNA and suppresses the cellular senescence possibly through telomerase activity. Finally, we report that FXR1-regulated senescence is irreversible and FXR1-depleted cells fail to form colonies to re-enter cellular proliferation. Collectively, FXR1 displays a novel mechanism of controlling the expression of p21 through p53-dependent manner to bypass cellular senescence in oral cancer cells. PMID:27606879

Pathophysiology of cardiac hypertrophy and heart failure: signaling pathways and novel therapeutic targets.

PubMed

Tham, Yow Keat; Bernardo, Bianca C; Ooi, Jenny Y Y; Weeks, Kate L; McMullen, Julie R

2015-09-01

The onset of heart failure is typically preceded by cardiac hypertrophy, a response of the heart to increased workload, a cardiac insult such as a heart attack or genetic mutation. Cardiac hypertrophy is usually characterized by an increase in cardiomyocyte size and thickening of ventricular walls. Initially, such growth is an adaptive response to maintain cardiac function; however, in settings of sustained stress and as time progresses, these changes become maladaptive and the heart ultimately fails. In this review, we discuss the key features of pathological cardiac hypertrophy and the numerous mediators that have been found to be involved in the pathogenesis of cardiac hypertrophy affecting gene transcription, calcium handling, protein synthesis, metabolism, autophagy, oxidative stress and inflammation. We also discuss new mediators including signaling proteins, microRNAs, long noncoding RNAs and new findings related to the role of calcineurin and calcium-/calmodulin-dependent protein kinases. We also highlight mediators and processes which contribute to the transition from adaptive cardiac remodeling to maladaptive remodeling and heart failure. Treatment strategies for heart failure commonly include diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers and β-blockers; however, mortality rates remain high. Here, we discuss new therapeutic approaches (e.g., RNA-based therapies, dietary supplementation, small molecules) either entering clinical trials or in preclinical development. Finally, we address the challenges that remain in translating these discoveries to new and approved therapies for heart failure.

The walking dead: macrophage inflammation and death in atherosclerosis.

PubMed

Kavurma, Mary M; Rayner, Katey J; Karunakaran, Denuja

2017-04-01

To highlight recent studies that describe novel inflammatory and signaling mechanisms that regulate macrophage death in atherosclerosis. Macrophages contribute to all stages of atherosclerosis. The traditional dogma states that in homeostatic conditions, macrophages undergo apoptosis and are efficiently phagocytosed to be cleared by a process called efferocytosis. In advanced atherosclerosis, however, defective efferocytosis results in secondary necrosis of these uncleared apoptotic cells, which ultimately contributes to the formation of the characteristic necrotic core and the vulnerable plaque. Here, we outline the different types of lesional macrophage death: apoptosis, autophagic and the newly defined necroptosis (i.e. a type of programmed necrosis). Recent discoveries demonstrate that macrophage necroptosis directly contributes to necrotic core formation and plaque instability. Further, promoting the resolution of inflammation using preresolving mediators has been shown to enhance efferocytosis and decrease plaque vulnerability. Finally, the canonical 'don't eat me' signal CD47 has recently been described as playing an important role in atherosclerotic lesion progression by impairing efficient efferocytosis. Although we have made significant strides in improving our understanding of cell death and clearance mechanisms in atherosclerosis, there still remains unanswered questions as to how these pathways can be harnessed using therapeutics to promote lesion regression and disease stability. Improving our understanding of the mechanisms that regulate macrophage death in atherosclerosis, in particular apoptosis, necroptosis and efferocytosis, will provide novel therapeutic opportunities to resolve atherosclerosis and promote plaque stability.

Oxygen Release Induced Chemomechanical Breakdown of Layered Cathode Materials

DOE PAGES

Mu, Linqin; Lin, Ruoqian; Xu, Rong; ...

2018-04-18

Chemical and mechanical properties interplay on the nanometric scale and collectively govern the functionalities of battery materials. Understanding the relationship between the two can inform the design of battery materials with optimal chemomechanical properties for long-life lithium batteries. Herein, we report a mechanism of nanoscale mechanical breakdown in layered oxide cathode materials, originating from oxygen release at high states of charge under thermal abuse conditions. Here, we observe that the mechanical breakdown of charged Li 1-xNi 0.4Mn 0.4Co 0.2O 2 materials proceeds via a two-step pathway involving intergranular and intragranular crack formation. Owing to the oxygen release, sporadic phase transformationsmore » from the layered structure to the spinel and/or rocksalt structures introduce local stress, which initiates microcracks along grain boundaries and ultimately leads to the detachment of primary particles; i.e., intergranular crack formation. Furthermore, intragranular cracks (pores and exfoliations) form, likely due to the accumulation of oxygen vacancies and continuous phase transformations at the surfaces of primary particles. Finally, finite element modeling confirms our experimental observation that the crack formation is attributable to formation of oxygen vacancies, oxygen release, and phase transformations. This study is designed to directly observe the chemomechanical behavior of layered oxide cathode materials and provides a chemical basis for strengthening primary and secondary particles by stabilizing the oxygen anions in the lattice.« less

Anther-preferential expressing gene PMR is essential for the mitosis of pollen development in rice.

PubMed

Liu, Yaqin; Xu, Ya; Ling, Sheng; Liu, Shasha; Yao, Jialing

2017-06-01

Phenotype identification, expression examination, and function prediction declared that the anther-preferential expressing gene PMR may participate in regulation of male gametophyte development in rice. Male germline development in flowering plants produces the pair of sperm cells for double fertilization and the pollen mitosis is a key process of it. Although the structural features of male gametophyte have been defined, the molecular mechanisms regulating the mitotic cell cycle are not well elucidated in rice. Here, we reported an anther-preferential expressing gene in rice, PMR (Pollen Mitosis Relative), playing an essential role in male gametogenesis. When PMR gene was suppressed via RNAi, the mitosis of microspore was severely damaged, and the plants formed unmatured pollens containing only one or two nucleuses at the anthesis, ultimately leading to serious reduction of pollen fertility and seed-setting. The CRISPR mutants, pmr-1 and pmr-2, both showed the similar defects as the PMR-RNAi lines. Further analysis revealed that PMR together with its co-expressing genes were liable to participate in the regulation of DNA metabolism in the nucleus, and affected the activities of some enzymes related to the cell cycle. We finally discussed that unknown protein PMR contained the PHD, SWIB and Plus-3 domains and they might have coordinating functions in regulation pathway of the pollen mitosis in rice.

Oxygen Release Induced Chemomechanical Breakdown of Layered Cathode Materials

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

Mu, Linqin; Lin, Ruoqian; Xu, Rong

Chemical and mechanical properties interplay on the nanometric scale and collectively govern the functionalities of battery materials. Understanding the relationship between the two can inform the design of battery materials with optimal chemomechanical properties for long-life lithium batteries. Herein, we report a mechanism of nanoscale mechanical breakdown in layered oxide cathode materials, originating from oxygen release at high states of charge under thermal abuse conditions. Here, we observe that the mechanical breakdown of charged Li 1-xNi 0.4Mn 0.4Co 0.2O 2 materials proceeds via a two-step pathway involving intergranular and intragranular crack formation. Owing to the oxygen release, sporadic phase transformationsmore » from the layered structure to the spinel and/or rocksalt structures introduce local stress, which initiates microcracks along grain boundaries and ultimately leads to the detachment of primary particles; i.e., intergranular crack formation. Furthermore, intragranular cracks (pores and exfoliations) form, likely due to the accumulation of oxygen vacancies and continuous phase transformations at the surfaces of primary particles. Finally, finite element modeling confirms our experimental observation that the crack formation is attributable to formation of oxygen vacancies, oxygen release, and phase transformations. This study is designed to directly observe the chemomechanical behavior of layered oxide cathode materials and provides a chemical basis for strengthening primary and secondary particles by stabilizing the oxygen anions in the lattice.« less

“Redundancy” of Endocannabinoid Inactivation: New Challenges and Opportunities for Pain Control

PubMed Central

2012-01-01

Redundancy of metabolic pathways and molecular targets is a typical feature of all lipid mediators, and endocannabinoids, which were originally defined as endogenous agonists at cannabinoid CB1 and CB2 receptors, are no exception. In particular, the two most studied endocannabinoids, anandamide and 2-arachidonoylglycerol, are inactivated through alternative biochemical routes, including hydrolysis and oxidation, and more than one enzyme might be used even for the same type of inactivating reaction. These enzymes also recognize as substrates other concurrent lipid mediators, whereas, in turn, endocannabinoids might interact with noncannabinoid receptors with subcellular distribution and ultimate biological actions either similar to or completely different from those of cannabinoid receptors. Even splicing variants of endocannabinoid hydrolyzing enzymes, such as FAAH-1, might play distinct roles in endocannabinoid inactivation. Finally, the products of endocannabinoid catabolism may have their own targets, with biological roles different from those of cannabinoid receptors. These peculiarities of endocannabinoid signaling have complicated the use of inhibitors of its inactivation mechanisms as a safer and more efficacious alternative to the direct targeting of cannabinoid receptors for the treatment of several pathological conditions, including pain. However, new strategies, including the rediscovery of “dirty drugs”, and the use of certain natural products (including non-THC cannabis constituents), are emerging that might allow us to make a virtue of necessity and exploit endocannabinoid redundancy to develop new analgesics. PMID:22860203

Management Options for Reducing the Release of Antibiotics and Antibiotic Resistance Genes to the Environment

PubMed Central

Pruden, Amy; Amézquita, Alejandro; Collignon, Peter; Brandt, Kristian K.; Graham, David W.; Lazorchak, James M.; Suzuki, Satoru; Silley, Peter; Snape, Jason R.; Topp, Edward; Zhang, Tong; Zhu, Yong-Guan

2013-01-01

Background: There is growing concern worldwide about the role of polluted soil and water environments in the development and dissemination of antibiotic resistance. Objective: Our aim in this study was to identify management options for reducing the spread of antibiotics and antibiotic-resistance determinants via environmental pathways, with the ultimate goal of extending the useful life span of antibiotics. We also examined incentives and disincentives for action. Methods: We focused on management options with respect to limiting agricultural sources; treatment of domestic, hospital, and industrial wastewater; and aquaculture. Discussion: We identified several options, such as nutrient management, runoff control, and infrastructure upgrades. Where appropriate, a cross-section of examples from various regions of the world is provided. The importance of monitoring and validating effectiveness of management strategies is also highlighted. Finally, we describe a case study in Sweden that illustrates the critical role of communication to engage stakeholders and promote action. Conclusions: Environmental releases of antibiotics and antibiotic-resistant bacteria can in many cases be reduced at little or no cost. Some management options are synergistic with existing policies and goals. The anticipated benefit is an extended useful life span for current and future antibiotics. Although risk reductions are often difficult to quantify, the severity of accelerating worldwide morbidity and mortality rates associated with antibiotic resistance strongly indicate the need for action. PMID:23735422

Final Technical Report- Virginia Solar Pathways Project

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

Bond, Katharine; Cosby, Sarah

This Report provides a technical review of the final results of a funding award to Virginia Electric and Power Company (Dominion Energy Virginia (DEV) or the Company) for a project under the U.S. Department of Energy’s Solar Energy Technologies Office. The three-year project was formally known as the Virginia Solar Pathways Project (VSPP or the Project). The purpose of the VSPP was to develop a collaborative utility-administered solar strategy (Solar Strategy) for DEV’s service territory in the Commonwealth that could serve as a replicable model for other states with similar policy environments.

The biomechanical strength of a hardware-free femoral press-fit method for ACL bone-tendon-bone graft fixation.

PubMed

Arnold, M P; Burger, L D; Wirz, D; Goepfert, B; Hirschmann, M T

2017-04-01

The purpose was to investigate graft slippage and ultimate load to failure of a femoral press-fit fixation technique for anterior cruciate ligament (ACL) reconstruction. Nine fresh-frozen knees were used. Standardized harvesting of the B-PT-B graft was performed. The femora were cemented into steel rods, and a tunnel was drilled outside-in into the native ACL footprint and expanded using a manual mill bit. The femoral bone block was fixed press-fit. To pull the free end of the graft, it was fixed to a mechanical testing machine using a deep-freezing technique. A motion capture system was used to assess three-dimensional micro-motion. After preconditioning of the graft, 1000 cycles of tensile loading were applied. Finally, an ultimate load to failure test was performed. Graft slippage in mm ultimate load to failure as well as type of failure was noted. In six of the nine measured specimens, a typical pattern of graft slippage was observed during cyclic loading. For technical reasons, the results of three knees had to be discarded. 78.6 % of total graft slippage occurred in the first 100 cycles. Once the block had settled, graft slippage converged to zero, highlighting the importance of initial preconditioning of the graft in the clinical setting. Graft slippage after 1000 cycles varied around 3.4 ± 3.2 mm (R = 1.3-9.8 mm) between the specimens. Ultimate loading (n = 9) revealed two characteristic patterns of failure. In four knees, the tendon ruptured, while in five knees the bone block was pulled out of the femoral tunnel. The median ultimate load to failure was 852 N (R = 448-1349 N). The implant-free femoral press-fit fixation provided adequate primary stability with ultimate load to failure pull forces at least equal to published results for interference screws; hence, its clinical application is shown to be safe.

Identification and Spectroscopic Characterization of Nonheme Iron(III) Hypochlorite Intermediates.

PubMed

Draksharapu, Apparao; Angelone, Davide; Quesne, Matthew G; Padamati, Sandeep K; Gómez, Laura; Hage, Ronald; Costas, Miquel; Browne, Wesley R; de Visser, Sam P

2015-03-27

Fe III -hypohalite complexes have been implicated in a wide range of important enzyme-catalyzed halogenation reactions including the biosynthesis of natural products and antibiotics and post-translational modification of proteins. The absence of spectroscopic data on such species precludes their identification. Herein, we report the generation and spectroscopic characterization of nonheme Fe III -hypohalite intermediates of possible relevance to iron halogenases. We show that Fe III -OCl polypyridylamine complexes can be sufficiently stable at room temperature to be characterized by UV/Vis absorption, resonance Raman and EPR spectroscopies, and cryo-ESIMS. DFT methods rationalize the pathways to the formation of the Fe III -OCl, and ultimately Fe IV =O, species and provide indirect evidence for a short-lived Fe II -OCl intermediate. The species observed and the pathways involved offer insight into and, importantly, a spectroscopic database for the investigation of iron halogenases.

Identification and Spectroscopic Characterization of Nonheme Iron(III) Hypochlorite Intermediates**

PubMed Central

Draksharapu, Apparao; Angelone, Davide; Quesne, Matthew G; Padamati, Sandeep K; Gómez, Laura; Hage, Ronald; Costas, Miquel; Browne, Wesley R; de Visser, Sam P

2015-01-01

FeIII–hypohalite complexes have been implicated in a wide range of important enzyme-catalyzed halogenation reactions including the biosynthesis of natural products and antibiotics and post-translational modification of proteins. The absence of spectroscopic data on such species precludes their identification. Herein, we report the generation and spectroscopic characterization of nonheme FeIII–hypohalite intermediates of possible relevance to iron halogenases. We show that FeIII-OCl polypyridylamine complexes can be sufficiently stable at room temperature to be characterized by UV/Vis absorption, resonance Raman and EPR spectroscopies, and cryo-ESIMS. DFT methods rationalize the pathways to the formation of the FeIII-OCl, and ultimately FeIV=O, species and provide indirect evidence for a short-lived FeII-OCl intermediate. The species observed and the pathways involved offer insight into and, importantly, a spectroscopic database for the investigation of iron halogenases. PMID:25663379

Secondary migration and leakage of methane from a major tight-gas system

NASA Astrophysics Data System (ADS)

Wood, James M.; Sanei, Hamed

2016-11-01

Tight-gas and shale-gas systems can undergo significant depressurization during basin uplift and erosion of overburden due primarily to the natural leakage of hydrocarbon fluids. To date, geologic factors governing hydrocarbon leakage from such systems are poorly documented and understood. Here we show, in a study of produced natural gas from 1,907 petroleum wells drilled into a Triassic tight-gas system in western Canada, that hydrocarbon fluid loss is focused along distinct curvilinear pathways controlled by stratigraphic trends with superior matrix permeability and likely also structural trends with enhanced fracture permeability. Natural gas along these pathways is preferentially enriched in methane because of selective secondary migration and phase separation processes. The leakage and secondary migration of thermogenic methane to surficial strata is part of an ongoing carbon cycle in which organic carbon in the deep sedimentary basin transforms into methane, and ultimately reaches the near-surface groundwater and atmosphere.

Chromatin landscape and circadian dynamics: Spatial and temporal organization of clock transcription

PubMed Central

Aguilar-Arnal, Lorena; Sassone-Corsi, Paolo

2015-01-01

Circadian rhythms drive the temporal organization of a wide variety of physiological and behavioral functions in ∼24-h cycles. This control is achieved through a complex program of gene expression. In mammals, the molecular clock machinery consists of interconnected transcriptional–translational feedback loops that ultimately ensure the proper oscillation of thousands of genes in a tissue-specific manner. To achieve circadian transcriptional control, chromatin remodelers serve the clock machinery by providing appropriate oscillations to the epigenome. Recent findings have revealed the presence of circadian interactomes, nuclear “hubs” of genome topology where coordinately expressed circadian genes physically interact in a spatial and temporal-specific manner. Thus, a circadian nuclear landscape seems to exist, whose interplay with metabolic pathways and clock regulators translates into specific transcriptional programs. Deciphering the molecular mechanisms that connect the circadian clock machinery with the nuclear landscape will reveal yet unexplored pathways that link cellular metabolism to epigenetic control. PMID:25378702

Secondary migration and leakage of methane from a major tight-gas system

PubMed Central

Wood, James M.; Sanei, Hamed

2016-01-01

Tight-gas and shale-gas systems can undergo significant depressurization during basin uplift and erosion of overburden due primarily to the natural leakage of hydrocarbon fluids. To date, geologic factors governing hydrocarbon leakage from such systems are poorly documented and understood. Here we show, in a study of produced natural gas from 1,907 petroleum wells drilled into a Triassic tight-gas system in western Canada, that hydrocarbon fluid loss is focused along distinct curvilinear pathways controlled by stratigraphic trends with superior matrix permeability and likely also structural trends with enhanced fracture permeability. Natural gas along these pathways is preferentially enriched in methane because of selective secondary migration and phase separation processes. The leakage and secondary migration of thermogenic methane to surficial strata is part of an ongoing carbon cycle in which organic carbon in the deep sedimentary basin transforms into methane, and ultimately reaches the near-surface groundwater and atmosphere. PMID:27874012

Intervention of Phytohormone Pathways by Pathogen Effectors[OPEN

PubMed Central

Kazan, Kemal; Lyons, Rebecca

2014-01-01

The constant struggle between plants and microbes has driven the evolution of multiple defense strategies in the host as well as offense strategies in the pathogen. To defend themselves from pathogen attack, plants often rely on elaborate signaling networks regulated by phytohormones. In turn, pathogens have adopted innovative strategies to manipulate phytohormone-regulated defenses. Tactics frequently employed by plant pathogens involve hijacking, evading, or disrupting hormone signaling pathways and/or crosstalk. As reviewed here, this is achieved mechanistically via pathogen-derived molecules known as effectors, which target phytohormone receptors, transcriptional activators and repressors, and other components of phytohormone signaling in the host plant. Herbivores and sap-sucking insects employ obligate pathogens such as viruses, phytoplasma, or symbiotic bacteria to intervene with phytohormone-regulated defenses. Overall, an improved understanding of phytohormone intervention strategies employed by pests and pathogens during their interactions with plants will ultimately lead to the development of new crop protection strategies. PMID:24920334

Trafficking to the Apical and Basolateral Membranes in Polarized Epithelial Cells

PubMed Central

Stoops, Emily H.

2014-01-01

Renal epithelial cells must maintain distinct protein compositions in their apical and basolateral membranes in order to perform their transport functions. The creation of these polarized protein distributions depends on sorting signals that designate the trafficking route and site of ultimate functional residence for each protein. Segregation of newly synthesized apical and basolateral proteins into distinct carrier vesicles can occur at the trans-Golgi network, recycling endosomes, or a growing assortment of stations along the cellular trafficking pathway. The nature of the specific sorting signal and the mechanism through which it is interpreted can influence the route a protein takes through the cell. Cell type–specific variations in the targeting motifs of a protein, as are evident for Na,K-ATPase, demonstrate a remarkable capacity to adapt sorting pathways to different developmental states or physiologic requirements. This review summarizes our current understanding of apical and basolateral trafficking routes in polarized epithelial cells. PMID:24652803

Emerging Metabolic Therapies in Pulmonary Arterial Hypertension

PubMed Central

Harvey, Lloyd D.; Chan, Stephen Y.

2017-01-01

Pulmonary hypertension (PH) is an enigmatic vascular disorder characterized by pulmonary vascular remodeling and increased pulmonary vascular resistance, ultimately resulting in pressure overload, dysfunction, and failure of the right ventricle. Current medications for PH do not reverse or prevent disease progression, and current diagnostic strategies are suboptimal for detecting early-stage disease. Thus, there is a substantial need to develop new diagnostics and therapies that target the molecular origins of PH. Emerging investigations have defined metabolic aberrations as fundamental and early components of disease manifestation in both pulmonary vasculature and the right ventricle. As such, the elucidation of metabolic dysregulation in pulmonary hypertension allows for greater therapeutic insight into preventing, halting, or even reversing disease progression. This review will aim to discuss (1) the reprogramming and dysregulation of metabolic pathways in pulmonary hypertension; (2) the emerging therapeutic interventions targeting these metabolic pathways; and (3) further innovation needed to overcome barriers in the treatment of this devastating disease. PMID:28375184

Unravelling signal escape through maintained EGFR activation in advanced non-small cell lung cancer (NSCLC): new treatment options

PubMed Central

Remon, Jordi; Besse, Benjamin

2016-01-01

The discovery of activating epidermal growth factor receptor (EGFR) mutations has opened up a new era in the development of more effective treatments for patients with non-small cell lung cancer (NSCLC). However, patients with EGFR-activating mutated NSCLC treated with EGFR tyrosine kinase inhibitors (TKIs) ultimately develop acquired resistance (AR). Among known cases of patients with AR, 70% of the mechanisms involved in the development of AR to EGFR TKI have been identified and may be categorised as either secondary EGFR mutations such as the T790M mutation, activation of bypass track signalling pathways such as MET amplification, or histologic transformation. EGFR-mutant NSCLC tumours maintain oncogenic addiction to the EGFR pathway beyond progression with EGFR TKI. Clinical strategies that can be implemented in daily clinical practice to potentially overcome this resistance and prolong the outcome in this subgroup of patients are presented. PMID:27843631

Generalized platform for antibody detection using the antibody catalyzed water oxidation pathway.

PubMed

Welch, M Elizabeth; Ritzert, Nicole L; Chen, Hongjun; Smith, Norah L; Tague, Michele E; Xu, Youyong; Baird, Barbara A; Abruña, Héctor D; Ober, Christopher K

2014-02-05

Infectious diseases, such as influenza, present a prominent global problem including the constant threat of pandemics that initiate in avian or other species and then pass to humans. We report a new sensor that can be specifically functionalized to detect antibodies associated with a wide range of infectious diseases in multiple species. This biosensor is based on electrochemical detection of hydrogen peroxide generated through the intrinsic catalytic activity of all antibodies: the antibody catalyzed water oxidation pathway (ACWOP). Our platform includes a polymer brush-modified surface where specific antibodies bind to conjugated haptens with high affinity and specificity. Hydrogen peroxide provides an electrochemical signal that is mediated by Resorufin/Amplex Red. We characterize the biosensor platform, using model anti-DNP antibodies, with the ultimate goal of designing a versatile device that is inexpensive, portable, reliable, and fast. We demonstrate detection of antibodies at concentrations that fall well within clinically relevant levels.

Mechanisms of acetylcholine- and bradykinin-induced preconditioning.

PubMed

Critz, Stuart D; Cohen, Michael V; Downey, James M

2005-01-01

Acetylcholine (ACh) and bradykinin (BK) are potent pharmacological agents which mimic ischemic preconditioning (IPC) enabling hearts to resist infarction during a subsequent period of ischemia. The cardioprotective pathways activated by BK but not ACh may also protect when activated at reperfusion. ACh and BK stimulate Gi/o-linked receptors and ultimately mediate protection by opening mitochondrial ATP-sensitive potassium channels with the generation of reactive oxygen species that act as second messengers to activate protein kinase C (PKC). There appear to be key differences, however, in the pathways prior to potassium channel opening for these two receptors. This review aims to summarize what is currently known about pharmacological preconditioning by ACh and BK with an emphasis on differences that are seen in the signal transduction cascades. Understanding the cellular basis of protection by ACh and BK is a critical step towards developing pharmacological agents that will prevent infarction during ischemia resulting from coronary occlusion or heart attack.

Targeting the androgen receptor in prostate and breast cancer – several new agents in development

PubMed Central

Proverbs-Singh, Tracy; Feldman, Jarett L.; Morris, Michael J.; Autio, Karen A.; Traina, Tiffany A.

2016-01-01

Prostate cancer and breast cancer share similarities as hormone-sensitive cancers with a wide heterogeneity of both phenotype and biology. The androgen receptor (AR) is a hormone receptor involved in both benign and malignant processes. Targeting androgen synthesis and the AR pathway has been and remains central to prostate cancer therapy. Recently, there is increased interest in the role of the AR in breast cancer development and growth, with data suggesting AR co-expression with estrogen, progesterone and human epidermal growth factor receptors, across all intrinsic subtypes of breast cancer. Targeting the AR axis is an evolving field with novel therapies in development which may ultimately be applicable for both tumor types. In this review, we offer an overview of available agents which target the AR axis in both prostate and breast cancer and provide insight into the novel drugs in development for targeting this signaling pathway. PMID:25722318

Abnormal gene expression profiles in human ovaries from polycystic ovary syndrome patients.

PubMed

Jansen, Erik; Laven, Joop S E; Dommerholt, Henri B R; Polman, Jan; van Rijt, Cindy; van den Hurk, Caroline; Westland, Jolanda; Mosselman, Sietse; Fauser, Bart C J M

2004-12-01

Polycystic ovary syndrome (PCOS) represents the most common cause of anovulatory infertility and affects 5-10% of women of reproductive age. The etiology of PCOS is still unknown. The current study is the first to describe consistent differences in gene expression profiles in human ovaries comparing PCOS patients vs. healthy normoovulatory individuals. The microarray analysis of PCOS vs. normal ovaries identifies dysregulated expression of genes encoding components of several biological pathways or systems such as Wnt signaling, extracellular matrix components, and immunological factors. Resulting data may provide novel clues for ovarian dysfunction in PCOS. Intriguingly, the gene expression profiles of ovaries from (long-term) androgen-treated female-to-male transsexuals (TSX) show considerable overlap with PCOS. This observation provides supportive evidence that androgens play a key role in the pathogenesis of PCOS. Presented data may contribute to a better understanding of dysregulated pathways in PCOS, which might ultimately reveal novel leads for therapeutic intervention.

Targeting cancer stem cell-specific markers and/or associated signaling pathways for overcoming cancer drug resistance.

PubMed

Ranji, Peyman; Salmani Kesejini, Tayyebali; Saeedikhoo, Sara; Alizadeh, Ali Mohammad

2016-10-01

Cancer stem cells (CSCs) are a small subpopulation of tumor cells with capabilities of self-renewal, dedifferentiation, tumorigenicity, and inherent chemo-and-radio therapy resistance. Tumor resistance is believed to be caused by CSCs that are intrinsically challenging to common treatments. A number of CSC markers including CD44, CD133, receptor tyrosine kinase, aldehyde dehydrogenases, epithelial cell adhesion molecule/epithelial specific antigen, and ATP-binding cassette subfamily G member 2 have been proved as the useful targets for defining CSC population in solid tumors. Furthermore, targeting CSC markers through new therapeutic strategies will ultimately improve treatments and overcome cancer drug resistance. Therefore, the identification of novel strategies to increase sensitivity of CSC markers has major clinical implications. This review will focus on the innovative treatment methods such as nano-, immuno-, gene-, and chemotherapy approaches for targeting CSC-specific markers and/or their associated signaling pathways.

76 FR 14660 - Public Comment on the Development of Final Guidance for Evaluating the Vapor Intrusion to Indoor...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-17

... Groundwater and Soils (Subsurface Vapor Intrusion Guidance) AGENCY: Environmental Protection Agency (EPA... Pathway from Contaminated Groundwater and Soil (Subsurface Vapor Intrusion Guidance). A draft of the... Evaluating Vapor Intrusion to Indoor Air Pathway from Contaminated Groundwater and Soil (Subsurface Vapor...

Developmental Education in Arkansas: Practices, Costs, and a Model Approach

ERIC Educational Resources Information Center

Carroll, Rhonda; Kersh, Lily; Sullivan, Ellen; Fincher, Mark

2012-01-01

This paper examines the origins of developmental education and explores the way developmental education is administered at selected colleges in Arkansas. Finally, the paper focuses on a model Career Pathways Initiative program at University of Arkansas Community College-Morrilton. Career Pathways invigorates partnerships between colleges and…

Evolution of amino acid metabolism inferred through cladistic analysis.

PubMed

Cunchillos, Chomin; Lecointre, Guillaume

2003-11-28

Because free amino acids were most probably available in primitive abiotic environments, their metabolism is likely to have provided some of the very first metabolic pathways of life. What were the first enzymatic reactions to emerge? A cladistic analysis of metabolic pathways of the 16 aliphatic amino acids and 2 portions of the Krebs cycle was performed using four criteria of homology. The analysis is not based on sequence comparisons but, rather, on coding similarities in enzyme properties. The properties used are shared specific enzymatic activity, shared enzymatic function without substrate specificity, shared coenzymes, and shared functional family. The tree shows that the earliest pathways to emerge are not portions of the Krebs cycle but metabolisms of aspartate, asparagine, glutamate, and glutamine. The views of Horowitz (Horowitz, N. H. (1945) Proc. Natl. Acad. Sci. U. S. A. 31, 153-157) and Cordón (Cordón, F. (1990) Tratado Evolucionista de Biologia, Aguilar, Madrid, Spain), according to which the upstream reactions in the catabolic pathways and the downstream reactions in the anabolic pathways are the earliest in evolution, are globally corroborated; however, with some exceptions. These are due to later opportunistic connections of pathways (actually already suggested by these authors). Earliest enzymatic functions are mostly catabolic; they were deaminations, transaminations, and decarboxylations. From the consensus tree we extracted four time spans for amino acid metabolism development. For some amino acids catabolism and biosynthesis occurred at the same time (Asp, Glu, Lys, Leu, Ala, Val, Ile, Pro, Arg). For others ultimate reactions that use amino acids as a substrate or as a product are distinct in time, with catabolism preceding anabolism for Asn, Gln, and Cys and anabolism preceding catabolism for Ser, Met, and Thr. Cladistic analysis of the structure of biochemical pathways makes hypotheses in biochemical evolution explicit and parsimonious.

The kynurenine pathway in schizophrenia and bipolar disorder.

PubMed

Erhardt, Sophie; Schwieler, Lilly; Imbeault, Sophie; Engberg, Göran

2017-01-01

The kynurenine pathway of tryptophan degradation generates several neuroactive compounds. Of those, kynurenic acid is an N-methyl-d-aspartate (NMDA) and alpha7 nicotinic receptor antagonist. The kynurenic acid hypothesis of schizophrenia is built upon the fact that kynurenic acid blocks glutamate receptors and is elevated in schizophrenia. Kynurenic acid tightly controls glutamatergic and dopaminergic neurotransmission and elevated brain levels appear related to psychotic symptoms and cognitive impairments. Contributing to enhanced production of kynurenic acid, the expression and enzyme activity of kynurenine 3-monooxygenase (KMO) are reduced in schizophrenia and in bipolar patients with a history of psychosis. The kynurenine pathway is also critically regulated by cytokines, and, indeed, the pro-inflammatory cytokines interleukin (IL)-1β and IL-6 are elevated in schizophrenia and bipolar disorder and stimulate the production of kynurenic acid. One physiological mechanism controlling the activity of the kynurenine pathway originates from the protein sorting nexin 7 (SNX7). This glial signaling pathway initiates a caspase-8-driven activation of IL-1β that induces tryptophan-2,3-dioxygenase 2 (TDO2), an enzyme in the kynurenine pathway. A recent study shows that a genetic variation resulting in decreased expression of SNX7 is linked to increased central levels of kynurenic acid and ultimately to psychosis and cognitive dysfunction in bipolar disorder. Experimental studies highlight the detrimental effects of increased synthesis of kynurenic acid during sensitive periods of early brain development. Furthermore, experimental studies strongly support inhibition of kynurenine aminotransferase (KAT) II as a novel target and a valuable pharmacological strategy in the treatment of psychosis and for improving cognitive performance relevant for schizophrenia. This article is part of the Special Issue entitled 'The Kynurenine Pathway in Health and Disease'. Copyright © 2016 Elsevier Ltd. All rights reserved.

Global Metabolic Profiling of Infection by an Oncogenic Virus: KSHV Induces and Requires Lipogenesis for Survival of Latent Infection

PubMed Central

Delgado, Tracie; Sanchez, Erica L.; Camarda, Roman; Lagunoff, Michael

2012-01-01

Like cancer cells, virally infected cells have dramatically altered metabolic requirements. We analyzed global metabolic changes induced by latent infection with an oncogenic virus, Kaposi's Sarcoma-associated herpesvirus (KSHV). KSHV is the etiologic agent of Kaposi's Sarcoma (KS), the most common tumor of AIDS patients. Approximately one-third of the nearly 200 measured metabolites were altered following latent infection of endothelial cells by KSHV, including many metabolites of anabolic pathways common to most cancer cells. KSHV induced pathways that are commonly altered in cancer cells including glycolysis, the pentose phosphate pathway, amino acid production and fatty acid synthesis. Interestingly, over half of the detectable long chain fatty acids detected in our screen were significantly increased by latent KSHV infection. KSHV infection leads to the elevation of metabolites involved in the synthesis of fatty acids, not degradation from phospholipids, and leads to increased lipid droplet organelle formation in the infected cells. Fatty acid synthesis is required for the survival of latently infected endothelial cells, as inhibition of key enzymes in this pathway led to apoptosis of infected cells. Addition of palmitic acid to latently infected cells treated with a fatty acid synthesis inhibitor protected the cells from death indicating that the products of this pathway are essential. Our metabolomic analysis of KSHV-infected cells provides insight as to how oncogenic viruses can induce metabolic alterations common to cancer cells. Furthermore, this analysis raises the possibility that metabolic pathways may provide novel therapeutic targets for the inhibition of latent KSHV infection and ultimately KS tumors. PMID:22916018

Multi-pathway Kinase Signatures of Multipotent Stromal Cells are Predictive for Osteogenic Differentiation

PubMed Central

Platt, Manu O.; Wilder, Catera L.; Wells, Alan; Griffith, Linda G.; Lauffenburger, Douglas A.

2010-01-01

Bone marrow-derived multi-potent stromal cells (MSCs) offer great promise for regenerating tissue. While certain transcription factors have been identified in association with tendency toward particular MSC differentiation phenotypes, the regulatory network of key receptor-mediated signaling pathways activated by extracellular ligands that induce various differentiation responses remain poorly understood. Attempts to predict differentiation fate tendencies from individual pathways in isolation are problematic due to the complex pathway interactions inherent in signaling networks. Accordingly, we have undertaken a multi-variate systems approach integrating experimental measurement of multiple kinase pathway activities and osteogenic differentiation in MSCs, together with computational analysis to elucidate quantitative combinations of kinase signals predictive of cell behavior across diverse contexts. In particular, for culture on polymeric biomaterials surfaces presenting tethered epidermal growth factor (tEGF), type-I collagen, neither, or both, we have found that a partial least-squares regression model yields successful prediction of phenotypic behavior on the basis of two principal components comprising the weighted sums of 8 intracellular phosphoproteins: p-EGFR, p-Akt, p-ERK1/2, p-Hsp27, p-c-jun, p-GSK3α/β, p-p38, and p-STAT3. This combination provides strongest predictive capability for 21-day differentiated phenotype status when calculated from day-7 signal measurements (99%); day-4 (88%) and day-14 (89%) signal measurements are also significantly predictive, indicating a broad time-frame during MSC osteogenesis wherein multiple pathways and states of the kinase signaling network are quantitatively integrated to regulate gene expression, cell processes, and ultimately, cell fate. PMID:19750537

Mechanism of Action of Two Flavone Isomers Targeting Cancer Cells with Varying Cell Differentiation Status

PubMed Central

Parsons, Laura B.; Miller, Gerald E.; Whitted, Crystal; Lynch, Kayla E.; Ramsauer, Robert E.; Patel, Jasmine U.; Wyatt, Jarrett E.; Street, Doris S.; Adams, Carolyn B.; McPherson, Brian; Tsui, Hei Man; Evans, Julie A.; Livesay, Christopher; Torrenegra, Ruben D.; Palau, Victoria E.

2015-01-01

Apoptosis can be triggered in two different ways, through the intrinsic or the extrinsic pathway. The intrinsic pathway is mediated by the mitochondria via the release of cytochrome C while the extrinsic pathway is prompted by death receptor signals and bypasses the mitochondria. These two pathways are closely related to cell proliferation and survival signaling cascades, which thereby constitute possible targets for cancer therapy. In previous studies we introduced two plant derived isomeric flavonoids, flavone A and flavone B which induce apoptosis in highly tumorigenic cancer cells of the breast, colon, pancreas, and the prostate. Flavone A displayed potent cytotoxic activity against more differentiated carcinomas of the colon (CaCo-2) and the pancreas (Panc28), whereas flavone B cytotoxic action is observed on poorly differentiated carcinomas of the colon (HCT 116) and pancreas (MIA PaCa). Apoptosis is induced by flavone A in better differentiated colon cancer CaCo-2 and pancreatic cancer Panc 28 cells via the intrinsic pathway by the inhibition of the activated forms of extracellular signal-regulated kinase (ERK) and pS6, and subsequent loss of phosphorylation of Bcl-2 associated death promoter (BAD) protein, while apoptosis is triggered by flavone B in poorly differentiated colon cancer HCT 116 and MIA PaCa pancreatic cancer cells through the extrinsic pathway with the concomitant upregulation of the phosphorylated forms of ERK and c-JUN at serine 73. These changes in protein levels ultimately lead to activation of apoptosis, without the involvement of AKT. PMID:26606169

Microstructures and properties of aluminum die casting alloys

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

M. M. Makhlouf; D. Apelian; L. Wang

1998-10-01

This document provides descriptions of the microstructure of different aluminum die casting alloys and to relate the various microstructures to the alloy chemistry. It relates the microstructures of the alloys to their main engineering properties such as ultimate tensile strength, yield strength, elongation, fatigue life, impact resistance, wear resistance, hardness, thermal conductivity and electrical conductivity. Finally, it serves as a reference source for aluminum die casting alloys.

IMPROVING PROCEDURES FOR PRODUCING OVERHEAD TRANSPARENCIES WITH THE ULTIMATE AIM OF INCORPORATING THESE TECHNIQUES INTO THE DEVELOPMENT OF A REGIONAL CURRICULAR MATERIALS CENTER FOR VOCATIONAL EDUCATION. FINAL REPORT.

ERIC Educational Resources Information Center

JENSEN, ARTHUR K.

THE INVESTIGATION RESULTED IN THE PRODUCTION OF 88 LOW-COST OVERHEAD PROJECTION TRANSPARENCIES ON THE BASIC PRINCIPLES OF POWER TRANSMISSION IN AGRICULTURAL MACHINERY. DEVELOPING TECHNIQUES FOR OFFSET PRINTING ON PLASTIC REQUIRED OVERCOMING PROBLEMS OF STATIC ELECTRICITY, INK ADHESION, OFFSETTING, AND DRYING. MACHINERY, ENVIRONMENT, AND INK WERE…

A unique friendship

NASA Astrophysics Data System (ADS)

Harris, Robert A.

2010-10-01

The beginning of the friendship between myself and H.F. Schaefer (hereafter 'Fritz') took place in Berkeley. The development of this friendship is best described by the question: How did a red diaper baby become good friends with one who had a totally different view of 'ultimate questions'? The essential role my wife, Christine Chapin Harris, plays in the friendship when Fritz moves to Georgia is next described. The story continues with Fritz's efforts over many years, finally successful, to encourage us to visit Georgia. This part of the history emphasizes Fritz's kindness towards Christine. I end this section with our adventures with Fritz in Georgia. The final section is about our old age common humanity.

Contribution of new technologies to characterization and prediction of adverse effects.

PubMed

Rouquié, David; Heneweer, Marjoke; Botham, Jane; Ketelslegers, Hans; Markell, Lauren; Pfister, Thomas; Steiling, Winfried; Strauss, Volker; Hennes, Christa

2015-02-01

Identification of the potential hazards of chemicals has traditionally relied on studies in laboratory animals where changes in clinical pathology and histopathology compared to untreated controls defined an adverse effect. In the past decades, increased consistency in the definition of adversity with chemically-induced effects in laboratory animals, as well as in the assessment of human relevance has been reached. More recently, a paradigm shift in toxicity testing has been proposed, mainly driven by concerns over animal welfare but also thanks to the development of new methods. Currently, in vitro approaches, toxicogenomic technologies and computational tools, are available to provide mechanistic insight in toxicological Mode of Action (MOA) of the adverse effects observed in laboratory animals. The vision described as Tox21c (Toxicity Testing in the 21st century) aims at predicting in vivo toxicity using a bottom-up-approach, starting with understanding of MOA based on in vitro data to ultimately predict adverse effects in humans. At present, a practical application of the Tox21c vision is still far away. While moving towards toxicity prediction based on in vitro data, a stepwise reduction of in vivo testing is foreseen by combining in vitro with in vivo tests. Furthermore, newly developed methods will also be increasingly applied, in conjunction with established methods in order to gain trust in these new methods. This confidence is based on a critical scientific prerequisite: the establishment of a causal link between data obtained with new technologies and adverse effects manifested in repeated-dose in vivo toxicity studies. It is proposed to apply the principles described in the WHO/IPCS framework of MOA to obtain this link. Finally, an international database of known MOAs obtained in laboratory animals using data-rich chemicals will facilitate regulatory acceptance and could further help in the validation of the toxicity pathway and adverse outcome pathway concepts.

Convergent functional genomics of schizophrenia: from comprehensive understanding to genetic risk prediction

PubMed Central

Ayalew, M; Le-Niculescu, H; Levey, D F; Jain, N; Changala, B; Patel, S D; Winiger, E; Breier, A; Shekhar, A; Amdur, R; Koller, D; Nurnberger, J I; Corvin, A; Geyer, M; Tsuang, M T; Salomon, D; Schork, N J; Fanous, A H; O'Donovan, M C; Niculescu, A B

2012-01-01

We have used a translational convergent functional genomics (CFG) approach to identify and prioritize genes involved in schizophrenia, by gene-level integration of genome-wide association study data with other genetic and gene expression studies in humans and animal models. Using this polyevidence scoring and pathway analyses, we identify top genes (DISC1, TCF4, MBP, MOBP, NCAM1, NRCAM, NDUFV2, RAB18, as well as ADCYAP1, BDNF, CNR1, COMT, DRD2, DTNBP1, GAD1, GRIA1, GRIN2B, HTR2A, NRG1, RELN, SNAP-25, TNIK), brain development, myelination, cell adhesion, glutamate receptor signaling, G-protein–coupled receptor signaling and cAMP-mediated signaling as key to pathophysiology and as targets for therapeutic intervention. Overall, the data are consistent with a model of disrupted connectivity in schizophrenia, resulting from the effects of neurodevelopmental environmental stress on a background of genetic vulnerability. In addition, we show how the top candidate genes identified by CFG can be used to generate a genetic risk prediction score (GRPS) to aid schizophrenia diagnostics, with predictive ability in independent cohorts. The GRPS also differentiates classic age of onset schizophrenia from early onset and late-onset disease. We also show, in three independent cohorts, two European American and one African American, increasing overlap, reproducibility and consistency of findings from single-nucleotide polymorphisms to genes, then genes prioritized by CFG, and ultimately at the level of biological pathways and mechanisms. Finally, we compared our top candidate genes for schizophrenia from this analysis with top candidate genes for bipolar disorder and anxiety disorders from previous CFG analyses conducted by us, as well as findings from the fields of autism and Alzheimer. Overall, our work maps the genomic and biological landscape for schizophrenia, providing leads towards a better understanding of illness, diagnostics and therapeutics. It also reveals the significant genetic overlap with other major psychiatric disorder domains, suggesting the need for improved nosology. PMID:22584867

Review of sample preparation strategies for MS-based metabolomic studies in industrial biotechnology.

PubMed

Causon, Tim J; Hann, Stephan

2016-09-28

Fermentation and cell culture biotechnology in the form of so-called "cell factories" now play an increasingly significant role in production of both large (e.g. proteins, biopharmaceuticals) and small organic molecules for a wide variety of applications. However, associated metabolic engineering optimisation processes relying on genetic modification of organisms used in cell factories, or alteration of production conditions remain a challenging undertaking for improving the final yield and quality of cell factory products. In addition to genomic, transcriptomic and proteomic workflows, analytical metabolomics continues to play a critical role in studying detailed aspects of critical pathways (e.g. via targeted quantification of metabolites), identification of biosynthetic intermediates, and also for phenotype differentiation and the elucidation of previously unknown pathways (e.g. via non-targeted strategies). However, the diversity of primary and secondary metabolites and the broad concentration ranges encompassed during typical biotechnological processes means that simultaneous extraction and robust analytical determination of all parts of interest of the metabolome is effectively impossible. As the integration of metabolome data with transcriptome and proteome data is an essential goal of both targeted and non-targeted methods addressing production optimisation goals, additional sample preparation steps beyond necessary sampling, quenching and extraction protocols including clean-up, analyte enrichment, and derivatisation are important considerations for some classes of metabolites, especially those present in low concentrations or exhibiting poor stability. This contribution critically assesses the potential of current sample preparation strategies applied in metabolomic studies of industrially-relevant cell factory organisms using mass spectrometry-based platforms primarily coupled to liquid-phase sample introduction (i.e. flow injection, liquid chromatography, or capillary electrophoresis). Particular focus is placed on the selectivity and degree of enrichment attainable, as well as demands of speed, absolute quantification, robustness and, ultimately, consideration of fully-integrated bioanalytical solutions to optimise sample handling and throughput. Copyright © 2016 Elsevier B.V. All rights reserved.

Shear-Induced Amyloid Formation in the Brain: I. Potential Vascular and Parenchymal Processes.

PubMed

Trumbore, Conrad N

2016-09-06

Shear distortion of amyloid-beta (Aβ) solutions accelerates amyloid cascade reactions that may yield different toxic oligomers than those formed in quiescent solutions. Recent experiments indicate that cerebrospinal fluid (CSF) and interstitial fluid (ISF) containing Aβ flow through narrow brain perivascular pathways and brain parenchyma. This paper suggests that such flow causes shear distortion of Aβ molecules involving conformation changes that may be one of the initiating events in the etiology of Alzheimer's disease. Aβ shearing can occur in or around brain arteries and arterioles and is suggested as the origin of cerebral amyloid angiopathy deposits in cerebrovascular walls. Comparatively low flow rates of ISF within the narrow extracellular spaces (ECS) of the brain parenchyma are suggested as a possible initiating factor in both the formation of neurotoxic Aβ42 oligomers and amyloid fibrils. Aβ42 in slow-flowing ISF can gain significant shear energy at or near the walls of tortuous brain ECS flow paths, promoting the formation of a shear-distorted, excited state hydrophobic Aβ42* conformation. This Aβ42* molecule could possibly be involved in one of two paths, one involving rapid adsorption to a brain membrane surface, ultimately forming neurotoxic oligomers on membranes, and the other ultimately forming plaque within the ECS flow pathways. Rising Aβ concentrations combined with shear at or near critical brain membranes are proposed as contributing factors to Alzheimer's disease neurotoxicity. These hypotheses may be applicable in other neurodegenerative diseases, including tauopathies and alpha-synucleinopathies, in which shear-distorted proteins also may form in the brain ECS.

Altered Helical Axis Patterns of the Lumbar Spine Indicate Increased Instability with Disc Degeneration

PubMed Central

Ellingson, Arin M.; Nuckley, David J.

2014-01-01

Although the causes of low back pain are poorly defined and indistinct, degeneration of the intervertebral disc is most often implicated as the origin of pain. The biochemical and mechanical changes associated with degeneration result in the discs’ inability to maintain structure and function, leading to spinal instability and ultimately pain. Traditionally, a clinical exam assessing functional range-of-motion coupled with T2-weighted MRI revealing disc morphology are used to evaluate spinal health; however, these subjective measures fail to correlate well with pain or provide useful patient stratification. Therefore, improved quantification of spinal motion and objective MRI measures of disc health are necessary. An instantaneous helical axis (IHA) approach provides rich temporal three-dimensional data describing the pathway of motion, which is easily visualized. Eighteen cadaveric osteoligamentous lumbar spines (L4-5) from throughout the degenerative spectrum were tested in a pure moment fashion. IHA were calculated for flexion-extension and lateral bending. A correlational study design was used to determine the relationship between disc measurements from quantitative T2* MRI and IHA metrics. Increased instability and out-of-plane rotation with diminished disc health was observed during lateral bending, but not flexion-extension. This new analysis strategy examines the entire pathway of motion, rather than simplifying spinal kinematics to its terminal ends of motion and provides a more sensitive kinematic measurement of disc health. Ultimately, through the use of 3D dynamic fluoroscopy or similar methods, a patient's functional IHA in lateral bending may be measured and used to assess their disc health for diagnosis, progression tracking, and treatment evaluation. PMID:25481221

Upregulation of MAPK/Erk and PI3K/Akt pathways in ulcerative colitis-associated colon cancer.

PubMed

Setia, Shruti; Nehru, Bimla; Sanyal, Sankar Nath

2014-10-01

An extracellular signal like a cytokine or chemokine, secreted in the inflammatory microenvironment can activate the mitogen activated protein kinase (MAPK) pathway by binding to a cytokine receptor tyrosine kinase, which further activates tyrosine kinases such as Janus Kinase-3 (Jak-3). This signal is transferred from Jak-3 to the DNA in the nucleus of the cell by a chain of kinases, ultimately activating extracellular receptor kinase (Erk/MAPK). The latter phosphorylates c-myc, an oncogene, which alters the levels and activities of many transcription factors leading to cell survival, proliferation and invasion. The oncogenic PI3K pathway plays a similar role by activating c-myc, leading to cell survival and proliferation. The present study explores the role of ulcerative colitis in colon cancer by investigating the activities of tyrosine kinase activated MAPK pathway and various components of the PI3K pathway including PI3K, PTEN, PDK1, GSK3β, Akt, mTOR, Wnt and β-catenin. This was done by western blot and fluorescent immunohistochemical analysis of the above-mentioned proteins. Also, the morphological and histological investigation of the colonic samples from various animal groups revealed significant alterations as compared to the control in both inflammatory as well as carcinogenic conditions. These effects were reduced to a large extent by the co-administration of celecoxib, a second-generation non-steroidal anti-inflammatory drug (NSAID). Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Effects of Deployment Investment on the Growth of the Biofuels Industry

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

Vimmerstedt, Laura J.; Bush, Brian W.

2013-12-01

In support of the national goals for biofuel use in the United States, numerous technologies have been developed that convert biomass to biofuels. Some of these biomass to biofuel conversion technology pathways are operating at commercial scales, while others are in earlier stages of development. The advancement of a new pathway toward commercialization involves various types of progress, including yield improvements, process engineering, and financial performance. Actions of private investors and public programs can accelerate the demonstration and deployment of new conversion technology pathways. These investors (both private and public) will pursue a range of pilot, demonstration, and pioneer scalemore » biorefinery investments; the most cost-effective set of investments for advancing the maturity of any given biomass to biofuel conversion technology pathway is unknown. In some cases, whether or not the pathway itself will ultimately be technically and financially successful is also unknown. This report presents results from the Biomass Scenario Model -- a system dynamics model of the biomass to biofuels system -- that estimate effects of investments in biorefineries at different maturity levels and operational scales. The report discusses challenges in estimating effects of such investments and explores the interaction between this deployment investment and a volumetric production incentive. Model results show that investments in demonstration and deployment have a substantial positive effect on the development of the biofuels industry. Results also show that other conditions, such as supportive policies, have major impacts on the effectiveness of such investments.« less

Evidence for two distinct phosphorylation pathways activated by high affinity immunoglobulin E receptors.

PubMed

Adamczewski, M; Paolini, R; Kinet, J P

1992-09-05

The high affinity receptor for immunoglobulin (Ig) E on mast cells, along with the antigen receptors on T and B cells and Fc receptors for IgG, belongs to a class of receptors which lack intrinsic kinase activity, but activate non-receptor tyrosine and serine/threonine kinases. Receptor engagement triggers a chain of signaling events leading from protein phosphorylation to activation of phosphatidylinositol-specific phospholipase C, an increase in intracellular calcium levels, and ultimately the activation of more specialized functions. IgE receptor disengagement leads to reversal of phosphorylation by undefined phosphatases and to inhibition of activation pathways. Here we show that phenylarsine oxide, a chemical which reacts with thiol groups and has been reported to inhibit tyrosine phosphatases, uncouples the IgE receptor-mediated phosphorylation signal from activation of phosphatidyl inositol metabolism, the increase in intracellular calcium levels, and serotonin release. Phenylarsine oxide inhibits neither the kinases (tyrosine and serine/threonine) phosphorylating the receptor and various cellular substrates nor, unexpectedly, the phosphatases responsible for the dephosphorylation following receptor disengagement. By contrast, it abolishes the receptor-mediated phosphorylation of phospholipase C-gamma 1, but not phospholipase C activity in vitro. Therefore the phosphorylation and activation of phospholipase C likely requires a phenylarsine oxide-sensitive element. Receptor aggregation thus activates at least two distinct phosphorylation pathways: a phenylarsine oxide-insensitive pathway leading to phosphorylation/dephosphorylation of the receptor and of various substrates and a sensitive pathway leading to phospholipase C-gamma 1 phosphorylation.

Novel applications of trophic factors, Wnt and WISP for neuronal repair and regeneration in metabolic disease

PubMed Central

Maiese, Kenneth

2015-01-01

Diabetes mellitus affects almost 350 million individuals throughout the globe resulting in significant morbidity and mortality. Of further concern is the growing population of individuals that remain undiagnosed but are susceptible to the detrimental outcomes of this disorder. Diabetes mellitus leads to multiple complications in the central and peripheral nervous systems that include cognitive impairment, retinal disease, neuropsychiatric disease, cerebral ischemia, and peripheral nerve degeneration. Although multiple strategies are being considered, novel targeting of trophic factors, Wnt signaling, Wnt1 inducible signaling pathway protein 1, and stem cell tissue regeneration are considered to be exciting prospects to overcome the cellular mechanisms that lead to neuronal injury in diabetes mellitus involving oxidative stress, apoptosis, and autophagy. Pathways that involve insulin-like growth factor-1, fibroblast growth factor, epidermal growth factor, and erythropoietin can govern glucose homeostasis and are intimately tied to Wnt signaling that involves Wnt1 and Wnt1 inducible signaling pathway protein 1 (CCN4) to foster control over stem cell proliferation, wound repair, cognitive decline, β-cell proliferation, vascular regeneration, and programmed cell death. Ultimately, cellular metabolism through Wnt signaling is driven by primary metabolic pathways of the mechanistic target of rapamycin and AMP activated protein kinase. These pathways offer precise biological control of cellular metabolism, but are exquisitely sensitive to the different components of Wnt signaling. As a result, unexpected clinical outcomes can ensue and therefore demand careful translation of the mechanisms that govern neural repair and regeneration in diabetes mellitus. PMID:26170801

Semiconductor Laser Low Frequency Noise Characterization

NASA Technical Reports Server (NTRS)

Maleki, Lute; Logan, Ronald T.

1996-01-01

This work summarizes the efforts in identifying the fundamental noise limit in semiconductor optical sources (lasers) to determine the source of 1/F noise and it's associated behavior. In addition, the study also addresses the effects of this 1/F noise on RF phased arrays. The study showed that the 1/F noise in semiconductor lasers has an ultimate physical limit based upon similar factors to fundamental noise generated in other semiconductor and solid state devices. The study also showed that both additive and multiplicative noise can be a significant detriment to the performance of RF phased arrays especially in regard to very low sidelobe performance and ultimate beam steering accuracy. The final result is that a noise power related term must be included in a complete analysis of the noise spectrum of any semiconductor device including semiconductor lasers.

The large-scale organization of shape processing in the ventral and dorsal pathways

PubMed Central

Culham, Jody C; Plaut, David C; Behrmann, Marlene

2017-01-01

Although shape perception is considered a function of the ventral visual pathway, evidence suggests that the dorsal pathway also derives shape-based representations. In two psychophysics and neuroimaging experiments, we characterized the response properties, topographical organization and perceptual relevance of these representations. In both pathways, shape sensitivity increased from early visual cortex to extrastriate cortex but then decreased in anterior regions. Moreover, the lateral aspect of the ventral pathway and posterior regions of the dorsal pathway were sensitive to the availability of fundamental shape properties, even for unrecognizable images. This apparent representational similarity between the posterior-dorsal and lateral-ventral regions was corroborated by a multivariate analysis. Finally, as with ventral pathway, the activation profile of posterior dorsal regions was correlated with recognition performance, suggesting a possible contribution to perception. These findings challenge a strict functional dichotomy between the pathways and suggest a more distributed model of shape processing. PMID:28980938

Roles of the Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways in controlling growth and sensitivity to therapy-implications for cancer and aging

PubMed Central

Steelman, Linda S.; Chappell, William H.; Abrams, Stephen L.; Kempf, C. Ruth; Long, Jacquelyn; Laidler, Piotr; Mijatovic, Sanja; Maksimovic-Ivanic, Danijela; Stivala, Franca; Mazzarino, Maria C.; Donia, Marco; Fagone, Paolo; Malaponte, Graziella; Nicoletti, Ferdinando; Libra, Massimo; Milella, Michele; Tafuri, Agostino; Bonati, Antonio; Bäsecke, Jörg; Cocco, Lucio; Evangelisti, Camilla; Martelli, Alberto M.; Montalto, Giuseppe; Cervello, Melchiorre; McCubrey, James A.

2011-01-01

Dysregulated signaling through the Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways is often the result of genetic alterations in critical components in these pathways or upstream activators. Unrestricted cellular proliferation and decreased sensitivity to apoptotic-inducing agents are typically associated with activation of these pro-survival pathways. This review discusses the functions these pathways have in normal and neoplastic tissue growth and how they contribute to resistance to apoptotic stimuli. Crosstalk and commonly identified mutations that occur within these pathways that contribute to abnormal activation and cancer growth will also be addressed. Finally the recently described roles of these pathways in cancer stem cells, cellular senescence and aging will be evaluated. Controlling the expression of these pathways could ameliorate human health. PMID:21422497

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

PubMed

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 < .0001) with a trend toward significance (P = .066) for radiation therapy modality. There was no difference between recurrent and non-recurrent disease (P = .267). Multivariable analysis revealed disease site was associated with time to peer review (P < .001), with lymphoma and skin/sarcoma most strongly influencing decision time >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 <1% selections ultimately rejected, suggesting that awareness of 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.

Identification of differential pathways in papillary thyroid carcinoma utilizing pathway co-expression analysis.

PubMed

Qiu, Wei-Hai; Chen, Gui-Yan; Cui, Lu; Zhang, Ting-Ming; Wei, Feng; Yang, Yong

2016-01-01

To identify differential pathways between papillary thyroid carcinoma (PTC) patients and normal controls utilizing a novel method which combined pathway with co-expression network. The proposed method included three steps. In the first step, we conducted pretreatments for background pathways and gained representative pathways in PTC. Subsequently, a co-expression network for representative pathways was constructed using empirical Bayes (EB) approach to assign a weight value for each pathway. Finally, random model was extracted to set the thresholds of identifying differential pathways. We obtained 1267 representative pathways and their weight values based on the co-expressed pathway network, and then by meeting the criterion (Weight > 0.0296), 87 differential pathways in total across PTC patients and normal controls were identified. The top three ranked differential pathways were CREB phosphorylation, attachment of GPI anchor to urokinase plasminogen activator receptor (uPAR) and loss of function of SMAD2/3 in cancer. In conclusion, we successfully identified differential pathways (such as CREB phosphorylation, attachment of GPI anchor to uPAR and post-translational modification: synthesis of GPI-anchored proteins) for PTC using the proposed pathway co-expression method, and these pathways might be potential biomarkers for target therapy and detection of PTC.

Acoustic emission analysis of fiber-reinforced composite in flexural testing.

PubMed

Alander, Pasi; Lassila, Lippo V J; Tezvergil, Arzu; Vallittu, Pekka K

2004-05-01

The aim of this study was to examine the emission of acoustic signals from six commercially available fiber-reinforced composites (FRC) used in the frameworks of fixed partial dentures in material bending. FRC test specimens were made of six commercially available fiber products of polyethylene or glass and five light-curing resins. FRC test specimens were polymerized with a hand light-curing unit or with a light-curing oven. The flexural test for determination of ultimate flexural strength of test specimens (n = 6) was based on the ISO 10477 standard after the specimens were stored in air or in water for two weeks. The acoustic emission (AE) signals were monitored during three-point loading test of the test specimens using a test with increasing loading levels until the specimens fractured. Generally, stress level required for the AE activity initiation ranged from 107 MPa (Ribbond) to 579 MPa (everStick). The ultimate flexural strength of FRC specimens were higher, ranging from 132 to 764 MPa, being highest with everStick and Vectris FRC, and lowest with Ribbond FRC. ANOVA showed a statistically significant difference between the initiation of AE activity and the ultimate flexural strength according to the brand (p < 0.001) storing conditions (p < 0.001) and polymerization procedure (p < 0.001). AE activity and ultimate flexural strength correlated significantly (p < 0.010, r = 0.887). The result of this study suggested that AE activity in FRC specimens started at a 19-32% lower stress level than occurred at final fracture.

Digital gene expression profiling analysis and its application in the identification of genes associated with improved response to neoadjuvant chemotherapy in breast cancer.

PubMed

Liu, Xiaozhen; Jin, Gan; Qian, Jiacheng; Yang, Hongjian; Tang, Hongchao; Meng, Xuli; Li, Yongfeng

2018-04-23

This study aimed to screen sensitive biomarkers for the efficacy evaluation of neoadjuvant chemotherapy in breast cancer. In this study, Illumina digital gene expression sequencing technology was applied and differentially expressed genes (DEGs) between patients presenting pathological complete response (pCR) and non-pathological complete response (NpCR) were identified. Further, gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were then performed. The genes in significant enriched pathways were finally quantified by quantitative real-time PCR (qRT-PCR) to confirm that they were differentially expressed. Additionally, GSE23988 from Gene Expression Omnibus database was used as the validation dataset to confirm the DEGs. After removing the low-quality reads, 715 DEGs were finally detected. After mapping to KEGG pathways, 10 DEGs belonging to the ubiquitin proteasome pathway (HECTD3, PSMB10, UBD, UBE2C, and UBE2S) and cytokine-cytokine receptor interactions (CCL2, CCR1, CXCL10, CXCL11, and IL2RG) were selected for further analysis. These 10 genes were finally quantified by qRT-PCR to confirm that they were differentially expressed (the log 2 fold changes of selected genes were - 5.34, 7.81, 6.88, 5.74, 3.11, 19.58, 8.73, 8.88, 7.42, and 34.61 for HECTD3, PSMB10, UBD, UBE2C, UBE2S, CCL2, CCR1, CXCL10, CXCL11, and IL2RG, respectively). Moreover, 53 common genes were confirmed by the validation dataset, including downregulated UBE2C and UBE2S. Our results suggested that these 10 genes belonging to these two pathways might be useful as sensitive biomarkers for the efficacy evaluation of neoadjuvant chemotherapy in breast cancer.

Aspartate Carbamyltransferase : Site of End-Product Inhibition of the Orotate Pathway in Intact Cells of Cucurbita pepo.

PubMed

Lovatt, C J; Cheng, A H

1984-07-01

Lovatt et al. (1979 Plant Physiol 64: 562-569) have previously demonstrated that end-product inhibition functions as a mechanism regulating the activity of the orotic acid pathway in intact cells of roots excised from 2-day-old squash plants (Cucurbita pepo L. cv Early Prolific Straightneck). Uridine (0.5 millimolar final concentration) or one of its metabolites inhibited the incorporation of NaH(14)CO(3), but not [(14)C]carbamylaspartate or [(14)C]orotic acid, into uridine nucleotides (SigmaUMP). Thus, regulation of de novo pyrimidine biosynthesis was demonstrated to occur at one or both of the first two reactions of the orotic acid pathway, those catalyzed by carbamylphosphate synthetase (CPSase) and aspartate carbamyltransferase (ACTase). The results of the present study provide evidence that ACTase alone is the site of feedback control by added uridine or one of its metabolites. Evidence demonstrating regulation of the orotic acid pathway by end-product inhibition at ACTase, but not at CPSase, includes the following observations: (a) addition of uridine (0.5 millimolar final concentration) inhibited the incorporation of NaH(14)CO(3) into SigmaUMP by 80% but did not inhibit the incorporation of NaH(14)CO(3) into arginine; (b) inhibition of the orotate pathway by added uridine was not reversed by supplying exogenous ornithine (5 millimolar final concentration), while the incorporation of NaH(14)CO(3) into arginine was stimulated more than 15-fold when both uridine and ornithine were added; (c) incorporation of NaH(14)CO(3) into arginine increased, with or without added ornithine when the de novo pyrimidine pathway was inhibited by added uridine; and (d) in assays employing cell-free extracts prepared from 2-day-old squash roots, the activity of ACTase, but not CPSase, was inhibited by added pyrimidine nucleotides.

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

PubMed

Liu, Chun-Han; Liu, Lian

2017-05-08

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

The development of a consensus-based nutritional pathway for infants with CHD before surgery using a modified Delphi process.

PubMed

Marino, Luise V; Johnson, Mark J; Hall, Nigel J; Davies, Natalie J; Kidd, Catherine S; Daniels, M Lowri; Robinson, Julia E; Richens, Trevor; Bharucha, Tara; Darlington, Anne-Sophie E

2018-04-29

IntroductionDespite improvements in the medical and surgical management of infants with CHD, growth failure before surgery in many infants continues to be a significant concern. A nutritional pathway was developed, the aim of which was to provide a structured approach to nutritional care for infants with CHD awaiting surgery.Materials and methodsThe modified Delphi process was development of a nutritional pathway; initial stakeholder meeting to finalise draft guidelines and develop questions; round 1 anonymous online survey; round 2 online survey; regional cardiac conference and pathway revision; and final expert meeting and pathway finalisation. Paediatric Dietitians from all 11 of the paediatric cardiology surgical centres in the United Kingdom contributed to the guideline development. In all, 33% of participants had 9 or more years of experience working with infants with CHD. By the end of rounds 1 and 2, 76 and 96% of participants, respectively, were in agreement with the statements. Three statements where consensus was not achieved by the end of round 2 were discussed and agreed at the final expert group meeting. Nutrition guidelines were developed for infants with CHD awaiting surgery, using a modified Delphi process, incorporating the best available evidence and expert opinion with regard to nutritional support in this group.

Perestroika: The End Game

DTIC Science & Technology

1990-08-01

of economic systems from feudalism, through capitalism, and finally to communism as the ultimate objective or goal. It is essential to appreciate that...capitalists-what it must do and how it must operate in order now to support them and their ecnomic and social efforts. In theorct... Marxism, the concept... essential for building socialism in countries such as the Soviet Union. If the Soviet leadership’s perception of how far democratic socialism has progressed

Materials Science and Physics at Micro/Nano-Scales. FINAL REPORT

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

Wu, Judy Z.

2009-09-07

The scope of this project is to study nanostructures of semiconductors and superconductors, which have been regarded as promising building blocks for nanoelectronic and nanoelectric devices. The emphasis of this project is on developing novel synthesis approaches for fabrication of nanostructures with desired physical properties. The ultimate goal is to achieve a full control of the nanostructure growth at microscopic scales. The major experimental achievements obtained are summarized

Physics of Artificial Gravity

NASA Technical Reports Server (NTRS)

Bukley, Angie; Paloski, William; Clement, Gilles

2006-01-01

This chapter discusses potential technologies for achieving artificial gravity in a space vehicle. We begin with a series of definitions and a general description of the rotational dynamics behind the forces ultimately exerted on the human body during centrifugation, such as gravity level, gravity gradient, and Coriolis force. Human factors considerations and comfort limits associated with a rotating environment are then discussed. Finally, engineering options for designing space vehicles with artificial gravity are presented.

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

PubMed

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.

Ultimate intra-wafer critical dimension uniformity control by using lithography and etch tool corrections

NASA Astrophysics Data System (ADS)

Kubis, Michael; Wise, Rich; Reijnen, Liesbeth; Viatkina, Katja; Jaenen, Patrick; Luca, Melisa; Mernier, Guillaume; Chahine, Charlotte; Hellin, David; Kam, Benjamin; Sobieski, Daniel; Vertommen, Johan; Mulkens, Jan; Dusa, Mircea; Dixit, Girish; Shamma, Nader; Leray, Philippe

2016-03-01

With shrinking design rules, the overall patterning requirements are getting aggressively tighter. For the 7-nm node and below, allowable CD uniformity variations are entering the Angstrom region (ref [1]). Optimizing inter- and intra-field CD uniformity of the final pattern requires a holistic tuning of all process steps. In previous work, CD control with either litho cluster or etch tool corrections has been discussed. Today, we present a holistic CD control approach, combining the correction capability of the etch tool with the correction capability of the exposure tool. The study is done on 10-nm logic node wafers, processed with a test vehicle stack patterning sequence. We include wafer-to-wafer and lot-to-lot variation and apply optical scatterometry to characterize the fingerprints. Making use of all available correction capabilities (lithography and etch), we investigated single application of exposure tool corrections and of etch tool corrections as well as combinations of both to reach the lowest CD uniformity. Results of the final pattern uniformity based on single and combined corrections are shown. We conclude on the application of this holistic lithography and etch optimization to 7nm High-Volume manufacturing, paving the way to ultimate within-wafer CD uniformity control.

Brotherly Advice: Letters from Hugo to Paul Ehrenfest in his Final Years

NASA Astrophysics Data System (ADS)

Halpern, Paul

2006-03-01

At the start of the 1930s, theoretician Paul Ehrenfest spent much of his time traveling through America and Europe while engaged in a steady stream of lectures. This traveling phase coincided with a frantic and intense period of negative self-examination, financial difficulty, and various other personal concerns that would ultimately lead to his 1933 suicide. Throughout these final years, he kept up a steady correspondence with his brother Hugo, a physician based in Saint Louis. Ten years older than Paul, Hugo freely doled out frank psychological advice about subjects ranging from the proper treatment of children to the dangers of self-pity. Through a look at some of the letters exchanged between the two brothers, this talk will examine the role Hugo played during the dark final years of Paul Ehrenfest's life.

The Nitrate-nitrite-NO pathway and its implications for Heart Failure and Preserved Ejection Fraction

PubMed Central

Chirinos, Julio A.; Zamani, Payman

2016-01-01

The pathogenesis of exercise intolerance in patients with heart failure and preserved ejection fraction (HFpEF) is likely multifactorial. In addition to cardiac abnormalities (diastolic dysfunction, abnormal contractile reserve, chronotropic incompetence), several peripheral abnormalities are likely to be involved. These include abnormal pulsatile hemodynamics, abnormal arterial vasodilatory responses to exercise, and abnormal peripheral O2 delivery, extraction and utilization. The nitrate-nitrite-NO pathway is emerging as a potential target to modify key physiologic abnormalities, including late systolic LV load from arterial wave reflections (which has deleterious short- and long-term consequences for the LV), arterial vasodilatory reserve, muscle O2 delivery, and skeletal muscle mitochondrial function. In a recently completed randomized trial, the administration of a single dose of exogenous inorganic nitrate has been shown exert various salutary arterial hemodynamic effects, ultimately leading to enhanced aerobic capacity in patients with HFpEF. These effects have the potential for both immediate improvements in exercise tolerance and for long-term “disease-modifying” effects. In this review, we provide an overview of key mechanistic contributors to exercise intolerance in HFpEF, and of the potential therapeutic role of drugs that target the nitrate-nitrite-NO pathway. PMID:26792295

The cytoskeleton as a novel target for treatment of renal fibrosis.

PubMed

Parrish, Alan R

2016-10-01

The incidence of chronic kidney disease (CKD) is increasing, with an estimated prevalence of 12% in the United States (Synder et al., 2009). While CKD may progress to end-stage renal disease (ESRD), which necessitates renal replacement therapy, i.e. dialysis or transplantation, most CKD patients never reach ESRD due to the increased risk of death from cardiovascular disease. It is well-established that regardless of the initiating insult - most often diabetes or hypertension - fibrosis is the common pathogenic pathway that leads to progressive injury and organ dysfunction (Eddy, 2014; Duffield, 2014). As such, there has been extensive research into the molecular and cellular mechanisms of renal fibrosis; however, translation to effective therapeutic strategies has been limited. While a role for the disruption of the cytoskeleton, most notably the actin network, has been established in acute kidney injury over the past two decades, a role in regulating renal fibrosis and CKD is only recently emerging. This review will focus on the role of the cytoskeleton in regulating pro-fibrotic pathways in the kidney, as well as data suggesting that these pathways represent novel therapeutic targets to manage fibrosis and ultimately CKD. Copyright © 2016. Published by Elsevier Inc.

Molecular Mechanisms of Diabetic Retinopathy, General Preventive Strategies, and Novel Therapeutic Targets

PubMed Central

Safi, Sher Zaman; Kumar, Selva; Ismail, Ikram Shah Bin

2014-01-01

The growing number of people with diabetes worldwide suggests that diabetic retinopathy (DR) and diabetic macular edema (DME) will continue to be sight threatening factors. The pathogenesis of diabetic retinopathy is a widespread cause of visual impairment in the world and a range of hyperglycemia-linked pathways have been implicated in the initiation and progression of this condition. Despite understanding the polyol pathway flux, activation of protein kinase C (KPC) isoforms, increased hexosamine pathway flux, and increased advanced glycation end-product (AGE) formation, pathogenic mechanisms underlying diabetes induced vision loss are not fully understood. The purpose of this paper is to review molecular mechanisms that regulate cell survival and apoptosis of retinal cells and discuss new and exciting therapeutic targets with comparison to the old and inefficient preventive strategies. This review highlights the recent advancements in understanding hyperglycemia-induced biochemical and molecular alterations, systemic metabolic factors, and aberrant activation of signaling cascades that ultimately lead to activation of a number of transcription factors causing functional and structural damage to retinal cells. It also reviews the established interventions and emerging molecular targets to avert diabetic retinopathy and its associated risk factors. PMID:25105142

Biotransformation pathways of fluorotelomer-based polyfluoroalkyl substances: a review.

PubMed

Butt, Craig M; Muir, Derek C G; Mabury, Scott A

2014-02-01

The study reviews the current state of knowledge regarding the biotransformation of fluorotelomer-based compounds, with a focus on compounds that ultimately degrade to form perfluoroalkyl carboxylates (PFCAs). Most metabolism studies have been performed with either microbial systems or rats and mice, and comparatively few studies have used fish models. Furthermore, biotransformation studies thus far have predominately used the 8:2 fluorotelomer alcohol (FTOH) as the substrate. However, there have been an increasing number of studies investigating 6:2 FTOH biotransformation as a result of industry's transition to shorter-chain fluorotelomer chemistry. Studies with the 8:2 FTOH metabolism universally show the formation of perfluorooctanoate (PFOA) and, to a smaller fraction, perfluorononanoate (PFNA) and lower-chain-length PFCAs. In general, the overall yield of PFOA is low, presumably because of the multiple branches in the biotransformation pathways, including conjugation reactions in animal systems. There have been a few studies of non-FTOH biotransformation, which include polyfluoroalkyl phosphates (PAPs), 8:2 fluorotelomer acrylate (8:2 FTAC), and fluorotelomer carboxylates (FTCAs, FTUCAs). The PAPs compounds and 8:2 FTAC were shown to be direct precursors to FTOHs and thus follow similar degradation pathways. © 2013 SETAC.

PI3K/AKT/mTOR Pathway in Ovarian Cancer Treatment: Are We on the Right Track?

PubMed Central

Gasparri, Maria Luisa; Bardhi, Erlisa; Ruscito, Ilary; Papadia, Andrea; Farooqi, Ammad Ahmad; Marchetti, Claudia; Bogani, Giorgio; Ceccacci, Irene; Mueller, Michael D.; Benedetti Panici, Pierluigi

2017-01-01

The high recurrence rate and the low overall survival in ovarian cancer suggest that a more specific therapeutic approach in addition to conventional treatment is required. Translational and clinical research is investigating new molecular targets in order to find an alternative way to affect tumor growth and to minimize the overlap of toxicity of antiblastic agents. Given its implication in many cellular activities including regulation of cell growth, motility, survival, proliferation, protein synthesis, autophagy, transcription, as well as angiogenesis, PI3K/AKT/mTOR is one of the most investigated intracellular signaling pathways. A dis-regulation of this pathway has been shown in several tumors, including ovarian cancer. In this setting, mTor proteins represent a potential target for inhibitors, which could ultimately play a pivotal role in counteracting cellular proliferation. Recently, mTor inhibitors have been approved in the treatment of pancreatic neuroendocrine tumors, mantle cell lymphoma and renal cancer. Clinical trials have assessed the safety of these drugs in ovarian cancer patients. Ongoing phase I and II studies are evaluating the oncologic outcome of mTor inhibitor treatment and its effect in combination with conventional chemotherapy and target agents. PMID:29093603

PI3K/AKT/mTOR Pathway in Ovarian Cancer Treatment: Are We on the Right Track?

PubMed

Gasparri, Maria Luisa; Bardhi, Erlisa; Ruscito, Ilary; Papadia, Andrea; Farooqi, Ammad Ahmad; Marchetti, Claudia; Bogani, Giorgio; Ceccacci, Irene; Mueller, Michael D; Benedetti Panici, Pierluigi

2017-10-01

The high recurrence rate and the low overall survival in ovarian cancer suggest that a more specific therapeutic approach in addition to conventional treatment is required. Translational and clinical research is investigating new molecular targets in order to find an alternative way to affect tumor growth and to minimize the overlap of toxicity of antiblastic agents. Given its implication in many cellular activities including regulation of cell growth, motility, survival, proliferation, protein synthesis, autophagy, transcription, as well as angiogenesis, PI3K/AKT/mTOR is one of the most investigated intracellular signaling pathways. A dis-regulation of this pathway has been shown in several tumors, including ovarian cancer. In this setting, mTor proteins represent a potential target for inhibitors, which could ultimately play a pivotal role in counteracting cellular proliferation. Recently, mTor inhibitors have been approved in the treatment of pancreatic neuroendocrine tumors, mantle cell lymphoma and renal cancer. Clinical trials have assessed the safety of these drugs in ovarian cancer patients. Ongoing phase I and II studies are evaluating the oncologic outcome of mTor inhibitor treatment and its effect in combination with conventional chemotherapy and target agents.

Transcription-Coupled Repair and Complex Biology.

PubMed

Portman, James R; Strick, Terence R

2018-05-04

All active living organisms mitigate DNA damage via DNA repair, and the so-called nucleotide excision repair pathway (NER) represents a functionally major part of the cell's DNA repair repertoire [1]. In this pathway, the damaged strand of DNA is incised and removed before being resynthesized. This form of DNA repair requires a multitude of proteins working in a complex choreography. Repair thus typically involves detection of a DNA lesion; validation of that detection event; search for an appropriate incision site and subsequent DNA incision; DNA unwinding/removal; and DNA resynthesis and religation. These activities are ultimately the result of molecules randomly diffusing and bumping into each other and acting in succession. It is also true however that repair components are often assembled into functional complexes which may be more efficient or regular in their mode of action. Studying DNA repair complexes for their mechanisms of assembly, action, and disassembly can help address fundamental questions such as whether DNA repair pathways are branched or linear; whether for instance they tolerate fluctuations in numbers of components; and more broadly how search processes between macromolecules take place or can be enhanced. Copyright © 2018. Published by Elsevier Ltd.

Optimizing megakaryocyte polyploidization by targeting multiple pathways of cytokinesis.

PubMed

Avanzi, Mauro P; Chen, Amanda; He, Wu; Mitchell, W Beau

2012-11-01

Large-scale in vitro production of platelets (PLTs) from cord blood stem cells is one goal of stem cell research. One step toward this goal will be to produce polyploid megakaryocytes capable of releasing high numbers of PLTs. Megakaryocyte polyploidization requires distinct cytoskeletal and cellular mechanisms, including actin polymerization, myosin activation, microtubule formation, and increased DNA production. In this study we variably combined inhibition of these principal mechanisms of cytokinesis with the goal of driving polyploidization in megakaryocytes. Megakaryocytes were derived from umbilical cord blood and cultured with reagents that inhibit distinct mechanisms of cytokinesis: Rho-Rock inhibitor (RRI), Src inhibitor (SI), nicotinamide (NIC), aurora B inhibitor (ABI), and myosin light chain kinase inhibitor (MLCKI). Combinations of reagents were used to determine their interactions and to maximize megakaryocyte ploidy. Treatment with RRI, NIC, SI, and ABI, but not with MLCKI, increased the final ploidy and RRI was the most effective single reagent. RRI and MLCKI, both inhibitors of MLC activation, resulted in opposite ploidy outcomes. Combinations of reagents also increased ploidy and the use of NIC, SI, and ABI was as effective as RRI alone. Addition of MLCKI to NIC, SI, and ABI reached the highest level of polyploidization. Megakaryocyte polyploidization results from modulation of a combination of distinct cytokinesis pathways. Reagents targeting distinct cytoskeletal pathways produced additive effects in final megakaryocyte ploidy. The RRI, however, showed no additive effect but produced a high final ploidy due to overlapping inhibition of multiple cytokinesis pathways. © 2012 American Association of Blood Banks.

Adapt or Perish – Updating the Pre-doctoral Training Model

PubMed Central

Chabowski, Dawid; Kadlec, Andrew; Dellostritto, Daniel; Gutterman, David

2017-01-01

The fate of biomedical research lies in the hands of future generations of scientists. In recent decades the diversity of scientific career opportunities has exploded multidimensionally. However, the educational system for maintaining a pipeline of talented biomedical trainees remains unidimensional and has become outdated. This Viewpoint identifies inadequacies in training and offers potential solutions and implementation strategies to stimulate interest in science at a younger age and to better align individualized training pathways with career opportunities (“precision training”). Both interventions support of the ultimate goal of attracting the best possible future leaders in biomedical science. PMID:28360347

Computer-assisted diagnosis of melanoma.

PubMed

Fuller, Collin; Cellura, A Paul; Hibler, Brian P; Burris, Katy

2016-03-01

The computer-assisted diagnosis of melanoma is an exciting area of research where imaging techniques are combined with diagnostic algorithms in an attempt to improve detection and outcomes for patients with skin lesions suspicious for malignancy. Once an image has been acquired, it undergoes a processing pathway which includes preprocessing, enhancement, segmentation, feature extraction, feature selection, change detection, and ultimately classification. Practicality for everyday clinical use remains a vital question. A successful model must obtain results that are on par or outperform experienced dermatologists, keep costs at a minimum, be user-friendly, and be time efficient with high sensitivity and specificity. ©2015 Frontline Medical Communications.

Research and Development Opportunities for Technologies to Influence Water Consumption Behavior

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

Levin, Todd; Horner, Robert M.; Muehleisen, Ralph T.

In April 2015, Argonne National Laboratory hosted a two-day workshop that convened water experts and stakeholders from across industry, government, and academia to undertake three primary tasks: 1) identify technology characteristics that are favorable for motivating behavioral change, 2) identify barriers that have prevented the development and market adoption of technologies with these characteristics in the water sector, and 3) identify concrete research and development pathways that could be undertaken to overcome these barriers, increase the penetration of technologies that influence water consumption behavior, and ultimately reduce domestic water consumption. While efforts to reduce water consumption have gained momentum inmore » recent years, there are a number of key barriers that have limited the effectiveness of such efforts. Chief among these is the fact that many consumers have limited awareness of their water consumption patterns because of poor data availability, and/or are unmotivated to reduce their consumption because of low costs and split incentives. Without improved data availability and stronger price signals, it will be difficult to effect true transformative behavioral change. This report also reviews a number of technology characteristics that have successfully motivated behavioral change in other sectors, as well as several technologies that could be developed specifically for the water sector. Workshop participants discussed how technologies that provide active feedback and promote measurable goals and social accountability have successfully influenced changes in other types of behavior. A range of regulatory and policy actions that could be implemented to support such efforts are also presented. These include institutional aggregation, revenue decoupling, and price structure reforms. Finally, several R&D pathways were proposed, including efforts to identify optimal communication strategies and to better understand consumer perceptions and psychology as they relate to human behavior regarding water consumption. The findings presented here can help to inform policy makers as they develop new policies and seek to support new research to help consumers use water more efficiently. It is our hope that these findings will also be utilized to prioritize topics for additional follow-up workshops to address individual issues and barriers more directly and in more detail. The goal of such future workshops will be to develop specific solutions, research plans, and technology development pathways that can be undertaken to increase the market penetration of technologies that effect behavioral change and reduce water consumption.« less

Competing Pathways and Multiple Folding Nuclei in a Large Multidomain Protein, Luciferase.

PubMed

Scholl, Zackary N; Yang, Weitao; Marszalek, Piotr E

2017-05-09

Proteins obtain their final functional configuration through incremental folding with many intermediate steps in the folding pathway. If known, these intermediate steps could be valuable new targets for designing therapeutics and the sequence of events could elucidate the mechanism of refolding. However, determining these intermediate steps is hardly an easy feat, and has been elusive for most proteins, especially large, multidomain proteins. Here, we effectively map part of the folding pathway for the model large multidomain protein, Luciferase, by combining single-molecule force-spectroscopy experiments and coarse-grained simulation. Single-molecule refolding experiments reveal the initial nucleation of folding while simulations corroborate these stable core structures of Luciferase, and indicate the relative propensities for each to propagate to the final folded native state. Both experimental refolding and Monte Carlo simulations of Markov state models generated from simulation reveal that Luciferase most often folds along a pathway originating from the nucleation of the N-terminal domain, and that this pathway is the least likely to form nonnative structures. We then engineer truncated variants of Luciferase whose sequences corresponded to the putative structure from simulation and we use atomic force spectroscopy to determine their unfolding and stability. These experimental results corroborate the structures predicted from the folding simulation and strongly suggest that they are intermediates along the folding pathway. Taken together, our results suggest that initial Luciferase refolding occurs along a vectorial pathway and also suggest a mechanism that chaperones may exploit to prevent misfolding. Copyright © 2017 Biophysical Society. Published by Elsevier Inc. All rights reserved.

The effect of post traumatic stress disorders on rehabilitation among combat-wounded veterans.

PubMed

Siddharthan, Kris

2012-01-01

In June 2008 the Congressionally Directed Medical Research Program provided a grant to the Research Foundation at the James A Haley Veterans Hospital in Tampa, Florida to provide care for wounded veterans from Operation Enduring Freedom (Afghanistan) and Operation Iraqi Freedom (OEF/OIF). The telerehabilitation for OEF/OIF returnees with mild or moderate combat related Traumatic Brain Injury (TBI) has as its objectives 1) care coordination for wounded veterans using distance technology via the internet and 2) monitoring of physical and mental health outcomes using a variety of instruments. A total of 75 veterans were enrolled in the study. Our initial findings indicate that 1) Functional capabilities measured by locomotion and mobility appear to have stabilized among our cohort of veterans while deficiencies in cognition (memory, problem solving), psychosocial adjustment (anger, emotional status) and problems in integrating into society pose challenges 2) Those with comorbid PTSD appear to linger in employability and ultimate integration into society as compared to those without the diagnosis 3) Individualized treatment pathways are needed for rehabilitation and ultimate integration into society.

Tgf-beta induced Erk phosphorylation of smad linker region regulates smad signaling.

PubMed

Hough, Chris; Radu, Maria; Doré, Jules J E

2012-01-01

The Transforming Growth Factor-Beta (TGF-β) family is involved in regulating a variety of cellular processes such as apoptosis, differentiation, and proliferation. TGF-β binding to a Serine/Threonine kinase receptor complex causes the recruitment and subsequent activation of transcription factors known as smad2 and smad3. These proteins subsequently translocate into the nucleus to negatively or positively regulate gene expression. In this study, we define a second signaling pathway leading to TGF-β receptor activation of Extracellular Signal Regulated Kinase (Erk) in a cell-type dependent manner. TGF-β induced Erk activation was found in phenotypically normal mesenchymal cells, but not normal epithelial cells. By activating phosphotidylinositol 3-kinase (PI3K), TGF-β stimulates p21-activated kinase2 (Pak2) to phosphorylate c-Raf, ultimately resulting in Erk activation. Activation of Erk was necessary for TGF-β induced fibroblast replication. In addition, Erk phosphorylated the linker region of nuclear localized smads, resulting in increased half-life of C-terminal phospho-smad 2 and 3 and increased duration of smad target gene transcription. Together, these data show that in mesenchymal cell types the TGF-β/PI3K/Pak2/Raf/MEK/Erk pathway regulates smad signaling, is critical for TGF-β-induced growth and is part of an integrated signaling web containing multiple interacting pathways rather than discrete smad/non-smad pathways.

Plasma membrane calcium ATPase isoform 4 inhibits vascular endothelial growth factor-mediated angiogenesis through interaction with calcineurin.

PubMed

Baggott, Rhiannon R; Alfranca, Arantzazu; López-Maderuelo, Dolores; Mohamed, Tamer M A; Escolano, Amelia; Oller, Jorge; Ornes, Beatriz C; Kurusamy, Sathishkumar; Rowther, Farjana B; Brown, James E; Oceandy, Delvac; Cartwright, Elizabeth J; Wang, Weiguang; Gómez-del Arco, Pablo; Martínez-Martínez, Sara; Neyses, Ludwig; Redondo, Juan Miguel; Armesilla, Angel Luis

2014-10-01

Vascular endothelial growth factor (VEGF) has been identified as a crucial regulator of physiological and pathological angiogenesis. Among the intracellular signaling pathways triggered by VEGF, activation of the calcineurin/nuclear factor of activated T cells (NFAT) signaling axis has emerged as a critical mediator of angiogenic processes. We and others previously reported a novel role for the plasma membrane calcium ATPase (PMCA) as an endogenous inhibitor of the calcineurin/NFAT pathway, via interaction with calcineurin, in cardiomyocytes and breast cancer cells. However, the functional significance of the PMCA/calcineurin interaction in endothelial pathophysiology has not been addressed thus far. Using in vitro and in vivo assays, we here demonstrate that the interaction between PMCA4 and calcineurin in VEGF-stimulated endothelial cells leads to downregulation of the calcineurin/NFAT pathway and to a significant reduction in the subsequent expression of the NFAT-dependent, VEGF-activated, proangiogenic genes RCAN1.4 and Cox-2. PMCA4-dependent inhibition of calcineurin signaling translates into a reduction in endothelial cell motility and blood vessel formation that ultimately impairs in vivo angiogenesis by VEGF. Given the importance of the calcineurin/NFAT pathway in the regulation of pathological angiogenesis, targeted modulation of PMCA4 functionality might open novel therapeutic avenues to promote or attenuate new vessel formation in diseases that occur with angiogenesis. © 2014 American Heart Association, Inc.

Signalling to eIF4E in cancer

PubMed Central

Siddiqui, Nadeem; Sonenberg, Nahum

2015-01-01

Translational control plays a critical role in the regulation of gene expression in eukaryotes and affects many essential cellular processes, including proliferation, apoptosis and differentiation. Under most circumstances, translational control occurs at the initiation step at which the ribosome is recruited to the mRNA. The eukaryotic translation initiation factor 4E (eIF4E), as part of the eIF4F complex, interacts first with the mRNA and facilitates the recruitment of the 40S ribosomal subunit. The activity of eIF4E is regulated at many levels, most profoundly by two major signalling pathways: PI3K (phosphoinositide 3-kinase)/Akt (also known and Protein Kinase B, PKB)/mTOR (mechanistic/mammalian target of rapamycin) and Ras (rat sarcoma)/MAPK (mitogen-activated protein kinase)/Mnk (MAPK-interacting kinases). mTOR directly phosphorylates the 4E-BPs (eIF4E-binding proteins), which are inhibitors of eIF4E, to relieve translational suppression, whereas Mnk phosphorylates eIF4E to stimulate translation. Hyperactivation of these pathways occurs in the majority of cancers, which results in increased eIF4E activity. Thus, translational control via eIF4E acts as a convergence point for hyperactive signalling pathways to promote tumorigenesis. Consequently, recent works have aimed to target these pathways and ultimately the translational machinery for cancer therapy. PMID:26517881

Re-Structuring Preservice Teacher Education: Introducing the School-Community Integrated Learning (SCIL) Pathway

ERIC Educational Resources Information Center

Hudson, Sue; Hudson, Peter

2013-01-01

Reviews into teacher education call for new models that develop preservice teachers' practical knowledge and skills. The study involved 9 mentor teachers and 14 mentees (final-year preservice teachers) working in a new teacher education model, the School-Community Integrated Learning (SCIL) pathway, and analysed data from a Likert survey with…

The Verriest Lecture: Short-wave-sensitive cone pathways across the life span

PubMed Central

Werner, John S.

2017-01-01

Structurally and functionally, the short-wave-sensitive (S) cone pathways are thought to decline more rapidly with normal aging than the middle- and long-wave-sensitive cone pathways. This would explain the celebrated results by Verriest and others demonstrating that the largest age-related color discrimination losses occur for stimuli on a tritan axis. Here, we challenge convention, arguing from psychophysical data that selective S-cone pathway losses do not cause declines in color discrimination. We show substantial declines in chromatic detection and discrimination, as well as in temporal and spatial vision tasks, that are mediated by S-cone pathways. These functional losses are not, however, unique to S-cone pathways. Finally, despite reduced photon capture by S cones, their postreceptoral pathways provide robust signals for the visual system to renormalize itself to maintain nearly stable color perception across the life span. PMID:26974914

The merged basins of signal transduction pathways in spatiotemporal cell biology.

PubMed

Hou, Yingchun; Hou, Yang; He, Siyu; Ma, Caixia; Sun, Mengyao; He, Huimin; Gao, Ning

2014-03-01

Numerous evidences have indicated that a signal system is composed by signal pathways, each pathway is composed by sub-pathways, and the sub-pathway is composed by the original signal terminals initiated with a protein/gene. We infer the terminal signals merged signal transduction system as "signal basin". In this article, we discussed the composition and regulation of signal basins, and the relationship between the signal basin control and triple W of spatiotemporal cell biology. Finally, we evaluated the importance of the systemic regulation to gene expression by signal basins under triple W. We hope our discussion will be the beginning to cause the attention for this area from the scientists of life science. © 2013 Wiley Periodicals, Inc.

The Hippo Pathway: Immunity and Cancer.

PubMed

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.

Application of Three Existing Stope Boundary Optimisation Methods in an Operating Underground Mine

NASA Astrophysics Data System (ADS)

Erdogan, Gamze; Yavuz, Mahmut

2017-12-01

The underground mine planning and design optimisation process have received little attention because of complexity and variability of problems in underground mines. Although a number of optimisation studies and software tools are available and some of them, in special, have been implemented effectively to determine the ultimate-pit limits in an open pit mine, there is still a lack of studies for optimisation of ultimate stope boundaries in underground mines. The proposed approaches for this purpose aim at maximizing the economic profit by selecting the best possible layout under operational, technical and physical constraints. In this paper, the existing three heuristic techniques including Floating Stope Algorithm, Maximum Value Algorithm and Mineable Shape Optimiser (MSO) are examined for optimisation of stope layout in a case study. Each technique is assessed in terms of applicability, algorithm capabilities and limitations considering the underground mine planning challenges. Finally, the results are evaluated and compared.

Blocking lactate export by inhibiting the Myc target MCT1 Disables glycolysis and glutathione synthesis.

PubMed

Doherty, Joanne R; Yang, Chunying; Scott, Kristen E N; Cameron, Michael D; Fallahi, Mohammad; Li, Weimin; Hall, Mark A; Amelio, Antonio L; Mishra, Jitendra K; Li, Fangzheng; Tortosa, Mariola; Genau, Heide Marika; Rounbehler, Robert J; Lu, Yunqi; Dang, Chi V; Kumar, K Ganesh; Butler, Andrew A; Bannister, Thomas D; Hooper, Andrea T; Unsal-Kacmaz, Keziban; Roush, William R; Cleveland, John L

2014-02-01

Myc oncoproteins induce genes driving aerobic glycolysis, including lactate dehydrogenase-A that generates lactate. Here, we report that Myc controls transcription of the lactate transporter SLC16A1/MCT1 and that elevated MCT1 levels are manifest in premalignant and neoplastic Eμ-Myc transgenic B cells and in human malignancies with MYC or MYCN involvement. Notably, disrupting MCT1 function leads to an accumulation of intracellular lactate that rapidly disables tumor cell growth and glycolysis, provoking marked alterations in glycolytic intermediates, reductions in glucose transport, and in levels of ATP, NADPH, and ultimately, glutathione (GSH). Reductions in GSH then lead to increases in hydrogen peroxide, mitochondrial damage, and ultimately, cell death. Finally, forcing glycolysis by metformin treatment augments this response and the efficacy of MCT1 inhibitors, suggesting an attractive combination therapy for MYC/MCT1-expressing malignancies.

Research on the Risk Early Warning Method of Material Supplier Performance in Power Industry

NASA Astrophysics Data System (ADS)

Chen, Peng; Zhang, Xi

2018-01-01

The early warning of supplier performance risk is still in the initial stage interiorly, and research on the early warning mechanism to identify, analyze and prevent the performance risk is few. In this paper, a new method aiming at marerial supplier performance risk in power industry is proposed, firstly, establishing a set of risk early warning indexes, Then use the ECM method to classify the indexes to form different risk grades. Then, improving Crock Ford risk quantization model by considering three indicators, including the stability of power system, economic losses and successful bid ratio to form the predictive risk grade, and ultimately using short board effect principle to form the ultimate risk grade to truly reflect the supplier performance risk. Finally, making empirical analysis on supplier performance and putting forward the counter measures and prevention strategies for different risks.

Analytical assessment of woven fabrics under vertical stabbing - The role of protective clothing.

PubMed

Hejazi, Sayyed Mahdi; Kadivar, Nastaran; Sajjadi, Ali

2016-02-01

Knives are being used more commonly in street fights and muggings. Therefore, this work presents an analytical model for woven fabrics under vertical stabbing loads. The model is based on energy method and the fabric is assumed to be unidirectional comprised of N layers. Thus, the ultimate stab resistance of fabric was determined based on structural parameters of fabric and geometrical characteristics of blade. Moreover, protective clothing is nowadays considered as a strategic branch in technical textile industry. The main idea of the present work is improving the stab resistance of woven textiles by using metal coating method. In the final, a series of vertical stabbing tests were conducted on cotton, polyester and polyamide fabrics. Consequently, it was found that the model predicts with a good accuracy the ultimate stab resistance of the sample fabrics. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Continuous-variable quantum probes for structured environments

NASA Astrophysics Data System (ADS)

Bina, Matteo; Grasselli, Federico; Paris, Matteo G. A.

2018-01-01

We address parameter estimation for structured environments and suggest an effective estimation scheme based on continuous-variables quantum probes. In particular, we investigate the use of a single bosonic mode as a probe for Ohmic reservoirs, and obtain the ultimate quantum limits to the precise estimation of their cutoff frequency. We assume the probe prepared in a Gaussian state and determine the optimal working regime, i.e., the conditions for the maximization of the quantum Fisher information in terms of the initial preparation, the reservoir temperature, and the interaction time. Upon investigating the Fisher information of feasible measurements, we arrive at a remarkable simple result: homodyne detection of canonical variables allows one to achieve the ultimate quantum limit to precision under suitable, mild, conditions. Finally, upon exploiting a perturbative approach, we find the invariant sweet spots of the (tunable) characteristic frequency of the probe, able to drive the probe towards the optimal working regime.

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

PubMed

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.

Chemotherapy and Drug Targeting in the Treatment of Leishmaniasis

DTIC Science & Technology

1989-05-30

in the catabolism of adenosine to inosine, and ultimately to the final breakdown product o2 purines, uric acid . Since sinefungin is an adenosine analog...chemotherapeutic value if they inhibit nucleic acid synthesis in the pathogen but not in the host. This sometimes occurs if the host enzymes are slightly...remove these organisms from the blood and bleeding secondary to portal hypertension. Currently there are major epidemics in India and Kenya . Figure 1

Semiannual Report to Congress on the Effectiveness of the Civil Aviation Security Program.

DTIC Science & Technology

1987-12-31

This report also provides data on the initiatives being implemented as a result of the review of domestic airport security by the Secretary’s Safety...enforcement support for airline and airport security measures. Finally, the passengers-the ultimate beneficiaries of the security program--pay for...of these airports is required to implement a security program which provides a secure operating environment for these air carriers. Airport security programs

Science and technology camp for girls. Final report

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

Not Available

1993-12-31

This document reports on the success of Pacific University`s camp held during the summers of 1992 and 1993; ultimate goal of this summer day camp was to increase the number of women in technical and scientific fields. Some experimentation was done with the age groups (7th and 8th grade girls). The curriculum was biology, chemistry, physics, and mathematics/computer science. Laboratory work and field trips were emphasized, along with socialization.

Application of Toxicity Identification and Evaluation Procedures for Dredged Material Management

DTIC Science & Technology

2017-02-01

that may pose a risk to human health and the environment. The potential for risk ultimately depends on the final disposition of the dredged material... human health and ecological receptors. This information is also useful when evaluating dredged material for open water disposal since it could eliminate...and potential for exposure to humans or ecological receptors. The Inland Testing and Ocean Disposal Manuals establish a multi-step testing protocol

U.S.-Brazil Security Cooperation and the State Partnership Program

DTIC Science & Technology

2015-06-01

the recognition they deserve, and the U.S. ultimately risks losing its influence.29 As the former Secretary of State, Hillary Clinton believed...remains strong. Therefore, as the political situation needs to be mended, one of the best and most logical ways for doing so is through security...demonstrate its political discontent by stagnating the agreements. The negative trend that began in 2013, however, is finally beginning to turn positive

Environmental Assessment for the California Space Center at Vandenberg Air Force Base, California

DTIC Science & Technology

2010-04-08

Occupational Safety and Health Administration P2 Pollution prevention Pb Lead PFC Perfluorocarbon PG& E Pacific Gas & Electric PM2.5 Particulate matter 2.5...services center, a commissary and staff lounge , a warehouse, Chapter 2. Description of the Proposed Action and Alternatives Final Draft...including tenants. Ultimately, the CSC would obtain service from Pacific Gas & Electric (PG& E ) for the entire Center, once a planned line is completed by

The problem solution on wedge penetration in an initially anisotropic medium within the rigid-plastic scheme

NASA Astrophysics Data System (ADS)

Chanyshev, AI; Abdulin, IM

2018-03-01

Two problems are solved in the paper: on ultimate loads in the initial stage of indentation of an absolutely rigid smooth wedge into a layer of an initially anisotropic plastic medium and in the final stage when the tool penetrates through the layer. The problems are solved with Chanyshev’s constitutive relations of plasticity of the initially anisotropic medium based on use of the eigen elasticity tensors.

West Europe Report

DTIC Science & Technology

1987-04-28

Els Flipsen; NRC HANDELSBLAD, 2 Mar 87) 75 Air Force Chief Reviews Aircrew, Budget, Equipment Problems (F. J. De Jong Interview; NRC HANDELSBLAD...to know what kind of government they will get. The crisis of the Christian People’s Party after Arne Bjerregaard s de - parture could ultimately...capacity will have a lot to do with the Israelis. Finally, it is obvious that we are drawn into recognition of Israel and des - pite our desire to

Azospirillum brasilense Chemotaxis Depends on Two Signaling Pathways Regulating Distinct Motility Parameters

PubMed Central

Mukherjee, Tanmoy; Kumar, Dhivya; Burriss, Nathan; Xie, Zhihong

2016-01-01

ABSTRACT The genomes of most motile bacteria encode two or more chemotaxis (Che) systems, but their functions have been characterized in only a few model systems. Azospirillum brasilense is a motile soil alphaproteobacterium able to colonize the rhizosphere of cereals. In response to an attractant, motile A. brasilense cells transiently increase swimming speed and suppress reversals. The Che1 chemotaxis pathway was previously shown to regulate changes in the swimming speed, but it has a minor role in chemotaxis and root surface colonization. Here, we show that a second chemotaxis system, named Che4, regulates the probability of swimming reversals and is the major signaling pathway for chemotaxis and wheat root surface colonization. Experimental evidence indicates that Che1 and Che4 are functionally linked to coordinate changes in the swimming motility pattern in response to attractants. The effect of Che1 on swimming speed is shown to enhance the aerotactic response of A. brasilense in gradients, likely providing the cells with a competitive advantage in the rhizosphere. Together, the results illustrate a novel mechanism by which motile bacteria utilize two chemotaxis pathways regulating distinct motility parameters to alter movement in gradients and enhance the chemotactic advantage. IMPORTANCE Chemotaxis provides motile bacteria with a competitive advantage in the colonization of diverse niches and is a function enriched in rhizosphere bacterial communities, with most species possessing at least two chemotaxis systems. Here, we identify the mechanism by which cells may derive a significant chemotactic advantage using two chemotaxis pathways that ultimately regulate distinct motility parameters. PMID:27068592

β1-adrenergic receptors activate two distinct signaling pathways in striatal neurons

PubMed Central

Meitzen, John; Luoma, Jessie I.; Stern, Christopher M.; Mermelstein, Paul G.

2010-01-01

Monoamine action in the dorsal striatum and nucleus accumbens plays essential roles in striatal physiology. Although research often focuses on dopamine and its receptors, norepinephrine and adrenergic receptors are also crucial in regulating striatal function. While noradrenergic neurotransmission has been identified in the striatum, little is known regarding the signaling pathways activated by β-adrenergic receptors in this brain region. Using cultured striatal neurons, we characterized a novel signaling pathway by which activation of β1-adrenergic receptors leads to the rapid phosphorylation of cAMP Response Element Binding Protein (CREB), a transcription-factor implicated as a molecular switch underlying long-term changes in brain function. Norepinephrine-mediated CREB phosphorylation requires β1-adrenergic receptor stimulation of a receptor tyrosine kinase, ultimately leading to the activation of a Ras/Raf/MEK/MAPK/MSK signaling pathway. Activation of β1-adrenergic receptors also induces CRE-dependent transcription and increased c-fos expression. In addition, stimulation of β1-adrenergic receptors produces cAMP production, but surprisingly, β1-adrenergic receptor activation of adenylyl cyclase was not functionally linked to rapid CREB phosphorylation. These findings demonstrate that activation of β1-adrenergic receptors on striatal neurons can stimulate two distinct signaling pathways. These adrenergic actions can produce long-term changes in gene expression, as well as rapidly modulate cellular physiology. By elucidating the mechanisms by which norepinephrine and β1-adrenergic receptor activation affects striatal physiology, we provide the means to more fully understand the role of monoamines in modulating striatal function, specifically how norepinephrine and β1-adrenergic receptors may affect striatal physiology. PMID:21143600

Azospirillum brasilense Chemotaxis Depends on Two Signaling Pathways Regulating Distinct Motility Parameters.

PubMed

Mukherjee, Tanmoy; Kumar, Dhivya; Burriss, Nathan; Xie, Zhihong; Alexandre, Gladys

2016-06-15

The genomes of most motile bacteria encode two or more chemotaxis (Che) systems, but their functions have been characterized in only a few model systems. Azospirillum brasilense is a motile soil alphaproteobacterium able to colonize the rhizosphere of cereals. In response to an attractant, motile A. brasilense cells transiently increase swimming speed and suppress reversals. The Che1 chemotaxis pathway was previously shown to regulate changes in the swimming speed, but it has a minor role in chemotaxis and root surface colonization. Here, we show that a second chemotaxis system, named Che4, regulates the probability of swimming reversals and is the major signaling pathway for chemotaxis and wheat root surface colonization. Experimental evidence indicates that Che1 and Che4 are functionally linked to coordinate changes in the swimming motility pattern in response to attractants. The effect of Che1 on swimming speed is shown to enhance the aerotactic response of A. brasilense in gradients, likely providing the cells with a competitive advantage in the rhizosphere. Together, the results illustrate a novel mechanism by which motile bacteria utilize two chemotaxis pathways regulating distinct motility parameters to alter movement in gradients and enhance the chemotactic advantage. Chemotaxis provides motile bacteria with a competitive advantage in the colonization of diverse niches and is a function enriched in rhizosphere bacterial communities, with most species possessing at least two chemotaxis systems. Here, we identify the mechanism by which cells may derive a significant chemotactic advantage using two chemotaxis pathways that ultimately regulate distinct motility parameters. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

The mevalonate pathway in neurons: It's not just about cholesterol.

PubMed

Moutinho, Miguel; Nunes, Maria João; Rodrigues, Elsa

2017-11-01

Cholesterol homeostasis greatly impacts neuronal function due to the essential role of this sterol in the brain. The mevalonate (MVA) pathway leads to the synthesis of cholesterol, but also supplies cells with many other intermediary molecules crucial for neuronal function. Compelling evidence point to a model in which neurons shutdown cholesterol synthesis, and rely on a shuttle derived from astrocytes to meet their cholesterol needs. Nevertheless, several reports suggest that neurons maintain the MVA pathway active, even with sustained cholesterol supply by astrocytes. Hence, in this review we focus not on cholesterol production, but rather on the role of the MVA pathway in the synthesis of particular intermediaries, namely isoprenoids, and on their role on neuronal function. Isoprenoids act as anchors for membrane association, after being covalently bound to proteins, such as most of the small guanosine triphosphate-binding proteins, which are critical to neuronal cell function. Based on literature, on our own results, and on the analysis of public transcriptomics databases, we raise the idea that in neurons there is a shift of the MVA pathway towards the non-sterol branch, responsible for isoprenoid synthesis, in detriment to post-squalene branch, and that this is ultimately essential for synaptic activity. Nevertheless new tools that facilitate imaging and the biochemical characterization and quantification of the prenylome in neurons and astrocytes are needed to understand the regulation of isoprenoid production and protein prenylation in the brain, and to analyze its differences on diverse physiological or pathological conditions, such as aging and neurodegenerative states. Copyright © 2017 Elsevier Inc. All rights reserved.

IFNβ/TNFα synergism induces a non-canonical STAT2/IRF9-dependent pathway triggering a novel DUOX2 NADPH Oxidase-mediated airway antiviral response

PubMed Central

Fink, Karin; Martin, Lydie; Mukawera, Esperance; Chartier, Stéfany; De Deken, Xavier; Brochiero, Emmanuelle; Miot, Françoise; Grandvaux, Nathalie

2013-01-01

Airway epithelial cells are key initial innate immune responders in the fight against respiratory viruses, primarily via the secretion of antiviral and proinflammatory cytokines that act in an autocrine/paracrine fashion to trigger the establishment of an antiviral state. It is currently thought that the early antiviral state in airway epithelial cells primarily relies on IFNβ secretion and the subsequent activation of the interferon-stimulated gene factor 3 (ISGF3) transcription factor complex, composed of STAT1, STAT2 and IRF9, which regulates the expression of a panoply of interferon-stimulated genes encoding proteins with antiviral activities. However, the specific pathways engaged by the synergistic action of different cytokines during viral infections, and the resulting physiological outcomes are still ill-defined. Here, we unveil a novel delayed antiviral response in the airways, which is initiated by the synergistic autocrine/paracrine action of IFNβ and TNFα, and signals through a non-canonical STAT2- and IRF9-dependent, but STAT1-independent cascade. This pathway ultimately leads to the late induction of the DUOX2 NADPH oxidase expression. Importantly, our study uncovers that the development of the antiviral state relies on DUOX2-dependent H2O2 production. Key antiviral pathways are often targeted by evasion strategies evolved by various pathogenic viruses. In this regard, the importance of the novel DUOX2-dependent antiviral pathway is further underlined by the observation that the human respiratory syncytial virus is able to subvert DUOX2 induction. PMID:23545780

Strategies for improved isopropanol-butanol production by a Clostridium strain from glucose and hemicellulose through consolidated bioprocessing.

PubMed

Xin, Fengxue; Chen, Tianpeng; Jiang, Yujiang; Dong, Weiliang; Zhang, Wenming; Zhang, Min; Wu, Hao; Ma, Jiangfeng; Jiang, Min

2017-01-01

High cost of traditional substrates and formation of by-products (such as acetone and ethanol) in acetone-butanol-ethanol (ABE) fermentation hindered the large-scale production of biobutanol. Here, we comprehensively characterized a newly isolated solventogenic and xylanolytic Clostridium species, which could produce butanol at a high ratio with elimination of ethanol and conversion of acetone to more value-added product, isopropanol. Ultimately, direct butanol production from hemicellulose was achieved with efficient expression of indigenous xylanase by the novel strain via consolidated bioprocessing. A novel wild-type Clostridium sp. strain NJP7 was isolated and characterized in this study, which was capable of fermenting monosaccharides, e.g., glucose into butanol via a fermentative acetone-isopropanol-butanol pathway. With enhancement of buffering capacity and alcohol dehydrogenase activities, butanol and isopropanol titer by Clostridium sp. strain NJP7 was improved to 12.21 and 1.92 g/L, respectively, and solvent productivity could be enhanced to 0.44 g/L/h. Furthermore, with in situ extraction with biodiesel, the amount of butanol and isopropanol was finally improved to 25.58 and 5.25 g/L in the fed-batch mode. Meanwhile, Clostridium sp. strain NJP7 shows capability of direct isopropanol-butanol production from hemicelluloses with expression of indigenous xylanase. 2.06 g/L of butanol and 0.54 g/L of isopropanol were finally achieved through the temperature-shift simultaneous saccharification and fermentation, representing the highest butanol production directly from hemicellulose. The co-production of isopropanol with butanol by the newly isolated Clostridium sp. strain NJP7 would add on the economical values for butanol fermentation. Furthermore, the high isopropanol-butanol production with in situ extraction would also greatly enhance the economic feasibility for fermentative production of butanol-isopropanol in large scale. Meanwhile, its direct production of butanol-isopropanol from polysaccharides, hemicellulose through secretion of indigenous thermostable xylanase, shows great potential using lignocellulosic wastes for biofuel production.

Histamine H4-Receptors Inhibit Mast Cell Renin Release in Ischemia/Reperfusion via Protein Kinase Cε-Dependent Aldehyde Dehydrogenase Type-2 Activation

PubMed Central

Aldi, Silvia; Takano, Ken-ichi; Tomita, Kengo; Koda, Kenichiro; Chan, Noel Y.-K.; Marino, Alice; Salazar-Rodriguez, Mariselis; Thurmond, Robin L.

2014-01-01

Renin released by ischemia/reperfusion (I/R) from cardiac mast cells (MCs) activates a local renin-angiotensin system (RAS) causing arrhythmic dysfunction. Ischemic preconditioning (IPC) inhibits MC renin release and consequent activation of this local RAS. We postulated that MC histamine H4-receptors (H4Rs), being Gαi/o-coupled, might activate a protein kinase C isotype–ε (PKCε)–aldehyde dehydrogenase type-2 (ALDH2) cascade, ultimately eliminating MC-degranulating and renin-releasing effects of aldehydes formed in I/R and associated arrhythmias. We tested this hypothesis in ex vivo hearts, human mastocytoma cells, and bone marrow–derived MCs from wild-type and H4R knockout mice. We found that activation of MC H4Rs mimics the cardioprotective anti-RAS effects of IPC and that protection depends on the sequential activation of PKCε and ALDH2 in MCs, reducing aldehyde-induced MC degranulation and renin release and alleviating reperfusion arrhythmias. These cardioprotective effects are mimicked by selective H4R agonists and disappear when H4Rs are pharmacologically blocked or genetically deleted. Our results uncover a novel cardioprotective pathway in I/R, whereby activation of H4Rs on the MC membrane, possibly by MC-derived histamine, leads sequentially to PKCε and ALDH2 activation, reduction of toxic aldehyde-induced MC renin release, prevention of RAS activation, reduction of norepinephrine release, and ultimately to alleviation of reperfusion arrhythmias. This newly discovered protective pathway suggests that MC H4Rs may represent a new pharmacologic and therapeutic target for the direct alleviation of RAS-induced cardiac dysfunctions, including ischemic heart disease and congestive heart failure. PMID:24696042

The strength of aversive and appetitive associations and maladaptive behaviors.

PubMed

Itzhak, Yossef; Perez-Lanza, Daniel; Liddie, Shervin

2014-08-01

Certain maladaptive behaviors are thought to be acquired through classical Pavlovian conditioning. Exaggerated fear response, which can develop through Pavlovian conditioning, is associated with acquired anxiety disorders such as post-traumatic stress disorders (PTSDs). Inflated reward-seeking behavior, which develops through Pavlovian conditioning, underlies some types of addictive behavior (e.g., addiction to drugs, food, and gambling). These maladaptive behaviors are dependent on associative learning and the development of long-term memory (LTM). In animal models, an aversive reinforcer (fear conditioning) encodes an aversive contextual and cued LTM. On the other hand, an appetitive reinforcer results in conditioned place preference (CPP) that encodes an appetitive contextual LTM. The literature on weak and strong associative learning pertaining to the development of aversive and appetitive LTM is relatively scarce; thus, this review is particularly focused on the strength of associative learning. The strength of associative learning is dependent on the valence of the reinforcer and the salience of the conditioned stimulus that ultimately sways the strength of the memory trace. Our studies suggest that labile (weak) aversive and appetitive LTM may share similar signaling pathways, whereas stable (strong) aversive and appetitive LTM is mediated through different pathways. In addition, we provide some evidence suggesting that extinction of aversive fear memory and appetitive drug memory is likely to be mediated through different signaling molecules. We put forward the importance of studies aimed to investigate the molecular mechanisms underlying the development of weak and strong memories (aversive and appetitive), which would ultimately help in the development of targeted pharmacotherapies for the management of maladaptive behaviors that arise from classical Pavlovian conditioning. © 2014 International Union of Biochemistry and Molecular Biology.

Relaxation pathways of photoexcited iodide-methanol clusters: a computational investigation.

PubMed

Mak, Chun C; Peslherbe, Gilles H

2014-06-26

Upon photoexcitation of iodide-methanol clusters, I(-)(CH3OH)n, to a charge-transfer-to-solvent (CTTS) excited state, extensive relaxation was found to occur, accompanied by a convoluted modulation of the stability of the excited electron, which ultimately decreases substantially. In order to develop a molecular-level understanding of the relaxation processes of CTTS excited I(-)(CH3OH)n, high-level quantum chemical calculations are first used to investigate the ground, excited, and ionized states of I(-)(CH3OH)n (n = 2). Because of the relatively small size of I(-)(CH3OH)2, it was possible to characterize the contributions of solvent-solvent interactions to the stability of the CTTS excited cluster relative to dissociation into methanol, iodine, and a free electron, which exhibits a substantial dependence on the cluster geometric configuration. Ab initio molecular dynamics simulations of CTTS excited I(-)(CH3OH)3 are then performed to shed some light onto the nature of the relaxation pathways involved in the modulation of the stability of the excited electron in larger clusters. Simulation results suggest that separation of I and (CH3OH)3(-) accompanied by solvent reorganization in the latter can initially stabilize the excited electron, while gradual cluster fragmentation to I, (CH3OH)2(-), and CH3OH ultimately destabilizes it. This work shows, for the first time, that the inability of small CTTS excited I(-)(CH3OH)n to retain a solvated electron may be attributed to the limited hydrogen-bonding capacity of CH3OH, which increases the propensity for fragmentation to smaller clusters with lower excess-electron binding energies, and highlights the critical role of intricate molecular interactions in the electron solvation process.

Behavioral toxicology in the 21st century: challenges and opportunities for behavioral scientists. Summary of a symposium presented at the annual meeting of the neurobehavioral teratology society, June, 2009.

PubMed

Bushnell, Philip J; Kavlock, Robert J; Crofton, Kevin M; Weiss, Bernard; Rice, Deborah C

2010-01-01

The National Research Council (NRC) of the National Academies of Science recently published a report of its vision of toxicity testing in the 21st century. The report proposes that the current toxicity testing paradigm that depends upon whole-animal tests be replaced with a strategy based upon in vitro tests, in silico models and evaluations of toxicity at the human population level. These goals are intended to set in motion changes that will transform risk assessment into a process in which adverse effects on public health are predicted by quantitative structure-activity relationship (QSAR) models and data from suites of high-throughput in vitro tests. The potential roles for whole-animal testing in this futuristic vision are both various and undefined. A symposium was convened at the annual meeting of the Neurobehavioral Teratology Society in Rio Grande, Puerto Rico in June, 2009 to discuss the potential challenges and opportunities for behavioral scientists in developing and/or altering this strategy toward the ultimate goal of protecting public health from hazardous chemicals. R. Kavlock described the NRC vision, introduced the concept of the 'toxicity pathway' (a central guiding principle of the NRC vision), and described the current status of an initial implementation this approach with the EPA's ToxCast(R) program. K. Crofton described a pathway based upon disruption of thyroid hormone metabolism during development, including agents, targets, and outcomes linked by this mode of action. P. Bushnell proposed a pathway linking the neural targets and cellular to behavioral effects of acute exposure to organic solvents, whose predictive power is limited by our incomplete understanding of the complex CNS circuitry that mediates the behavioral responses to solvents. B. Weiss cautioned the audience regarding a pathway approach to toxicity testing, using the example of the developmental toxicity of phthalates, whose effects on mammalian sexual differentiation would be difficult to identify based on screening tests in vitro. Finally, D. Rice raised concerns regarding the use of data derived from toxicity screening tests to human health risk assessments. Discussion centered around opportunities and challenges for behavioral toxicologists regarding this impending paradigm shift. Opportunities include: identifying and characterizing toxicity pathways; informing the conditions and limits of extrapolation; addressing issues of susceptibility and variability; providing reality-checks on selected positives and negatives from screens; and performing targeted testing and dose-response assessments of chemicals flagged during screening. Challenges include: predicting behavior using models of complex neurobiological pathways; standardizing study designs and dependent variables to facilitate creation of databases; and managing the cost and efficiency of behavioral assessments. Thus, while progress is being made in approaching the vision of 21st century toxicology, we remain a long way from replacing whole-animal tests; indeed, some animal testing will be essential for the foreseeable future at least. Initial advances will likely provide better prioritization tools so that animal resources are used more efficiently and effectively.

How does surgery compare with advanced intra-articular therapies in knee osteoarthritis: current thoughts

PubMed Central

Wehling, Peter; Moser, Carsten; Maixner, William

2016-01-01

The objectives of osteoarthritis (OA) management are to reduce pain and inflammation, slow cartilage degradation, improve function and reduce disability. Current strategies for managing knee OA include nonpharmacological interventions, oral pharmacological treatments, localized intra-articular injections, and surgery. It has become evident that the inflammatory response is a key contributor to the development and progression of knee OA. Signaling pathways involving growth factors and cytokines are being investigated for the development of new therapies that target the underlying biological processes causing the disease. This concept of ‘molecular orthopedics’ enables more patient-centered diagnostic and treatment strategies. In contrast to other conservative therapies, which ultimately only address OA symptoms, intra-articular injections, in particular autologous conditioned serum (ACS), provide benefits that have the potential to outweigh those of established pharmacological treatments and surgery. Surgery has historically been considered the final solution for treatment of knee OA, both by treating physicians and by patients; however, there are increasing concerns regarding the lack of randomized clinical trials providing evidence to support this opinion. Intra-articular injection of ACS has demonstrated efficacy as a treatment for knee OA in a number of studies, with a very low rate of adverse events and side effects, compared with surgery. Treatment with ACS utilizes the release of anti-inflammatory cytokines and regenerative growth factors to support the natural healing processes in the knee, and has the potential to provide a valuable alternative to surgical intervention. PMID:27247634

Genome annotation provides insight into carbon monoxide and hydrogen metabolism in Rubrivivax gelatinosus

DOE PAGES

Wawrousek, Karen; Noble, Scott; Korlach, Jonas; ...

2014-12-05

In this article, we report here the sequencing and analysis of the genome of the purple non-sulfur photosynthetic bacterium Rubrivivax gelatinosus CBS. This microbe is a model for studies of its carboxydotrophic life style under anaerobic condition, based on its ability to utilize carbon monoxide (CO) as the sole carbon substrate and water as the electron acceptor, yielding CO 2 and H 2 as the end products. The CO-oxidation reaction is known to be catalyzed by two enzyme complexes, the CO dehydrogenase and hydrogenase. As expected, analysis of the genome of Rx. gelatinosus CBS reveals the presence of genes encodingmore » both enzyme complexes. The CO-oxidation reaction is CO-inducible, which is consistent with the presence of two putative CO-sensing transcription factors in its genome. Genome analysis also reveals the presence of two additional hydrogenases, an uptake hydrogenase that liberates the electrons in H 2 in support of cell growth, and a regulatory hydrogenase that senses H 2 and relays the signal to a two-component system that ultimately controls synthesis of the uptake hydrogenase. The genome also contains two sets of hydrogenase maturation genes which are known to assemble the catalytic metallocluster of the hydrogenase NiFe active site. Finally and collectively, the genome sequence and analysis information reveals the blueprint of an intricate network of signal transduction pathways and its underlying regulation that enables Rx. gelatinosus CBS to thrive on CO or H 2 in support of cell growth.« less

The toolbox of Trichoderma spp. in the biocontrol of Botrytis cinerea disease.

PubMed

Vos, Christine M F; De Cremer, Kaat; Cammue, Bruno P A; De Coninck, Barbara

2015-05-01

Botrytis cinerea is a necrotrophic fungal pathogen causing disease in many plant species, leading to economically important crop losses. So far, fungicides have been widely used to control this pathogen. However, in addition to their detrimental effects on the environment and potential risks for human health, increasing fungicide resistance has been observed in the B. cinerea population. Biological control, that is the application of microbial organisms to reduce disease, has gained importance as an alternative or complementary approach to fungicides. In this respect, the genus Trichoderma constitutes a promising pool of organisms with potential for B. cinerea control. In the first part of this article, we review the specific mechanisms involved in the direct interaction between the two fungi, including mycoparasitism, the production of antimicrobial compounds and enzymes (collectively called antagonism), and competition for nutrients and space. In addition, biocontrol has also been observed when Trichoderma is physically separated from the pathogen, thus implying an indirect systemic plant defence response. Therefore, in the second part, we describe the consecutive steps leading to induced systemic resistance (ISR), starting with the initial Trichoderma-plant interaction and followed by the activation of downstream signal transduction pathways and, ultimately, the defence response resulting in ISR (ISR-prime phase). Finally, we discuss the ISR-boost phase, representing the effect of ISR priming by Trichoderma spp. on plant responses after additional challenge with B. cinerea. © 2014 BSPP AND JOHN WILEY & SONS LTD.

Propitious Dendritic Cu2O-Pt Nanostructured Anodes for Direct Formic Acid Fuel Cells.

PubMed

El-Nagar, Gumaa A; Mohammad, Ahmad M; El-Deab, Mohamed S; El-Anadouli, Bahgat E

2017-06-14

This study introduces a novel competent dendritic copper oxide-platinum nanocatalyst (nano-Cu 2 O-Pt) immobilized onto a glassy carbon (GC) substrate for formic acid (FA) electro-oxidation (FAO); the prime reaction in the anodic compartment of direct formic acid fuel cells (DFAFCs). Interestingly, the proposed catalyst exhibited an outstanding improvement for FAO compared to the traditional platinum nanoparticles (nano-Pt) modified GC (nano-Pt/GC) catalyst. This was evaluated from steering the reaction mechanism toward the desired direct route producing carbon dioxide (CO 2 ); consistently with mitigating the other undesired indirect pathway producing carbon monoxide (CO); the potential poison deteriorating the catalytic activity of typical Pt-based catalysts. Moreover, the developed catalyst showed a reasonable long-term catalytic stability along with a significant lowering in onset potential of direct FAO that ultimately reduces the polarization and amplifies the fuel cell's voltage. The observed catalytic enhancement was believed to originate bifunctionally; while nano-Pt represented the base for the FA adsorption, nanostructured copper oxide (nano-Cu 2 O) behaved as a catalytic mediator facilitating the charge transfer during FAO and providing the oxygen atmosphere inspiring the poison's (CO) oxidation at relatively lower potential. Surprisingly, moreover, nano-Cu 2 O induced a surface retrieval of nano-Pt active sites by capturing the poisoning CO via "a spillover mechanism" to renovate the Pt surface for the direct FAO. Finally, the catalytic tolerance of the developed catalyst toward halides' poisoning was discussed.

Breaking self-tolerance during autoimmunity and cancer immunity: Myeloid cells and type I IFN response regulation.

PubMed

Tarbell, Kristin V; Egen, Jackson G

2018-02-02

The generation and regulation of innate immune signals are key determinants of autoimmune pathogenesis. Emerging evidence suggests that parallel processes operating in the setting of solid tumors can similarly determine the balance between tolerance and immunity and ultimately the effectiveness of the antitumor immune response. In both contexts, self-specific responses start with innate immune cell activation that leads to the initial break in self-tolerance, which can be followed by immune response amplification and maturation through innate-adaptive crosstalk, and finally immune-mediated tissue/tumor destruction that can further potentiate inflammation. Of particular importance for these processes is type I IFN, which is induced in response to endogenous ligands, such as self-nucleic acids, and acts on myeloid cells to promote the expansion of autoreactive or tumor-specific T cells and their influx into the target tissue. Evidence from the study of human disease pathophysiology and genetics and mouse models of disease has revealed an extensive and complex network of negative regulatory pathways that has evolved to restrain type I IFN production and activity. Here, we review the overlapping features of self- and tumor-specific immune responses, including the central role that regulators of the type I IFN response and innate immune cell activation play in maintaining tolerance, and discuss how a better understanding of the pathophysiology of autoimmunity can help to identify new approaches to promote immune-mediated tumor destruction. ©2018 Society for Leukocyte Biology.

Central mediators involved in the febrile response: effects of antipyretic drugs

PubMed Central

Zampronio, Aleksander R; Soares, Denis M; Souza, Glória E P

2015-01-01

Fever is a complex signal of inflammatory and infectious diseases. It is generally initiated when peripherally produced endogenous pyrogens reach areas that surround the hypothalamus. These peripheral endogenous pyrogens are cytokines that are produced by leukocytes and other cells, the most known of which are interleukin-1β, tumor necrosis factor-α, and interleukin-6. Because of the capacity of these molecules to induce their own synthesis and the synthesis of other cytokines, they can also be synthesized in the central nervous system. However, these pyrogens are not the final mediators of the febrile response. These cytokines can induce the synthesis of cyclooxygenase-2, which produces prostaglandins. These prostanoids alter hypothalamic temperature control, leading to an increase in heat production, the conservation of heat, and ultimately fever. The effect of antipyretics is based on blocking prostaglandin synthesis. In this review, we discuss recent data on the importance of prostaglandins in the febrile response, and we show that some endogenous mediators can still induce the febrile response even when known antipyretics reduce the levels of prostaglandins in the central nervous system. These studies suggest that centrally produced mediators other than prostaglandins participate in the genesis of fever. Among the most studied central mediators of fever are corticotropin-releasing factor, endothelins, chemokines, endogenous opioids, and substance P, which are discussed herein. Additionally, recent evidence suggests that these different pathways of fever induction may be activated during different pathological conditions. PMID:27227071

CaMKII Signaling Stimulates Mef2c Activity In Vitro but Only Minimally Affects Murine Long Bone Development in vivo

PubMed Central

Amara, Chandra S.; Fabritius, Christine; Houben, Astrid; Wolff, Lena I.; Hartmann, Christine

2017-01-01

The long bones of vertebrate limbs form by endochondral ossification, whereby mesenchymal cells differentiate into chondrogenic progenitors, which then differentiate into chondrocytes. Chondrocytes undergo further differentiation from proliferating to prehypertrophic, and finally to hypertrophic chondrocytes. Several signaling pathways and transcription factors regulate this process. Previously, we and others have shown in chicken that overexpression of an activated form of Calcium/calmodulin-dependent kinase II (CaMKII) results in ectopic chondrocyte maturation. Here, we show that this is not the case in the mouse. Although, in vitro Mef2c activity was upregulated by about 55-fold in response to expression of an activated form of CaMKII (DACaMKII), transgenic mice that expressed a dominant-active form of CaMKII under the control of the Col2a1 regulatory elements display only a very transient and mild phenotype. Here, only the onset of chondrocyte hypertrophy at E12.5 is accelerated. It is also this early step in chondrocyte differentiation that is temporarily delayed around E13.5 in transgenic mice expressing the peptide inhibitor CaM-KIIN from rat (rKIIN) under the control of the Col2a1 regulatory elements. Yet, ultimately DACaMKII, as well as rKIIN transgenic mice are born with completely normal skeletal elements with regard to their length and growth plate organization. Hence, our in vivo analysis suggests that CaMKII signaling plays a minor role in chondrocyte maturation in mice. PMID:28361052

A novel biological function of soluble biglycan: Induction of erythropoietin production and polycythemia.

PubMed

Frey, Helena; Moreth, Kristin; Hsieh, Louise Tzung-Harn; Zeng-Brouwers, Jinyang; Rathkolb, Birgit; Fuchs, Helmut; Gailus-Durner, Valérie; Iozzo, Renato V; de Angelis, Martin Hrabě; Schaefer, Liliana

2017-06-01

Secondary polycythemia, a disease characterized by a selective increase in circulating mature erythrocytes, is caused by enhanced erythropoietin (Epo) concentrations triggered by hypoxia-inducible factor-2α (HIF-2α). While mechanisms of hypoxia-dependent stabilization of HIF-2α protein are well established, data regarding oxygen-independent regulation of HIF-2α are sparse. In this study, we generated a novel transgenic mouse model, in which biglycan was constitutively overexpressed and secreted by hepatocytes (BGN Tg ), thereby providing a constant source of biglycan released into the blood stream. We discovered that although the mice were apparently normal, they harbored an increase in mature circulating erythrocytes. In addition to erythrocytosis, the BGN Tg mice showed elevated hemoglobin concentrations, hematocrit values and enhanced total iron binding capacity, revealing a clinical picture of polycythemia. In BGN Tg mice markedly enhanced Epo mRNA expression was observed in the liver and kidney, while elevated Epo protein levels were found in liver, kidney and blood. Mechanistically, we showed that the transgenic animals had an abundance of HIF-2α protein in the liver and kidney. Finally, by transiently overexpressing circulating biglycan in mice deficient in various Toll-like receptors (TLRs), we determined that this novel function of biglycan to promote Epo synthesis was specifically mediated by a selective interaction with TLR2. Thus, we discovered a novel biological pathway of soluble biglycan inducing HIF-2α protein stabilization and Epo production presumably in an oxygen-independent manner, ultimately giving rise to secondary polycythemia.

Antioxidant agents against trichothecenes: new hints for oxidative stress treatment

PubMed Central

Nepovimova, Eugenie; Wang, Yun; Yang, Hualin; Li, Li; Zhang, Xiujuan; Kuca, Kamil

2017-01-01

Trichothecenes are a group of mycotoxins mainly produced by fungi of genus Fusarium. Due to high toxicity and widespread dissemination, T-2 toxin and deoxynivalenol (DON) are considered to be the most important compounds of this class. Trichothecenes generate free radicals, including reactive oxygen species (ROS), which induce lipid peroxidation, decrease levels of antioxidant enzymes, and ultimately lead to apoptosis. Consequently, oxidative stress is an active area of research on the toxic mechanisms of trichothecenes, and identification of antioxidant agents that could be used against trichothecenes is crucial for human health. Numerous natural compounds have been analyzed and have shown to function very effectively as antioxidants against trichothecenes. In this review, we summarize the molecular mechanisms underlying oxidative stress induced by these compounds, and discuss current knowledge regarding such antioxidant agents as vitamins, quercetin, selenium, glucomannan, nucleotides, antimicrobial peptides, bacteria, polyunsaturated fatty acids, oligosaccharides, and plant extracts. These products inhibit trichothecene-induced oxidative stress by (1) inhibiting ROS generation and induced DNA damage and lipid peroxidation; (2) increasing antioxidant enzyme activity; (3) blocking the MAPK and NF-κB signaling pathways; (4) inhibiting caspase activity and apoptosis; (5) protecting mitochondria; and (6) regulating anti-inflammatory actions. Finally, we summarize some decontamination methods, including bacterial and yeast biotransformation and degradation, as well as mycotoxin-binding agents. This review provides a comprehensive overview of antioxidant agents against trichothecenes and casts new light on the attenuation of oxidative stress. PMID:29299181

Aggregatibacter actinomycetemcomitans, a potent immunoregulator of the periodontal host defense system and alveolar bone homeostasis

PubMed Central

Herbert, Bethany A.; Novince, Chad M.; Kirkwood, Keith L.

2015-01-01

Summary Aggregatibacter actinomycetemcomitans is a perio-pathogenic bacteria that has long been associated with localized aggressive periodontitis. The mechanisms of its pathogenicity have been studied in humans and pre-clinical experimental models. Although different serotypes of A. actinomycetemcomitans have differential virulence factor expression, A. actinomycetemcomitans cytolethal distending toxin (CDT), leukotoxin, and lipopolysaccharide (LPS) have been most extensively studied in the context of modulating the host immune response. Following colonization and attachment in the oral cavity, A. actinomycetemcomitans employs CDT, leukotoxin, and LPS to evade host innate defense mechanisms and drive a pathophysiologic inflammatory response. This supra-physiologic immune response state perturbs normal periodontal tissue remodeling/turnover and ultimately has catabolic effects on periodontal tissue homeostasis. In this review, we have divided the host response into two systems: non-hematopoietic and hematopoietic. Non-hematopoietic barriers include epithelium and fibroblasts that initiate the innate immune host response. The hematopoietic system contains lymphoid and myeloid-derived cell lineages that are responsible for expanding the immune response and driving the pathophysiologic inflammatory state in the local periodontal microenvironment. Effector systems and signaling transduction pathways activated and utilized in response to A. actinomycetemcomitans will be discussed to further delineate immune cell mechanisms during A. actinomycetemcomitans infection. Finally, we will discuss the osteo-immunomodulatory effects induced by A. actinomycetemcomitans and dissect the catabolic disruption of balanced osteoclast-osteoblast mediated bone remodeling, which subsequently leads to net alveolar bone loss. PMID:26197893

Global issues in pediatric nutrition: AIDS.

PubMed

Ball, C S

1998-10-01

Nutrition is a final common pathway in chronic disease, and weight loss is a major manifestation of acquired immunodeficiency syndrome (AIDS). In sub-Saharan Africa, studies have shown that 25% of children with malnutrition have human immunodeficiency virus (HIV) infection, although patterns of malnutrition are indistinguishable from those who are HIV negative. Breast-feeding increases the risk of vertical transmission, and the overall risk versus benefit needs continuing careful consideration in relation to local mortality from gastroenteritis and malnutrition. Chronic diarrhea is much more common in HIV-infected children in Africa and may have a multiplicity of causes, including infection with adherent forms of Escherichia coli, protozoa, and even direct HIV infection of intestinal mucosal cells. The HIV wasting syndrome produces reduction in bioelectrical impedence, fat, lean body mass, and body cell mass, but the changes can be predicted from equations used in starvation states. Micronutrients may be important, but observed changes may be due to immune mediator activation, rather than malnutrition. Calorie supplementation is beneficial when delivered by any route, but is likely to produce the greatest positive change when CD4 counts are highest in relation to calorie intake. Paradoxically, HIV-infected children may be obese early in the disease until AIDS develops. There is an inextricable link between disease and nutritional status. In children with AIDS wasting syndrome, a low CD4 count and high viral load are likely so that effective antiviral treatment may ultimately produce the greatest improvement in health, including nutritional status.

Quantum chemical study of the mechanism of action of vitamin K epoxide reductase (VKOR)

NASA Astrophysics Data System (ADS)

Deerfield, David, II; Davis, Charles H.; Wymore, Troy; Stafford, Darrel W.; Pedersen, Lee G.

Possible model, but simplistic, mechanisms for the action of vitamin K epoxide reductase (VKOR) are investigated with quantum mechanical methods (B3LYP/6-311G**). The geometries of proposed model intermediates in the mechanisms are energy optimized. Finally, the energetics of the proposed (pseudo-enzymatic) pathways are compared. We find that the several pathways are all energetically feasible. These results will be useful for designing quantum mechanical/molecular mechanical method (QM/MM) studies of the enzymatic pathway once three-dimensional structural data are determined and available for VKOR.

Understanding the Warburg effect: the metabolic requirements of cell proliferation.

PubMed

Vander Heiden, Matthew G; Cantley, Lewis C; Thompson, Craig B

2009-05-22

In contrast to normal differentiated cells, which rely primarily on mitochondrial oxidative phosphorylation to generate the energy needed for cellular processes, most cancer cells instead rely on aerobic glycolysis, a phenomenon termed "the Warburg effect." Aerobic glycolysis is an inefficient way to generate adenosine 5'-triphosphate (ATP), however, and the advantage it confers to cancer cells has been unclear. Here we propose that the metabolism of cancer cells, and indeed all proliferating cells, is adapted to facilitate the uptake and incorporation of nutrients into the biomass (e.g., nucleotides, amino acids, and lipids) needed to produce a new cell. Supporting this idea are recent studies showing that (i) several signaling pathways implicated in cell proliferation also regulate metabolic pathways that incorporate nutrients into biomass; and that (ii) certain cancer-associated mutations enable cancer cells to acquire and metabolize nutrients in a manner conducive to proliferation rather than efficient ATP production. A better understanding of the mechanistic links between cellular metabolism and growth control may ultimately lead to better treatments for human cancer.

An unexpected reaction pathway in the synthesis of the ABCE framework of strychnine-type alkaloids - A multidisciplinary study

NASA Astrophysics Data System (ADS)

Šoral, Michal; Markus, Jozef; Doháňošová, Jana; Šoralová, Stanislava; Dvoranová, Dana; Chyba, Andrej; Moncol, Ján; Berkeš, Dušan; Liptaj, Tibor

2017-01-01

Acid-catalyzed cyclization of spirocyclic 1‧-benzyl-2‧-(prop-2-en-1-yl)spiro[indole-3,3‧-pyrrolidine]-5‧-one (1) was performed. The pentacyclic product of Povarov-like imino-Diels-Alder reaction was isolated in high yield instead of expected tetracyclic aza-Prins intermediate. The unusual exotic alkaloid-type structure of the resulting molecule 2 was unambiguously confirmed by a detailed NMR analysis using a set of 2D NMR spectra including an INADEQUATE experiment. The relative configuration of 2 was predicted from the synthesis mechanism and DFT geometry calculations and independently confirmed using NOESY and residual dipolar coupling (RDC) assisted NMR analysis in stretched crosslinked polystyrene gels. The reversibility of the cycloaddition in aprotic solvents was observed. A new reaction pathway yielding a rare 6-5-5-5 tetracyclic spiroindoline 3 was suggested. The relative configuration within the tetracyclic framework was ultimately proved using Single-crystal X-ray diffraction analysis of compound 4.

Suffering in Silence: Impact of Tobacco Use on Communication Dynamics Within Vietnamese and Chinese Immigrant Families.

PubMed

Petersen, Anne Berit; Tsoh, Janice Y; Nguyen, Tung T; McPhee, Stephen J; Burke, Nancy J

2015-12-29

The goal of this project was to explore family communication dynamics and their implications for smoking cessation. We conducted 39 in-depth dyadic and individual qualitative interviews with 13 immigrant smoker-family member pairs of Vietnamese (n = 9 dyads, 18 individuals) and Chinese (n = 4 dyads, 8 individuals) descent, including seven current and six former smokers and 13 family members. All 13 dyadic and 26 individual interviews were analyzed using a collaborative crystallization process as well as grounded theory methods. We identified three interrelated pathways by which tobacco use in immigrant Vietnamese and Chinese families impacts family processes and communication dynamics. Using a two-dimensional model, we illustrate how the shared consequences of these pathways can contribute to a dynamic of avoidance and noncommunication, resulting in individual family members "suffering in silence" and ultimately smoking being reinforced. We discuss the implications of these findings for development of smoking cessation interventions. © The Author(s) 2015.

Inactivation of AKT Induces Cellular Senescence in Uterine Leiomyoma

PubMed Central

Xu, Xiaofei; Lu, Zhenxiao; Qiang, Wenan; Vidimar, Vania; Kong, Beihua

2014-01-01

Uterine leiomyomas (fibroids) are a major public health problem. Current medical treatments with GnRH analogs do not provide long-term benefit. Thus, permanent shrinkage or inhibition of fibroid growth via medical means remains a challenge. The AKT pathway is a major growth and survival pathway for fibroids. We propose that AKT inhibition results in a transient regulation of specific mechanisms that ultimately drive cells into cellular senescence or cell death. In this study, we investigated specific mechanisms of AKT inhibition that resulted in senescence. We observed that administration of MK-2206, an allosteric AKT inhibitor, increased levels of reactive oxygen species, up-regulated the microRNA miR-182 and several senescence-associated genes (including p16, p53, p21, and β-galactosidase), and drove leiomyoma cells into stress-induced premature senescence (SIPS). Moreover, induction of SIPS was mediated by HMGA2, which colocalized to senescence-associated heterochromatin foci. This study provides a conceivable molecular mechanism of SIPS by AKT inhibition in fibroids. PMID:24476133

The lysosomal storage disease continuum with ageing-related neurodegenerative disease.

PubMed

Lloyd-Evans, Emyr; Haslett, Luke J

2016-12-01

Lysosomal storage diseases and diseases of ageing share many features both at the physiological level and with respect to the mechanisms that underlie disease pathogenesis. Although the exact pathophysiology is not exactly the same, it is astounding how many similar pathways are altered in all of these diseases. The aim of this review is to provide a summary of the shared disease mechanisms, outlining the similarities and differences and how genetics, insight into rare diseases and functional research has changed our perspective on the causes underlying common diseases of ageing. The lysosome should no longer be considered as just the stomach of the cell or as a suicide bag, it has an emerging role in cellular signalling, nutrient sensing and recycling. The lysosome is of fundamental importance in the pathophysiology of diseases of ageing and by comparing against the LSDs we not only identify common pathways but also therapeutic targets so that ultimately more effective treatments can be developed for all neurodegenerative diseases. Copyright © 2016. Published by Elsevier B.V.

Synthetic biology to access and expand nature’s chemical diversity

PubMed Central

Smanski, Michael J.; Zhou, Hui; Claesen, Jan; Shen, Ben; Fischbach, Michael; Voigt, Christopher A.

2016-01-01

Bacterial genomes encode the biosynthetic potential to produce hundreds of thousands of complex molecules with diverse applications, from medicine to agriculture and materials. Economically accessing the potential encoded within sequenced genomes promises to reinvigorate waning drug discovery pipelines and provide novel routes to intricate chemicals. This is a tremendous undertaking, as the pathways often comprise dozens of genes spanning as much as 100+ kiliobases of DNA, are controlled by complex regulatory networks, and the most interesting molecules are made by non-model organisms. Advances in synthetic biology address these issues, including DNA construction technologies, genetic parts for precision expression control, synthetic regulatory circuits, computer aided design, and multiplexed genome engineering. Collectively, these technologies are moving towards an era when chemicals can be accessed en mass based on sequence information alone. This will enable the harnessing of metagenomic data and massive strain banks for high-throughput molecular discovery and, ultimately, the ability to forward design pathways to complex chemicals not found in nature. PMID:26876034

An Update on ToxCast™ | Science Inventory | US EPA

EPA Pesticide Factsheets

In its first phase, ToxCast™ is profiling over 300 well-characterized chemicals (primarily pesticides) in over 400 HTS endpoints. These endpoints include biochemical assays of protein function, cell-based transcriptional reporter assays, multi-cell interaction assays, transcriptomics on primary cell cultures, and developmental assays in zebrafish embryos. Almost all of the compounds being examined in Phase 1 of ToxCast™ have been tested in traditional toxicology tests, including developmental toxicity, multi-generation studies, and sub-chronic and chronic rodent bioassays Lessons learned to date for ToxCast: Large amounts of quality HTS data can be economically obtained. Large scale data sets will be required to understand potential for biological activity. Value in having multiple assays with overlapping coverage of biological pathways and a variety of methodologies Concentration-response will be important for ultimate interpretation Data transparency will be important for acceptance. Metabolic capabilities and coverage of developmental toxicity pathways will need additional attention. Need to define the gold standard Partnerships are needed to bring critical mass and expertise.

Early adverse experience and substance addiction: dopamine, oxytocin, and glucocorticoid pathways

PubMed Central

Kim, Sohye; Kwok, Stephanie; Mayes, Linda C.; Potenza, Marc N.; Rutherford, Helena J. V.; Strathearn, Lane

2016-01-01

Substance addiction may follow a chronic, relapsing course and critically undermine the physical and psychological well-being of the affected individual and the social units of which the individual is a member. Despite the public health burden associated with substance addiction, treatment options remain suboptimal, with relapses often seen. The present review synthesizes growing insights from animal and human research to shed light upon developmental and neurobiological pathways that may increase susceptibility to addiction. We examine the dopamine system, the oxytocin system, and the glucocorticoid system, as they are particularly relevant to substance addiction. Our aim is to delineate how early adverse experience may induce long-lasting alterations in each of these systems at molecular, neuroendocrine, and behavioral levels and ultimately lead to heightened vulnerability to substance addiction. We further discuss how substance addiction in adulthood may increase the risk of suboptimal caregiving for the next generation, perpetuating the intergenerational cycle of early adverse experiences and addiction. PMID:27508337

Current Therapy and New Directions in the Treatment of Hairy Cell Leukemia: A Review.

PubMed

Sarvaria, Aditya; Topp, Zheng; Saven, Alan

2016-01-01

Hairy cell leukemia (HCL) is a chronic B-cell leukemia noted for an indolent course that ultimately results in cytopenias and massive splenomegaly. Whereas treatment with the nucleoside purine analogues cladribine and pentostatin results in lengthy remissions in nearly all patients with HCL, most patients will experience relapse while a small percentage of patients' disease fails to respond to therapy in the first place. Retreatment with a purine nucleoside analogue often leads to an effective but limited response. For decades, few other viable therapeutic options were available to these patients who required retreatment. Recently, new insights into the mechanism of disease of HCL have led to research in new potential treatment agents, either alone or with a purine nucleoside analogue. Clinical trials with rituximab, bendamustine, and conjugate immunotoxins will reveal what role these therapies will have in HCL treatment. A better understanding of the BRAF/MEK/ERK pathway and the B-cell signaling pathway has allowed further exploration into the novel drugs vemurafenib, dabrafenib, trametinib, and ibrutinib.

Frontiers in the pathogenesis of Alzheimer’s disease

PubMed Central

Sambamurti, Kumar; Jagannatha Rao, K. S.; Pappolla, Miguel A.

2009-01-01

Alzheimer’s disease (AD) is characterized by progressive dementia and brain deposits of the amyloid β protein (Aβ) as senile plaques and the microtubule-associated protein, Tau, as neurofibrillary tangles (NFT). The current treatment of AD is limited to drugs that attempt to correct deficits in the cholinergic pathway or glutamate toxicity. These drugs show some improvement over a short period of time but the disease ultimately requires treatment to prevent and stop the neurodegeneration that affects multiple pathways. The currently favored hypothesis is that Aβ aggregates to toxic forms that induce neurodegeneration. Drugs that reduce Aβ successfully treat transgenic mouse models of AD, but the most promising anti-Aβ vaccination approach did not successfully treat AD in a clinical trial. These studies suggest that AD pathogenesis is a complex phenomenon and requires a more broad-based approach to identify mechanisms of neurodegeneration. Multiple hypotheses have been proposed and the field is ready for a new generation of ideas to develop early diagnostic approaches and develop successful treatment plans. PMID:21416019

Discovering causal pathways linking genomic events to transcriptional states using Tied Diffusion Through Interacting Events (TieDIE).

PubMed

Paull, Evan O; Carlin, Daniel E; Niepel, Mario; Sorger, Peter K; Haussler, David; Stuart, Joshua M

2013-11-01

Identifying the cellular wiring that connects genomic perturbations to transcriptional changes in cancer is essential to gain a mechanistic understanding of disease initiation, progression and ultimately to predict drug response. We have developed a method called Tied Diffusion Through Interacting Events (TieDIE) that uses a network diffusion approach to connect genomic perturbations to gene expression changes characteristic of cancer subtypes. The method computes a subnetwork of protein-protein interactions, predicted transcription factor-to-target connections and curated interactions from literature that connects genomic and transcriptomic perturbations. Application of TieDIE to The Cancer Genome Atlas and a breast cancer cell line dataset identified key signaling pathways, with examples impinging on MYC activity. Interlinking genes are predicted to correspond to essential components of cancer signaling and may provide a mechanistic explanation of tumor character and suggest subtype-specific drug targets. Software is available from the Stuart lab's wiki: https://sysbiowiki.soe.ucsc.edu/tiedie. jstuart@ucsc.edu. Supplementary data are available at Bioinformatics online.

Sub-nanometre resolution of atomic motion during electronic excitation in phase-change materials.

PubMed

Mitrofanov, Kirill V; Fons, Paul; Makino, Kotaro; Terashima, Ryo; Shimada, Toru; Kolobov, Alexander V; Tominaga, Junji; Bragaglia, Valeria; Giussani, Alessandro; Calarco, Raffaella; Riechert, Henning; Sato, Takahiro; Katayama, Tetsuo; Ogawa, Kanade; Togashi, Tadashi; Yabashi, Makina; Wall, Simon; Brewe, Dale; Hase, Muneaki

2016-02-12

Phase-change materials based on Ge-Sb-Te alloys are widely used in industrial applications such as nonvolatile memories, but reaction pathways for crystalline-to-amorphous phase-change on picosecond timescales remain unknown. Femtosecond laser excitation and an ultrashort x-ray probe is used to show the temporal separation of electronic and thermal effects in a long-lived (>100 ps) transient metastable state of Ge2Sb2Te5 with muted interatomic interaction induced by a weakening of resonant bonding. Due to a specific electronic state, the lattice undergoes a reversible nondestructive modification over a nanoscale region, remaining cold for 4 ps. An independent time-resolved x-ray absorption fine structure experiment confirms the existence of an intermediate state with disordered bonds. This newly unveiled effect allows the utilization of non-thermal ultra-fast pathways enabling artificial manipulation of the switching process, ultimately leading to a redefined speed limit, and improved energy efficiency and reliability of phase-change memory technologies.

Sub-nanometre resolution of atomic motion during electronic excitation in phase-change materials

DOE PAGES

Mitrofanov, Kirill V.; Fons, Paul; Makino, Kotaro; ...

2016-02-12

Phase-change materials based on Ge-Sb-Te alloys are widely used in industrial applications such as nonvolatile memories, but reaction pathways for crystalline-to-amorphous phase-change on picosecond timescales remain unknown. Femtosecond laser excitation and an ultrashort x-ray probe is used to show the temporal separation of electronic and thermal effects in a long-lived (>100 ps) transient metastable state of Ge 2Sb 2Te 5 with muted interatomic interaction induced by a weakening of resonant bonding. Due to a specific electronic state, the lattice undergoes a reversible nondestructive modification over a nanoscale region, remaining cold for 4 ps. An independent time-resolved x-ray absorption fine structuremore » experiment confirms the existence of an intermediate state with disordered bonds. Furthermore, this newly unveiled effect allows the utilization of non-thermal ultra-fast pathways enabling artificial manipulation of the switching process, ultimately leading to a redefined speed limit, and improved energy efficiency and reliability of phase-change memory technologies.« less

A Six-Year Predictive Test of Adolescent Family Relationship Quality and Effortful Control Pathways to Emerging Adult Social and Emotional Health

PubMed Central

Fosco, Gregory M.; Caruthers, Allison S.; Dishion, Thomas J.

2012-01-01

This longitudinal study examined how a multimethod (youth report, parent report, direct observation) assessment of family relationship quality (cohesion and conflict) in adolescence (age 16 –17) predicted growth and maintenance of effortful control across ages 17, 22, and 23 years old, and, ultimately, subjective well-being, emotional distress, and aggressive behavior in emerging adulthood (23). A diverse sample of 792 youth at age 17 and their families, and youth at ages 22 and 23, were studied to examine family cohesion and conflict and the growth and maintenance of effortful control as predictors of emerging adult social and emotional health. Results indicated that family cohesion and conflict during late adolescence and mean-level effortful control at age 22 each served as unique pathways to emerging adult adjustment. These findings underscore the importance of family functioning during adolescence and the maintenance of effortful control into emerging adulthood for understanding adjustment during the emerging adulthood period. PMID:22709261

Systems pharmacology, pharmacogenetics, and clinical trial design in network medicine.

PubMed

Antman, Elliott; Weiss, Scott; Loscalzo, Joseph

2012-01-01

The rapidly growing disciplines of systems biology and network science are now poised to meet the fields of clinical medicine and pharmacology. Principles of systems pharmacology can be applied to drug design and, ultimately, testing in human clinical trials. Rather than focusing exclusively on single drug targets, systems pharmacology examines the holistic response of a phenotype-dependent pathway or pathways to drug perturbation. Knowledge of individual pharmacogenetic profiles further modulates the responses to these drug perturbations, moving the field toward more individualized ('personalized') drug development. The speed with which the information required to assess these system responses and their genomic underpinnings is changing and the importance of identifying the optimal drug or drug combinations for maximal benefit and minimal risk require that clinical trial design strategies be adaptable. In this paper, we review the tenets of adaptive clinical trial design as they may apply to an era of expanding knowledge of systems pharmacology and pharmacogenomics, and clinical trail design in network medicine. Copyright © 2012 Wiley Periodicals, Inc.

The regulation of vascular endothelial growth factor-induced microvascular permeability requires Rac and reactive oxygen species.

PubMed

Monaghan-Benson, Elizabeth; Burridge, Keith

2009-09-18

Vascular permeability is a complex process involving the coordinated regulation of multiple signaling pathways in the endothelial cell. It has long been documented that vascular endothelial growth factor (VEGF) greatly enhances microvascular permeability; however, the molecular mechanisms controlling VEGF-induced permeability remain unknown. Treatment of microvascular endothelial cells with VEGF led to an increase in reactive oxygen species (ROS) production. ROS are required for VEGF-induced permeability as treatment with the free radical scavenger, N-acetylcysteine, inhibited this effect. Additionally, treatment with VEGF caused ROS-dependent tyrosine phosphorylation of both vascular-endothelial (VE)-cadherin and beta-catenin. Rac1 was required for the VEGF-induced increase in permeability and adherens junction protein phosphorylation. Knockdown of Rac1 inhibited VEGF-induced ROS production consistent with Rac lying upstream of ROS in this pathway. Collectively, these data suggest that VEGF leads to a Rac-mediated generation of ROS, which, in turn, elevates the tyrosine phosphorylation of VE-cadherin and beta-catenin, ultimately regulating adherens junction integrity.

Trafficking to the apical and basolateral membranes in polarized epithelial cells.

PubMed

Stoops, Emily H; Caplan, Michael J

2014-07-01

Renal epithelial cells must maintain distinct protein compositions in their apical and basolateral membranes in order to perform their transport functions. The creation of these polarized protein distributions depends on sorting signals that designate the trafficking route and site of ultimate functional residence for each protein. Segregation of newly synthesized apical and basolateral proteins into distinct carrier vesicles can occur at the trans-Golgi network, recycling endosomes, or a growing assortment of stations along the cellular trafficking pathway. The nature of the specific sorting signal and the mechanism through which it is interpreted can influence the route a protein takes through the cell. Cell type-specific variations in the targeting motifs of a protein, as are evident for Na,K-ATPase, demonstrate a remarkable capacity to adapt sorting pathways to different developmental states or physiologic requirements. This review summarizes our current understanding of apical and basolateral trafficking routes in polarized epithelial cells. Copyright © 2014 by the American Society of Nephrology.

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

Matz, Dallas L.; Schalnat, Matthew C.; Pemberton, Jeanne E.

The reaction between small organic molecules and low work function metals is of interest in organometallic, astronomical, and optoelectronic device chemistry. Here, thin, solid-state, amorphous benzene and pyridine films are reacted with Ca at 30 K under ultrahigh vacuum with the reaction progress monitored by Raman spectroscopy. Although both films react with Ca to produce product species identifiable by their vibrational spectroscopic signatures, benzene is less reactive with Ca than pyridine. Benzene reacts by electron transfer from Ca to benzene producing multiple species including the phenyl radical anion, the phenyl radical, and the benzyne diradical. Pyridine initially reacts along amore » similar electron transfer pathway as indicated by the presence of the corresponding pyridyl radical and pyridyne diradical species, but these pyridyl radicals are less stable and subject to further ring-opening reactions that lead to a complex array of smaller molecule reaction products and ultimately amorphous carbon. The elucidation of this reaction pathway provides insight into the reactions of aromatics with Ca that are relevant in the areas of catalysis, astrochemistry, and organic optoelectronics.« less

Petri net-based method for the analysis of the dynamics of signal propagation in signaling pathways.

PubMed

Hardy, Simon; Robillard, Pierre N

2008-01-15

Cellular signaling networks are dynamic systems that propagate and process information, and, ultimately, cause phenotypical responses. Understanding the circuitry of the information flow in cells is one of the keys to understanding complex cellular processes. The development of computational quantitative models is a promising avenue for attaining this goal. Not only does the analysis of the simulation data based on the concentration variations of biological compounds yields information about systemic state changes, but it is also very helpful for obtaining information about the dynamics of signal propagation. This article introduces a new method for analyzing the dynamics of signal propagation in signaling pathways using Petri net theory. The method is demonstrated with the Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) regulation network. The results constitute temporal information about signal propagation in the network, a simplified graphical representation of the network and of the signal propagation dynamics and a characterization of some signaling routes as regulation motifs.

Neuronal Calcium Signaling in Metabolic Regulation and Adaptation to Nutrient Stress.

PubMed

Jayakumar, Siddharth; Hasan, Gaiti

2018-01-01

All organisms can respond physiologically and behaviorally to environmental fluxes in nutrient levels. Different nutrient sensing pathways exist for specific metabolites, and their inputs ultimately define appropriate nutrient uptake and metabolic homeostasis. Nutrient sensing mechanisms at the cellular level require pathways such as insulin and target of rapamycin (TOR) signaling that integrates information from different organ systems like the fat body and the gut. Such integration is essential for coordinating growth with development. Here we review the role of a newly identified set of integrative interneurons and the role of intracellular calcium signaling within these neurons, in regulating nutrient sensing under conditions of nutrient stress. A comparison of the identified Drosophila circuit and cellular mechanisms employed in this circuit, with vertebrate systems, suggests that the identified cell signaling mechanisms may be conserved for neural circuit function related to nutrient sensing by central neurons. The ideas proposed are potentially relevant for understanding the molecular basis of metabolic disorders, because these are frequently linked to nutritional stress.

Genome-wide pathway-based association analysis identifies risk pathways associated with Parkinson's disease.

PubMed

Zhang, Mingming; Mu, Hongbo; Shang, Zhenwei; Kang, Kai; Lv, Hongchao; Duan, Lian; Li, Jin; Chen, Xinren; Teng, Yanbo; Jiang, Yongshuai; Zhang, Ruijie

2017-01-06

Parkinson's disease (PD) is the second most common neurodegenerative disease. It is generally believed that it is influenced by both genetic and environmental factors, but the precise pathogenesis of PD is unknown to date. In this study, we performed a pathway analysis based on genome-wide association study (GWAS) to detect risk pathways of PD in three GWAS datasets. We first mapped all SNP markers to autosomal genes in each GWAS dataset. Then, we evaluated gene risk values using the minimum P-value of the tagSNPs. We took a pathway as a unit to identify the risk pathways based on the cumulative risks of the genes in the pathway. Finally, we combine the analysis results of the three datasets to detect the high risk pathways associated with PD. We found there were five same pathways in the three datasets. Besides, we also found there were five pathways which were shared in two datasets. Most of these pathways are associated with nervoussystem. Five pathways had been reported to be PD-related pathways in the previous literature. Our findings also implied that there was a close association between immune response and PD. Continued investigation of these pathways will further help us explain the pathogenesis of PD. Copyright © 2016. Published by Elsevier Ltd.

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

PubMed Central

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

Crosstalk between the IGF-1R/AKT/mTORC1 pathway and the tumor suppressors p53 and p27 determines cisplatin sensitivity and limits the effectiveness of an IGF-1R pathway inhibitor

PubMed Central

Davaadelger, Batzaya; Duan, Lei; Perez, Ricardo E.; Gitelis, Steven; Maki, Carl G.

2016-01-01

The insulin-like growth factor-1 receptor (IGF-1R) signaling pathway is aberrantly activated in multiple cancers and can promote proliferation and chemotherapy resistance. Multiple IGF-1R inhibitors have been developed as potential therapeutics. However, these inhibitors have failed to increase patient survival when given alone or in combination with chemotherapy agents. The reason(s) for the disappointing clinical effect of these inhibitors is not fully understood. Cisplatin (CP) activated the IGF-1R/AKT/mTORC1 pathway and stabilized p53 in osteosarcoma (OS) cells. p53 knockdown reduced IGF-1R/AKT/mTORC1 activation by CP, and IGF-1R inhibition reduced the accumulation of p53. These data demonstrate positive crosstalk between p53 and the IGF-1R/AKT/mTORC1 pathway in response to CP. Further studies showed the effect of IGF-1R inhibition on CP response is dependent on p53 status. In p53 wild-type cells treated with CP, IGF-1R inhibition increased p53s apoptotic function but reduced p53-dependent senescence, and had no effect on long term survival. In contrast, in p53-null/knockdown cells, IGF-1R inhibition reduced apoptosis in response to CP and increased long term survival. These effects were due to p27 since IGF-1R inhibition stabilized p27 in CP-treated cells, and p27 depletion restored apoptosis and reduced long term survival. Together, the results demonstrate 1) p53 expression determines the effect of IGF-1R inhibition on cancer cell CP response, and 2) crosstalk between the IGF-1R/AKT/mTORC1 pathway and p53 and p27 can reduce cancer cell responsiveness to chemotherapy and may ultimately limit the effectiveness of IGF-1R pathway inhibitors in the clinic. PMID:27050276

Identification of Differentially Expressed Genes and Pathways for Myofiber Characteristics in Soleus Muscles between Chicken Breeds Differing in Meat Quality.

PubMed

Du, Y F; Ding, Q L; Li, Y M; Fang, W R

2017-04-03

In the modern chicken industry, fast-growing broilers have undergone strong artificial selection for muscle growth, which has led to remarkable phenotypic variations compared with slow-growing chickens. However, the molecular mechanism underlying these phenotypes differences remains unknown. In this study, a systematic identification of candidate genes and new pathways related to myofiber development and composition in chicken Soleus muscle (SOL) has been made using gene expression profiles of two distinct breeds: Qingyuan partridge (QY), a slow-growing Chinese breed possessing high meat quality and Cobb 500 (CB), a commercial fast-growing broiler line. Agilent cDNA microarray analyses were conducted to determine gene expression profiles of soleus muscle sampled at sexual maturity age of QY (112 d) and CB (42 d). The 1318 genes with at least 2-fold differences were identified (P < 0.05, FDR <0.05, FC ≥ 2) in SOL muscles of QY and CB chickens. Differentially expressed genes (DEGs) related to muscle development, energy metabolism or lipid metabolism processes were examined further in each breed based on Gene Ontology (GO) analysis, and 11 genes involved in these processes were selected for further validation studies by qRT-PCR. In addition, based on KEGG pathway analysis of DEGs in both QY and CB chickens, it was found that in addition to pathways affecting myogenic fibre-type development and differentiation (pathways for Hedgehog & Calcium signaling), energy metabolism (Phosphatidylinositol signaling system, VEGF signaling pathway, Purine metabolism, Pyrimidine metabolism) were also enriched and might form a network with pathways related to muscle metabolism to influence the development of myofibers. This study is the first stage in the understanding of molecular mechanisms underlying variations in poultry meat quality. Large scale analyses are now required to validate the role of the genes identified and ultimately to find molecular markers that can be used for selection or to optimize rearing practices.

Development of seismic fragility curves for low-rise masonry infilled reinforced concrete buildings by a coefficient-based method

NASA Astrophysics Data System (ADS)

Su, Ray Kai Leung; Lee, Chien-Liang

2013-06-01

This study presents a seismic fragility analysis and ultimate spectral displacement assessment of regular low-rise masonry infilled (MI) reinforced concrete (RC) buildings using a coefficient-based method. The coefficient-based method does not require a complicated finite element analysis; instead, it is a simplified procedure for assessing the spectral acceleration and displacement of buildings subjected to earthquakes. A regression analysis was first performed to obtain the best-fitting equations for the inter-story drift ratio (IDR) and period shift factor of low-rise MI RC buildings in response to the peak ground acceleration of earthquakes using published results obtained from shaking table tests. Both spectral acceleration- and spectral displacement-based fragility curves under various damage states (in terms of IDR) were then constructed using the coefficient-based method. Finally, the spectral displacements of low-rise MI RC buildings at the ultimate (or nearcollapse) state obtained from this paper and the literature were compared. The simulation results indicate that the fragility curves obtained from this study and other previous work correspond well. Furthermore, most of the spectral displacements of low-rise MI RC buildings at the ultimate state from the literature fall within the bounded spectral displacements predicted by the coefficient-based method.

The Hippo Pathway: Immunity and Cancer

PubMed Central

J. Janse van Rensburg, Helena

2018-01-01

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. PMID:29597279

General Aspects of Colorectal Cancer

PubMed Central

Centelles, Josep J.

2012-01-01

Colorectal cancer (CRC) is one of the main causes of death. Cancer is initiated by several DNA damages, affecting proto-oncogenes, tumour suppressor genes, and DNA repairing genes. The molecular origins of CRC are chromosome instability (CIN), microsatellite instability (MSI), and CpG island methylator phenotype (CIMP). A brief description of types of CRC cancer is presented, including sporadic CRC, hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndromes, familiar adenomatous polyposis (FAP), MYH-associated polyposis (MAP), Peutz-Jeghers syndrome (PJS), and juvenile polyposis syndrome (JPS). Some signalling systems for CRC are also described, including Wnt-β-catenin pathway, tyrosine kinase receptors pathway, TGF-β pathway, and Hedgehog pathway. Finally, this paper describes also some CRC treatments. PMID:23209942

Wnt and lithium: a common destiny in the therapy of nervous system pathologies?

PubMed

Meffre, Delphine; Grenier, Julien; Bernard, Sophie; Courtin, Françoise; Dudev, Todor; Shackleford, Ghjuvan'Ghjacumu; Jafarian-Tehrani, Mehrnaz; Massaad, Charbel

2014-04-01

Wnt signaling is required for neurogenesis, the fate of neural progenitors, the formation of neuronal circuits during development, neuron positioning and polarization, axon and dendrite development and finally for synaptogenesis. This signaling pathway is also implicated in the generation and differentiation of glial cells. In this review, we describe the mechanisms of action of Wnt signaling pathways and their implication in the development and correct functioning of the nervous system. We also illustrate how a dysregulated Wnt pathway could lead to psychiatric, neurodegenerative and demyelinating pathologies. Lithium, used for the treatment of bipolar disease, inhibits GSK3β, a central enzyme of the Wnt/β-catenin pathway. Thus, lithium could, to some extent, mimic Wnt pathway. We highlight the possible dialogue between lithium therapy and modulation of Wnt pathway in the treatment of the diseases of the nervous system.

Emerging functions of the Fanconi anemia pathway at a glance.

PubMed

Sumpter, Rhea; Levine, Beth

2017-08-15

Fanconi anemia (FA) is a rare disease, in which homozygous or compound heterozygous inactivating mutations in any of 21 genes lead to genomic instability, early-onset bone marrow failure and increased cancer risk. The FA pathway is essential for DNA damage response (DDR) to DNA interstrand crosslinks. However, proteins of the FA pathway have additional cytoprotective functions that may be independent of DDR. We have shown that many FA proteins participate in the selective autophagy pathway that is required for the destruction of unwanted intracellular constituents. In this Cell Science at a Glance and the accompanying poster, we briefly review the role of the FA pathway in DDR and recent findings that link proteins of the FA pathway to selective autophagy of viruses and mitochondria. Finally, we discuss how perturbations in FA protein-mediated selective autophagy may contribute to inflammatory as well as genotoxic stress. © 2017. Published by The Company of Biologists Ltd.

Pathways for virus assembly around nucleic acids

PubMed Central

Perlmutter, Jason D; Perkett, Matthew R

2014-01-01

Understanding the pathways by which viral capsid proteins assemble around their genomes could identify key intermediates as potential drug targets. In this work we use computer simulations to characterize assembly over a wide range of capsid protein-protein interaction strengths and solution ionic strengths. We find that assembly pathways can be categorized into two classes, in which intermediates are either predominantly ordered or disordered. Our results suggest that estimating the protein-protein and the protein-genome binding affinities may be sufficient to predict which pathway occurs. Furthermore, the calculated phase diagrams suggest that knowledge of the dominant assembly pathway and its relationship to control parameters could identify optimal strategies to thwart or redirect assembly to block infection. Finally, analysis of simulation trajectories suggests that the two classes of assembly pathways can be distinguished in single molecule fluorescence correlation spectroscopy or bulk time resolved small angle x-ray scattering experiments. PMID:25036288

Implementing best practice in hospital multidisciplinary nutritional care: an example of using the knowledge-to-action process for a research program.

PubMed

Laur, Celia; Keller, Heather H

2015-01-01

Prospective use of knowledge translation and implementation science frameworks can increase the likelihood of meaningful improvements in health care practices. An example of this creation and application of knowledge is the series of studies conducted by and with the Canadian Malnutrition Task Force (CMTF). Following a cohort study and synthesis of evidence regarding best practice for identification, treatment, and prevention of malnutrition in hospitals, CMTF created an evidence-informed, consensus-based pathway for nutritional care in hospitals. The purpose of this paper is to detail the steps taken in this research program, through four studies, as an example of the knowledge-to-action (KTA) process. The KTA process includes knowledge creation and action cycles. The steps of the action cycle within this program of research are iterative, and up to this point have been informed by three studies, with a fourth underway. The first study identified the magnitude of the malnutrition problem upon admission to hospital and how it is undetected and undertreated (study 1). Knowledge creation resulted in an evidence-based pathway established to address care gaps (study 2) and the development of monitoring tools (study 3). The study was then adapted to local context: focus groups validated face validate the evidence-based pathway; during the final phase, study site implementation teams will continue to adapt the pathway (studies 2 and 4). Barriers to implementation were also assessed; focus groups and interviews were conducted to inform the pathway implementation (studies 1, 2, and 4). In the next step, specific interventions were selected, tailored, and implemented. In the final study in this research program, plan-do-study-act cycles will be used to make changes and to implement the pathway (study 4). To monitor knowledge use and to evaluate outcomes, audits, staff surveys, patient outcomes, etc will be used to record process evaluations (studies 3 and 4). Finally, a sustainability plan will be incorporated into the final study of the program (study 4) to sustain knowledge use. Use of frameworks can increase the likelihood of meaningful and sustainable improvements in health care practice. The example of this program of research demonstrates how existing evidence has been used to identify, create, and adapt knowledge, and how multidisciplinary teams have been used to effect changes in the hospital setting. Effective implementation is essential in nutritional health care, and this multidisciplinary program of research provides an example of how the KTA process can facilitate implementation and promote sustainability.

The plasticity of descending controls in pain: translational probing.

PubMed

Bannister, Kirsty; Dickenson, A H

2017-07-01

Descending controls, comprising pathways that originate in midbrain and brainstem regions and project onto the spinal cord, have long been recognised as key links in the multiple neural networks that interact to produce the overall pain experience. There is clear evidence from preclinical and clinical studies that both peripheral and central sensitisation play important roles in determining the level of pain perceived. Much emphasis has been put on spinal cord mechanisms in central excitability, but it is now becoming clear that spinal hyperexcitability can be regulated by descending pathways from the brain that originate from predominantly noradrenergic and serotonergic systems. One pain can inhibit another. In this respect diffuse noxious inhibitory controls (DNIC) are a unique form of endogenous descending inhibitory pathway since they can be easily evoked and quantified in animals and man. The spinal pharmacology of pathways that subserve DNIC are complicated; in the normal situation these descending controls produce a final inhibitory effect through the actions of noradrenaline at spinal α 2 -adrenoceptors, although serotonin, acting on facilitatory spinal 5-HT 3 receptors, influences the final expression of DNIC also. These descending pathways are altered in neuropathy and the effects of excess serotonin may now become inhibitory through activation of spinal 5-HT 7 receptors. Conditioned pain modulation (CPM) is the human counterpart of DNIC and requires a descending control also. Back and forward translational studies between DNIC and CPM, gauged between bench and bedside, are key for the development of analgesic therapies that exploit descending noradrenergic and serotonergic control pathways. © 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.

Pathways to Practice. A Series of Final Reports on the SREB Nursing Curriculum Project.

ERIC Educational Resources Information Center

Haase, Patricia T.

Five final reports on the Nursing Curriculum Project of the Southern Regional Education Board are presented. The reports include (1) RN (Registered Nursing) Education: The Basic Issues; (2) Types of RN Programs; (3) Planning and Operating an RN Program; (4) Acclimating the Novice Nurse: Whose Responsibility? and (5) Statewide Planning for Nursing.…

Human Factors in the 21st Century(Les facteurs humains au 21th siecle)

DTIC Science & Technology

2002-05-01

abstract thinking so as to become a systems supervisor and ultimately, a systems manager. • Finally, we must not lose sight of the fact that the...information at the right level of abstraction may become the dominant theme. Human factors specialists with a strong background in cognition and deep...of the underlying system and then helping pilots acquire an accurate cognitive model of the system during training. Instruction about cockpit

Lieutenant General Pete Quesada and Generalfeldmarschall Wolfram Von Richthofen: What Made Them Great

DTIC Science & Technology

2009-06-01

targets as oil was always in short supply. By “destroying his air force, and disrupting his supply lines,” NACAF would prevent the Nazis from evacuating...to NACAF.106 After a long, arduous, yet ultimately successful struggle to dislodge the Nazis from Tunisia, the Allies finally began making their...supremacy camouflage is second in importance to performance.” They stopped painting everything except the insignia and tail numbers.149 Although not

Stromagenesis: the changing face of fibroblastic microenvironments during tumor progression.

PubMed

Beacham, Dorothy A; Cukierman, Edna

2005-10-01

During tumorigenesis, reciprocal changes in stromal fibroblasts and tumor cells induce changes to the neoplastic microenvironmental landscape. In stromagenesis, both the complex network of bi-directional stromal fibroblastic signaling pathways and the stromal extracellular matrix are modified. The presence of a 'primed' stroma during the early, reversible stage of tumorigenesis is optimal for stromal-directed therapeutic intervention. Three-dimensional (3D) cell culture systems have been developed that mimic the in vivo microenvironment. These systems provide unique experimental tools to identify early alterations in stromagenesis that are supportive of tumor progression with the ultimate goal of blocking neoplastic permissiveness and restoring normal phenotypes.

Integrated network analysis and effective tools in plant systems biology

PubMed Central

Fukushima, Atsushi; Kanaya, Shigehiko; Nishida, Kozo

2014-01-01

One of the ultimate goals in plant systems biology is to elucidate the genotype-phenotype relationship in plant cellular systems. Integrated network analysis that combines omics data with mathematical models has received particular attention. Here we focus on the latest cutting-edge computational advances that facilitate their combination. We highlight (1) network visualization tools, (2) pathway analyses, (3) genome-scale metabolic reconstruction, and (4) the integration of high-throughput experimental data and mathematical models. Multi-omics data that contain the genome, transcriptome, proteome, and metabolome and mathematical models are expected to integrate and expand our knowledge of complex plant metabolisms. PMID:25408696

Cancer heterogeneity: origins and implications for genetic association studies

PubMed Central

Urbach, Davnah; Lupien, Mathieu; Karagas, Margaret R.; Moore, Jason H.

2012-01-01

Genetic association studies have become standard approaches to characterize the genetic and epigenetic variability associated with cancer development, including predispositions and mutations. However, the bewildering genetic and phenotypic heterogeneity inherent in cancer both magnifies the conceptual and methodological problems associated with these approaches and renders the translation of available genetic information into a knowledge that is both biologically sound and clinically relevant difficult. Here, we elaborate on the underlying causes of this complexity, illustrate why it represents a challenge for genetic association studies, and briefly discuss how it can be reconciled with the ultimate goal of identifying targetable disease pathways and successfully treating individual patients. PMID:22858414

The Original Social Network: White Matter and Social Cognition.

PubMed

Wang, Yin; Olson, Ingrid R

2018-06-01

Social neuroscience has traditionally focused on the functionality of gray matter regions, ignoring the critical role played by axonal fiber pathways in supporting complex social processes. In this paper, we argue that research on white matter is essential for understanding a range of topics in social neuroscience, such as face processing, theory of mind, empathy, and imitation, as well as clinical disorders defined by aberrant social behavior, such as prosopagnosia, autism, and schizophrenia. We provide practical advice on how best to carry out these studies, which ultimately will substantially deepen our understanding of the neurobiological basis of social behavior. Copyright © 2018 Elsevier Ltd. All rights reserved.

Developing a pro-regenerative biomaterial scaffold microenvironment requires T helper 2 cells.

PubMed

Sadtler, Kaitlyn; Estrellas, Kenneth; Allen, Brian W; Wolf, Matthew T; Fan, Hongni; Tam, Ada J; Patel, Chirag H; Luber, Brandon S; Wang, Hao; Wagner, Kathryn R; Powell, Jonathan D; Housseau, Franck; Pardoll, Drew M; Elisseeff, Jennifer H

2016-04-15

Immune-mediated tissue regeneration driven by a biomaterial scaffold is emerging as an innovative regenerative strategy to repair damaged tissues. We investigated how biomaterial scaffolds shape the immune microenvironment in traumatic muscle wounds to improve tissue regeneration. The scaffolds induced a pro-regenerative response, characterized by an mTOR/Rictor-dependent T helper 2 pathway that guides interleukin-4-dependent macrophage polarization, which is critical for functional muscle recovery. Manipulating the adaptive immune system using biomaterials engineering may support the development of therapies that promote both systemic and local pro-regenerative immune responses, ultimately stimulating tissue repair. Copyright © 2016, American Association for the Advancement of Science.

Developing a pro-regenerative biomaterial scaffold microenvironment requires T helper 2 cells

PubMed Central

Sadtler, Kaitlyn; Estrellas, Kenneth; Allen, Brian W.; Wolf, Matthew T.; Fan, Hongni; Tam, Ada J.; Patel, Chirag H.; Luber, Brandon S.; Wang, Hao; Wagner, Kathryn R.; Powell, Jonathan D.; Housseau, Franck; Pardoll, Drew M.

2016-01-01

Immune-mediated tissue regeneration driven by a biomaterial scaffold is emerging as an innovative regenerative strategy to repair damaged tissues. We investigated how biomaterial scaffolds shape the immune microenvironment in traumatic muscle wounds to improve tissue regeneration. The scaffolds induced a pro-regenerative response, characterized by an mTOR/Rictor-dependent T helper 2 pathway that guides interleukin-4–dependent macrophage polarization, which is critical for functional muscle recovery. Manipulating the adaptive immune system using biomaterials engineering may support the development of therapies that promote both systemic and local pro-regenerative immune responses, ultimately stimulating tissue repair. PMID:27081073

Complete Obstruction of Endotracheal Tube in an Infant with a Retropharyngeal and Anterior Mediastinal Abscess.

PubMed

Thapa, Dennis B; Greene, Nathaniel H; Udani, Andrea G

2017-01-01

Intraoperative ventilatory failure is not an uncommon complication; however, acute endotracheal obstruction by a foreign body or blood clot can be difficult to quickly discriminate from other causes. Once the diagnosis is made, quick action is needed to restore ventilation. The ultimate solution is to exchange the endotracheal tube; however, there can be other ways of resolving this in situations where reintubation would be difficult or unsafe. This case report discusses such an event in an infant with multiple airway challenges including a retropharyngeal and anterior mediastinal abscess. We have also formulated a pathway based on various case reports involving complete ETT obstruction.

Epigenetics and Developmental Plasticity Across Species

PubMed Central

Champagne, Frances A.

2012-01-01

Plasticity is a typical feature of development and can lead to divergent phenotypes. There is increasing evidence that epigenetic mechanisms, such as DNA methylation, are present across species, are modifiable by the environment, and are involved in developmental plasticity. Thus, in the context of the concept of developmental homology, epigenetic mechanisms may serve to create a process homology between species by providing a common molecular pathway through which environmental experiences shape development, ultimately leading to phenotypic diversity. This article will highlight evidence derived from across-species investigations of epigenetics, development, and plasticity which may contribute to our understanding of the homology that exists between species and between ancestors and descendants. PMID:22711291

Evidence that biosynthesis of the second and third sugars of the archaellin Tetrasaccharide in the archaeon Methanococcus maripaludis occurs by the same pathway used by Pseudomonas aeruginosa to make a di-N-acetylated sugar.

PubMed

Siu, Sarah; Robotham, Anna; Logan, Susan M; Kelly, John F; Uchida, Kaoru; Aizawa, Shin-Ichi; Jarrell, Ken F

2015-05-01

Methanococcus maripaludis has two surface appendages, archaella and type IV pili, which are composed of glycoprotein subunits. Archaellins are modified with an N-linked tetrasaccharide with the structure Sug-1,4-β-ManNAc3NAmA6Thr-1,4-β-GlcNAc3NAcA-1,3-β-GalNAc, where Sug is (5S)-2-acetamido-2,4-dideoxy-5-O-methyl-α-L-erythro-hexos-5-ulo-1,5-pyranose. The pilin glycan has an additional hexose attached to GalNAc. In this study, genes located in two adjacent, divergently transcribed operons (mmp0350-mmp0354 and mmp0359-mmp0355) were targeted for study based on annotations suggesting their involvement in biosynthesis of N-glycan sugars. Mutants carrying deletions in mmp0350, mmp0351, mmp0352, or mmp0353 were nonarchaellated and synthesized archaellins modified with a 1-sugar glycan, as estimated from Western blots. Mass spectroscopy analysis of pili purified from the Δmmp0352 strain confirmed a glycan with only GalNAc, suggesting mmp0350 to mmp0353 were all involved in biosynthesis of the second sugar (GlcNAc3NAcA). The Δmmp0357 mutant was archaellated and had archaellins with a 2-sugar glycan, as confirmed by mass spectroscopy of purified archaella, indicating a role for MMP0357 in biosynthesis of the third sugar (ManNAc3NAmA6Thr). M. maripaludis mmp0350, mmp0351, mmp0352, mmp0353, and mmp0357 are proposed to be functionally equivalent to Pseudomonas aeruginosa wbpABEDI, involved in converting UDP-N-acetylglucosamine to UDP-2,3-diacetamido-2,3-dideoxy-d-mannuronic acid, an O5-specific antigen sugar. Cross-domain complementation of the final step of the P. aeruginosa pathway with mmp0357 supports this hypothesis. This work identifies a series of genes in adjacent operons that are shown to encode the enzymes that complete the entire pathway for generation of the second and third sugars of the N-linked tetrasaccharide that modifies archaellins of Methanococcus maripaludis. This posttranslational modification of archaellins is important, as it is necessary for archaellum assembly. Pilins are modified with a different N-glycan consisting of the archaellin tetrasaccharide but with an additional hexose attached to the linking sugar. Mass spectrometry analysis of the pili of one mutant strain provided insight into how this different glycan might ultimately be assembled. This study includes a rare example of an archaeal gene functionally replacing a bacterial gene in a complex sugar biosynthesis pathway. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Evidence that Biosynthesis of the Second and Third Sugars of the Archaellin Tetrasaccharide in the Archaeon Methanococcus maripaludis Occurs by the Same Pathway Used by Pseudomonas aeruginosa To Make a Di-N-Acetylated Sugar

PubMed Central

Siu, Sarah; Robotham, Anna; Logan, Susan M.; Kelly, John F.; Uchida, Kaoru; Aizawa, Shin-Ichi

2015-01-01

ABSTRACT Methanococcus maripaludis has two surface appendages, archaella and type IV pili, which are composed of glycoprotein subunits. Archaellins are modified with an N-linked tetrasaccharide with the structure Sug-1,4-β-ManNAc3NAmA6Thr-1,4-β-GlcNAc3NAcA-1,3-β-GalNAc, where Sug is (5S)-2-acetamido-2,4-dideoxy-5-O-methyl-α-l-erythro-hexos-5-ulo-1,5-pyranose. The pilin glycan has an additional hexose attached to GalNAc. In this study, genes located in two adjacent, divergently transcribed operons (mmp0350-mmp0354 and mmp0359-mmp0355) were targeted for study based on annotations suggesting their involvement in biosynthesis of N-glycan sugars. Mutants carrying deletions in mmp0350, mmp0351, mmp0352, or mmp0353 were nonarchaellated and synthesized archaellins modified with a 1-sugar glycan, as estimated from Western blots. Mass spectroscopy analysis of pili purified from the Δmmp0352 strain confirmed a glycan with only GalNAc, suggesting mmp0350 to mmp0353 were all involved in biosynthesis of the second sugar (GlcNAc3NAcA). The Δmmp0357 mutant was archaellated and had archaellins with a 2-sugar glycan, as confirmed by mass spectroscopy of purified archaella, indicating a role for MMP0357 in biosynthesis of the third sugar (ManNAc3NAmA6Thr). M. maripaludis mmp0350, mmp0351, mmp0352, mmp0353, and mmp0357 are proposed to be functionally equivalent to Pseudomonas aeruginosa wbpABEDI, involved in converting UDP-N-acetylglucosamine to UDP-2,3-diacetamido-2,3-dideoxy-d-mannuronic acid, an O5-specific antigen sugar. Cross-domain complementation of the final step of the P. aeruginosa pathway with mmp0357 supports this hypothesis. IMPORTANCE This work identifies a series of genes in adjacent operons that are shown to encode the enzymes that complete the entire pathway for generation of the second and third sugars of the N-linked tetrasaccharide that modifies archaellins of Methanococcus maripaludis. This posttranslational modification of archaellins is important, as it is necessary for archaellum assembly. Pilins are modified with a different N-glycan consisting of the archaellin tetrasaccharide but with an additional hexose attached to the linking sugar. Mass spectrometry analysis of the pili of one mutant strain provided insight into how this different glycan might ultimately be assembled. This study includes a rare example of an archaeal gene functionally replacing a bacterial gene in a complex sugar biosynthesis pathway. PMID:25733616

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

Hurlbut, D. J.; Haase, S.; Brinkman, G.

Pursuant to the Clean Air Act, the U.S. Environmental Protection Agency (EPA) announced in 2009 its intent to issue rules for controlling emissions from Navajo Generating Station that could affect visibility at the Grand Canyon and at several other national parks and wilderness areas. The final rule will conform to what EPA determines is the best available retrofit technology (BART) for the control of haze-causing air pollutants, especially nitrogen oxides. While EPA is ultimately responsible for setting Navajo Generating Station's BART standards in its final rule, it will be the U.S. Department of the Interior's responsibility to manage compliance andmore » the related impacts. This study aims to assist both Interior and EPA by providing an objective assessment of issues relating to the power sector.« less

Representing Something Out of Nothing: The Dawning of Zero.

PubMed

Nieder, Andreas

2016-11-01

Zero stands for emptiness, for nothing, and yet it is considered to be one of the greatest achievements of humankind. This review first recapitulates the discovery of the number zero in human history, then follows its progression in human development, traces its evolution in the animal kingdom, and finally elucidates how the brain transforms 'nothing' into an abstract zero category. It is argued that the emergence of zero passes through four corresponding representations in all of these interrelated realms: first, sensory 'nothing'; then categorical 'something'; then quantitative empty sets; and finally the number zero. The concept of zero shows how the brain, originally evolved to represent stimuli ('something'), detaches from empirical properties to achieve ultimate abstract thinking. Copyright © 2016 Elsevier Ltd. All rights reserved.

The genetic makeup of the Drosophila piRNA pathway.

PubMed

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.

Regulation of the Hippo-YAP Pathway by Glucose Sensor O-GlcNAcylation.

PubMed

Peng, Changmin; Zhu, Yue; Zhang, Wanjun; Liao, Qinchao; Chen, Yali; Zhao, Xinyuan; Guo, Qiang; Shen, Pan; Zhen, Bei; Qian, Xiaohong; Yang, Dong; Zhang, Jin-San; Xiao, Dongguang; Qin, Weijie; Pei, Huadong

2017-11-02

The Hippo pathway is crucial in organ size control and tissue homeostasis, with deregulation leading to cancer. An extracellular nutrition signal, such as glucose, regulates the Hippo pathway activation. However, the mechanisms are still not clear. Here, we found that the Hippo pathway is directly regulated by the hexosamine biosynthesis pathway (HBP) in response to metabolic nutrients. Mechanistically, the core component of Hippo pathway (YAP) is O-GlcNAcylated by O-GlcNAc transferase (OGT) at serine 109. YAP O-GlcNAcylation disrupts its interaction with upstream kinase LATS1, prevents its phosphorylation, and activates its transcriptional activity. And this activation is not dependent on AMPK. We also identified OGT as a YAP-regulated gene that forms a feedback loop. Finally, we confirmed that glucose-induced YAP O-GlcNAcylation and activation promoted tumorigenesis. Together, our data establish a molecular mechanism and functional significance of the HBP in directly linking extracellular glucose signal to the Hippo-YAP pathway and tumorigenesis. Copyright © 2017 Elsevier Inc. All rights reserved.

Genome-wide characterization of differentially expressed genes provides insights into regulatory network of heat stress response in radish (Raphanus sativus L.).

PubMed

Wang, Ronghua; Mei, Yi; Xu, Liang; Zhu, Xianwen; Wang, Yan; Guo, Jun; Liu, Liwang

2018-03-01

Heat stress (HS) causes detrimental effects on plant morphology, physiology, and biochemistry that lead to drastic reduction in plant biomass production and economic yield worldwide. To date, little is known about HS-responsive genes involved in thermotolerance mechanism in radish. In this study, a total of 6600 differentially expressed genes (DEGs) from the control and Heat24 cDNA libraries of radish were isolated by high-throughput sequencing. With Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, some genes including MAPK, DREB, ERF, AP2, GST, Hsf, and Hsp were predominantly assigned in signal transductions, metabolic pathways, and biosynthesis and abiotic stress-responsive pathways. These pathways played significant roles in reducing stress-induced damages and enhancing heat tolerance in radish. Expression patterns of 24 candidate genes were validated by reverse-transcription quantitative PCR (RT-qPCR). Based mainly on the analysis of DEGs combining with the previous miRNAs analysis, the schematic model of HS-responsive regulatory network was proposed. To counter the effects of HS, a rapid response of the plasma membrane leads to the opening of specific calcium channels and cytoskeletal reorganization, after which HS-responsive genes are activated to repair damaged proteins and ultimately facilitate further enhancement of thermotolerance in radish. These results could provide fundamental insight into the regulatory network underlying heat tolerance in radish and facilitate further genetic manipulation of thermotolerance in root vegetable crops.

Influenza virus induces apoptosis via BAD-mediated mitochondrial dysregulation.

PubMed

Tran, Anh T; Cortens, John P; Du, Qiujiang; Wilkins, John A; Coombs, Kevin M

2013-01-01

Influenza virus infection results in host cell death and major tissue damage. Specific components of the apoptotic pathway, a signaling cascade that ultimately leads to cell death, are implicated in promoting influenza virus replication. BAD is a cell death regulator that constitutes a critical control point in the intrinsic apoptosis pathway, which occurs through the dysregulation of mitochondrial outer membrane permeabilization and the subsequent activation of downstream apoptogenic factors. Here we report a novel proviral role for the proapoptotic protein BAD in influenza virus replication. We show that influenza virus-induced cytopathology and cell death are considerably inhibited in BAD knockdown cells and that both virus replication and viral protein production are dramatically reduced, which suggests that virus-induced apoptosis is BAD dependent. Our data showed that influenza viruses induced phosphorylation of BAD at residues S112 and S136 in a temporal manner. Viral infection also induced BAD cleavage, late in the viral life cycle, to a truncated form that is reportedly a more potent inducer of apoptosis. We further demonstrate that knockdown of BAD resulted in reduced cytochrome c release and suppression of the intrinsic apoptotic pathway during influenza virus replication, as seen by an inhibition of caspases-3, caspase-7, and procyclic acidic repetitive protein (PARP) cleavage. Our data indicate that influenza viruses carefully modulate the activation of the apoptotic pathway that is dependent on the regulatory function of BAD and that failure of apoptosis activation resulted in unproductive viral replication.

Identification of novel resistance mechanisms to NAMPT inhibition via the de novo NAD+ biosynthesis pathway and NAMPT mutation.

PubMed

Guo, Jun; Lam, Lloyd T; Longenecker, Kenton L; Bui, Mai H; Idler, Kenneth B; Glaser, Keith B; Wilsbacher, Julie L; Tse, Chris; Pappano, William N; Huang, Tzu-Hsuan

2017-09-23

Cancer cells have an unusually high requirement for the central and intermediary metabolite nicotinamide adenine dinucleotide (NAD + ), and NAD + depletion ultimately results in cell death. The rate limiting step within the NAD + salvage pathway required for converting nicotinamide to NAD + is catalyzed by nicotinamide phosphoribosyltransferase (NAMPT). Targeting NAMPT has been investigated as an anti-cancer strategy, and several highly selective small molecule inhibitors have been found to potently inhibit NAMPT in cancer cells, resulting in NAD + depletion and cytotoxicity. To identify mechanisms that could cause resistance to NAMPT inhibitor treatment, we generated a human fibrosarcoma cell line refractory to the highly potent and selective NAMPT small molecule inhibitor, GMX1778. We uncovered novel and unexpected mechanisms of resistance including significantly increased expression of quinolinate phosphoribosyl transferase (QPRT), a key enzyme in the de novo NAD + synthesis pathway. Additionally, exome sequencing of the NAMPT gene in the resistant cells identified a single heterozygous point mutation that was not present in the parental cell line. The combination of upregulation of the NAD + de novo synthesis pathway through QPRT over-expression and NAMPT mutation confers resistance to GMX1778, but the cells are only partially resistant to next-generation NAMPT inhibitors. The resistance mechanisms uncovered herein provide a potential avenue to continue exploration of next generation NAMPT inhibitors to treat neoplasms in the clinic. Copyright © 2017 Elsevier Inc. All rights reserved.

Influenza Virus Induces Apoptosis via BAD-Mediated Mitochondrial Dysregulation

PubMed Central

Tran, Anh T.; Cortens, John P.; Du, Qiujiang; Wilkins, John A.

2013-01-01

Influenza virus infection results in host cell death and major tissue damage. Specific components of the apoptotic pathway, a signaling cascade that ultimately leads to cell death, are implicated in promoting influenza virus replication. BAD is a cell death regulator that constitutes a critical control point in the intrinsic apoptosis pathway, which occurs through the dysregulation of mitochondrial outer membrane permeabilization and the subsequent activation of downstream apoptogenic factors. Here we report a novel proviral role for the proapoptotic protein BAD in influenza virus replication. We show that influenza virus-induced cytopathology and cell death are considerably inhibited in BAD knockdown cells and that both virus replication and viral protein production are dramatically reduced, which suggests that virus-induced apoptosis is BAD dependent. Our data showed that influenza viruses induced phosphorylation of BAD at residues S112 and S136 in a temporal manner. Viral infection also induced BAD cleavage, late in the viral life cycle, to a truncated form that is reportedly a more potent inducer of apoptosis. We further demonstrate that knockdown of BAD resulted in reduced cytochrome c release and suppression of the intrinsic apoptotic pathway during influenza virus replication, as seen by an inhibition of caspases-3, caspase-7, and procyclic acidic repetitive protein (PARP) cleavage. Our data indicate that influenza viruses carefully modulate the activation of the apoptotic pathway that is dependent on the regulatory function of BAD and that failure of apoptosis activation resulted in unproductive viral replication. PMID:23135712

Human T-lymphotropic virus proteins and post-translational modification pathways

PubMed Central

Bidoia, Carlo

2012-01-01

Cell life from the cell cycle to the signaling transduction and response to stimuli is finely tuned by protein post-translational modifications (PTMs). PTMs alter the conformation, the stability, the localization, and hence the pattern of interactions of the targeted protein. Cell pathways involve the activation of enzymes, like kinases, ligases and transferases, that, once activated, act on many proteins simultaneously, altering the state of the cell and triggering the processes they are involved in. Viruses enter a balanced system and hijack the cell, exploiting the potential of PTMs either to activate viral encoded proteins or to alter cellular pathways, with the ultimate consequence to perpetuate through their replication. Human T-lymphotropic virus type 1 (HTLV-1) is known to be highly oncogenic and associates with adult T-cell leukemia/lymphoma, HTLV-1-associated myelopathy/tropical spastic paraparesis and other inflammatory pathological conditions. HTLV-1 protein activity is controlled by PTMs and, in turn, viral activity is associated with the modulation of cellular pathways based on PTMs. More knowledge is acquired about the PTMs involved in the activation of its proteins, like Tax, Rex, p12, p13, p30, HTLV-I basic leucine zipper factor and Gag. However, more has to be understood at the biochemical level in order to counteract the associated fatal outcomes. This review will focus on known PTMs that directly modify HTLV-1 components and on enzymes whose activity is modulated by viral proteins. PMID:24175216

Stress transgenerationally programs metabolic pathways linked to altered mental health.

PubMed

Kiss, Douglas; Ambeskovic, Mirela; Montina, Tony; Metz, Gerlinde A S

2016-12-01

Stress is among the primary causes of mental health disorders, which are the most common reason for disability worldwide. The ubiquity of these disorders, and the costs associated with them, lends a sense of urgency to the efforts to improve prediction and prevention. Down-stream metabolic changes are highly feasible and accessible indicators of pathophysiological processes underlying mental health disorders. Here, we show that remote and cumulative ancestral stress programs central metabolic pathways linked to mental health disorders. The studies used a rat model consisting of a multigenerational stress lineage (the great-great-grandmother and each subsequent generation experienced stress during pregnancy) and a transgenerational stress lineage (only the great-great-grandmother was stressed during pregnancy). Urine samples were collected from adult male F4 offspring and analyzed using 1 H NMR spectroscopy. The results of variable importance analysis based on random variable combination were used for unsupervised multivariate principal component analysis and hierarchical clustering analysis, as well as metabolite set enrichment analysis (MSEA) and pathway analysis. We identified distinct metabolic profiles associated with the multigenerational and transgenerational stress phenotype, with consistent upregulation of hippurate and downregulation of tyrosine, threonine, and histamine. MSEA and pathway analysis showed that these metabolites are involved in catecholamine biosynthesis, immune responses, and microbial host interactions. The identification of metabolic signatures linked to ancestral programming assists in the discovery of gene targets for future studies of epigenetic regulation in pathogenic processes. Ultimately, this research can lead to biomarker discovery for better prediction and prevention of mental health disorders.

Putative adverse outcome pathways relevant to neurotoxicity

PubMed Central

Bal-Price, Anna; Crofton, Kevin M.; Sachana, Magdalini; Shafer, Timothy J.; Behl, Mamta; Forsby, Anna; Hargreaves, Alan; Landesmann, Brigitte; Lein, Pamela J.; Louisse, Jochem; Monnet-Tschudi, Florianne; Paini, Alicia; Rolaki, Alexandra; Schrattenholz, André; Suñol, Cristina; van Thriel, Christoph; Whelan, Maurice; Fritsche, Ellen

2016-01-01

The Adverse Outcome Pathway (AOP) framework provides a template that facilitates understanding of complex biological systems and the pathways of toxicity that result in adverse outcomes (AOs). The AOP starts with an molecular initiating event (MIE) in which a chemical interacts with a biological target(s), followed by a sequential series of KEs, which are cellular, anatomical, and/or functional changes in biological processes, that ultimately result in an AO manifest in individual organisms and populations. It has been developed as a tool for a knowledge-based safety assessment that relies on understanding mechanisms of toxicity, rather than simply observing its adverse outcome. A large number of cellular and molecular processes are known to be crucial to proper development and function of the central (CNS) and peripheral nervous systems (PNS). However, there are relatively few examples of well-documented pathways that include causally linked MIEs and KEs that result in adverse outcomes in the CNS or PNS. As a first step in applying the AOP framework to adverse health outcomes associated with exposure to exogenous neurotoxic substances, the EU Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM) organized a workshop (March 2013, Ispra, Italy) to identify potential AOPs relevant to neurotoxic and developmental neurotoxic outcomes. Although the AOPs outlined during the workshop are not fully described, they could serve as a basis for further, more detailed AOP development and evaluation that could be useful to support human health risk assessment in a variety of ways. PMID:25605028

Influence of lithofacies and diagensis on Norwegian North Sea chalk reservoirs

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

Brasher, J.E.; Vagle, K.R.

1996-05-01

The depositional mechanism of chalk is a key influence in the chalk`s ultimate reservoir quality. Classically, the depositional mechanism is interpreted from core descriptions. Where core data are lacking, dipmeter and borehole imagery logs have proven useful in making lithofacies assessments. Criteria for recognition of three chalk categories are established. Category III chalks correspond to those chalks that have been deposited by gravity flows or slumping and tend to have the best reservoir parameters. Category I chalks are most often affiliated with pelagic deposition and tend to have the poorest reservoir parameters. Category II chalks are intermediate between I andmore » III. Anomalously high primary porosities have been maintained in Norwegian North Sea chalks where the effects of mechanical and chemical compaction have been limited. The diagenetic pathway of a chalk reflects changes brought about by mechanical and chemical compaction. Five factors most heavily influence the diagenetic pathway: (1) burial depth, (2) chalk type, (3) overpressuring, (4) presence of hydrocarbons, and (5) original grain size. Assessments of the sedimentological model, diagenetic pathway, and resultant reservoir quality are provided in case studies of Edda, Tor, and Eldfisk fields. Because the distribution of chalk is largely independent of existing structures, most fields have a component of stratigraphic/diagenetic trapping. Each case study shows unique examples of how petrophysical and reservoir engineering data can be incorporated in assessments of chalk type and the diagenetic pathway and how they may affect reservoir parameters and productivity.« less

Learning cellular sorting pathways using protein interactions and sequence motifs.

PubMed

Lin, Tien-Ho; Bar-Joseph, Ziv; Murphy, Robert F

2011-11-01

Proper subcellular localization is critical for proteins to perform their roles in cellular functions. Proteins are transported by different cellular sorting pathways, some of which take a protein through several intermediate locations until reaching its final destination. The pathway a protein is transported through is determined by carrier proteins that bind to specific sequence motifs. In this article, we present a new method that integrates protein interaction and sequence motif data to model how proteins are sorted through these sorting pathways. We use a hidden Markov model (HMM) to represent protein sorting pathways. The model is able to determine intermediate sorting states and to assign carrier proteins and motifs to the sorting pathways. In simulation studies, we show that the method can accurately recover an underlying sorting model. Using data for yeast, we show that our model leads to accurate prediction of subcellular localization. We also show that the pathways learned by our model recover many known sorting pathways and correctly assign proteins to the path they utilize. The learned model identified new pathways and their putative carriers and motifs and these may represent novel protein sorting mechanisms. Supplementary results and software implementation are available from http://murphylab.web.cmu.edu/software/2010_RECOMB_pathways/.

Drug-Path: a database for drug-induced pathways

PubMed Central

Zeng, Hui; Cui, Qinghua

2015-01-01

Some databases for drug-associated pathways have been built and are publicly available. However, the pathways curated in most of these databases are drug-action or drug-metabolism pathways. In recent years, high-throughput technologies such as microarray and RNA-sequencing have produced lots of drug-induced gene expression profiles. Interestingly, drug-induced gene expression profile frequently show distinct patterns, indicating that drugs normally induce the activation or repression of distinct pathways. Therefore, these pathways contribute to study the mechanisms of drugs and drug-repurposing. Here, we present Drug-Path, a database of drug-induced pathways, which was generated by KEGG pathway enrichment analysis for drug-induced upregulated genes and downregulated genes based on drug-induced gene expression datasets in Connectivity Map. Drug-Path provides user-friendly interfaces to retrieve, visualize and download the drug-induced pathway data in the database. In addition, the genes deregulated by a given drug are highlighted in the pathways. All data were organized using SQLite. The web site was implemented using Django, a Python web framework. Finally, we believe that this database will be useful for related researches. Database URL: http://www.cuilab.cn/drugpath PMID:26130661

Drug-Path: a database for drug-induced pathways.

PubMed

Zeng, Hui; Qiu, Chengxiang; Cui, Qinghua

2015-01-01

Some databases for drug-associated pathways have been built and are publicly available. However, the pathways curated in most of these databases are drug-action or drug-metabolism pathways. In recent years, high-throughput technologies such as microarray and RNA-sequencing have produced lots of drug-induced gene expression profiles. Interestingly, drug-induced gene expression profile frequently show distinct patterns, indicating that drugs normally induce the activation or repression of distinct pathways. Therefore, these pathways contribute to study the mechanisms of drugs and drug-repurposing. Here, we present Drug-Path, a database of drug-induced pathways, which was generated by KEGG pathway enrichment analysis for drug-induced upregulated genes and downregulated genes based on drug-induced gene expression datasets in Connectivity Map. Drug-Path provides user-friendly interfaces to retrieve, visualize and download the drug-induced pathway data in the database. In addition, the genes deregulated by a given drug are highlighted in the pathways. All data were organized using SQLite. The web site was implemented using Django, a Python web framework. Finally, we believe that this database will be useful for related researches. © The Author(s) 2015. Published by Oxford University Press.

Development of algae biorefinery concepts for biofuels and bioproducts; a perspective on process-compatible products and their impact on cost-reduction

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

Laurens, Lieve M. L.; Markham, Jennifer; Templeton, David W.

Identifying and addressing critical improvements in biomass, bioproduct and biofuel productivity is a priority for the nascent algae-based bioeconomy. Economic and sustainability principles should guide these developing improvements and help to unravel the contentious water–food–energy–environment nexus that algae inhabit. Understanding the biochemistry of the storage carbon metabolism of algae to produce biofuels and bioproducts can bring to light the key barriers that currently limit the overall carbon efficiency and the photosynthetic efficiency, and ultimately guide productivity and commercial viability in the context of limiting resources. In the analysis reported here, we present different potential pathways for a conceptual algae biorefinerymore » framework, with each pathway addressing one of the main identified barriers to future deployment. We highlight the molecular identification, in the form of an extensive literature review, of potential bioproducts that may be derived directly from both biomass and fractions produced through a conversion pathway, for three important commercially-relevant genera of algae, Scenedesmus, Chlorella and Nannochloropsis. Here, we establish a relationship between each of the potential bioproducts, describe relevant conversion and extraction processes, and discuss market opportunities with values and sizes as they relate to commercial development of the products.« less

AMPK governs lineage specification through Tfeb-dependent regulation of lysosomes.

PubMed

Young, Nathan P; Kamireddy, Anwesh; Van Nostrand, Jeanine L; Eichner, Lillian J; Shokhirev, Maxim Nikolaievich; Dayn, Yelena; Shaw, Reuben J

2016-03-01

Faithful execution of developmental programs relies on the acquisition of unique cell identities from pluripotent progenitors, a process governed by combinatorial inputs from numerous signaling cascades that ultimately dictate lineage-specific transcriptional outputs. Despite growing evidence that metabolism is integrated with many molecular networks, how pathways that control energy homeostasis may affect cell fate decisions is largely unknown. Here, we show that AMP-activated protein kinase (AMPK), a central metabolic regulator, plays critical roles in lineage specification. Although AMPK-deficient embryonic stem cells (ESCs) were normal in the pluripotent state, these cells displayed profound defects upon differentiation, failing to generate chimeric embryos and preferentially adopting an ectodermal fate at the expense of the endoderm during embryoid body (EB) formation. AMPK(-/-) EBs exhibited reduced levels of Tfeb, a master transcriptional regulator of lysosomes, leading to diminished endolysosomal function. Remarkably, genetic loss of Tfeb also yielded endodermal defects, while AMPK-null ESCs overexpressing this transcription factor normalized their differential potential, revealing an intimate connection between Tfeb/lysosomes and germ layer specification. The compromised endolysosomal system resulting from AMPK or Tfeb inactivation blunted Wnt signaling, while up-regulating this pathway restored expression of endodermal markers. Collectively, these results uncover the AMPK pathway as a novel regulator of cell fate determination during differentiation. © 2016 Young et al.; Published by Cold Spring Harbor Laboratory Press.

The Role of the Melanocortin System in Metabolic Disease: New Developments and Advances.

PubMed

Hill, Jennifer W; Faulkner, Latrice D

2017-01-01

Obesity is increasing in prevalence across all sectors of society, and with it a constellation of associated ailments including hypertension, type 2 diabetes, and eating disorders. The melanocortin system is a critical neural system underlying the control of body weight and other functions. Deficits in the melanocortin system may promote or exacerbate the comorbidities of obesity. This system has therefore generated great interest as a potential target for treatment of obesity. However, drugs targeting melanocortin receptors are plagued by problematic side effects, including undesirable increases in sympathetic nervous system activity, heart rate, and blood pressure. Circumnavigating this roadblock will require a clearer picture of the precise neural circuits that mediate the functions of melanocortins. Recent, novel experimental approaches have significantly advanced our understanding of these pathways. We here review the latest advances in our understanding of the role of melanocortins in food intake, reward pathways, blood pressure, glucose control, and energy expenditure. The evidence suggests that downstream melanocortin-responsive circuits responsible for different physiological actions do diverge. Ultimately, a more complete understanding of melanocortin pathways and their myriad roles should allow treatments tailored to the mix of metabolic disorders in the individual patient. © 2016 The Author(s) Published by S. Karger AG, Basel.

FGFR and PTEN signaling interact during lens development to regulate cell survival

PubMed Central

Chaffee, Blake R.; Hoang, Thanh V.; Leonard, Melissa R.; Bruney, Devin G.; Wagner, Brad D.; Dowd, Joseph Richard; Leone, Gustavo; Ostrowski, Michael C.; Robinson, Michael L.

2016-01-01

Lens epithelial cells express many receptor tyrosine kinases (RTKs) that stimulate PI3K-AKT and RAS-RAF-MEK-ERK intracellular signaling pathways. These pathways ultimately activate the phosphorylation of key cellular transcription factors and other proteins that control proliferation, survival, metabolism, and differentiation in virtually all cells. Among RTKs in the lens, only stimulation of fibroblast growth factor receptors (FGFRs) elicits a lens epithelial cell to fiber cell differentiation response in mammals. Moreover, although the lens expresses three different Fgfr genes, the isolated removal of Fgfr2 at the lens placode stage inhibits both lens cell survival and fiber cell differentiation. Phosphatase and tensin homolog (PTEN), commonly known as a tumor suppressor, inhibits ERK and AKT activation and initiates both apoptotic pathways, and cell cycle arrest. Here, we show that the combined deletion of Fgfr2 and Pten rescues the cell death phenotype associated with Fgfr2 loss alone. Additionally, Pten removal increased AKT and ERK activation, above the levels of controls, in the presence or absence of Fgfr2. However, isolated deletion of Pten failed to stimulate ectopic fiber cell differentiation, and the combined deletion of Pten and Fgfr2 failed to restore differentiation-specific Aquaporin0 and DnaseIIβ expression in the lens fiber cells. PMID:26764128

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

Hornibrook, E.R.C.; Longstaffe, F.J.; Fyfe, W.S.

The identity and distribution of substrates that support CH{sub 4} production in wetlands is poorly known at present. Organic compounds are the primary methanogenic precursor at all depths within anoxic wetland soils; however, the distribution of microbial processes by which these compounds are ultimately converted to CH{sub 4} is uncertain. Based on stable isotope measurements of CH{sub 4} and {Sigma}CO{sub 2} extracted from soil porewaters in two temperate zone wetlands, we present evidence that a systematic spatial distribution of microbial methanogenic pathways can exist in certain anoxic, organic-rich soils. CH{sub 4} production by the acetate fermentation pathway is favored inmore » the shallow subsurface. while methanogenesis from the reduction of CO{sub 2} with H{sub 2} becomes more predominant in older, less reactive peat at depth. This distribution can account for many of the reported CH{sub 4} emission characteristics of wetlands, in particular, their sensitivity to changes in primary productivity, temperature, and hydrology. These factors play an important role in controlling the short-term supply of labile substrates to fermentive methanogens in the shallow subsurface where the most intense CH{sub 4} production occurs. Predominance of the CO{sub 2}-reduction pathway at depth may help to explain reports of CH{sub 4} with a semifossil age in lower peat layers. 60 refs., 7 figs., 1 tab.« less

Enzymes involved in plastid-targeted phosphatidic acid synthesis are essential for Plasmodium yoelii liver stage development

PubMed Central

Lindner, Scott E.; Sartain, Mark J.; Hayes, Kiera; Harupa, Anke; Moritz, Robert L.; Kappe, Stefan H. I.; Vaughan, Ashley M.

2014-01-01

SUMMARY Malaria parasites scavenge nutrients from their host but also harbor enzymatic pathways for de novo macromolecule synthesis. One such pathway is apicoplast-targeted type II fatty acid synthesis, which is essential for late liver stage development in rodent malaria. It is likely that fatty acids synthesized in the apicoplast are ultimately incorporated into membrane phospholipids necessary for exoerythrocytic merozoite formation. We hypothesized that these synthesized fatty acids are being utilized for apicoplast-targeted phosphatidic acid synthesis, the phospholipid precursor. Phosphatidic acid is typically synthesized in a three-step reaction utilizing three enzymes: glycerol 3-phosphate dehydrogenase, glycerol 3-phosphate acyltransferase and lysophosphatidic acid acyltransferase. The Plasmodium genome is predicted to harbor genes for both apicoplast- and cytosol/endoplasmic reticulum-targeted phosphatidic synthesis. Our research shows that apicoplast-targeted P. yoelii glycerol 3-phosphate dehydrogenase and glycerol 3-phosphate acyltransferase are expressed only during liver stage development and deletion of the encoding genes resulted in late liver stage growth arrest and lack of merozoite differentiation. However, the predicted apicoplast-targeted lysophosphatidic acid acyltransferase gene was refractory to deletion and was expressed solely in the endoplasmic reticulum throughout the parasite lifecycle. Our results suggest that P. yoelii has an incomplete apicoplast-targeted phosphatidic acid synthesis pathway that is essential for liver stage maturation. PMID:24330260

Crosstalk among Jasmonate, Salicylate and Ethylene Signaling Pathways in Plant Disease and Immune Responses.

PubMed

Yang, You-Xin; Ahammed, Golam J; Wu, Caijun; Fan, Shu-ying; Zhou, Yan-Hong

2015-01-01

Phytohormone crosstalk is crucial for plant defenses against pathogens and insects in which salicylic acid (SA), jasmonic acid (JA), and ethylene (ET) play key roles. These low molecular mass signals critically trigger and modulate plant resistance against biotrophic as well as necrotrophic pathogens through a complex signaling network that even involves participation of other hormones. Crosstalk among SA, JA and ET is mediated by different molecular players, considered as integral part of these crosscommunicating signal transduction pathways. Recent progress has revealed that the positive versus negative interactions among those pathways ultimately enable a plant to fine-tune its defense against specific aggressors. On the other hand, pathogens have evolved strategies to manipulate the signaling network to their favour in order to intensify virulence on host plant. Here we review recent advances and current knowledge on the role of classical primary defense hormones SA, JA and ET as well as their synergistic and antagonistic interaction in plant disease and immune responses. Crosstalk with other hormones such as abscisic acid, auxin, brassinosteroids, cytokinins and melatonin is also discussed mainly in plant disease resistance. In addition to our keen focus on hormonal crosstalk, this review also highlights potential implication of positive and negative regulatory interactions for developing an efficient disease management strategy through manipulation of hormone signaling in plant.

Phosphatidylinositol 3-Kinase: A Link Between Inflammation and Pancreatic Cancer

PubMed Central

Birtolo, Chiara; Go, Vay Liang W.; Ptasznik, Andrzej; Eibl, Guido; Pandol, Stephen J.

2016-01-01

Even though a strong association between inflammation and cancer has been widely accepted, the underlying precise molecular mechanisms are still largely unknown. A complex signaling network between tumor and stromal cells is responsible for the infiltration of inflammatory cells into the cancer micro-environment. Tumor stromal cells such as pancreatic stellate cells (PSCs) and immune cells create a microenvironment that protects cancer cells through a complex interaction, ultimately facilitating their local proliferation and their migration to different sites. Furthermore, PSCs have multiple functions related to local immunity, angiogenesis, inflammation and fibrosis. Recently, many studies have shown that members of the phosphoinositol-3-phosphate kinase (PI3K) family are activated in tumor cells, PSCs and tumor infiltrating inflammatory cells to promote cancer growth. Pro-inflammatory cytokines and chemokines secreted by immune cells and fibroblasts within the tumor environment can activate the PI3K pathway both in cancer and inflammatory cells. In this review, we focus on the central role of the PI3K pathway in regulating the cross-talk between immune/stromal cells and cancer cells. Understanding the role of the PI3K pathway in the development of chronic pancreatitis and cancer is crucial for the discovery of novel and efficacious treatment options. PMID:26658038

Combined Cytological and Transcriptomic Analysis Reveals a Nitric Oxide Signaling Pathway Involved in Cold-Inhibited Camellia sinensis Pollen Tube Growth

PubMed Central

Wang, Weidong; Sheng, Xianyong; Shu, Zaifa; Li, Dongqin; Pan, Junting; Ye, Xiaoli; Chang, Pinpin; Li, Xinghui; Wang, Yuhua

2016-01-01

Nitric oxide (NO) as a signaling molecule plays crucial roles in many abiotic stresses in plant development processes, including pollen tube growth. Here, the signaling networks dominated by NO during cold stress that inhibited Camellia sinensis pollen tube growth are investigated in vitro. Cytological analysis show that cold-induced NO is involved in the inhibition of pollen tube growth along with disruption of the cytoplasmic Ca2+ gradient, increase in ROS content, acidification of cytoplasmic pH and abnormalities in organelle ultrastructure and cell wall component distribution in the pollen tube tip. Furthermore, differentially expressed genes (DEGs)-related to signaling pathway, such as NO synthesis, cGMP, Ca2+, ROS, pH, actin, cell wall, and MAPK cascade signal pathways, are identified and quantified using transcriptomic analyses and qRT-PCR, which indicate a potential molecular mechanism for the above cytological results. Taken together, these findings suggest that a complex signaling network dominated by NO, including Ca2+, ROS, pH, RACs signaling and the crosstalk among them, is stimulated in the C. sinensis pollen tube in response to cold stress, which further causes secondary and tertiary alterations, such as ultrastructural abnormalities in organelles and cell wall construction, ultimately resulting in perturbed pollen tube extension. PMID:27148289

Development of algae biorefinery concepts for biofuels and bioproducts; a perspective on process-compatible products and their impact on cost-reduction

DOE PAGES

Laurens, Lieve M. L.; Markham, Jennifer; Templeton, David W.; ...

2017-07-10

Identifying and addressing critical improvements in biomass, bioproduct and biofuel productivity is a priority for the nascent algae-based bioeconomy. Economic and sustainability principles should guide these developing improvements and help to unravel the contentious water–food–energy–environment nexus that algae inhabit. Understanding the biochemistry of the storage carbon metabolism of algae to produce biofuels and bioproducts can bring to light the key barriers that currently limit the overall carbon efficiency and the photosynthetic efficiency, and ultimately guide productivity and commercial viability in the context of limiting resources. In the analysis reported here, we present different potential pathways for a conceptual algae biorefinerymore » framework, with each pathway addressing one of the main identified barriers to future deployment. We highlight the molecular identification, in the form of an extensive literature review, of potential bioproducts that may be derived directly from both biomass and fractions produced through a conversion pathway, for three important commercially-relevant genera of algae, Scenedesmus, Chlorella and Nannochloropsis. Here, we establish a relationship between each of the potential bioproducts, describe relevant conversion and extraction processes, and discuss market opportunities with values and sizes as they relate to commercial development of the products.« less

Genetic Validation of Cell Proliferation via Ras-Independent Activation of the Raf/Mek/Erk Pathway.

PubMed

Lechuga, Carmen G; Simón-Carrasco, Lucía; Jacob, Harrys K C; Drosten, Matthias

2017-01-01

Signaling transmitted by the Ras family of small GTPases (H-, N-, and K-Ras) is essential for proliferation of mouse embryonic fibroblasts (MEFs). However, constitutive activation of the downstream Raf/Mek/Erk pathway can bypass the requirement for Ras proteins and allow cells to proliferate in the absence of the three Ras isoforms. Here we describe a protocol for a colony formation assay that permits evaluating the role of candidate proteins that are positive or negative regulators of cell proliferation mediated via Ras-independent Raf/Mek/Erk pathway activation. K-Ras lox (H-Ras -/- , N-Ras -/- , K-Ras lox/lox , RERT ert/ert ) MEFs are infected with retro- or lentiviral vectors expressing wild-type or constitutively activated candidate cDNAs, shRNAs, or sgRNAs in combination with Cas9 to ascertain the possibility of candidate proteins to function either as an activator or inhibitor of Ras-independent Raf/Mek/Erk activation. These cells are then seeded in the absence or presence of 4-Hydroxytamoxifen (4-OHT), which activates the resident CreERT2 alleles resulting in elimination of the conditional K-Ras alleles and ultimately generating Rasless cells. Colony formation in the presence of 4-OHT indicates cell proliferation via Ras-independent Raf/Mek/Erk activation.

Tetraploidization or autophagy: The ultimate fate of senescent human endometrial stem cells under ATM or p53 inhibition.

PubMed

Borodkina, Aleksandra V; Shatrova, Alla N; Deryabin, Pavel I; Grukova, Anastasiya A; Nikolsky, Nikolay N; Burova, Elena B

2016-01-01

Previously we demonstrated that endometrium-derived human mesenchymal stem cells (hMESCs) via activation of the ATM/p53/p21/Rb pathway enter the premature senescence in response to oxidative stress. Down regulation effects of the key components of this signaling pathway, particularly ATM and p53, on a fate of stressed hMESCs have not yet been investigated. In the present study by using the specific inhibitors Ku55933 and Pifithrin-α, we confirmed implication of both ATM and p53 in H(2)O(2)-induced senescence of hMESCs. ATM or p53 down regulation was shown to modulate differently the cellular fate of H(2)O(2)-treated hMESCs. ATM inhibition allowed H(2)O(2)-stimulated hMESCs to escape the permanent cell cycle arrest due to loss of the functional ATM/p53/p21/Rb pathway, and induced bypass of mitosis and re-entry into S phase, resulting in tetraploid cells. On the contrary, suppression of the p53 transcriptional activity caused a pronounced cell death of H(2)O(2)-treated hMESCs via autophagy induction. The obtained data clearly demonstrate that down regulation of ATM or p53 shifts senescence of human endometrial stem cells toward tetraploidization or autophagy.

Cultural, social and intrapersonal factors associated with clusters of co-occurring health-related behaviours among adolescents.

PubMed

Klein Velderman, Mariska; Dusseldorp, Elise; van Nieuwenhuijzen, Maroesjka; Junger, Marianne; Paulussen, Theo G W M; Reijneveld, Sijmen A

2015-02-01

Adverse health-related behaviours (HRBs) have been shown to co-occur in adolescents. Evidence lacks on factors associated with these co-occurring HRBs. The Theory of Triadic Influence (TTI) offers a route to categorize these determinants according to type (social, cultural and intrapersonal) and distance in the causal pathway (ultimate or distal). Our aims were to identify cultural, social and intrapersonal factors associated with co-occurring HRBs and to assess the relative importance of ultimate and distal factors for each cluster of co-occurring HRBs. Respondents concerned a random sample of 898 adolescents aged 12-18 years, stratified by age, sex and educational level of head of household. Data were collected via face-to-face computer-assisted interviewing and internet questionnaires. Analyses were performed for young (12-15 years) and late (16-18 years) adolescents regarding two and three clusters of HRB, respectively. For each cluster of HRBs (e.g. smoking, delinquency), associated factors were found. These accounted for 27 to 57% of the total variance per cluster. Factors came in particular from the intrapersonal stream of the TTI at the ultimate level and the social stream at the distal level. Associations were strongest for parenting practices, risk behaviours of friends and parents and self-control. Results of this study confirm that it is possible to identify a selection of cultural, social and intrapersonal factors associated with co-occurring HRBs among adolescents. © The Author 2014. Published by Oxford University Press on behalf of the European Public Health Association. All rights reserved.

Evaluation of the effect of post-translational modification toward protein structure: Chemical synthesis of glycosyl crambins having either a high mannose-type or a complex-type oligosaccharide.

PubMed

Dedola, Simone; Izumi, Masayuki; Makimura, Yutaka; Ito, Yukishige; Kajihara, Yasuhiro

2016-11-04

Glycoproteins are assembled and folded in the endoplasmic reticulum (ER) and transported to the Golgi for further processing of their oligosaccharides. During these processes, two types of oligosaccharides are used: that is, high mannose-type oligosaccharide in the ER and complex-type oligosaccharide in the Golgi. We were interested to know how two different types of oligosaccharides could influence the folding pathway or the final three-dimensional structure of the glycoproteins. For this purpose, we synthesized a new glycosyl crambin having complex-type oligosaccharide and evaluated the folding process, the final protein structure analyzed by NMR, and compared the CD spectra with previously synthesized glycosyl crambin bearing high mannose-type oligosaccharides. From our analysis, we found that the two different oligosaccharides do not influence the folding pathway in vitro and the final structure of the small glycoproteins. © 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 446-452, 2016. © 2015 Wiley Periodicals, Inc.

Investigating dysregulated pathways in Staphylococcus aureus (SA) exposed macrophages based on pathway interaction network.

PubMed

Zhou, Wei; Zhang, Yan; Li, Yue-Hua; Wang, Shuang; Zhang, Jing-Jing; Zhang, Cui-Xia; Zhang, Zhi-Sheng

2017-02-01

This work aimed to identify dysregulated pathways for Staphylococcus aureus (SA) exposed macrophages based on pathway interaction network (PIN). The inference of dysregulated pathways was comprised of four steps: preparing gene expression data, protein-protein interaction (PPI) data and pathway data; constructing a PIN dependent on the data and Pearson correlation coefficient (PCC); selecting seed pathway from PIN by computing activity score for each pathway according to principal component analysis (PCA) method; and investigating dysregulated pathways in a minimum set of pathways (MSP) utilizing seed pathway and the area under the receiver operating characteristics curve (AUC) index implemented in support vector machines (SVM) model. A total of 20,545 genes, 449,833 interactions and 1189 pathways were obtained in the gene expression data, PPI data and pathway data, respectively. The PIN was consisted of 8388 interactions and 1189 nodes, and Respiratory electron transport, ATP synthesis by chemiosmotic coupling, and heat production by uncoupling proteins was identified as the seed pathway. Finally, 15 dysregulated pathways in MSP (AUC=0.999) were obtained for SA infected samples, such as Respiratory electron transport and DNA Replication. We have identified 15 dysregulated pathways for SA infected macrophages based on PIN. The findings might provide potential biomarkers for early detection and therapy of SA infection, and give insights to reveal the molecular mechanism underlying SA infections. However, how these dysregulated pathways worked together still needs to be studied. Copyright © 2016 Elsevier Ltd. All rights reserved.

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

PubMed

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.

Characterization of biomarkers in stroke based on ego-networks and pathways.

PubMed

Li, Haixia; Guo, Qianqian

2017-12-01

To explore potential biomarkers in stroke based on ego-networks and pathways. EgoNet method was applied to search for the underlying biomarkers in stroke using transcription profiling of E-GEOD-58294 and protein-protein interaction (PPI) data. Eight ego-genes were identified from PPI network according to the degree characteristics at the criteria of top 5% ranked z-sore and degree >1. Eight candidate ego-networks with classification accuracy ≥0.9 were selected. After performed randomization test, seven significant ego-networks with adjusted p value < 0.05 were identified. Pathway enrichment analysis was then conducted with these ego-networks to search for the significant pathways. Finally, two significant pathways were identified, and six of seven ego-networks were enriched to "3'-UTR-mediated translational regulation" pathway, indicating that this pathway performs an important role in the development of stroke. Seven ego-networks were constructed using EgoNet and two significant enriched by pathways were identified. These may provide new insights into the potential biomarkers for the development of stroke.

Biobehavioral Influences on Cancer Progression

PubMed Central

Costanzo, Erin S.; Sood, Anil K.; Lutgendorf, Susan K.

2010-01-01

Synopsis This review focuses on the contributions of stress-related behavioral factors to cancer growth and metastasis and the biobehavioral mechanisms underlying these relationships. We describe behavioral factors that are important in modulation of the stress response and the pivotal role of neuroendocrine regulation in the downstream alteration of physiological pathways relevant to cancer control, including the cellular immune response, inflammation, and tumor angiogenesis, invasion, and cell-signaling pathways. Consequences for cancer progression and metastasis, as well as quality of life, are delineated. Finally, behavioral and pharmacological interventions for cancer patients with the potential to alter these biobehavioral pathways are discussed. PMID:21094927

Effects of Deployment Investment on the Growth of the Biofuels Industry. 2016 Update

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

Vimmerstedt, Laura J.; Warner, Ethan S.; Stright, Dana

This report updates the 2013 report of the same title. Some text originally published in that report is retained and indicated in gray. In support of the national goals for biofuel use in the United States, numerous technologies have been developed that convert biomass to biofuels. Some of these biomass to biofuel conversion technology pathways are operating at commercial scales, while others are in earlier stages of development. The advancement of a new pathway toward commercialization involves various types of progress, including yield improvements, process engineering, and financial performance. Actions of private investors and public programs can accelerate the demonstrationmore » and deployment of new conversion technology pathways. These investors (both private and public) will pursue a range of pilot, demonstration, and pioneer scale biorefinery investments; the most cost-effective set of investments for advancing the maturity of any given biomass to biofuel conversion technology pathway is unknown. In some cases, whether or not the pathway itself will ultimately be technically and financially successful is also unknown. This report presents results from the Biomass Scenario Model--a system dynamics model of the biomass to biofuels system--that estimate effects of investments in biorefineries at different maturity levels and operational scales. The report discusses challenges in estimating effects of such investments and explores the interaction between this deployment investment and a volumetric production incentive. Model results show that investments in demonstration and deployment have a substantial growth impact on the development of the biofuels industry. Results also show that other conditions, such as accompanying incentives, have major impacts on the effectiveness of such investments. Results from the 2013 report are compared to new results. This report does not advocate for or against investments, incentives, or policies, but analyzes simulations of their hypothetical effects.« less

Congenital diaphragmatic hernia (CDH) etiology as revealed by pathway genetics.

PubMed

Kantarci, Sibel; Donahoe, Patricia K

2007-05-15

Congenital diaphragmatic hernia (CDH) is a common birth defect with high mortality and morbidity. Two hundred seventy CDH patients were ascertained, carefully phenotyped, and classified as isolated (diaphragm defects alone) or complex (with additional anomalies) cases. We established different strategies to reveal CDH-critical chromosome loci and genes in humans. Candidate genes for sequencing analyses were selected from CDH animal models, genetic intervals of recurrent chromosomal aberration in humans, such as 15q26.1-q26.2 or 1q41-q42.12, as well as genes in the retinoic acid and related pathways and those known to be involved in embryonic lung development. For instance, FOG2, GATA4, and COUP-TFII are all needed for both normal diaphragm and lung development and are likely all in the same genetic and molecular pathway. Linkage analysis was applied first in a large inbred family and then in four multiplex families with Donnai-Barrow syndrome (DBS) associated with CDH. 10K SNP chip and microsatellite markers revealed a DBS locus on chromosome 2q23.3-q31.1. We applied array-based comparative genomic hybridization (aCGH) techniques to over 30, mostly complex, CDH patients and found a de novo microdeletion in a patient with Fryns syndrome related to CDH. Fluorescence in situ hybridization (FISH) and multiplex ligation-dependent probe amplification (MLPA) techniques allowed us to further define the deletion interval. Our aim is to identify genetic intervals and, in those, to prioritize genes that might reveal molecular pathways, mutations in any step of which, might contribute to the same phenotype. More important, the elucidation of pathways may ultimately provide clues to treatment strategies. (c) 2007 Wiley-Liss, Inc.