Similarities and differences between the Wnt and reelin pathways in the forming brain.

PubMed

Reiner, Orly; Sapir, Tamar

2005-01-01

One of the key features in development is the reutilization of successful signaling pathways. Here, we emphasize the involvement of the Wnt pathway, one of the five kinds of signal transduction pathway predominating early embryonic development of all animals, in regulating the formation of brain structure. We discuss the interrelationships between the Wnt and reelin pathways in the regulation of cortical layering. We summarize data emphasizing key molecules, which, when mutated, result in abnormal brain development. This integrated view, which is based on conservation of pathways, reveals the relative position of participants in the pathway, points to control mechanisms, and allows raising testable working hypotheses. Nevertheless, although signaling pathways are highly conserved from flies to humans, the overall morphology is not. We propose that future studies directed at understanding of diversification will provide fruitful insights on mammalian brain formation.

COMPUGIRLS: Stepping Stone to Future Computer-Based Technology Pathways

ERIC Educational Resources Information Center

Lee, Jieun; Husman, Jenefer; Scott, Kimberly A.; Eggum-Wilkens, Natalie D.

2015-01-01

The COMPUGIRLS: Culturally relevant technology program for adolescent girls was developed to promote underrepresented girls' future possible selves and career pathways in computer-related technology fields. We hypothesized that the COMPUGIRLS would promote academic possible selves and self-regulation to achieve these possible selves. We compared…

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

PubMed

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

2017-09-01

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

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

USGS Publications Warehouse

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

2016-01-01

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

How will climate change pathways and mitigation options alter incidence of vector-borne diseases? A framework for leishmaniasis in South and Meso-America

PubMed Central

Masante, Dario; Golding, Nicholas; Pigott, David; Day, John C.; Ibañez-Bernal, Sergio; Kolb, Melanie; Jones, Laurence

2017-01-01

The enormous global burden of vector-borne diseases disproportionately affects poor people in tropical, developing countries. Changes in vector-borne disease impacts are often linked to human modification of ecosystems as well as climate change. For tropical ecosystems, the health impacts of future environmental and developmental policy depend on how vector-borne disease risks trade off against other ecosystem services across heterogeneous landscapes. By linking future socio-economic and climate change pathways to dynamic land use models, this study is amongst the first to analyse and project impacts of both land use and climate change on continental-scale patterns in vector-borne diseases. Models were developed for cutaneous and visceral leishmaniasis in the Americas—ecologically complex sand fly borne infections linked to tropical forests and diverse wild and domestic mammal hosts. Both diseases were hypothesised to increase with available interface habitat between forest and agricultural or domestic habitats and with mammal biodiversity. However, landscape edge metrics were not important as predictors of leishmaniasis. Models including mammal richness were similar in accuracy and predicted disease extent to models containing only climate and land use predictors. Overall, climatic factors explained 80% and land use factors only 20% of the variance in past disease patterns. Both diseases, but especially cutaneous leishmaniasis, were associated with low seasonality in temperature and precipitation. Since such seasonality increases under future climate change, particularly under strong climate forcing, both diseases were predicted to contract in geographical extent to 2050, with cutaneous leishmaniasis contracting by between 35% and 50%. Whilst visceral leishmaniasis contracted slightly more under strong than weak management for carbon, biodiversity and ecosystem services, future cutaneous leishmaniasis extent was relatively insensitive to future alternative socio-economic pathways. Models parameterised at narrower geographical scales may be more sensitive to land use pattern and project more substantial changes in disease extent under future alternative socio-economic pathways. PMID:29020041

How will climate change pathways and mitigation options alter incidence of vector-borne diseases? A framework for leishmaniasis in South and Meso-America.

PubMed

Purse, Bethan V; Masante, Dario; Golding, Nicholas; Pigott, David; Day, John C; Ibañez-Bernal, Sergio; Kolb, Melanie; Jones, Laurence

2017-01-01

The enormous global burden of vector-borne diseases disproportionately affects poor people in tropical, developing countries. Changes in vector-borne disease impacts are often linked to human modification of ecosystems as well as climate change. For tropical ecosystems, the health impacts of future environmental and developmental policy depend on how vector-borne disease risks trade off against other ecosystem services across heterogeneous landscapes. By linking future socio-economic and climate change pathways to dynamic land use models, this study is amongst the first to analyse and project impacts of both land use and climate change on continental-scale patterns in vector-borne diseases. Models were developed for cutaneous and visceral leishmaniasis in the Americas-ecologically complex sand fly borne infections linked to tropical forests and diverse wild and domestic mammal hosts. Both diseases were hypothesised to increase with available interface habitat between forest and agricultural or domestic habitats and with mammal biodiversity. However, landscape edge metrics were not important as predictors of leishmaniasis. Models including mammal richness were similar in accuracy and predicted disease extent to models containing only climate and land use predictors. Overall, climatic factors explained 80% and land use factors only 20% of the variance in past disease patterns. Both diseases, but especially cutaneous leishmaniasis, were associated with low seasonality in temperature and precipitation. Since such seasonality increases under future climate change, particularly under strong climate forcing, both diseases were predicted to contract in geographical extent to 2050, with cutaneous leishmaniasis contracting by between 35% and 50%. Whilst visceral leishmaniasis contracted slightly more under strong than weak management for carbon, biodiversity and ecosystem services, future cutaneous leishmaniasis extent was relatively insensitive to future alternative socio-economic pathways. Models parameterised at narrower geographical scales may be more sensitive to land use pattern and project more substantial changes in disease extent under future alternative socio-economic pathways.

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.

The Brisbane Longitudinal Twin Study Pathways to Cannabis Use, Abuse and Dependence Project: Current status, preliminary results and future directions

PubMed Central

Gillespie, NA; Henders, AK; Davenport, TA; Hermens, DF; Wright, MJ; Martin, NG; Hickie, IB

2013-01-01

We describe the data being collected from the Brisbane Longitudinal Twin Study (BLTS) in Australia as part of the US National Institute on Drug Abuse (NIDA) funded project Pathways to Cannabis Use, Abuse and Dependence. The history, recruitment, assessment and retention of twin families in this project are described in detail along with preliminary findings and plans for future research. The goal of this NIDA project is to make a significant contribution to the discovery of quantitative trait loci (QTL) influencing cannabis use disorders. Although the focus is cannabis use, abuse and dependence in young adults, measures of comorbid illicit drug use disorders are also being collected. In addition, a variety of internalizing and externalizing disorders are being assessed, funded by support from the Australian National Health and Medical Research Council. Because these same twins have participated in numerous twin studies since 1992, future plans will include linking different phenotypes to investigate relationships between drug use, psychiatric disorders and psychological phenotypes within cross-sectional and longitudinal or developmental frameworks. PMID:23187020

The Brisbane Longitudinal Twin Study: Pathways to Cannabis Use, Abuse, and Dependence project-current status, preliminary results, and future directions.

PubMed

Gillespie, Nathan A; Henders, Anjali K; Davenport, Tracy A; Hermens, Daniel F; Wright, Margie J; Martin, Nicholas G; Hickie, Ian B

2013-02-01

We describe the data being collected from the Brisbane Longitudinal Twin Study in Australia as part of the US National Institute on Drug Abuse (NIDA)-funded project, Pathways to Cannabis Use, Abuse and Dependence. The history, recruitment, assessment, and retention of twin families in this project are described in detail, along with preliminary findings and plans for future research. The goal of this NIDA project is to make a significant contribution to the discovery of quantitative trait loci influencing cannabis use disorders. Although the focus is cannabis use, abuse, and dependence in young adults, measures of comorbid illicit drug use disorders are also being collected. In addition, a variety of internalizing and externalizing disorders are being assessed, funded by support from the Australian National Health and Medical Research Council. Because these same twins have participated in numerous twin studies since 1992, future plans will include linking different phenotypes to investigate relationships between drug use, psychiatric disorders, and psychological phenotypes within cross-sectional and longitudinal or developmental frameworks.

Multi-path transportation futures study: Results from Phase 1

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

Patterson, Phil; Singh, Margaret; Plotkin, Steve

2007-03-09

This PowerPoint briefing provides documentation and details for Phase 1 of the Multi-Path Transportation Futures Study, which compares alternative ways to make significant reductions in oil use and carbon emissions from U.S. light vehicles to 2050. Phase I, completed in 2006, was a scoping study, aimed at identifying key analytic issues and constructing a study design. The Phase 1 analysis included an evaluation of several pathways and scenarios; however, these analyses were limited in number and scope and were designed to be preliminary.

Benzo[a]pyrene exposure under future ocean acidification scenarios weakens the immune responses of blood clam, Tegillarca granosa.

PubMed

Su, Wenhao; Zha, Shanjie; Wang, Yichen; Shi, Wei; Xiao, Guoqiang; Chai, Xueliang; Wu, Hongxi; Liu, Guangxu

2017-04-01

Persistent organic pollutants (POPs) are known to converge into the ocean and accumulate in the sediment, posing great threats to marine organisms such as the sessile bottom burrowing bivalves. However, the immune toxicity of POPs, such as B[a]P, under future ocean acidification scenarios remains poorly understood to date. Therefore, in the present study, the impacts of B[a]P exposure on the immune responses of a bivalve species, Tegillarca granosa, under present and future ocean acidification scenarios were investigated. Results obtained revealed an increased immune toxicity of B[a]P under future ocean acidification scenarios in terms of reduced THC, altered haemocyte composition, and hampered phagocytosis, which may attribute to the synergetic effects of B[a]P and ocean acidification. In addition, the gene expressions of pathogen pattern recognition receptors (TLR1, TLR2, TLR4, TLR6), pathway mediators (TRAF6, TAK1, TAB2, IKKα and Myd88), and effectors (NF-ĸB) of the important immune related pathways were significantly down-regulated upon exposure to B[a]P under future ocean acidification scenarios. Results of the present study suggested an increased immune toxicity of B[a]P under future ocean acidification scenarios, which will significantly hamper the immune responses of T. granosa and subsequently render individuals more susceptible to pathogens challenges. Copyright © 2017 Elsevier Ltd. All rights reserved.

DNA repair targeted therapy: the past or future of cancer treatment?

PubMed Central

Gavande, Navnath S.; VanderVere-Carozza, Pamela S.; Hinshaw, Hilary D.; Jalal, Shadia I.; Sears, Catherine R.; Pawelczak, Katherine S.; Turchi, John J.

2016-01-01

The repair of DNA damage is a complex process that relies on particular pathways to remedy specific types of damage to DNA. The range of insults to DNA includes small, modest changes in structure including mismatched bases and simple methylation events to oxidized bases, intra- and interstrand DNA crosslinks, DNA double strand breaks and protein-DNA adducts. Pathways required for the repair of these lesions include mismatch repair, base excision repair, nucleotide excision repair, and the homology directed repair/Fanconi anemia pathway. Each of these pathways contributes to genetic stability, and mutations in genes encoding proteins involved in these pathways have been demonstrated to promote genetic instability and cancer. In fact, it has been suggested all cancers display defects in DNA repair. It has also been demonstrated that the ability of cancer cells to repair therapeutically induced DNA damage impacts therapeutic efficacy. This has led to targeting DNA repair pathways and proteins to develop anti-cancer agents that will increase sensitivity to traditional chemotherapeutics. While initial studies languished and were plagued by a lack of specificity and a defined mechanism of action, more recent approaches to exploit synthetic lethal interaction and develop high affinity chemical inhibitors have proven considerably more effective. In this review we will highlight recent advances and discuss previous failures in targeting DNA repair to pave the way for future DNA repair targeted agents and their use in cancer therapy. PMID:26896565

Current Status and Future Agenda for the Theory, Research, and Practice of Childhood Career Development

ERIC Educational Resources Information Center

Schultheiss, Donna E. Palladino

2008-01-01

This article reviews the current status and a future agenda for childhood career development theory, research, and practice. The fragmented nature of the current state of the literature is noted, and a call is made for a reexamination and reconsideration of the childhood developmental pathways of life's work. It is suggested that the study of…

Sensitivity of projected long-term CO2 emissions across the Shared Socioeconomic Pathways

NASA Astrophysics Data System (ADS)

Marangoni, G.; Tavoni, M.; Bosetti, V.; Borgonovo, E.; Capros, P.; Fricko, O.; Gernaat, D. E. H. J.; Guivarch, C.; Havlik, P.; Huppmann, D.; Johnson, N.; Karkatsoulis, P.; Keppo, I.; Krey, V.; Ó Broin, E.; Price, J.; van Vuuren, D. P.

2017-01-01

Scenarios showing future greenhouse gas emissions are needed to estimate climate impacts and the mitigation efforts required for climate stabilization. Recently, the Shared Socioeconomic Pathways (SSPs) have been introduced to describe alternative social, economic and technical narratives, spanning a wide range of plausible futures in terms of challenges to mitigation and adaptation. Thus far the key drivers of the uncertainty in emissions projections have not been robustly disentangled. Here we assess the sensitivities of future CO2 emissions to key drivers characterizing the SSPs. We use six state-of-the-art integrated assessment models with different structural characteristics, and study the impact of five families of parameters, related to population, income, energy efficiency, fossil fuel availability, and low-carbon energy technology development. A recently developed sensitivity analysis algorithm allows us to parsimoniously compute both the direct and interaction effects of each of these drivers on cumulative emissions. The study reveals that the SSP assumptions about energy intensity and economic growth are the most important determinants of future CO2 emissions from energy combustion, both with and without a climate policy. Interaction terms between parameters are shown to be important determinants of the total sensitivities.

The Hippo pathway in intestinal regeneration and disease.

PubMed

Hong, Audrey W; Meng, Zhipeng; Guan, Kun-Liang

2016-06-01

The Hippo pathway is a signalling cascade conserved from Drosophila melanogaster to mammals. The mammalian core kinase components comprise MST1 and MST2, SAV1, LATS1 and LATS2 and MOB1A and MOB1B. The transcriptional co-activators YAP1 and TAZ are the downstream effectors of the Hippo pathway and regulate target gene expression. Hippo signalling has crucial roles in the control of organ size, tissue homeostasis and regeneration, and dysregulation of the Hippo pathway can lead to uncontrolled cell growth and malignant transformation. Mammalian intestine consists of a stem cell compartment as well as differentiated cells, and its ability to regenerate rapidly after injury makes it an excellent model system to study tissue homeostasis, regeneration and tumorigenesis. Several studies have established the important role of the Hippo pathway in these processes. In addition, crosstalk between Hippo and other signalling pathways provides tight, yet versatile, regulation of tissue homeostasis. In this Review, we summarize studies on the role of the Hippo pathway in the intestine on these physiological processes and the underlying mechanisms responsible, and discuss future research directions and potential therapeutic strategies targeting Hippo signalling in intestinal disease.

The Hippo pathway in intestinal regeneration and disease

PubMed Central

Hong, Audrey W.; Meng, Zhipeng; Guan, Kun-Liang

2017-01-01

The Hippo pathway is a signalling cascade conserved from Drosophila melanogaster to mammals. The mammalian core kinase components comprise MST1 and MST2, SAV1, LATS1 and LATS2 and MOB1A and MOB1B. The transcriptional co-activators YAP1 and TAZ are the downstream effectors of the Hippo pathway and regulate target gene expression. Hippo signalling has crucial roles in the control of organ size, tissue homeostasis and regeneration, and dysregulation of the Hippo pathway can lead to uncontrolled cell growth and malignant transformation. Mammalian intestine consists of a stem cell compartment as well as differentiated cells, and its ability to regenerate rapidly after injury makes it an excellent model system to study tissue homeostasis, regeneration and tumorigenesis. Several studies have established the important role of the Hippo pathway in these processes. In addition, crosstalk between Hippo and other signalling pathways provides tight, yet versatile, regulation of tissue homeostasis. In this Review, we summarize studies on the role of the Hippo pathway in the intestine on these physiological processes and the underlying mechanisms responsible, and discuss future research directions and potential therapeutic strategies targeting Hippo signalling in intestinal disease. PMID:27147489

Greening the Grid: Pathways to Integrate 175 Gigawatts of Renewable Energy into India's Electric Grid, Vol. II - Regional Study

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

Cochran, Jaquelin M.; Palchak, Joseph D; McBennett, Brendan

The higher-spatial-resolution model of 'Greening the Grid: Pathways to Integrate 175 Gigawatts of Renewable Energy into India's Electric Grid, Vol. II - Regional Study' (the Regional Study), which better represents the impact of congestion on least-cost scheduling and dispatch, provides a deeper understanding of the relationship among renewable energy (RE) location, transmission, and system flexibility with regard to RE integration, compared to 'Greening the Grid: Pathways to Integrate 175 Gigawatts of Renewable Energy into India's Electric Grid, Vol. I - National Study.' The Regional Study validates the relative value of mitigation strategies demonstrated in the National Study - namely, coordinatedmore » operations among states reduce production costs, and reducing coal minimum generation levels reduces RE curtailment. Significantly, the Regional Study also highlights a potential barrier to realizing the value of these mitigation strategies: when locations of RE development are planned independently of state-level transmission, intrastate congestion can result in undesirable levels of RE curtailment. Therefore a key objective of this study is to illustrate to state-level power system planners and operators, in particular, how a higher-resolution model, inclusive of intrastate granularity, can be used as a planning tool for two primary purposes: -To better anticipate, understand, and mitigate system constraints that could affect RE integration; and - To provide a modeling framework that can be used as part of future transmission studies and planning efforts. The Regional Study is not intended to predict precisely how RE will affect state-level operations. There is considerable uncertainty regarding the locations of the RE development, as well as how contract terms can affect access to the inherent physical flexibility of the system. But the scenarios analyzed identify the types of issues that can arise under various RE and transmission expansion pathways. The model developed for this study provides a rigorous framework for future work and can be updated with the characteristics of new capacity as more information on the future power system is known.« less

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

Representative Agricultural Pathways and Climate Impact Assessment for Pacific Northwest Agricultural Systems

NASA Astrophysics Data System (ADS)

MU, J.; Antle, J. M.; Zhang, H.; Capalbo, S. M.; Eigenbrode, S.; Kruger, C.; Stockle, C.; Wolfhorst, J. D.

2013-12-01

Representative Agricultural Pathways (RAPs) are projections of plausible future biophysical and socio-economic conditions used to carry out climate impact assessments for agriculture. The development of RAPs iss motivated by the fact that the various global and regional models used for agricultural climate change impact assessment have been implemented with individualized scenarios using various data and model structures, often without transparent documentation or public availability. These practices have hampered attempts at model inter-comparison, improvement, and synthesis of model results across studies. This paper aims to (1) present RAPs developed for the principal wheat-producing region of the Pacific Northwest, and to (2) combine these RAPs with downscaled climate data, crop model simulations and economic model simulations to assess climate change impacts on winter wheat production and farm income. This research was carried out as part of a project funded by the USDA known as the Regional Approaches to Climate Change in the Pacific Northwest (REACCH). The REACCH study region encompasses the major winter wheat production area in Pacific Northwest and preliminary research shows that farmers producing winter wheat could benefit from future climate change. However, the future world is uncertain in many dimensions, including commodity and input prices, production technology, and policies, as well as increased probability of disturbances (pests and diseases) associated with a changing climate. Many of these factors cannot be modeled, so they are represented in the regional RAPS. The regional RAPS are linked to global agricultural and shared social-economic pathways, and used along with climate change projections to simulate future outcomes for the wheat-based farms in the REACCH region.

Emerging evidence on the role of the Hippo/YAP pathway in liver physiology and cancer.

PubMed

Yimlamai, Dean; Fowl, Brendan H; Camargo, Fernando D

2015-12-01

The Hippo pathway and its regulatory target, YAP, has recently emerged as an important biochemical signaling pathway that tightly governs epithelial tissue growth. Initially defined in Drosophilia, this pathway has shown remarkable conservation in vertebrate systems with many components of the Hippo/YAP pathway showing biochemical and functional conservation. The liver is particularly sensitive to changes in Hippo/YAP signaling with rapid increases in liver size becoming manifest on the order of days to weeks after perturbation. The first identified direct targets of Hippo/YAP signaling were pro-proliferative and anti-apoptotic gene programs, but recent work has now implicated this pathway in cell fate choice, stem cell maintenance/renewal, epithelial to mesenchymal transition, and oncogenesis. The mechanisms by which Hippo/YAP signaling is changed endogenously are beginning to come to light as well as how this pathway interacts with other signaling pathways, and important details for designing new therapeutic interventions. This review focuses on the known roles for Hippo/YAP signaling in the liver and promising avenues for future study. Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Adjusting Mitigation Pathways to Stabilize Climate at 1.5°C and 2.0°C Rise in Global Temperatures to Year 2300

NASA Astrophysics Data System (ADS)

Goodwin, Philip; Brown, Sally; Haigh, Ivan David; Nicholls, Robert James; Matter, Juerg M.

2018-03-01

To avoid the most dangerous consequences of anthropogenic climate change, the Paris Agreement provides a clear and agreed climate mitigation target of stabilizing global surface warming to under 2.0°C above preindustrial, and preferably closer to 1.5°C. However, policy makers do not currently know exactly what carbon emissions pathways to follow to stabilize warming below these agreed targets, because there is large uncertainty in future temperature rise for any given pathway. This large uncertainty makes it difficult for a cautious policy maker to avoid either: (1) allowing warming to exceed the agreed target or (2) cutting global emissions more than is required to satisfy the agreed target, and their associated societal costs. This study presents a novel Adjusting Mitigation Pathway (AMP) approach to restrict future warming to policy-driven targets, in which future emissions reductions are not fully determined now but respond to future surface warming each decade in a self-adjusting manner. A large ensemble of Earth system model simulations, constrained by geological and historical observations of past climate change, demonstrates our self-adjusting mitigation approach for a range of climate stabilization targets ranging from 1.5°C to 4.5°C, and generates AMP scenarios up to year 2300 for surface warming, carbon emissions, atmospheric CO2, global mean sea level, and surface ocean acidification. We find that lower 21st century warming targets will significantly reduce ocean acidification this century, and will avoid up to 4 m of sea-level rise by year 2300 relative to a high-end scenario.

Adaptation Pathway of Low Impact Development Planning under Climate Change for a Sustainable Rural Community

NASA Astrophysics Data System (ADS)

Chen, P. Y.; Tung, C. P.

2016-12-01

The study focuses on developing the methodology of adaptation pathway for storm water management in a community scale. Following previous results on adaptation procedures including problem and goal setup, current risk assessment and analysis, future risk assessment and analysis, and adaptation options identification and evaluation, the study aims at analyzing adaptation pathway planning and implementation, namely the fifth step, for applying low impact development (LID). Based on the efficacy analyses of the feasible adaptation options, an adaptation pathway map can be build. Each pathway is a combination of the adaptation measures arranged in certain order. The developed adaptation pathway map visualizes the relative effectiveness and the connection of the adaptation measures. In addition, the tipping points of the system can be clearly identified and the triggers can be defined accordingly. There are multiple choices of pathways in an adaptation pathway map, which can be referred as pathway candidates. To ensure the applicability and operability, the methodology of adaptation pathway analysis is applied to a case study. Required information for developing an adaptation pathway map includes the scores of the adaptation options on the criteria, namely the effects, costs, immediacy, and side effect. Feasible adaptation options for the design case are dredging, pipeline expansion, pumping station, LID and detention pond. By ranking the options according to the criteria, LID is found dominating dredging and pumping station in this case. The information of the pathway candidates can be further used by the stakeholders to select the most suitable and promising pathway.

Evaluation of additional biogeochemical impacts on mitigation pathways in an energy sytem integrated assessment model.

NASA Astrophysics Data System (ADS)

Dessens, O.

2017-12-01

Within the last IPCC AR5 a large and systematic sensitivity study around available technologies and timing of policies applied in IAMs to achieve the 2°C target has been conducted. However the simple climate representations included in IAMs are generally tuned to the results of ensemble means. This may result in hiding within the ensemble mean results possible challenging mitigation pathways for the economy or the technology future scenarios. This work provides new insights on the sensitivity of the socio-economic response to different climate factors under a 2°C climate change target in order to help guide future efforts to reduce uncertainty in the climate mitigation decisions. The main objective is to understand and bring new insights on how future global warming will affect the natural biochemical feedbacks on the climate system and what could be the consequences of these feedbacks on the anthropogenic emission pathways with a specific focus on the energy-economy system. It specifically focuses on three issues of the climate representation affecting the energy system transformation and GHG emissions pathways: 1- Impacts of the climate sensitivity (or TCR); 2- Impacts of warming on the radiative forcing (cloudiness,...); 3- Impacts of warming on the carbon cycle (carbon cycle feedback). We use the integrated assessment model TIAM-UCL to examine the mitigation pathways compatible with the 2C target depending on assumptions regarding the 3 issues of the climate representation introduced above. The following key conclusions drawn from this study are that mitigation to 2°C is still possible under strong climate sensitivity (TCR), strong carbon cycle amplification or positive radiative forcing feedback. However, this level of climate mitigation will require a significant transformation in the way we produce and consume energy. Carbon capture and sequestration on electricity generation, industry and biomass is part of the technology pool needed to achieve this level of decarbonisation. In extreme condition (positive correlation between the 3 issues discussed) the integrated assessment model TIAM-UCL creates pathways requiring additional negative emission technologies at the end of this century to keep temperature change well below 2°C.

Businesses Partner with Schools, Community to Create Alternative Career Pathways

ERIC Educational Resources Information Center

Overman, Stephenie

2012-01-01

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

Constraints on biomass energy deployment in mitigation pathways: the case of water scarcity

NASA Astrophysics Data System (ADS)

Séférian, Roland; Rocher, Matthias; Guivarch, Céline; Colin, Jeanne

2018-05-01

To limit global warming to well below 2 ° most of the IPCC-WGIII future stringent mitigation pathways feature a massive global-scale deployment of negative emissions technologies (NETs) before the end of the century. The global-scale deployment of NETs like Biomass Energy with Carbon Capture and Storage (BECCS) can be hampered by climate constraints that are not taken into account by Integrated assessment models (IAMs) used to produce those pathways. Among the various climate constraints, water scarcity appears as a potential bottleneck for future land-based mitigation strategies and remains largely unexplored. Here, we assess climate constraints relative to water scarcity in response to the global deployment of BECCS. To this end, we confront results from an Earth system model (ESM) and an IAM under an array of 25 stringent mitigation pathways. These pathways are compatible with the Paris Agreement long-term temperature goal and with cumulative carbon emissions ranging from 230 Pg C and 300 Pg C from January 1st onwards. We show that all stylized mitigation pathways studied in this work limit warming below 2 °C or even 1.5 °C by 2100 but all exhibit a temperature overshoot exceeding 2 °C after 2050. According to the IAM, a subset of 17 emission pathways are feasible when evaluated in terms of socio-economic and technological constraints. The ESM however shows that water scarcity would limit the deployment of BECCS in all the mitigation pathways assessed in this work. Our findings suggest that the evolution of the water resources under climate change can exert a significant constraint on BECCS deployment before 2050. In 2100, the BECCS water needs could represent more than 30% of the total precipitation in several regions like Europe or Asia.

Geoscience Academic Provenance: A Comparison of Undergraduate Students' Pathways to Faculty Pathways

NASA Astrophysics Data System (ADS)

Houlton, H. R.; Keane, C. M.; Wilson, C. E.

2012-12-01

Most Science, Technology, Engineering and Mathematics (STEM) disciplines have a direct recruiting method of high school science courses to supply their undergraduate majors. However, recruitment and retention of students into geoscience academic programs, who will be the future workforce, remains an important issue. The geoscience community is reaching a critical point in its ability to supply enough geoscientists to meet the current and near-future demand. Previous work done by Houlton (2010) determined that undergraduate geoscience majors follow distinct pathways when pursuing their degree and career. These pathways are comprised of students' interests, experiences, goals and career aspirations, which are depicted in six pathway steps. Three population groups were determined from the original 17 participants, which exhibited differences in pathway trajectories. Continued data collection efforts developed and refined the pathway framework. As part of an informal workshop activity, data were collected from 27 participants who are underrepresented minority early-career and future faculty in the geosciences. In addition, 20 geoscience departments' Heads and Chairs participated in an online survey about their pathway trajectories. Pathways were determined from each of these new sample populations and compared against the original geoscience undergraduate student participants. Several pathway components consistently spanned across sample populations. Identification of these themes have illuminated broad geoscience-related interests, experiences and aspirations that can be used to broadly impact recruitment and retention initiatives for our discipline. Furthermore, fundamental differences between participants' ages, stages in career and racial/ethnic backgrounds have exhibited subtle nuances in their geoscience pathway trajectories. In particular, those who've had research experiences, who think "creativity" is an important aspect of a geoscience career and those who want to share their knowledge with students may be more inclined to pursue academic positions. Indicators, like these, expand the pathway model and foster the development of a more robust framework for recruitment and retention in academia, as well as industry.

Design of Adaptive Policy Pathways under Deep Uncertainties

NASA Astrophysics Data System (ADS)

Babovic, Vladan

2013-04-01

The design of large-scale engineering and infrastructural systems today is growing in complexity. Designers need to consider sociotechnical uncertainties, intricacies, and processes in the long- term strategic deployment and operations of these systems. In this context, water and spatial management is increasingly challenged not only by climate-associated changes such as sea level rise and increased spatio-temporal variability of precipitation, but also by pressures due to population growth and particularly accelerating rate of urbanisation. Furthermore, high investment costs and long term-nature of water-related infrastructure projects requires long-term planning perspective, sometimes extending over many decades. Adaptation to such changes is not only determined by what is known or anticipated at present, but also by what will be experienced and learned as the future unfolds, as well as by policy responses to social and water events. As a result, a pathway emerges. Instead of responding to 'surprises' and making decisions on ad hoc basis, exploring adaptation pathways into the future provide indispensable support in water management decision-making. In this contribution, a structured approach for designing a dynamic adaptive policy based on the concepts of adaptive policy making and adaptation pathways is introduced. Such an approach provides flexibility which allows change over time in response to how the future unfolds, what is learned about the system, and changes in societal preferences. The introduced flexibility provides means for dealing with complexities of adaptation under deep uncertainties. It enables engineering systems to change in the face of uncertainty to reduce impacts from downside scenarios while capitalizing on upside opportunities. This contribution presents comprehensive framework for development and deployment of adaptive policy pathway framework, and demonstrates its performance under deep uncertainties on a case study related to urban water catchment in Singapore. Ingredients of this approach are: (a) transient scenarios (time series of various uncertain developments such as climate change, economic developments, societal changes), (b) a methodology for exploring many options and sequences of these options across different futures, and (c) a stepwise policy analysis. The strategy is applied on case of flexible deployment of novel, so-called Next Generation Infrastructure, and assessed in context of the proposed. Results of the study show that flexible design alternatives deliver much enhanced performance compared to systems optimized under deterministic forecasts of the future. The work also demonstrates that explicit incorporation of uncertainty and flexibility into decision-making process reduces capital expenditures while allowing decision makers to learn about system evolution throughout the lifetime of the project.

Biomarkers and patient selection for PI3K/Akt/mTOR targeted therapies: current status and future directions.

PubMed

Bartlett, John M S

2010-11-01

The phosphatidylinositol 3-kinase (PI3K)/Akt/ mammalian target of rapamycin (mTOR) pathway regulates a broad spectrum of physiologic and pathologic processes. In breast cancer mutation, amplification, deletion, methylation, and posttranslational modifications lead to significant dysregulation of this pathway leading to more aggressive and potentially drug-resistant disease. Multiple novel agents, targeting different nodes within the pathway are currently under development by both commercial and academic partners. The key to the successful validation of these markers is selection of the appropriate patient groups using biomarkers. This article reviews current progress in this area, highlighting the key molecular alterations described in genes within the PI3K/Akt/mTOR pathway that may have an effect on response to current and future therapeutic interventions. Herein, gaps in current knowledge are highlighted and suggestions for future research directions given that may facilitate biomarker development in partnership with current drug development.

A New Method of Providing Communities With High-Resolution Maps of Present and Future Inundation Pathways: Two Examples From Massachusetts

NASA Astrophysics Data System (ADS)

Borrelli, M.; Mague, S. T.; Smith, T. L.

2015-12-01

A new method of mapping storm-tide (inundation) pathways and linking those data with tidal elevations in real-time for local managers is being developed. Separate, ongoing studies in two coastal towns in Massachusetts have demonstrated the strengths of this method. High-resolution lidar datasets are imported into 3D data visualization software and water levels are raised incrementally from the highest spring tide of the year to the storm of record +1 m. This range was identified to include 'nuisance flooding' as well as present and future inundation pathways not yet observed by local authorities caused by storms superimposed on projected sea level rise. Potential storm-tide pathways are identified using Lidar data but are then verified with extensive fieldwork using RTK-GPS instruments (tested vertical accuracy of 4.9 cm at 95%) to overcome the vertical uncertainty associated with Lidar data. The fieldwork serves two purposes, first is to field check the lidar data with the highest resolution instrument available and, second to verify and document the presence or absence of a storm-tide pathway. Having developed the map of storm tide pathways within a GIS environment referenced to a geodetic datum (NAVD88), a tide gauge or staff is installed in the town's harbor or other sheltered coastal area and the elevations of all storm tide pathways are then referenced to the local tidal datum. The benefit here is three-fold. First, local officials can use the high-resolution data set that is tied to a local tidal datum to autonomously monitor predicted storm surges and be prepared for inundation at sites prior to flooding. Second, storm-tide pathways that have heretofore never been inundated can be identified and steps can be taken to remove or minimize flooding hazards. Finally, identification of present and future storm tide pathways can be used to prioritize and budget proactive solutions in response to increases in chronic, nuisance and more frequent flooding associated with sea level rise and climate change. This method does not rely on costly numerical models that are often too coarsely gridded to be of use on a street-by-street basis. Lidar data are publicly available in many coastal areas and can be used with little training to new or already existing local or regional GIS staff.

Ethnic identity and mental health in American Indian youth: examining mediation pathways through self-esteem, and future optimism.

PubMed

Smokowski, Paul R; Evans, Caroline B R; Cotter, Katie L; Webber, Kristina C

2014-03-01

Mental health functioning in American Indian youth is an understudied topic. Given the increased rates of depression and anxiety in this population, further research is needed. Using multiple group structural equation modeling, the current study illuminates the effect of ethnic identity on anxiety symptoms, depressive symptoms, and externalizing behavior in a group of Lumbee adolescents and a group of Caucasian, African American, and Latino/Hispanic adolescents. This study examined two possible pathways (i.e., future optimism and self-esteem) through which ethnic identity is associated with adolescent mental health. The sample (N = 4,714) is 28.53% American Indian (Lumbee) and 51.38% female. The study findings indicate that self-esteem significantly mediated the relationships between ethnic identity and anxiety symptoms, depressive symptoms, and externalizing behavior for all racial/ethnic groups (i.e., the total sample). Future optimism significantly mediated the relationship between ethnic identity and externalizing behavior for all racial/ethnic groups and was a significant mediator between ethnic identity and depressive symptoms for American Indian youth only. Fostering ethnic identity in all youth serves to enhance mental health functioning, but is especially important for American Indian youth due to the collective nature of their culture.

Coping Skills Help Explain How Future-Oriented Adolescents Accrue Greater Well-Being Over Time.

PubMed

Chua, Li Wen; Milfont, Taciano L; Jose, Paul E

2015-11-01

Adolescents who endorse greater levels of future orientation report greater well-being over time, but we do not know the mechanism by which this happens. The present longitudinal study examined whether both adaptive as well as maladaptive coping strategies might explain how future orientation leads to ill-being and well-being over time in young New Zealanders. A sample of 1,774 preadolescents and early adolescents (51.9 % female) aged 10-15 years at Time 1 completed a self-report survey three times with 1 year intervals in between. Longitudinal mediation path models were constructed to determine whether and how maladaptive and adaptive coping strategies at Time 2 functioned as mediators between future orientation at Time 1 and ill-being and well-being at Time 3. Results showed that future orientation predicted lower maladaptive coping, which in turn predicted lower substance use and self-harming behavior. All three well-being outcomes (i.e., happiness with weight, vitality, and sleep) were consistently predicted by future orientation, and all three pathways were mediated by both lower maladaptive and higher adaptive coping strategies (with the exception of happiness with weight, which was mediated only by lower maladaptive coping). The results suggest that several pathways by which future orientation leads to greater well-being occurs through an increased use of adaptive coping, a decreased use of maladaptive coping, or both.

An Evaluation of the Implementation of Maternal Obesity Pathways of Care: A Mixed Methods Study with Data Integration

PubMed Central

Heslehurst, Nicola; Dinsdale, Sarah; Sedgewick, Gillian; Simpson, Helen; Sen, Seema; Summerbell, Carolyn Dawn; Rankin, Judith

2015-01-01

Objectives Maternal obesity has multiple associated risks and requires substantial intervention. This research evaluated the implementation of maternal obesity care pathways from multiple stakeholder perspectives. Study Design A simultaneous mixed methods model with data integration was used. Three component studies were given equal priority. 1: Semi-structured qualitative interviews explored obese pregnant women’s experiences of being on the pathways. 2: A quantitative and qualitative postal survey explored healthcare professionals’ experiences of delivering the pathways. 3: A case note audit quantitatively assessed pathway compliance. Data were integrated using following a thread and convergence coding matrix methods to search for agreement and disagreement between studies. Results Study 1: Four themes were identified: women’s overall (positive and negative) views of the pathways; knowledge and understanding of the pathways; views on clinical and weight management advice and support; and views on the information leaflet. Key results included positive views of receiving additional clinical care, negative experiences of risk communication, and weight management support was considered a priority. Study 2: Healthcare professionals felt the pathways were worthwhile, facilitated good practice, and increased confidence. Training was consistently identified as being required. Healthcare professionals predominantly focussed on women’s response to sensitive obesity communication. Study 3: There was good compliance with antenatal clinical interventions. However, there was poor compliance with public health and postnatal interventions. There were some strong areas of agreement between component studies which can inform future development of the pathways. However, disagreement between studies included a lack of shared priorities between healthcare professionals and women, different perspectives on communication issues, and different perspectives on women’s prioritisation of weight management. Conclusion The differences between healthcare professionals’ and women’s priorities and perspectives are important factors to consider when developing care pathways. Shared perspectives could help facilitate more effective implementation of the pathway interventions that have poor compliance. PMID:26018338

Unemployment, informal work, precarious employment, child labor, slavery, and health inequalities: pathways and mechanisms.

PubMed

Muntaner, Carles; Solar, Orielle; Vanroelen, Christophe; Martínez, José Miguel; Vergara, Montserrat; Santana, Vilma; Castedo, Antía; Kim, Il-Ho; Benach, Joan

2010-01-01

The study explores the pathways and mechanisms of the relation between employment conditions and health inequalities. A significant amount of published research has proved that workers in several risky types of labor--precarious employment, unemployment, informal labor, child and bonded labor--are exposed to behavioral, psychosocial, and physio-pathological pathways leading to physical and mental health problems. Other pathways, linking employment to health inequalities, are closely connected to hazardous working conditions (material and social deprivation, lack of social protection, and job insecurity), excessive demands, and unattainable work effort, with little power and few rewards (in salaries, fringe benefits, or job stability). Differences across countries in the social contexts and types of jobs result in varying pathways, but the general conceptual model suggests that formal and informal power relations between employees and employers can determine health conditions. In addition, welfare state regimes (unionization and employment protection) can increase or decrease the risk of mortality, morbidity, and occupational injury. In a multilevel context, however, these micro- and macro-level pathways have yet to be fully studied, especially in middle- and low-income countries. The authors recommend some future areas of study on the pathways leading to employment-related health inequalities, using worldwide standard definitions of the different forms of labor, authentic data, and a theoretical framework.

Proteomic analysis of peel browning of 'Nanguo' pears after low-temperature storage.

PubMed

Wang, Jun-Wei; Zhou, Xin; Zhou, Qian; Liu, Zhi-Yong; Sheng, Lei; Wang, Long; Cheng, Shun-Chang; Ji, Shu-Juan

2017-06-01

Postharvest ripening of the 'Nanguo' pear (Pyrus ussuriensis Maxim.) can be impeded by low-temperature storage. However, pears after long-term refrigeration are prone to peel browning when returned to room temperature conditions. This study investigated the browning mechanism of 'Nanguo' pear stored at a low temperature by analysing the differentially expressed proteins between healthy fruit and fruit with peel browning. The results showed that 181 proteins underwent statistically significant changes. A categorisation of the disparately accumulated proteins was performed using gene ontology annotation. The results showed that the 'metabolic process', 'cellular process', 'catalytic activity', and 'binding' proteins were the most affected after low-temperature storage. Further analysis revealed that the differentially expressed proteins, which are related to peel browning, are primarily involved in the phenylpropanoid pathway, linoleic acid pathways, fatty acid biosynthesis pathway, glutathione metabolism pathway, photosynthesis pathway, oxidative phosphorylation pathway, and glycolysis pathway. This study reveals that there are variations in key proteins in 'Nanguo' pear after low-temperature storage, and the identification of these proteins will be valuable in future functional genomics studies, as well as provide protein resources that can be used in the efforts to improve pear quality. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.

Lens fibre cell differentiation and organelle loss: many paths lead to clarity

PubMed Central

Wride, Michael A.

2011-01-01

The programmed removal of organelles from differentiating lens fibre cells contributes towards lens transparency through formation of an organelle-free zone (OFZ). Disruptions in OFZ formation are accompanied by the persistence of organelles in lens fibre cells and can contribute towards cataract. A great deal of work has gone into elucidating the nature of the mechanisms and signalling pathways involved. It is apparent that multiple, parallel and redundant pathways are involved in this process and that these pathways form interacting networks. Furthermore, it is possible that the pathways can functionally compensate for each other, for example in mouse knockout studies. This makes sense given the importance of lens clarity in an evolutionary context. Apoptosis signalling and proteolytic pathways have been implicated in both lens fibre cell differentiation and organelle loss, including the Bcl-2 and inhibitor of apoptosis families, tumour necrosis factors, p53 and its regulators (such as Mdm2) and proteolytic enzymes, including caspases, cathepsins, calpains and the ubiquitin–proteasome pathway. Ongoing approaches being used to dissect the molecular pathways involved, such as transgenics, lens-specific gene deletion and zebrafish mutants, are discussed here. Finally, some of the remaining unresolved issues and potential areas for future studies are highlighted. PMID:21402582

Characterization of Chiton Ischnochiton hakodadensis Foot Based on Transcriptome Sequencing

NASA Astrophysics Data System (ADS)

Dou, Huaiqian; Miao, Yan; Li, Yuli; Li, Yangping; Dai, Xiaoting; Zhang, Xiaokang; Liang, Pengyu; Liu, Weizhi; Wang, Shi; Bao, Zhenmin

2018-06-01

Chiton ( Ischnochiton hakodadensis) is one of marine mollusks well known for its eight separate shell plates. I. hakodadensis is important, which plays a vital role in the ecosystems it inhabits. So far, the genetic studies on the chiton are scarce due in part to insufficient genomic resources available for this species. In this study, we investigated the transcriptome of the chiton foot using Illumina sequencing technology. The reads were assembled and clustered into 256461 unigenes, of which 42247 were divided into diverse functional categories by Gene Ontology (GO) annotation terms, and 17256 mapped onto 365 pathways by KEGG pathway mapping. Meanwhile, a set of differentially expressed genes (DEGs) between distal and proximal muscles were identified as the foot adhesive locomotion associated, thus were useful for our future studies. Moreover, up to 679384 high-quality single nucleotide polymorphisms (SNPs) and 19814 simple sequence repeats (SSRs) were identified in this study, which are valuable for subsequent studies on genetic diversity and variation. The transcriptomic resource obtained in this study should aid to future genetic and genomic studies of chiton.

Info-Gap robustness pathway method for transitioning of urban drainage systems under deep uncertainties.

PubMed

Zischg, Jonatan; Goncalves, Mariana L R; Bacchin, Taneha Kuzniecow; Leonhardt, Günther; Viklander, Maria; van Timmeren, Arjan; Rauch, Wolfgang; Sitzenfrei, Robert

2017-09-01

In the urban water cycle, there are different ways of handling stormwater runoff. Traditional systems mainly rely on underground piped, sometimes named 'gray' infrastructure. New and so-called 'green/blue' ambitions aim for treating and conveying the runoff at the surface. Such concepts are mainly based on ground infiltration and temporal storage. In this work a methodology to create and compare different planning alternatives for stormwater handling on their pathways to a desired system state is presented. Investigations are made to assess the system performance and robustness when facing the deeply uncertain spatial and temporal developments in the future urban fabric, including impacts caused by climate change, urbanization and other disruptive events, like shifts in the network layout and interactions of 'gray' and 'green/blue' structures. With the Info-Gap robustness pathway method, three planning alternatives are evaluated to identify critical performance levels at different stages over time. This novel methodology is applied to a real case study problem where a city relocation process takes place during the upcoming decades. In this case study it is shown that hybrid systems including green infrastructures are more robust with respect to future uncertainties, compared to traditional network design.

Whole genome survey of coding SNPs reveals a reproducible pathway determinant of Parkinson disease

PubMed Central

Srinivasan, Balaji S; Doostzadeh, Jaleh; Absalan, Farnaz; Mohandessi, Sharareh; Jalili, Roxana; Bigdeli, Saharnaz; Wang, Justin; Mahadevan, Jaydev; Lee, Caroline LG; Davis, Ronald W; William Langston, J; Ronaghi, Mostafa

2009-01-01

It is quickly becoming apparent that situating human variation in a pathway context is crucial to understanding its phenotypic significance. Toward this end, we have developed a general method for finding pathways associated with traits that control for pathway size. We have applied this method to a new whole genome survey of coding SNP variation in 187 patients afflicted with Parkinson disease (PD) and 187 controls. We show that our dataset provides an independent replication of the axon guidance association recently reported by Lesnick et al. [PLoS Genet 2007;3:e98], and also indicates that variation in the ubiquitin-mediated proteolysis and T-cell receptor signaling pathways may predict PD susceptibility. Given this result, it is reasonable to hypothesize that pathway associations are more replicable than individual SNP associations in whole genome association studies. However, this hypothesis is complicated by a detailed comparison of our dataset to the second recent PD association study by Fung et al. [Lancet Neurol 2006;5:911–916]. Surprisingly, we find that the axon guidance pathway does not rank at the very top of the Fung dataset after controlling for pathway size. More generally, in comparing the studies, we find that SNP frequencies replicate well despite technologically different assays, but that both SNP and pathway associations are globally uncorrelated across studies. We thus have a situation in which an association between axon guidance pathway variation and PD has been found in 2 out of 3 studies. We conclude by relating this seeming inconsistency to the molecular heterogeneity of PD, and suggest future analyses that may resolve such discrepancies. PMID:18853455

Communication of Career Pathways Through Associate Degree Program Web Sites: A Baseline Assessment.

PubMed

Becker, Ellen A; Vargas, Jenny

2018-05-08

The American Association for Respiratory Care sponsored a series of conferences that addressed the competency of the future workforce of respiratory therapists (RTs). Based upon the findings from those conferences, several initiatives emerged that support RTs earning a baccalaureate (or bachelor's) degree. The objective of this study was to identify the ways that associate degree programs communicate career pathways toward a baccalaureate degree through their Web sites. This cross-sectional observational study used a random sample of 100 of the 362 associate degree programs approved by the Commission on Accreditation for Respiratory Care. Data were collected from 3 specific categories: demographic data, baccalaureate completion information, and the Web page location for the program. The presence of statements related to any pathway toward a bachelor's degree, transfer credits, articulation agreements, and links for baccalaureate completion were recorded. The descriptive statistics in this study were reported as total numbers and percentages. Of the 100 programs in the random sample, only 89 were included in the study. Only 39 (44%) programs had links on their program Web site that had any content related to bachelor's degrees, 16 (18%) identified college transfer courses toward a bachelor's degree, and 26 (29%) programs included baccalaureate articulation agreements on their Web site. A minority of associate degree programs communicated career pathway information to their prospective and current students through program Web sites. An informative Web site would make the path more transparent for entry-level students to meet their future educational needs as their careers progress. Copyright © 2018 by Daedalus Enterprises.

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

PubMed

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

2017-08-01

The objective of the present study was to identify altered pathways in breast cancer based on the individualized pathway aberrance score (iPAS) method combined with the normal reference (nRef). There were 4 steps to identify altered pathways using the iPAS method: Data preprocessing conducted by the robust multi-array average (RMA) algorithm; gene-level statistics based on average Z ; pathway-level statistics according to iPAS; and a significance test dependent on 1 sample Wilcoxon test. The altered pathways were validated by calculating the changed percentage of each pathway in tumor samples and comparing them with pathways from differentially expressed genes (DEGs). A total of 688 altered pathways with P<0.01 were identified, including kinesin (KIF)- and polo-like kinase (PLK)-mediated events. When the percentage of change reached 50%, 310 pathways were involved in the total 688 altered pathways, which may validate the present results. In addition, there were 324 DEGs and 155 common genes between DEGs and pathway genes. DEGs and common genes were enriched in the same 9 significant terms, which also were members of altered pathways. The iPAS method was suitable for identifying altered pathways in breast cancer. Altered pathways (such as KIF and PLK mediated events) were important for understanding breast cancer mechanisms and for the future application of customized therapeutic decisions.

Rising utilization of inpatient pediatric asthma pathways.

PubMed

Kaiser, Sunitha V; Rodean, Jonathan; Bekmezian, Arpi; Hall, Matt; Shah, Samir S; Mahant, Sanjay; Parikh, Kavita; Morse, Rustin; Puls, Henry; Cabana, Michael D

2018-02-01

Clinical pathways are detailed care plans that operationalize evidence-based guidelines into an accessible format for health providers. Their goal is to link evidence to practice to optimize patient outcomes and delivery efficiency. It is unknown to what extent inpatient pediatric asthma pathways are being utilized nationally. (1) Describe inpatient pediatric asthma pathway design and implementation across a large hospital network. (2) Compare characteristics of hospitals with and without pathways. We conducted a descriptive, cross-sectional, survey study of hospitals in the Pediatric Research in Inpatient Settings Network (75% children's hospitals, 25% community hospitals). Our survey determined if each hospital used a pathway and pathway characteristics (e.g. pathway elements, implementation methods). Hospitals with and without pathways were compared using Chi-square tests (categorical variables) and Student's t-tests (continuous variables). Surveys were distributed to 3-5 potential participants from each hospital and 302 (74%) participants responded, representing 86% (106/123) of surveyed hospitals. From 2005-2015, the proportion of hospitals utilizing inpatient asthma pathways increased from 27% to 86%. We found variation in pathway elements, implementation strategies, electronic medical record integration, and compliance monitoring across hospitals. Hospitals with pathways had larger inpatient pediatric programs [mean 12.1 versus 6.1 full-time equivalents, p = 0.04] and were more commonly free-standing children's hospitals (52% versus 23%, p = 0.05). From 2005-2015, there was a dramatic rise in implementation of inpatient pediatric asthma pathways. We found variation in many aspects of pathway design and implementation. Future studies should determine optimal implementation strategies to better support hospital-level efforts in improving pediatric asthma care and outcomes.

Pathways to delinquency and substance use among African American youth: Does future orientation mediate the effects of peer norms and parental monitoring?

PubMed

Marotta, Phillip L; Voisin, Dexter R

2017-10-01

The following study assessed whether future orientation mediated the effects of peer norms and parental monitoring on delinquency and substance use among 549 African American adolescents. Structural equation modeling computed direct and indirect (meditational) relationships between parental monitoring and peer norms through future orientation. Parental monitoring significantly correlated with lower delinquency through future orientation ( B = -.05, standard deviation = .01, p < .01). Future orientation mediated more than quarter (27.70%) of the total effect of parental monitoring on delinquency. Overall findings underscore the importance of strengthening resilience factors for African American youth, especially those who live in low-income communities.

Scenarios for the risk of hunger in the twenty-first century using Shared Socioeconomic Pathways

NASA Astrophysics Data System (ADS)

Hasegawa, Tomoko; Fujimori, Shinichiro; Takahashi, Kiyoshi; Masui, Toshihiko

2015-01-01

Shared socioeconomic pathways (SSPs) are being developed internationally for cross-sectoral assessments of climate change impacts, adaptation, and mitigation. These are five scenarios that include both qualitative and quantitative information for mitigation and adaptation challenges to climate change. In this study, we quantified scenarios for the risk of hunger in the 21st century using SSPs, and clarified elements that influence future hunger risk. There were two primary findings: (1) risk of hunger in the 21st-century greatly differed among five SSPs; and (2) population growth, improvement in the equality of food distribution within a country, and increases in food consumption mainly driven by income growth greatly influenced future hunger risk and were important elements in its long-term assessment.

Base excision repair in Archaea: back to the future in DNA repair.

PubMed

Grasso, Stefano; Tell, Gianluca

2014-09-01

Together with Bacteria and Eukarya, Archaea represents one of the three domain of life. In contrast with the morphological difference existing between Archaea and Eukarya, these two domains are closely related. Phylogenetic analyses confirm this evolutionary relationship showing that most of the proteins involved in DNA transcription and replication are highly conserved. On the contrary, information is scanty about DNA repair pathways and their mechanisms. In the present review the most important proteins involved in base excision repair, namely glycosylases, AP lyases, AP endonucleases, polymerases, sliding clamps, flap endonucleases, and ligases, will be discussed and compared with bacterial and eukaryotic ones. Finally, possible applications and future perspectives derived from studies on Archaea and their repair pathways, will be taken into account. Copyright © 2014 Elsevier B.V. All rights reserved.

A transcriptional profile of the decidua in preeclampsia

PubMed Central

LØSET, Mari; MUNDAL, Siv B.; JOHNSON, Matthew P.; FENSTAD, Mona H.; FREED, Katherine A.; LIAN, Ingrid A.; EIDE, Irina P.; BJØRGE, Line; BLANGERO, John; MOSES, Eric K.; AUSTGULEN, Rigmor

2010-01-01

OBJECTIVE To obtain insight into possible mechanisms underlying preeclampsia using genome-wide transcriptional profiling in decidua basalis. STUDY DESIGN Genome-wide transcriptional profiling was performed on decidua basalis tissue from preeclamptic (n = 37) and normal pregnancies (n = 58). Differentially expressed genes were identified and merged into canonical pathways and networks. RESULTS Of the 26,504 expressed transcripts detected, 455 were differentially expressed (P <0.05, FDR P <0.1). Both novel (ARL5B, SLITRK4) and previously reported preeclampsia-associated genes (PLA2G7, HMOX1) were identified. Pathway analysis revealed that ‘tryptophan metabolism’, ‘endoplasmic reticulum stress’, ‘linoleic acid metabolism’, ‘notch signaling’, ‘fatty acid metabolism’, ‘arachidonic acid metabolism’ and ‘NRF2-mediated oxidative stress response’ were overrepresented canonical pathways. CONCLUSION In the present study single genes, canonical pathways and gene-gene networks that are likely to play an important role in the pathogenesis of preeclampsia, have been identified. Future functional studies are needed to accomplish a greater understanding of the mechanisms involved. PMID:20934677

When Clock Time Governs Interaction: How Time Influences Health Professionals' Intersectoral Collaboration.

PubMed

Bendix Andersen, Anne; Beedholm, Kirsten; Kolbæk, Raymond; Frederiksen, Kirsten

2018-06-01

When setting up patient pathways that cross health care sectors, professionals in emergency units strive to fulfill system requirements by creating efficient patient pathways that comply with standards for length of stay. We conducted an ethnographic field study, focusing on health professionals' collaboration, of 10 elderly patients with chronic illnesses, following them from discharge to their home or other places where they received health care services. We found that clock time not only governed the professionals' ways of collaborating, but acceleration of patient pathways also became an overall goal in health care delivery. Professionals' efforts to save time came to represent a "monetary value," leading to speedier planning of patient pathways and consequent risks of disregarding important issues when treating and caring for elderly patients. We suggest that such issues are significant to the future planning and improvement of patient pathways that involve elderly citizens who are in need of intersectoral health care delivery.

Supporting Adaptive Learning Pathways through the Use of Learning Analytics: Developments, Challenges and Future Opportunities

ERIC Educational Resources Information Center

Mavroudi, Anna; Giannakos, Michail; Krogstie, John

2018-01-01

Learning Analytics (LA) and adaptive learning are inextricably linked since they both foster technology-supported learner-centred education. This study identifies developments focusing on their interplay and emphasises insufficiently investigated directions which display a higher innovation potential. Twenty-one peer-reviewed studies are…

Cellular Organization and Cytoskeletal Regulation of the Hippo Signaling Network

PubMed Central

Sun, Shuguo; Irvine, Kenneth D.

2016-01-01

The Hippo signaling network integrates diverse upstream signals to control cell fate decisions and regulate organ growth. Recent studies have provided new insights into the cellular organization of Hippo signaling, its relationship to cell-cell junctions, and how the cytoskeleton modulates Hippo signaling. Cell-cell junctions serve as platforms for Hippo signaling by localizing scaffolding proteins that interact with core components of the pathway. Interactions of Hippo pathway components with cell-cell junctions and the cytoskeleton also suggest potential mechanisms for the regulation of the pathway by cell contact and cell polarity. As our understanding of the complexity of Hippo signaling increases, a future challenge will be to understand how the diverse inputs into the pathway are integrated, and to define their respective contributions in vivo. PMID:27268910

Dynamic regulation of genetic pathways and targets during aging in Caenorhabditis elegans.

PubMed

He, Kan; Zhou, Tao; Shao, Jiaofang; Ren, Xiaoliang; Zhao, Zhongying; Liu, Dahai

2014-03-01

Numerous genetic targets and some individual pathways associated with aging have been identified using the worm model. However, less is known about the genetic mechanisms of aging in genome wide, particularly at the level of multiple pathways as well as the regulatory networks during aging. Here, we employed the gene expression datasets of three time points during aging in Caenorhabditis elegans (C. elegans) and performed the approach of gene set enrichment analysis (GSEA) on each dataset between adjacent stages. As a result, multiple genetic pathways and targets were identified as significantly down- or up-regulated. Among them, 5 truly aging-dependent signaling pathways including MAPK signaling pathway, mTOR signaling pathway, Wnt signaling pathway, TGF-beta signaling pathway and ErbB signaling pathway as well as 12 significantly associated genes were identified with dynamic expression pattern during aging. On the other hand, the continued declines in the regulation of several metabolic pathways have been demonstrated to display age-related changes. Furthermore, the reconstructed regulatory networks based on three of aging related Chromatin immunoprecipitation experiments followed by sequencing (ChIP-seq) datasets and the expression matrices of 154 involved genes in above signaling pathways provide new insights into aging at the multiple pathways level. The combination of multiple genetic pathways and targets needs to be taken into consideration in future studies of aging, in which the dynamic regulation would be uncovered.

Genetic overlap between type 2 diabetes and major depressive disorder identified by bioinformatics analysis.

PubMed

Ji, Hong-Fang; Zhuang, Qi-Shuai; Shen, Liang

2016-04-05

Our study investigated the shared genetic etiology underlying type 2 diabetes (T2D) and major depressive disorder (MDD) by analyzing large-scale genome wide association studies statistics. A total of 496 shared SNPs associated with both T2D and MDD were identified at p-value ≤ 1.0E-07. Functional enrichment analysis showed that the enriched pathways pertained to immune responses (Fc gamma R-mediated phagocytosis, T cell and B cell receptors signaling), cell signaling (MAPK, Wnt signaling), lipid metabolism, and cancer associated pathways. The findings will have potential implications for future interventional studies of the two diseases.

Shared cognitive processes underlying past and future thinking: the impact of imagery and concurrent task demands on event specificity.

PubMed

Anderson, Rachel J; Dewhurst, Stephen A; Nash, Robert A

2012-03-01

Recent literature has argued that whereas remembering the past and imagining the future make use of shared cognitive substrates, simulating future events places heavier demands on executive resources. These propositions were explored in 3 experiments comparing the impact of imagery and concurrent task demands on speed and accuracy of past event retrieval and future event simulation. Results provide support for the suggestion that both past and future episodes can be constructed through 2 mechanisms: a noneffortful "direct" pathway and a controlled, effortful "generative" pathway. However, limited evidence emerged for the suggestion that simulating of future, compared with retrieving past, episodes places heavier demands on executive resources; only under certain conditions did it emerge as a more error prone and lengthier process. The findings are discussed in terms of how retrieval and simulation make use of the same cognitive substrates in subtly different ways. 2012 APA, all rights reserved

Does performance level affect initial ball flight kinematics in finger and wrist-spin cricket bowlers?

PubMed

Spratford, Wayne; Whiteside, David; Elliott, Bruce; Portus, Marc; Brown, Nicholas; Alderson, Jacqueline

2018-03-01

Spin bowling plays a fundamental role within the game of cricket yet little is known about the initial ball kinematics in elite and pathway spin bowlers or their relationship to performance. Therefore, the purpose of this study was to record three-dimensional ball kinematics in a large and truly high level cohort of elite and pathway finger-spin (FS) and wrist-spin (WS) bowlers, identifying potential performance measures that can be subsequently used in future research. A 22-camera Vicon motion analysis system captured retro-reflective markers placed on the seam (static) and ball (dynamic) to quantify ball kinematics in 36 FS (12 elite and 24 pathway) and 20 WS (eight elite and 12 pathway) bowlers. Results indicated that FS bowlers delivered the ball with an increased axis of rotation elevation, while wrist-spin bowlers placed greater amounts of revolutions on the ball. It also highlighted that ball release (BR) velocity, revolutions and velocity/revolution index scores for both groups and seam stability for FS bowlers, and seam azimuth angle and spin axis elevation angle for WS bowlers, were discriminators of playing level. As such these variables could be used as indicators of performance (i.e. performance measures) in future research.

Proteases for Processing Proneuropeptides into Peptide Neurotransmitters and Hormones

PubMed Central

Hook, Vivian; Funkelstein, Lydiane; Lu, Douglas; Bark, Steven; Wegrzyn, Jill; Hwang, Shin-Rong

2009-01-01

Peptide neurotransmitters and peptide hormones, collectively known as neuropeptides, are required for cell-cell communication in neurotransmission and for regulation of endocrine functions. Neuropeptides are synthesized from protein precursors (termed proneuropeptides or prohormones) that require proteolytic processing primarily within secretory vesicles that store and secrete the mature neuropeptides to control target cellular and organ systems. This review describes interdisciplinary strategies that have elucidated two primary protease pathways for prohormone processing consisting of the cysteine protease pathway mediated by secretory vesicle cathepsin L and the well-known subtilisin-like proprotein convertase pathway that together support neuropeptide biosynthesis. Importantly, this review discusses important areas of current and future biomedical neuropeptide research with respect to biological regulation, inhibitors, structural features of proneuropeptide and protease interactions, and peptidomics combined with proteomics for systems biological approaches. Future studies that gain in-depth understanding of protease mechanisms for generating active neuropeptides will be instrumental for translational research to develop pharmacological strategies for regulation of neuropeptide functions. Pharmacological applications for neuropeptide research may provide valuable therapeutics in health and disease. PMID:18184105

Comparison of human cell signaling pathway databases—evolution, drawbacks and challenges

PubMed Central

Chowdhury, Saikat; Sarkar, Ram Rup

2015-01-01

Elucidating the complexities of cell signaling pathways is of immense importance to gain understanding about various biological phenomenon, such as dynamics of gene/protein expression regulation, cell fate determination, embryogenesis and disease progression. The successful completion of human genome project has also helped experimental and theoretical biologists to analyze various important pathways. To advance this study, during the past two decades, systematic collections of pathway data from experimental studies have been compiled and distributed freely by several databases, which also integrate various computational tools for further analysis. Despite significant advancements, there exist several drawbacks and challenges, such as pathway data heterogeneity, annotation, regular update and automated image reconstructions, which motivated us to perform a thorough review on popular and actively functioning 24 cell signaling databases. Based on two major characteristics, pathway information and technical details, freely accessible data from commercial and academic databases are examined to understand their evolution and enrichment. This review not only helps to identify some novel and useful features, which are not yet included in any of the databases but also highlights their current limitations and subsequently propose the reasonable solutions for future database development, which could be useful to the whole scientific community. PMID:25632107

Enhanced recovery pathways in pancreatic surgery: State of the art

PubMed Central

Pecorelli, Nicolò; Nobile, Sara; Partelli, Stefano; Cardinali, Luca; Crippa, Stefano; Balzano, Gianpaolo; Beretta, Luigi; Falconi, Massimo

2016-01-01

Pancreatic surgery is being offered to an increasing number of patients every year. Although postoperative outcomes have significantly improved in the last decades, even in high-volume centers patients still experience significant postoperative morbidity and full recovery after surgery takes longer than we think. In recent years, enhanced recovery pathways incorporating a large number of evidence-based perioperative interventions have proved to be beneficial in terms of improved postoperative outcomes, and accelerated patient recovery in the context of gastrointestinal, genitourinary and orthopedic surgery. The role of these pathways for pancreatic surgery is still unclear as high-quality randomized controlled trials are lacking. To date, non-randomized studies have shown that care pathways for pancreaticoduodenectomy and distal pancreatectomy are safe with no difference in postoperative morbidity, leading to early discharge and no increase in hospital readmissions. Hospital costs are reduced due to better organization of care and resource utilization. However, further research is needed to clarify the effect of enhanced recovery pathways on patient recovery and post-discharge outcomes following pancreatic resection. Future studies should be prospective and follow recent recommendations for the design and reporting of enhanced recovery pathways. PMID:27605881

Eight-step method to build the clinical content of an evidence-based care pathway: the case for COPD exacerbation

PubMed Central

2012-01-01

Background Optimization of the clinical care process by integration of evidence-based knowledge is one of the active components in care pathways. When studying the impact of a care pathway by using a cluster-randomized design, standardization of the care pathway intervention is crucial. This methodology paper describes the development of the clinical content of an evidence-based care pathway for in-hospital management of chronic obstructive pulmonary disease (COPD) exacerbation in the context of a cluster-randomized controlled trial (cRCT) on care pathway effectiveness. Methods The clinical content of a care pathway for COPD exacerbation was developed based on recognized process design and guideline development methods. Subsequently, based on the COPD case study, a generalized eight-step method was designed to support the development of the clinical content of an evidence-based care pathway. Results A set of 38 evidence-based key interventions and a set of 24 process and 15 outcome indicators were developed in eight different steps. Nine Belgian multidisciplinary teams piloted both the set of key interventions and indicators. The key intervention set was judged by the teams as being valid and clinically applicable. In addition, the pilot study showed that the indicators were feasible for the involved clinicians and patients. Conclusions The set of 38 key interventions and the set of process and outcome indicators were found to be appropriate for the development and standardization of the clinical content of the COPD care pathway in the context of a cRCT on pathway effectiveness. The developed eight-step method may facilitate multidisciplinary teams caring for other patient populations in designing the clinical content of their future care pathways. PMID:23190552

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.

Replication and extension of the dual pathway model of disordered eating: The role of fear of negative evaluation, suggestibility, rumination, and self-compassion.

PubMed

Maraldo, Toni M; Zhou, Wanni; Dowling, Jessica; Vander Wal, Jillon S

2016-12-01

The dual pathway model, a theoretical model of eating disorder development, suggests that thin ideal internalization leads to body dissatisfaction which leads to disordered eating via the dual pathways of negative affect and dietary restraint. While the dual pathway model has been a valuable guide for eating disorder prevention, greater knowledge of characteristics that predict thin ideal internalization is needed. The present study replicated and extended the dual pathway model by considering the addition of fear of negative evaluation, suggestibility, rumination, and self-compassion in a sample of community women and female university students. Results showed that fear of negative evaluation and suggestibility predicted thin ideal internalization whereas rumination and self-compassion (inversely) predicted body dissatisfaction. Negative affect was predicted by fear of negative evaluation, rumination, and self-compassion (inversely). The extended model fit the data well in both samples. Analogue and longitudinal study of these constructs is warranted in future research. Copyright © 2016 Elsevier Ltd. All rights reserved.

A System-Level Pathway-Phenotype Association Analysis Using Synthetic Feature Random Forest

PubMed Central

Pan, Qinxin; Hu, Ting; Malley, James D.; Andrew, Angeline S.; Karagas, Margaret R.; Moore, Jason H.

2015-01-01

As the cost of genome-wide genotyping decreases, the number of genome-wide association studies (GWAS) has increased considerably. However, the transition from GWAS findings to the underlying biology of various phenotypes remains challenging. As a result, due to its system-level interpretability, pathway analysis has become a popular tool for gaining insights on the underlying biology from high-throughput genetic association data. In pathway analyses, gene sets representing particular biological processes are tested for significant associations with a given phenotype. Most existing pathway analysis approaches rely on single-marker statistics and assume that pathways are independent of each other. As biological systems are driven by complex biomolecular interactions, embracing the complex relationships between single-nucleotide polymorphisms (SNPs) and pathways needs to be addressed. To incorporate the complexity of gene-gene interactions and pathway-pathway relationships, we propose a system-level pathway analysis approach, synthetic feature random forest (SF-RF), which is designed to detect pathway-phenotype associations without making assumptions about the relationships among SNPs or pathways. In our approach, the genotypes of SNPs in a particular pathway are aggregated into a synthetic feature representing that pathway via Random Forest (RF). Multiple synthetic features are analyzed using RF simultaneously and the significance of a synthetic feature indicates the significance of the corresponding pathway. We further complement SF-RF with pathway-based Statistical Epistasis Network (SEN) analysis that evaluates interactions among pathways. By investigating the pathway SEN, we hope to gain additional insights into the genetic mechanisms contributing to the pathway-phenotype association. We apply SF-RF to a population-based genetic study of bladder cancer and further investigate the mechanisms that help explain the pathway-phenotype associations using SEN. The bladder cancer associated pathways we found are both consistent with existing biological knowledge and reveal novel and plausible hypotheses for future biological validations. PMID:24535726

Genome wide transcriptome profiling reveals differential gene expression in secondary metabolite pathway of Cymbopogon winterianus.

PubMed

Devi, Kamalakshi; Mishra, Surajit K; Sahu, Jagajjit; Panda, Debashis; Modi, Mahendra K; Sen, Priyabrata

2016-02-15

Advances in transcriptome sequencing provide fast, cost-effective and reliable approach to generate large expression datasets especially suitable for non-model species to identify putative genes, key pathway and regulatory mechanism. Citronella (Cymbopogon winterianus) is an aromatic medicinal grass used for anti-tumoral, antibacterial, anti-fungal, antiviral, detoxifying and natural insect repellent properties. Despite of having number of utilities, the genes involved in terpenes biosynthetic pathway is not yet clearly elucidated. The present study is a pioneering attempt to generate an exhaustive molecular information of secondary metabolite pathway and to increase genomic resources in Citronella. Using high-throughput RNA-Seq technology, root and leaf transcriptome was analysed at an unprecedented depth (11.7 Gb). Targeted searches identified majority of the genes associated with metabolic pathway and other natural product pathway viz. antibiotics synthesis along with many novel genes. Terpenoid biosynthesis genes comparative expression results were validated for 15 unigenes by RT-PCR and qRT-PCR. Thus the coverage of these transcriptome is comprehensive enough to discover all known genes of major metabolic pathways. This transcriptome dataset can serve as important public information for gene expression, genomics and function genomics studies in Citronella and shall act as a benchmark for future improvement of the crop.

Pathways to Late-Life Suicidal Behavior: Cluster Analysis and Predictive Validation of Suicidal Behavior in a Sample of Older Adults With Major Depression.

PubMed

Szanto, Katalin; Galfalvy, Hanga; Vanyukov, Polina M; Keilp, John G; Dombrovski, Alexandre Y

Clinical heterogeneity is a key challenge to understanding suicidal risk, as different pathways to suicidal behavior are likely to exist. We aimed to identify such pathways by uncovering latent classes of late-life depression cases and relating them to prior and future suicidal behavior. Data were collected from June 2010 to September 2015. In this longitudinal study we examined distinct associations of clinical and cognitive/decision-making factors with suicidal behavior in 194 older (50+ years) nondemented, depressed patients; 57 nonpsychiatric healthy controls provided benchmark data. The DSM-IV was used to establish diagnostic criteria. We identified multivariate patterns of risk factors, defining clusters based on personality traits, perceived social support, cognitive performance, and decision-making in an analysis blinded to participants' history of suicidal behavior. We validated these clusters using past and prospective suicidal ideation and behavior. Of 5 clusters identified, 3 were associated with high risk for suicidal behavior: (1) cognitive deficits, dysfunctional personality, low social support, high willingness to delay future rewards, and overrepresentation of high-lethality attempters; (2) high-personality pathology (ie, low self-esteem), minimal or no cognitive deficits, and overrepresentation of low-lethality attempters and ideators; (3) cognitive deficits, inability to delay future rewards, and similar distribution of high- and low-lethality attempters. There were significant between-cluster differences in number (P < .001) and lethality (P = .002) of past suicide attempts and in the likelihood of future suicide attempts (P = .010, 30 attempts by 22 patients, 2 fatal) and emergency psychiatric hospitalizations to prevent suicide (P = .005, 31 participants). Three pathways to suicidal behavior in older patients were found, marked by (1) very high levels of cognitive and dispositional risk factors suggesting a dementia prodrome, (2) dysfunctional personality traits, and (3) impulsive decision-making and cognitive deficits. © Copyright 2018 Physicians Postgraduate Press, Inc.

Genome-Wide Transcriptome Analysis Reveals Extensive Alternative Splicing Events in the Protoscoleces of Echinococcus granulosus and Echinococcus multilocularis

PubMed Central

Liu, Shuai; Zhou, Xiaosu; Hao, Lili; Piao, Xianyu; Hou, Nan; Chen, Qijun

2017-01-01

Alternative splicing (AS), as one of the most important topics in the post-genomic era, has been extensively studied in numerous organisms. However, little is known about the prevalence and characteristics of AS in Echinococcus species, which can cause significant health problems to humans and domestic animals. Based on high-throughput RNA-sequencing data, we performed a genome-wide survey of AS in two major pathogens of echinococcosis-Echinococcus granulosus and Echinococcus multilocularis. Our study revealed that the prevalence and characteristics of AS in protoscoleces of the two parasites were generally consistent with each other. A total of 6,826 AS events from 3,774 E. granulosus genes and 6,644 AS events from 3,611 E. multilocularis genes were identified in protoscolex transcriptomes, indicating that 33–36% of genes were subject to AS in the two parasites. Strikingly, intron retention instead of exon skipping was the predominant type of AS in Echinococcus species. Moreover, analysis of the Kyoto Encyclopedia of Genes and Genomes pathway indicated that genes that underwent AS events were significantly enriched in multiple pathways mainly related to metabolism (e.g., purine, fatty acid, galactose, and glycerolipid metabolism), signal transduction (e.g., Jak-STAT, VEGF, Notch, and GnRH signaling pathways), and genetic information processing (e.g., RNA transport and mRNA surveillance pathways). The landscape of AS obtained in this study will not only facilitate future investigations on transcriptome complexity and AS regulation during the life cycle of Echinococcus species, but also provide an invaluable resource for future functional and evolutionary studies of AS in platyhelminth parasites. PMID:28588571

Developmental Pathways to Conduct Disorder: Implications for Future Directions in Research, Assessment, and Treatment

ERIC Educational Resources Information Center

Frick, Paul J.

2012-01-01

Research has indicated that there are several common pathways through which children and adolescents develop conduct disorder, each with different risk factors and each with different underlying developmental mechanisms leading to the child's aggressive and antisocial behavior. The current article briefly summarizes research on these pathways,…

Global and regional health effects of future food production under climate change: a modelling study.

PubMed

Springmann, Marco; Mason-D'Croz, Daniel; Robinson, Sherman; Garnett, Tara; Godfray, H Charles J; Gollin, Douglas; Rayner, Mike; Ballon, Paola; Scarborough, Peter

2016-05-07

One of the most important consequences of climate change could be its effects on agriculture. Although much research has focused on questions of food security, less has been devoted to assessing the wider health impacts of future changes in agricultural production. In this modelling study, we estimate excess mortality attributable to agriculturally mediated changes in dietary and weight-related risk factors by cause of death for 155 world regions in the year 2050. For this modelling study, we linked a detailed agricultural modelling framework, the International Model for Policy Analysis of Agricultural Commodities and Trade (IMPACT), to a comparative risk assessment of changes in fruit and vegetable consumption, red meat consumption, and bodyweight for deaths from coronary heart disease, stroke, cancer, and an aggregate of other causes. We calculated the change in the number of deaths attributable to climate-related changes in weight and diets for the combination of four emissions pathways (a high emissions pathway, two medium emissions pathways, and a low emissions pathway) and three socioeconomic pathways (sustainable development, middle of the road, and more fragmented development), which each included six scenarios with variable climatic inputs. The model projects that by 2050, climate change will lead to per-person reductions of 3·2% (SD 0·4%) in global food availability, 4·0% (0·7%) in fruit and vegetable consumption, and 0·7% (0·1%) in red meat consumption. These changes will be associated with 529,000 climate-related deaths worldwide (95% CI 314,000-736,000), representing a 28% (95% CI 26-33) reduction in the number of deaths that would be avoided because of changes in dietary and weight-related risk factors between 2010 and 2050. Twice as many climate-related deaths were associated with reductions in fruit and vegetable consumption than with climate-related increases in the prevalence of underweight, and most climate-related deaths were projected to occur in south and east Asia. Adoption of climate-stabilisation pathways would reduce the number of climate-related deaths by 29-71%, depending on their stringency. The health effects of climate change from changes in dietary and weight-related risk factors could be substantial, and exceed other climate-related health impacts that have been estimated. Climate change mitigation could prevent many climate-related deaths. Strengthening of public health programmes aimed at preventing and treating diet and weight-related risk factors could be a suitable climate change adaptation strategy. Oxford Martin Programme on the Future of Food. Copyright © 2016 Elsevier Ltd. All rights reserved.

Cellular Organization and Cytoskeletal Regulation of the Hippo Signaling Network.

PubMed

Sun, Shuguo; Irvine, Kenneth D

2016-09-01

The Hippo signaling network integrates diverse upstream signals to control cell fate decisions and regulate organ growth. Recent studies have provided new insights into the cellular organization of Hippo signaling, its relationship to cell-cell junctions, and how the cytoskeleton modulates Hippo signaling. Cell-cell junctions serve as platforms for Hippo signaling by localizing scaffolding proteins that interact with core components of the pathway. Interactions of Hippo pathway components with cell-cell junctions and the cytoskeleton also suggest potential mechanisms for the regulation of the pathway by cell contact and cell polarity. As our understanding of the complexity of Hippo signaling increases, a future challenge will be to understand how the diverse inputs into the pathway are integrated and to define their respective contributions in vivo. Copyright © 2016 Elsevier Ltd. All rights reserved.

Targeting disease through novel pathways of apoptosis and autophagy.

PubMed

Maiese, Kenneth; Chong, Zhao Zhong; Shang, Yan Chen; Wang, Shaohui

2012-12-01

Apoptosis and autophagy impact cell death in multiple systems of the body. Development of new therapeutic strategies that target these processes must address their complex role during developmental cell growth as well as during the modulation of toxic cellular environments. Novel signaling pathways involving Wnt1-inducible signaling pathway protein 1 (WISP1), phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), β-catenin and mammalian target of rapamycin (mTOR) govern apoptotic and autophagic pathways during oxidant stress that affect the course of a broad spectrum of disease entities including Alzheimer's disease, Parkinson's disease, myocardial injury, skeletal system trauma, immune system dysfunction and cancer progression. Implications of potential biological and clinical outcome for these signaling pathways are presented. The CCN family member WISP1 and its intimate relationship with canonical and non-canonical wingless signaling pathways of PI3K, Akt1, β-catenin and mTOR offer an exciting approach for governing the pathways of apoptosis and autophagy especially in clinical disorders that are currently without effective treatments. Future studies that can elucidate the intricate role of these cytoprotective pathways during apoptosis and autophagy can further the successful translation and development of these cellular targets into robust and safe clinical therapeutic strategies.

Renewable Electricity Futures Study. Volume 1: Exploration of High-Penetration Renewable Electricity Futures

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

Mai, T.; Wiser, R.; Sandor, D.

2012-06-01

The Renewable Electricity Futures (RE Futures) Study investigated the challenges and impacts of achieving very high renewable electricity generation levels in the contiguous United States by 2050. The analysis focused on the sufficiency of the geographically diverse U.S. renewable resources to meet electricity demand over future decades, the hourly operational characteristics of the U.S. grid with high levels of variable wind and solar generation, and the potential implications of deploying high levels of renewables in the future. RE Futures focused on technical aspects of high penetration of renewable electricity; it did not focus on how to achieve such a futuremore » through policy or other measures. Given the inherent uncertainties involved with analyzing alternative long-term energy futures as well as the multiple pathways that might be taken to achieve higher levels of renewable electricity supply, RE Futures explored a range of scenarios to investigate and compare the impacts of renewable electricity penetration levels (30%-90%), future technology performance improvements, potential constraints to renewable electricity development, and future electricity demand growth assumptions. RE Futures was led by the National Renewable Energy Laboratory (NREL) and the Massachusetts Institute of Technology (MIT).« less

Gene expression profiling of canine osteosarcoma reveals genes associated with short and long survival times

PubMed Central

Selvarajah, Gayathri T; Kirpensteijn, Jolle; van Wolferen, Monique E; Rao, Nagesha AS; Fieten, Hille; Mol, Jan A

2009-01-01

Background Gene expression profiling of spontaneous tumors in the dog offers a unique translational opportunity to identify prognostic biomarkers and signaling pathways that are common to both canine and human. Osteosarcoma (OS) accounts for approximately 80% of all malignant bone tumors in the dog. Canine OS are highly comparable with their human counterpart with respect to histology, high metastatic rate and poor long-term survival. This study investigates the prognostic gene profile among thirty-two primary canine OS using canine specific cDNA microarrays representing 20,313 genes to identify genes and cellular signaling pathways associated with survival. This, the first report of its kind in dogs with OS, also demonstrates the advantages of cross-species comparison with human OS. Results The 32 tumors were classified into two prognostic groups based on survival time (ST). They were defined as short survivors (dogs with poor prognosis: surviving fewer than 6 months) and long survivors (dogs with better prognosis: surviving 6 months or longer). Fifty-one transcripts were found to be differentially expressed, with common upregulation of these genes in the short survivors. The overexpressed genes in short survivors are associated with possible roles in proliferation, drug resistance or metastasis. Several deregulated pathways identified in the present study, including Wnt signaling, Integrin signaling and Chemokine/cytokine signaling are comparable to the pathway analysis conducted on human OS gene profiles, emphasizing the value of the dog as an excellent model for humans. Conclusion A molecular-based method for discrimination of outcome for short and long survivors is useful for future prognostic stratification at initial diagnosis, where genes and pathways associated with cell cycle/proliferation, drug resistance and metastasis could be potential targets for diagnosis and therapy. The similarities between human and canine OS makes the dog a suitable pre-clinical model for future 'novel' therapeutic approaches where the current research has provided new insights on prognostic genes, molecular pathways and mechanisms involved in OS pathogenesis and disease progression. PMID:19735553

Gene Expression Profiling of Lung Tissue of Rats Exposed to Lunar Dust Particles

NASA Technical Reports Server (NTRS)

Zhang, Ye; Feiveson, Alan H.; Lam, Chiu-Wing; Kidane, Yared H.; Ploutz-Snyder Robert; Yeshitla, Samrawit; Zalesak, Selina M.; Scully, Robert R.; Wu, Honglu; James, John T.

2014-01-01

The purpose of the study is to analyze the dynamics of global gene expression changes in the lung tissue of rats exposed to lunar dust particles. Multiple pathways and transcription factors were identified using the Ingenuity Pathway Analysis tool, showing the potential networks of these signaling regulations involved in lunar dust-induced prolonged proflammatory response and toxicity. The data presented in this study, for the first time, explores the molecular mechanisms of lunar dust induced toxicity. This work contributes not only to the risk assessment for future space exploration, but also to the understanding of the dust-induced toxicity to humans on earth.

Situating adaptation: How governance challenges and perceptions of uncertainty influence adaptation in the Rocky Mountains

Treesearch

Carina Wyborn; Laurie Yung; Daniel Murphy; Daniel R. Williams

2015-01-01

Adaptation is situated within multiple, interacting social, political, and economic forces. Adaptation pathways envision adaptation as a continual pathway of change and response embedded within this broader sociopolitical context. Pathways emphasize that current decisions are both informed by past actions and shape the landscape of future options. This research...

Renewable Electricity Futures Study. Volume 4: Bulk Electric Power Systems: Operations and Transmission Planning

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

Milligan, M.; Ela, E.; Hein, J.

2012-06-01

The Renewable Electricity Futures (RE Futures) Study investigated the challenges and impacts of achieving very high renewable electricity generation levels in the contiguous United States by 2050. The analysis focused on the sufficiency of the geographically diverse U.S. renewable resources to meet electricity demand over future decades, the hourly operational characteristics of the U.S. grid with high levels of variable wind and solar generation, and the potential implications of deploying high levels of renewables in the future. RE Futures focused on technical aspects of high penetration of renewable electricity; it did not focus on how to achieve such a futuremore » through policy or other measures. Given the inherent uncertainties involved with analyzing alternative long-term energy futures as well as the multiple pathways that might be taken to achieve higher levels of renewable electricity supply, RE Futures explored a range of scenarios to investigate and compare the impacts of renewable electricity penetration levels (30%-90%), future technology performance improvements, potential constraints to renewable electricity development, and future electricity demand growth assumptions. RE Futures was led by the National Renewable Energy Laboratory (NREL) and the Massachusetts Institute of Technology (MIT).« less

Renewable Electricity Futures Study. Volume 3: End-Use Electricity Demand

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

Hostick, D.; Belzer, D.B.; Hadley, S.W.

2012-06-01

The Renewable Electricity Futures (RE Futures) Study investigated the challenges and impacts of achieving very high renewable electricity generation levels in the contiguous United States by 2050. The analysis focused on the sufficiency of the geographically diverse U.S. renewable resources to meet electricity demand over future decades, the hourly operational characteristics of the U.S. grid with high levels of variable wind and solar generation, and the potential implications of deploying high levels of renewables in the future. RE Futures focused on technical aspects of high penetration of renewable electricity; it did not focus on how to achieve such a futuremore » through policy or other measures. Given the inherent uncertainties involved with analyzing alternative long-term energy futures as well as the multiple pathways that might be taken to achieve higher levels of renewable electricity supply, RE Futures explored a range of scenarios to investigate and compare the impacts of renewable electricity penetration levels (30%-90%), future technology performance improvements, potential constraints to renewable electricity development, and future electricity demand growth assumptions. RE Futures was led by the National Renewable Energy Laboratory (NREL) and the Massachusetts Institute of Technology (MIT).« less

Renewable Electricity Futures Study. Volume 2: Renewable Electricity Generation and Storage Technologies

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

Augustine, C.; Bain, R.; Chapman, J.

2012-06-01

The Renewable Electricity Futures (RE Futures) Study investigated the challenges and impacts of achieving very high renewable electricity generation levels in the contiguous United States by 2050. The analysis focused on the sufficiency of the geographically diverse U.S. renewable resources to meet electricity demand over future decades, the hourly operational characteristics of the U.S. grid with high levels of variable wind and solar generation, and the potential implications of deploying high levels of renewables in the future. RE Futures focused on technical aspects of high penetration of renewable electricity; it did not focus on how to achieve such a futuremore » through policy or other measures. Given the inherent uncertainties involved with analyzing alternative long-term energy futures as well as the multiple pathways that might be taken to achieve higher levels of renewable electricity supply, RE Futures explored a range of scenarios to investigate and compare the impacts of renewable electricity penetration levels (30%-90%), future technology performance improvements, potential constraints to renewable electricity development, and future electricity demand growth assumptions. RE Futures was led by the National Renewable Energy Laboratory (NREL) and the Massachusetts Institute of Technology (MIT).« less

Renewable Electricity Futures Study. Executive Summary

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

Mai, T.; Sandor, D.; Wiser, R.

2012-12-01

The Renewable Electricity Futures (RE Futures) Study investigated the challenges and impacts of achieving very high renewable electricity generation levels in the contiguous United States by 2050. The analysis focused on the sufficiency of the geographically diverse U.S. renewable resources to meet electricity demand over future decades, the hourly operational characteristics of the U.S. grid with high levels of variable wind and solar generation, and the potential implications of deploying high levels of renewables in the future. RE Futures focused on technical aspects of high penetration of renewable electricity; it did not focus on how to achieve such a futuremore » through policy or other measures. Given the inherent uncertainties involved with analyzing alternative long-term energy futures as well as the multiple pathways that might be taken to achieve higher levels of renewable electricity supply, RE Futures explored a range of scenarios to investigate and compare the impacts of renewable electricity penetration levels (30%-90%), future technology performance improvements, potential constraints to renewable electricity development, and future electricity demand growth assumptions. RE Futures was led by the National Renewable Energy Laboratory (NREL) and the Massachusetts Institute of Technology (MIT).« less

Modelling the impact of future socio-economic and climate change scenarios on river microbial water quality.

PubMed

Islam, M M Majedul; Iqbal, Muhammad Shahid; Leemans, Rik; Hofstra, Nynke

2018-03-01

Microbial surface water quality is important, as it is related to health risk when the population is exposed through drinking, recreation or consumption of irrigated vegetables. The microbial surface water quality is expected to change with socio-economic development and climate change. This study explores the combined impacts of future socio-economic and climate change scenarios on microbial water quality using a coupled hydrodynamic and water quality model (MIKE21FM-ECOLab). The model was applied to simulate the baseline (2014-2015) and future (2040s and 2090s) faecal indicator bacteria (FIB: E. coli and enterococci) concentrations in the Betna river in Bangladesh. The scenarios comprise changes in socio-economic variables (e.g. population, urbanization, land use, sanitation and sewage treatment) and climate variables (temperature, precipitation and sea-level rise). Scenarios have been developed building on the most recent Shared Socio-economic Pathways: SSP1 and SSP3 and Representative Concentration Pathways: RCP4.5 and RCP8.5 in a matrix. An uncontrolled future results in a deterioration of the microbial water quality (+75% by the 2090s) due to socio-economic changes, such as higher population growth, and changes in rainfall patterns. However, microbial water quality improves under a sustainable scenario with improved sewage treatment (-98% by the 2090s). Contaminant loads were more influenced by changes in socio-economic factors than by climatic change. To our knowledge, this is the first study that combines climate change and socio-economic development scenarios to simulate the future microbial water quality of a river. This approach can also be used to assess future consequences for health risks. Copyright © 2017 The Authors. Published by Elsevier GmbH.. All rights reserved.

A systematic review of transmission dynamic studies of methicillin-resistant Staphylococcus aureus in non-hospital residential facilities.

PubMed

Kwok, Kin On; Read, Jonathan M; Tang, Arthur; Chen, Hong; Riley, Steven; Kam, Kai Man

2018-04-18

Non-hospital residential facilities are important reservoirs for MRSA transmission. However, conclusions and public health implications drawn from the many mathematical models depicting nosocomial MRSA transmission may not be applicable to these settings. Therefore, we reviewed the MRSA transmission dynamics studies in defined non-hospital residential facilities to: (1) provide an overview of basic epidemiology which has been addressed; (2) identify future research direction; and (3) improve future model implementation. A review was conducted by searching related keywords in PUBMED without time restriction as well as internet searches via Google search engine. We included only articles describing the epidemiological transmission pathways of MRSA/community-associated MRSA within and between defined non-hospital residential settings. Among the 10 included articles, nursing homes (NHs) and correctional facilities (CFs) were two settings considered most frequently. Importation of colonized residents was a plausible reason for MRSA outbreaks in NHs, where MRSA was endemic without strict infection control interventions. The importance of NHs over hospitals in increasing nosocomial MRSA prevalence was highlighted. Suggested interventions in NHs included: appropriate staffing level, screening and decolonizing, and hand hygiene. On the other hand, the small population amongst inmates in CFs has no effect on MRSA community transmission. Included models ranged from system-level compartmental models to agent-based models. There was no consensus over the course of disease progression in these models, which were mainly featured with NH residents /CF inmates/ hospital patients as transmission pathways. Some parameters used by these models were outdated or unfit. Importance of NHs has been highlighted from these current studies addressing scattered aspects of MRSA epidemiology. However, the wide variety of non-hospital residential settings suggest that more work is needed before robust conclusions can be drawn. Learning from existing work for hospitals, we identified critical future research direction in this area from infection control, ecological and economic perspectives. From current model deficiencies, we suggest more transmission pathways be specified to depict MRSA transmission, and further empirical studies be stressed to support evidence-based mathematical models of MRSA in non-hospital facilities. Future models should be ready to cope with the aging population structure.

Are implicit policy assumptions about climate adaptation trying to push drinking water utilities down an impossible path?

NASA Astrophysics Data System (ADS)

Klasic, M. R.; Ekstrom, J.; Bedsworth, L. W.; Baker, Z.

2017-12-01

Extreme events such as wildfires, droughts, and flooding are projected to be more frequent and intense under a changing climate, increasing challenges to water quality management. To protect and improve public health, drinking water utility managers need to understand and plan for climate change and extreme events. This three year study began with the assumption that improved climate projections were key to advancing climate adaptation at the local level. Through a survey (N = 259) and interviews (N = 61) with California drinking water utility managers during the peak of the state's recent drought, we found that scientific information was not a key barrier hindering adaptation. Instead, we found that managers fell into three distinct mental models based on their interaction with, perceptions, and attitudes, towards scientific information and the future of water in their system. One of the mental models, "modeled futures", is a concept most in line with how climate change scientists talk about the use of information. Drinking water utilities falling into the "modeled future" category tend to be larger systems that have adequate capacity to both receive and use scientific information. Medium and smaller utilities in California, that more often serve rural low income communities, tend to fall into the other two mental models, "whose future" and "no future". We show evidence that there is an implicit presumption that all drinking water utility managers should strive to align with "modeled future" mental models. This presentation questions this assumption as it leaves behind many utilities that need to adapt to climate change (several thousand in California alone), but may not have the technical, financial, managerial, or other capacity to do so. It is clear that no single solution or pathway to drought resilience exists for water utilities, but we argue that a more explicit understanding and definition of what it means to be a resilient drinking water utility is necessary. By highlighting, then questioning, the assumption that all utility managers should strive to have "modeled future" mentalities, this presentation seeks to foster an open dialogue around which pathway or pathways are most feasible for supporting drinking water utility managers planning for climate change.

An Interactive Platform to Visualize Data-Driven Clinical Pathways for the Management of Multiple Chronic Conditions.

PubMed

Zhang, Yiye; Padman, Rema

2017-01-01

Patients with multiple chronic conditions (MCC) pose an increasingly complex health management challenge worldwide, particularly due to the significant gap in our understanding of how to provide coordinated care. Drawing on our prior research on learning data-driven clinical pathways from actual practice data, this paper describes a prototype, interactive platform for visualizing the pathways of MCC to support shared decision making. Created using Python web framework, JavaScript library and our clinical pathway learning algorithm, the visualization platform allows clinicians and patients to learn the dominant patterns of co-progression of multiple clinical events from their own data, and interactively explore and interpret the pathways. We demonstrate functionalities of the platform using a cluster of 36 patients, identified from a dataset of 1,084 patients, who are diagnosed with at least chronic kidney disease, hypertension, and diabetes. Future evaluation studies will explore the use of this platform to better understand and manage MCC.

Current understanding on aflatoxin biosynthesis and future perspective in reducing aflatoxin contamination.

PubMed

Yu, Jiujiang

2012-10-25

Traditional molecular techniques have been used in research in discovering the genes and enzymes that are involved in aflatoxin formation and genetic regulation. We cloned most, if not all, of the aflatoxin pathway genes. A consensus gene cluster for aflatoxin biosynthesis was discovered in 2005. The factors that affect aflatoxin formation have been studied. In this report, the author summarized the current status of research progress and future possibilities that may be used for solving aflatoxin contamination.

Current Understanding on Aflatoxin Biosynthesis and Future Perspective in Reducing Aflatoxin Contamination

PubMed Central

Yu, Jiujiang

2012-01-01

Traditional molecular techniques have been used in research in discovering the genes and enzymes that are involved in aflatoxin formation and genetic regulation. We cloned most, if not all, of the aflatoxin pathway genes. A consensus gene cluster for aflatoxin biosynthesis was discovered in 2005. The factors that affect aflatoxin formation have been studied. In this report, the author summarized the current status of research progress and future possibilities that may be used for solving aflatoxin contamination. PMID:23202305

European Union Students Studying in English Higher Education Institutions. DIUS Research Report 08-09

ERIC Educational Resources Information Center

Morris, Marian; Rutt, Simon

2008-01-01

This study aimed to identify the pathways, intentions and relevant perceptions of (non-UK) European Union (EU) students entering English higher education. It sought to identify why students wished to obtain an English HE qualification, their attitudes towards the uptake and repayment of tuition fee loans and their future career plans. Drawing on…

Predicting Family Poverty and Other Disadvantaged Conditions for Child Rearing from Childhood Aggression and Social Withdrawal: A 30-Year Longitudinal Study

ERIC Educational Resources Information Center

Serbin, Lisa A.; Temcheff, Caroline E.; Cooperman, Jessica M.; Stack, Dale M.; Ledingham, Jane; Schwartzman, Alex E.

2011-01-01

This 30-year longitudinal study examined pathways from problematic childhood behavior patterns to future disadvantaged conditions for family environment and child rearing in adulthood. Participants were mothers (n = 328) and fathers (n = 222) with lower income backgrounds participating in the ongoing Concordia Longitudinal Risk Project. Structural…

Pathway analyses and understanding disease associations

PubMed Central

Liu, Yu; Chance, Mark R

2013-01-01

High throughput technologies have been applied to investigate the underlying mechanisms of complex diseases, identify disease-associations and help to improve treatment. However it is challenging to derive biological insight from conventional single gene based analysis of “omics” data from high throughput experiments due to sample and patient heterogeneity. To address these challenges, many novel pathway and network based approaches were developed to integrate various “omics” data, such as gene expression, copy number alteration, Genome Wide Association Studies, and interaction data. This review will cover recent methodological developments in pathway analysis for the detection of dysregulated interactions and disease-associated subnetworks, prioritization of candidate disease genes, and disease classifications. For each application, we will also discuss the associated challenges and potential future directions. PMID:24319650

Pathway modulations and epigenetic alterations in ovarian tumorbiogenesis

PubMed Central

Saldanha, Sabita N.; Tollefsbol, Trygve O.

2013-01-01

Cellular pathways are numerous and are highly integrated in function in the control of cellular systems. They collectively regulate cell division, proliferation, survival and apoptosis of cells and mutagenesis of key genes that control these pathways can initiate neoplastic transformations. Understanding these pathways is crucial to future therapeutic and preventive strategies of the disease. Ovarian cancers are of three major types; epithelial, germ-cell and stromal. However, ovarian cancers of epithelial origin, arising from the mesothelium, are the predominant form. Of the subtypes of ovarian cancer, the high-grade serous tumors are fatal, with low survival rate due to late detection and poor response to treatments. Close examination of preserved ovarian tissues and in vitro studies have provided insights into the mechanistic changes occurring in cells mediated by a few key genes. This review will focus on pathways and key genes of the pathways that are mutated or have aberrant functions in the pathology of ovarian cancer. Non-genetic mechanisms that are gaining prominence in the pathology of ovarian cancer, miRNAs and epigenetics, will also be discussed in the review. PMID:24105793

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

Renewable Electricity Futures Study. Volume 1. Exploration of High-Penetration Renewable Electricity Futures

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

Hand, M. M.; Baldwin, S.; DeMeo, E.

2012-06-15

The Renewable Electricity Futures (RE Futures) Study investigated the challenges and impacts of achieving very high renewable electricity generation levels in the contiguous United States by 2050. The analysis focused on the sufficiency of the geographically diverse U.S. renewable resources to meet electricity demand over future decades, the hourly operational characteristics of the U.S. grid with high levels of variable wind and solar generation, and the potential implications of deploying high levels of renewables in the future. RE Futures focused on technical aspects of high penetration of renewable electricity; it did not focus on how to achieve such a futuremore » through policy or other measures. Given the inherent uncertainties involved with analyzing alternative long-term energy futures as well as the multiple pathways that might be taken to achieve higher levels of renewable electricity supply, RE Futures explored a range of scenarios to investigate and compare the impacts of renewable electricity penetration levels (30%–90%), future technology performance improvements, potential constraints to renewable electricity development, and future electricity demand growth assumptions. RE Futures was led by the National Renewable Energy Laboratory (NREL) and the Massachusetts Institute of Technology (MIT). Learn more at the RE Futures website. http://www.nrel.gov/analysis/re_futures/« less

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

Penev, Michael; Melaina, Marc; Bush, Brian

This report improves on the understanding of the long-term technology potential of low-carbon natural gas (LCNG) supply pathways by exploring transportation market adoption potential through 2035 in California. Techno-economic assessments of each pathway are developed to compare the capacity, cost, and greenhouse gas (GHG) emissions of select LCNG production pathways. The study analyzes the use of fuel from these pathways in light-, medium-, and heavy-duty vehicle applications. Economic and life-cycle GHG emissions analysis suggest that landfill gas resources are an attractive and relatively abundant resource in terms of cost and GHG reduction potential, followed by waste water treatment plants andmore » biomass with gasification and methanation. Total LCNG production potential is on the order of total natural gas demand anticipated in a success scenario for future natural gas vehicle adoption by 2035 across light-, medium-, and heavy-duty vehicle markets (110 trillion Btu/year).« less

Comparison of different two-pathway models for describing the combined effect of DO and nitrite on the nitrous oxide production by ammonia-oxidizing bacteria.

PubMed

Lang, Longqi; Pocquet, Mathieu; Ni, Bing-Jie; Yuan, Zhiguo; Spérandio, Mathieu

2017-02-01

The aim of this work is to compare the capability of two recently proposed two-pathway models for predicting nitrous oxide (N 2 O) production by ammonia-oxidizing bacteria (AOB) for varying ranges of dissolved oxygen (DO) and nitrite. The first model includes the electron carriers whereas the second model is based on direct coupling of electron donors and acceptors. Simulations are confronted to extensive sets of experiments (43 batches) from different studies with three different microbial systems. Despite their different mathematical structures, both models could well and similarly describe the combined effect of DO and nitrite on N 2 O production rate and emission factor. The model-predicted contributions for nitrifier denitrification pathway and hydroxylamine pathway also matched well with the available isotopic measurements. Based on sensitivity analysis, calibration procedures are described and discussed for facilitating the future use of those models.

The potential role of the antioxidant and detoxification properties of glutathione in autism spectrum disorders: a systematic review and meta-analysis

PubMed Central

2012-01-01

Background Glutathione has a wide range of functions; it is an endogenous anti-oxidant and plays a key role in the maintenance of intracellular redox balance and detoxification of xenobiotics. Several studies have indicated that children with autism spectrum disorders may have altered glutathione metabolism which could play a key role in the condition. Methods A systematic literature review and meta-analysis was conducted of studies examining metabolites, interventions and/or genes of the glutathione metabolism pathways i.e. the γ-glutamyl cycle and trans-sulphuration pathway in autism spectrum disorders. Results Thirty nine studies were included in the review comprising an in vitro study, thirty two metabolite and/or co-factor studies, six intervention studies and six studies with genetic data as well as eight studies examining enzyme activity. Conclusions The review found evidence for the involvement of the γ-glutamyl cycle and trans-sulphuration pathway in autistic disorder is sufficiently consistent, particularly with respect to the glutathione redox ratio, to warrant further investigation to determine the significance in relation to clinical outcomes. Large, well designed intervention studies that link metabolites, cofactors and genes of the γ-glutamyl cycle and trans-sulphuration pathway with objective behavioural outcomes in children with autism spectrum disorders are required. Future risk factor analysis should include consideration of multiple nutritional status and metabolite biomarkers of pathways linked with the γ-glutamyl cycle and the interaction of genotype in relation to these factors. PMID:22524510

Enhancing microbial production of biofuels by expanding microbial metabolic pathways.

PubMed

Yu, Ping; Chen, Xingge; Li, Peng

2017-09-01

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

The Role of Adipokines in Intervertebral Disc Degeneration.

PubMed

Sharma, Anirudh

2018-04-24

Intervertebral disc degeneration (IDD) is an important cause of low back pain. Recent evidence suggests that in addition to abnormal and excessive mechanical loading, inflammation may be a key driver for both IDD and low back pain. Obesity, a known mechanical risk factor of IDD, is now increasingly being recognized as a systemic inflammatory state with adipokines being postulated as likely inflammatory mediators. The aim of this review was to summarize the current literature regarding the inflammatory role of adipokines in the pathophysiology of IDD. A systematic literature search was performed using the OVID Medline, EMBASE and PubMed databases to identify all studies assessing IDD and adipokines. Fifteen studies were included in the present review. Leptin was the most commonly assessed adipokine. Ten of 15 studies were conducted in humans; three in rats and two in both humans and rats. Studies focused on a variety of topics ranging from receptor identification, pathway analysis, genetic associations, and proteonomics. Currently, data from both human and animal experiments demonstrate significant effects of leptin and adiponectin on the internal milieu of intervertebral discs. However, future studies are needed to determine the molecular pathway relationships between adipokines in the pathophysiology of IDD as avenues for future therapeutic targets.

Natural Mentors, Racial Identity, and Educational Attainment among African American Adolescents: Exploring Pathways to Success

PubMed Central

Hurd, Noelle M.; Sánchez, Bernadette; Zimmerman, Marc A.; Caldwell, Cleopatra H.

2012-01-01

The present study explored how relationships with natural mentors may contribute to African American adolescents’ long-term educational attainment by influencing adolescents’ racial identity and academic beliefs. This study included 541 academically at-risk African American adolescents transitioning into adulthood (54% female). Results of the current study indicated that relationships with natural mentors promoted more positive long-term educational attainment among participants through increased private regard (a dimension of racial identity) and stronger beliefs in the importance of doing well in school for future success. Implications of these findings and directions for future research are discussed. PMID:22537308

Harnessing pain heterogeneity and RNA transcriptome to identify blood–based pain biomarkers: a novel correlational study design and bioinformatics approach in a graded chronic constriction injury model

PubMed Central

Grace, Peter M.; Hurley, Daniel; Barratt, Daniel T.; Tsykin, Anna; Watkins, Linda R.; Rolan, Paul E.; Hutchinson, Mark R.

2017-01-01

A quantitative, peripherally accessible biomarker for neuropathic pain has great potential to improve clinical outcomes. Based on the premise that peripheral and central immunity contribute to neuropathic pain mechanisms, we hypothesized that biomarkers could be identified from the whole blood of adult male rats, by integrating graded chronic constriction injury (CCI), ipsilateral lumbar dorsal quadrant (iLDQ) and whole blood transcriptomes, and pathway analysis with pain behavior. Correlational bioinformatics identified a range of putative biomarker genes for allodynia intensity, many encoding for proteins with a recognized role in immune/nociceptive mechanisms. A selection of these genes was validated in a separate replication study. Pathway analysis of the iLDQ transcriptome identified Fcγ and Fcε signaling pathways, among others. This study is the first to employ the whole blood transcriptome to identify pain biomarker panels. The novel correlational bioinformatics, developed here, selected such putative biomarkers based on a correlation with pain behavior and formation of signaling pathways with iLDQ genes. Future studies may demonstrate the predictive ability of these biomarker genes across other models and additional variables. PMID:22697386

Educational Inequalities and Ukrainian Orphans' Future Pathways: Social Reproduction or Transformation through the Hidden Curriculum?

ERIC Educational Resources Information Center

Korzh, Alla

2013-01-01

This qualitative multi-site case study, situated in the context of Ukraine's post-Soviet political economy, examined how orphanage educators' expectations and beliefs about orphans' academic abilities and potential, curriculum, peer relationships, and education policy shaped orphans' post-secondary education decisions and trajectories. Examination…

Renewable Electricity Futures Study. Volume 2. Renewable Electricity Generation and Storage Technologies

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

Augustine, Chad; Bain, Richard; Chapman, Jamie

2012-06-15

The Renewable Electricity Futures (RE Futures) Study investigated the challenges and impacts of achieving very high renewable electricity generation levels in the contiguous United States by 2050. The analysis focused on the sufficiency of the geographically diverse U.S. renewable resources to meet electricity demand over future decades, the hourly operational characteristics of the U.S. grid with high levels of variable wind and solar generation, and the potential implications of deploying high levels of renewables in the future. RE Futures focused on technical aspects of high penetration of renewable electricity; it did not focus on how to achieve such a futuremore » through policy or other measures. Given the inherent uncertainties involved with analyzing alternative long-term energy futures as well as the multiple pathways that might be taken to achieve higher levels of renewable electricity supply, RE Futures explored a range of scenarios to investigate and compare the impacts of renewable electricity penetration levels (30%–90%), future technology performance improvements, potential constraints to renewable electricity development, and future electricity demand growth assumptions. RE Futures was led by the National Renewable Energy Laboratory (NREL) and the Massachusetts Institute of Technology (MIT). Learn more at the RE Futures website. http://www.nrel.gov/analysis/re_futures/« less

Renewable Electricity Futures Study. Volume 3. End-Use Electricity Demand

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

Hostick, Donna; Belzer, David B.; Hadley, Stanton W.

2012-06-15

The Renewable Electricity Futures (RE Futures) Study investigated the challenges and impacts of achieving very high renewable electricity generation levels in the contiguous United States by 2050. The analysis focused on the sufficiency of the geographically diverse U.S. renewable resources to meet electricity demand over future decades, the hourly operational characteristics of the U.S. grid with high levels of variable wind and solar generation, and the potential implications of deploying high levels of renewables in the future. RE Futures focused on technical aspects of high penetration of renewable electricity; it did not focus on how to achieve such a futuremore » through policy or other measures. Given the inherent uncertainties involved with analyzing alternative long-term energy futures as well as the multiple pathways that might be taken to achieve higher levels of renewable electricity supply, RE Futures explored a range of scenarios to investigate and compare the impacts of renewable electricity penetration levels (30%–90%), future technology performance improvements, potential constraints to renewable electricity development, and future electricity demand growth assumptions. RE Futures was led by the National Renewable Energy Laboratory (NREL) and the Massachusetts Institute of Technology (MIT). Learn more at the RE Futures website. http://www.nrel.gov/analysis/re_futures/« less

Renewable Electricity Futures Study. Volume 4: Bulk Electric Power Systems. Operations and Transmission Planning

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

Milligan, Michael; Ela, Erik; Hein, Jeff

2012-06-15

The Renewable Electricity Futures (RE Futures) Study investigated the challenges and impacts of achieving very high renewable electricity generation levels in the contiguous United States by 2050. The analysis focused on the sufficiency of the geographically diverse U.S. renewable resources to meet electricity demand over future decades, the hourly operational characteristics of the U.S. grid with high levels of variable wind and solar generation, and the potential implications of deploying high levels of renewables in the future. RE Futures focused on technical aspects of high penetration of renewable electricity; it did not focus on how to achieve such a futuremore » through policy or other measures. Given the inherent uncertainties involved with analyzing alternative long-term energy futures as well as the multiple pathways that might be taken to achieve higher levels of renewable electricity supply, RE Futures explored a range of scenarios to investigate and compare the impacts of renewable electricity penetration levels (30%–90%), future technology performance improvements, potential constraints to renewable electricity development, and future electricity demand growth assumptions. RE Futures was led by the National Renewable Energy Laboratory (NREL) and the Massachusetts Institute of Technology (MIT). Learn more at the RE Futures website. http://www.nrel.gov/analysis/re_futures/« less

Greening the Grid: Integrating 175 Gigawatts of Renewable Energy into India's Electric Grid - A Detailed Look at the Southern Region

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

Cochran, Jaquelin M

The higher-spatial-resolution model of 'Greening the Grid: Pathways to Integrate 175 Gigawatts of Renewable Energy into India's Electric Grid, Vol. II - Regional Study' (the Regional Study), which better represents the impact of congestion on least-cost scheduling and dispatch, provides a deeper understanding of the relationship among renewable energy (RE) location, transmission, and system flexibility with regard to RE integration, compared to 'Greening the Grid: Pathways to Integrate 175 Gigawatts of Renewable Energy into India's Electric Grid, Vol. I - National Study.' The Regional Study validates the relative value of mitigation strategies demonstrated in the National Study - namely, coordinatedmore » operations among states reduce production costs, and reducing coal minimum generation levels reduces RE curtailment. Significantly, the Regional Study also highlights a potential barrier to realizing the value of these mitigation strategies: when locations of RE development are planned independently of state-level transmission, intrastate congestion can result in undesirable levels of RE curtailment. Therefore a key objective of this study is to illustrate to state-level power system planners and operators, in particular, how a higher-resolution model, inclusive of intrastate granularity, can be used as a planning tool for two primary purposes: to better anticipate, understand, and mitigate system constraints that could affect RE integration; and to provide a modeling framework that can be used as part of future transmission studies and planning efforts. The Regional Study is not intended to predict precisely how RE will affect state-level operations. There is considerable uncertainty regarding the locations of the RE development, as well as how contract terms can affect access to the inherent physical flexibility of the system. But the scenarios analyzed identify the types of issues that can arise under various RE and transmission expansion pathways. The model developed for this study provides a rigorous framework for future work and can be updated with the characteristics of new capacity as more information on the future power system is known.« less

Greening the Grid: Integrating 175 Gigawatts of Renewable Energy into India's Electric Grid - A Detailed Look at the Western Region

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

Cochran, Jaquelin

The higher-spatial-resolution model of 'Greening the Grid: Pathways to Integrate 175 Gigawatts of Renewable Energy into India's Electric Grid, Vol. II - Regional Study' (the Regional Study), which better represents the impact of congestion on least-cost scheduling and dispatch, provides a deeper understanding of the relationship among renewable energy (RE) location, transmission, and system flexibility with regard to RE integration, compared to 'Greening the Grid: Pathways to Integrate 175 Gigawatts of Renewable Energy into India's Electric Grid, Vol. I - National Study.' The Regional Study validates the relative value of mitigation strategies demonstrated in the National Study - namely, coordinatedmore » operations among states reduce production costs, and reducing coal minimum generation levels reduces RE curtailment. Significantly, the Regional Study also highlights a potential barrier to realizing the value of these mitigation strategies: when locations of RE development are planned independently of state-level transmission, intrastate congestion can result in undesirable levels of RE curtailment. Therefore a key objective of this study is to illustrate to state-level power system planners and operators, in particular, how a higher-resolution model, inclusive of intrastate granularity, can be used as a planning tool for two primary purposes: -To better anticipate, understand, and mitigate system constraints that could affect RE integration; and - To provide a modeling framework that can be used as part of future transmission studies and planning efforts. The Regional Study is not intended to predict precisely how RE will affect state-level operations. There is considerable uncertainty regarding the locations of the RE development, as well as how contract terms can affect access to the inherent physical flexibility of the system. But the scenarios analyzed identify the types of issues that can arise under various RE and transmission expansion pathways. The model developed for this study provides a rigorous framework for future work and can be updated with the characteristics of new capacity as more information on the future power system is known.« less

Cytochrome P450 and Lipoxygenase Metabolites on Renal Function

PubMed Central

Imig, John D.; Hye Khan, Md. Abdul

2018-01-01

Arachidonic acid metabolites have a myriad of biological actions including effects on the kidney to alter renal hemodynamics and tubular transport processes. Cyclooxygenase metabolites are products of an arachidonic acid enzymatic pathway that has been extensively studied in regards to renal function. Two lesser-known enzymatic pathways of arachidonic acid metabolism are the lipoxygenase (LO) and cytochrome P450 (CYP) pathways. The importance of LO and CYP metabolites to renal hemodynamics and tubular transport processes is now being recognized. LO and CYP metabolites have actions to alter renal blood flow and glomerular filtration rate. Proximal and distal tubular sodium transport and fluid and electrolyte homeostasis are also significantly influenced by renal CYP and LO levels. Metabolites of the LO and CYP pathways also have renal actions that influence renal inflammation, proliferation, and apoptotic processes at vascular and epithelial cells. These renal LO and CYP pathway actions occur through generation of specific metabolites and cell-signaling mechanisms. Even though the renal physiological importance and actions for LO and CYP metabolites are readily apparent, major gaps remain in our understanding of these lipid mediators to renal function. Future studies will be needed to fill these major gaps regarding LO and CYP metabolites on renal function. PMID:26756638

Anesthesia for the patient undergoing total knee replacement: current status and future prospects

PubMed Central

Turnbull, Zachary A; Sastow, Dahniel; Giambrone, Gregory P; Tedore, Tiffany

2017-01-01

Total knee arthroplasty (TKA) has become one of the most common orthopedic surgical procedures performed nationally. As the population and surgical techniques for TKAs have evolved over time, so have the anesthesia and analgesia used for these procedures. General anesthesia has been the dominant form of anesthesia utilized for TKA in the past, but regional anesthetic techniques are on the rise. Multiple studies have shown the potential for regional anesthesia to improve patient outcomes, such as a decrease in intraoperative blood loss, length of stay, and patient mortality. Anesthesiologists are also moving toward multimodal analgesia, which includes peripheral nerve blockade, periarticular injection, and preemptive analgesia. The goal of multimodal analgesia is to improve perioperative pain control while minimizing systemic narcotic consumption. With improved postoperative pain management and rapid patient rehabilitation, new clinical pathways have been engineered to fast track patient recovery after orthopedic procedures. The aim of these clinical pathways was to improve quality of care, minimize unnecessary variations in care, and reduce cost by using streamlined procedures and protocols. The future of TKA care will be formalized clinical pathways and tracks to better optimize perioperative algorithms with regard to pain control and perioperative rehabilitation. PMID:28331362

Anesthesia for the patient undergoing total knee replacement: current status and future prospects.

PubMed

Turnbull, Zachary A; Sastow, Dahniel; Giambrone, Gregory P; Tedore, Tiffany

2017-01-01

Total knee arthroplasty (TKA) has become one of the most common orthopedic surgical procedures performed nationally. As the population and surgical techniques for TKAs have evolved over time, so have the anesthesia and analgesia used for these procedures. General anesthesia has been the dominant form of anesthesia utilized for TKA in the past, but regional anesthetic techniques are on the rise. Multiple studies have shown the potential for regional anesthesia to improve patient outcomes, such as a decrease in intraoperative blood loss, length of stay, and patient mortality. Anesthesiologists are also moving toward multimodal analgesia, which includes peripheral nerve blockade, periarticular injection, and preemptive analgesia. The goal of multimodal analgesia is to improve perioperative pain control while minimizing systemic narcotic consumption. With improved postoperative pain management and rapid patient rehabilitation, new clinical pathways have been engineered to fast track patient recovery after orthopedic procedures. The aim of these clinical pathways was to improve quality of care, minimize unnecessary variations in care, and reduce cost by using streamlined procedures and protocols. The future of TKA care will be formalized clinical pathways and tracks to better optimize perioperative algorithms with regard to pain control and perioperative rehabilitation.

Neurobiological Pathways Linking Socioeconomic Position and Health

PubMed Central

Gianaros, Peter J.; Manuck, Stephen B.

2010-01-01

Across individuals, risk for poor health varies inversely with socioeconomic position (SEP). The pathways by which SEP affects health have been viewed from many epidemiological perspectives. Central to these perspectives is the notion that socioeconomic health disparities arise from an interplay between nested, recursive, and cumulative environmental, social, familial, psychological, behavioral, and physiological processes that unfold over the life span. Epidemiological perspectives on socioeconomic health disparities, however, have not yet formally integrated emerging findings from neuropharmacological, molecular genetic, and neuroimaging studies demonstrating that indicators of SEP relate to patterns of brain neurotransmission, brain morphology, and brain functionality implicated in the etiology of chronic medical conditions and psychological disorders. Here, we survey these emerging findings and consider how future neurobiological studies in this area can enhance our understanding of the pathways by which different dimensions of SEP become embodied by the brain to influence health throughout life. PMID:20498294

Ultrasound Produces Extensive Brain Activation via a Cochlear Pathway.

PubMed

Guo, Hongsun; Hamilton, Mark; Offutt, Sarah J; Gloeckner, Cory D; Li, Tianqi; Kim, Yohan; Legon, Wynn; Alford, Jamu K; Lim, Hubert H

2018-06-06

Ultrasound (US) can noninvasively activate intact brain circuits, making it a promising neuromodulation technique. However, little is known about the underlying mechanism. Here, we apply transcranial US and perform brain mapping studies in guinea pigs using extracellular electrophysiology. We find that US elicits extensive activation across cortical and subcortical brain regions. However, transection of the auditory nerves or removal of cochlear fluids eliminates the US-induced activity, revealing an indirect auditory mechanism for US neural activation. Our findings indicate that US activates the ascending auditory system through a cochlear pathway, which can activate other non-auditory regions through cross-modal projections. This cochlear pathway mechanism challenges the idea that US can directly activate neurons in the intact brain, suggesting that future US stimulation studies will need to control for this effect to reach reliable conclusions. Copyright © 2018 Elsevier Inc. All rights reserved.

Clinical development of mTOR inhibitors in breast cancer

PubMed Central

2014-01-01

The mammalian target of rapamycin (mTOR) pathway is a central pathway that regulates mRNA translation, protein synthesis, glucose metabolism, lipid synthesis and autophagy, and is involved in malignant transformation. Several randomized trials have shown that the use of mTOR inhibitors could improve patient outcome with hormone receptor-positive or human epidermal growth factor receptor-2-positive breast cancer. This review analyzes new perspectives from these trials. Preclinical studies have suggested that the mTOR pathway may play a role in the resistance to hormone therapy, trastuzumab and chemotherapy for breast cancer. This concept has been tested in clinical trials for neoadjuvant treatment and for metastatic breast cancer patients. Also, much effort has gone into the identification of biomarkers that will allow for more precise stratification of patients. Findings from these studies will provide indispensable tools for the design of future clinical trials and identify new perspectives and challenges for researchers and clinicians. PMID:25189767

Deep Uncertainty Surrounding Coastal Flood Risk Projections: A Case Study for New Orleans

NASA Astrophysics Data System (ADS)

Wong, Tony E.; Keller, Klaus

2017-10-01

Future sea-level rise drives severe risks for many coastal communities. Strategies to manage these risks hinge on a sound characterization of the uncertainties. For example, recent studies suggest that large fractions of the Antarctic ice sheet (AIS) may rapidly disintegrate in response to rising global temperatures, leading to potentially several meters of sea-level rise during the next few centuries. It is deeply uncertain, for example, whether such an AIS disintegration will be triggered, how much this would increase sea-level rise, whether extreme storm surges intensify in a warming climate, or which emissions pathway future societies will choose. Here, we assess the impacts of these deep uncertainties on projected flooding probabilities for a levee ring in New Orleans, LA. We use 18 scenarios, presenting probabilistic projections within each one, to sample key deeply uncertain future projections of sea-level rise, radiative forcing pathways, storm surge characterization, and contributions from rapid AIS mass loss. The implications of these deep uncertainties for projected flood risk are thus characterized by a set of 18 probability distribution functions. We use a global sensitivity analysis to assess which mechanisms contribute to uncertainty in projected flood risk over the course of a 50-year design life. In line with previous work, we find that the uncertain storm surge drives the most substantial risk, followed by general AIS dynamics, in our simple model for future flood risk for New Orleans.

Adaptive Control Model Reveals Systematic Feedback and Key Molecules in Metabolic Pathway Regulation

PubMed Central

Moffitt, Richard A.; Merrill, Alfred H.; Wang, May D.

2011-01-01

Abstract Robust behavior in metabolic pathways resembles stabilized performance in systems under autonomous control. This suggests we can apply control theory to study existing regulation in these cellular networks. Here, we use model-reference adaptive control (MRAC) to investigate the dynamics of de novo sphingolipid synthesis regulation in a combined theoretical and experimental case study. The effects of serine palmitoyltransferase over-expression on this pathway are studied in vitro using human embryonic kidney cells. We report two key results from comparing numerical simulations with observed data. First, MRAC simulations of pathway dynamics are comparable to simulations from a standard model using mass action kinetics. The root-sum-square (RSS) between data and simulations in both cases differ by less than 5%. Second, MRAC simulations suggest systematic pathway regulation in terms of adaptive feedback from individual molecules. In response to increased metabolite levels available for de novo sphingolipid synthesis, feedback from molecules along the main artery of the pathway is regulated more frequently and with greater amplitude than from other molecules along the branches. These biological insights are consistent with current knowledge while being new that they may guide future research in sphingolipid biology. In summary, we report a novel approach to study regulation in cellular networks by applying control theory in the context of robust metabolic pathways. We do this to uncover potential insight into the dynamics of regulation and the reverse engineering of cellular networks for systems biology. This new modeling approach and the implementation routines designed for this case study may be extended to other systems. Supplementary Material is available at www.liebertonline.com/cmb. PMID:21314456

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

PubMed

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

2017-01-01

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

Qualifications for the Future: A Study of Tripartite and Other Divisions in Post-16 Education and Training.

ERIC Educational Resources Information Center

Stanton, Geoff, Ed.; Richardson, William, Ed.

1997-01-01

This document contains eight papers examining different aspects of categorization, divisions, and choice in further education (FE) that were commissioned during a study of tripartite pathways (for example, academic, vocational and applied) in education and training for 16-19 year olds in the United Kingdom. The following papers are included:…

Pathways to Resilience: How Drawings Reveal Pre-Service Teachers' Core Narratives Underpinning Their Future Teacher-Selves

ERIC Educational Resources Information Center

Dinham, Judith; Chalk, Beryl; Beltman, Susan; Glass, Christine; Nguyen, Bich

2017-01-01

For this study of teacher-identity, which is part of a larger research project on teacher resilience, preservice teachers were invited to draw "the kind of teacher you hope to become". In this, our study recognises drawing as a semiotic system of meaning-making and communication. The drawings were examined in terms of the…

Exploring hypertension genome-wide association studies findings and impact on pathophysiology, pathways, and pharmacogenetics.

PubMed

Cabrera, Claudia P; Ng, Fu Liang; Warren, Helen R; Barnes, Michael R; Munroe, Patricia B; Caulfield, Mark J

2015-01-01

Hypertension is a major risk factor for global mortality. Recent genome-wide association studies (GWAS) have led to successful identification of many genetic loci influencing blood pressure, although these studies account for less than 5% of heritability. While genetic discovery efforts continue, it is timely to pause and reflect on what information has been gained to date from reported loci. Knowledge from GWAS findings inform our understanding of the pathways and pleiotropy underpinning hypertension and aid in the identification of potential druggable targets. By reviewing blood pressure loci we aim to determine how much potential the current observations have for future clinical utility. The authors have declared no conflicts of interest for this article. © 2015 Wiley Periodicals, Inc.

Insights from human genetic studies of lung and organ fibrosis.

PubMed

Garcia, Christine Kim

2018-01-02

Genetic investigations of fibrotic diseases, including those of late onset, often yield unanticipated insights into disease pathogenesis. This Review focuses on pathways underlying lung fibrosis that are generalizable to other organs. Herein, we discuss genetic variants subdivided into those that shorten telomeres, activate the DNA damage response, change resident protein expression or function, or affect organelle activity. Genetic studies provide a window into the downstream cascade of maladaptive responses and pathways that lead to tissue fibrosis. In addition, these studies reveal interactions between genetic variants, environmental factors, and age that influence the phenotypic spectrum of disease. The discovery of forces counterbalancing inherited risk alleles identifies potential therapeutic targets, thus providing hope for future prevention or reversal of fibrosis.

Common mechanisms of excitatory and inhibitory imbalance in schizophrenia and autism spectrum disorders.

PubMed

Gao, R; Penzes, P

2015-01-01

Autism Spectrum Disorders (ASD) and Schizophrenia (SCZ) are cognitive disorders with complex genetic architectures but overlapping behavioral phenotypes, which suggests common pathway perturbations. Multiple lines of evidence implicate imbalances in excitatory and inhibitory activity (E/I imbalance) as a shared pathophysiological mechanism. Thus, understanding the molecular underpinnings of E/I imbalance may provide essential insight into the etiology of these disorders and may uncover novel targets for future drug discovery. Here, we review key genetic, physiological, neuropathological, functional, and pathway studies that suggest alterations to excitatory/inhibitory circuits are keys to ASD and SCZ pathogenesis.

[Moffitt's developmental taxonomy as seen by new results--some remarks on the "adolescence-limited" delinquency].

PubMed

Roth, Marcus; Bartsch, Benno

2004-12-01

In her taxonomy Moffitt describes two developmental pathways into delinquent behaviour: an episodic, "adolescence-limited" occurrence of delinquent behavior and a pathway characterised by an early onset and a stable course of delinquent behavior ("life-course-persistent"). Referring to the results of recent longitudinal studies the present paper inspects the empirical validity of the theory. The reported studies support both pathways postulated by Moffitt and emphasise the relevance of the onset of delinquent behaviour in the developmental course (childhood-onset vs. adolescence-onset). However, contrary to Moffitts model, the results also pointed out, that "adolescence-onset" can not be put on one level with "adolescence-limited". The results let us rather assume that there exists another pathway beside the two postulated by Moffitt, in which delinquent behaviour starts in adolescence (without an antisocial history in childhood) and continues into adulthood. Based on these results a broadening of perspective is pled for, in which the adolescence is also expected as a "sensible period" to the beginning of a delinquent development. The questions arising from this are outlined for future research.

Dietary Bioactive Diallyl Trisulfide in Cancer Prevention and Treatment.

PubMed

Puccinelli, Michael T; Stan, Silvia D

2017-07-28

Bioactive dietary agents have been shown to regulate multiple cancer hallmark pathways. Epidemiologic studies have linked consumption of Allium vegetables, such as garlic and onions, to decreased incidence of cancer. Diallyl trisulfide (DATS), a bioactive compound derived from Allium vegetables, has been investigated as an anti-cancer and chemopreventive agent. Preclinical studies provide ample evidence that DATS regulates multiple cancer hallmark pathways including cell cycle, apoptosis, angiogenesis, invasion, and metastasis. DATS has been shown to arrest cancer cells at multiple stages of the cell cycle with the G2/M arrest being the most widely reported. Additionally, increased pro-apoptotic capacity as a result of regulating intrinsic and extrinsic apoptotic pathway components has been widely reported following DATS treatment. Invasion, migration, and angiogenesis represent emerging targets of DATS and support its anti-cancer properties. This review summarizes DATS mechanisms of action as an anti-cancer and chemopreventive agent. These studies provide rationale for future investigation into its use as a cancer chemopreventive agent.

PHEOCHROMOCYTOMA: IMPLICATIONS IN TUMORIGENESIS AND THE ACTUAL MANAGEMENT

PubMed Central

Shah, Urvi; Giubellino, Alessio; Pacak, Karel

2012-01-01

Pheochromocytomas and paragangliomas are rare neuroendocrine catecholamine producing tumors with varied clinical presentations, biochemistries and genetic makeup. These features outline the complexity and the difficulties in studying and understanding the oncogenesis of these tumors. The study of families with genetically inherited mutations in pheochromocytoma susceptibility genes has greatly enhanced our understanding of the pathophysiology and mechanisms of oncogenesis of the disease, and consequently changed our clinical approach. Several molecular pathways and mutations in their important regulatory proteins have been identified. Such mutations are responsible for the dysregulation of metabolic pathways involved in oxygen and nutrient sensing, apoptosis regulation, cell proliferation, migration and invasion. The knowledge derived from the study of these pathways will be fundamental in the future clinical management of these patients. As a rare disease that often masks its clinical presentation, the diagnosis is frequently missed and a high level of suspicion is required. Management of this disease requires a multidisciplinary team approach and has been discussed along with advances in its treatment. PMID:22691888

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

Elgowainy, Amgad; Han, Jeongwoo; Ward, Jacob

This study provides a comprehensive lifecycle analysis (LCA), or cradle-to-grave (C2G) analysis, of the cost and greenhouse gas (GHG) emissions of a variety of vehicle-fuel pathways, as well as the levelized cost of driving (LCD) and cost of avoided GHG emissions. This study also estimates the technology readiness levels (TRLs) of key fuel and vehicle technologies along the pathways. The C2G analysis spans a full portfolio of midsize light-duty vehicles (LDVs), including conventional internal combustion engine vehicles (ICEVs), flexible fuel vehicles (FFVs), hybrid electric vehicles (HEVs), plug-in hybrid electric vehicles (PHEVs), battery electric vehicles (BEVs), and fuel cell electric vehiclesmore » (FCEVs). In evaluating the vehicle-fuel combinations, this study considers both low-volume and high-volume “CURRENT TECHNOLOGY” cases (nominally 2015) and a high-volume “FUTURE TECHNOLOGY” lower-carbon case (nominally 2025–2030). For the CURRENT TECHNOLOGY case, low-volume vehicle and fuel production pathways are examined to determine costs in the near term.« less

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

Elgowainy, Amgad; Han, Jeongwoo; Ward, Jacob

This study provides a comprehensive life-cycle analysis (LCA), or cradle-to-grave (C2G) analysis, of the cost and greenhouse gas (GHG) emissions of a variety of vehicle-fuel pathways, as well as the levelized cost of driving (LCD) and cost of avoided GHG emissions. This study also estimates the technology readiness levels (TRLs) of key fuel and vehicle technologies along the pathways. The C2G analysis spans a full portfolio of midsize light-duty vehicles (LDVs), including conventional internal combustion engine vehicles (ICEVs), flexible fuel vehicles (FFVs), hybrid electric vehicles (HEVs), plug-in hybrid electric vehicles (PHEVs), battery electric vehicles (BEVs), and fuel cell electric vehiclesmore » (FCEVs). In evaluating the vehicle-fuel combinations, this study considers both low-volume and high-volume “CURRENT TECHNOLOGY” cases (nominally 2015) and a high-volume “FUTURE TECHNOLOGY” lower-carbon case (nominally 2025–2030). For the CURRENT TECHNOLOGY case, low-volume vehicle and fuel production pathways are examined to determine costs in the near term.« less

Pheochromocytoma: implications in tumorigenesis and the actual management.

PubMed

Shah, U; Giubellino, A; Pacak, K

2012-06-01

Pheochromocytomas and paragangliomas are rare neuroendocrine catecholamine producing tumors with varied clinical presentations, biochemistries and genetic makeup. These features outline the complexity and the difficulties in studying and understanding the oncogenesis of these tumors. The study of families with genetically inherited mutations in pheochromocytoma susceptibility genes has greatly enhanced our understanding of the pathophysiology and mechanisms of oncogenesis of the disease, and consequently changed our clinical approach. Several molecular pathways and mutations in their important regulatory proteins have been identified. Such mutations are responsible for the dysregulation of metabolic pathways involved in oxygen and nutrient sensing, apoptosis regulation, cell proliferation, migration and invasion. The knowledge derived from the study of these pathways will be fundamental in the future clinical management of these patients. As a rare disease that often masks its clinical presentation, the diagnosis is frequently missed and a high level of suspicion is required. Management of this disease requires a multidisciplinary team approach and will be discussed along with advances in its treatment.

Dietary Bioactive Diallyl Trisulfide in Cancer Prevention and Treatment

PubMed Central

Puccinelli, Michael T.; Stan, Silvia D.

2017-01-01

Bioactive dietary agents have been shown to regulate multiple cancer hallmark pathways. Epidemiologic studies have linked consumption of Allium vegetables, such as garlic and onions, to decreased incidence of cancer. Diallyl trisulfide (DATS), a bioactive compound derived from Allium vegetables, has been investigated as an anti-cancer and chemopreventive agent. Preclinical studies provide ample evidence that DATS regulates multiple cancer hallmark pathways including cell cycle, apoptosis, angiogenesis, invasion, and metastasis. DATS has been shown to arrest cancer cells at multiple stages of the cell cycle with the G2/M arrest being the most widely reported. Additionally, increased pro-apoptotic capacity as a result of regulating intrinsic and extrinsic apoptotic pathway components has been widely reported following DATS treatment. Invasion, migration, and angiogenesis represent emerging targets of DATS and support its anti-cancer properties. This review summarizes DATS mechanisms of action as an anti-cancer and chemopreventive agent. These studies provide rationale for future investigation into its use as a cancer chemopreventive agent. PMID:28788092

Non-Genomic Effects of Xenoestrogen Mixtures

PubMed Central

Viñas, René; Jeng, Yow-Jiun; Watson, Cheryl S.

2012-01-01

Xenoestrogens (XEs) are chemicals derived from a variety of natural and anthropogenic sources that can interfere with endogenous estrogens by either mimicking or blocking their responses via non-genomic and/or genomic signaling mechanisms. Disruption of estrogens’ actions through the less-studied non-genomic pathway can alter such functional end points as cell proliferation, peptide hormone release, catecholamine transport, and apoptosis, among others. Studies of potentially adverse effects due to mixtures and to low doses of endocrine-disrupting chemicals have recently become more feasible, though few so far have included actions via the non-genomic pathway. Physiologic estrogens and XEs evoke non-monotonic dose responses, with different compounds having different patterns of actions dependent on concentration and time, making mixture assessments all the more challenging. In order to understand the spectrum of toxicities and their mechanisms, future work should focus on carefully studying individual and mixture components across a range of concentrations and cellular pathways in a variety of tissue types. PMID:23066391

Extending the Shared Socioeconomic Pathways for sub-national impacts, adaptation, and vulnerability studies

DOE PAGES

Absar, Syeda Mariya; Preston, Benjamin L.

2015-05-25

The exploration of alternative socioeconomic futures is an important aspect of understanding the potential consequences of climate change. While socioeconomic scenarios are common and, at times essential, tools for the impact, adaptation and vulnerability and integrated assessment modeling research communities, their approaches to scenario development have historically been quite distinct. However, increasing convergence of impact, adaptation and vulnerability and integrated assessment modeling research in terms of scales of analysis suggests there may be value in the development of a common framework for socioeconomic scenarios. The Shared Socioeconomic Pathways represents an opportunity for the development of such a common framework. However,more » the scales at which these global storylines have been developed are largely incommensurate with the sub-national scales at which impact, adaptation and vulnerability, and increasingly integrated assessment modeling, studies are conducted. Our objective for this study was to develop sub-national and sectoral extensions of the global SSP storylines in order to identify future socioeconomic challenges for adaptation for the U.S. Southeast. A set of nested qualitative socioeconomic storyline elements, integrated storylines, and accompanying quantitative indicators were developed through an application of the Factor-Actor-Sector framework. Finally, in addition to revealing challenges and opportunities associated with the use of the SSPs as a basis for more refined scenario development, this study generated sub-national storyline elements and storylines that can subsequently be used to explore the implications of alternative subnational socioeconomic futures for the assessment of climate change impacts and adaptation.« less

Hanford Site Composite Analysis Technical Approach Description: Groundwater Pathway Dose Calculation.

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

Morgans, D. L.; Lindberg, S. L.

The purpose of this technical approach document (TAD) is to document the assumptions, equations, and methods used to perform the groundwater pathway radiological dose calculations for the revised Hanford Site Composite Analysis (CA). DOE M 435.1-1, states, “The composite analysis results shall be used for planning, radiation protection activities, and future use commitments to minimize the likelihood that current low-level waste disposal activities will result in the need for future corrective or remedial actions to adequately protect the public and the environment.”

Enhancing the Quantitative Representation of Socioeconomic Conditions in the Shared Socio-economic Pathways (SSPs) using the International Futures Model

NASA Astrophysics Data System (ADS)

Rothman, D. S.; Siraj, A.; Hughes, B.

2013-12-01

The international research community is currently in the process of developing new scenarios for climate change research. One component of these scenarios are the Shared Socio-economic Pathways (SSPs), which describe a set of possible future socioeconomic conditions. These are presented in narrative storylines with associated quantitative drivers. The core quantitative drivers include total population, average GDP per capita, educational attainment, and urbanization at the global, regional, and national levels. At the same time there have been calls, particularly by the IAV community, for the SSPs to include additional quantitative information on other key social factors, such as income inequality, governance, health, and access to key infrastructures, which are discussed in the narratives. The International Futures system (IFs), based at the Pardee Center at the University of Denver, is able to provide forecasts of many of these indicators. IFs cannot use the SSP drivers as exogenous inputs, but we are able to create development pathways that closely reproduce the core quantitative drivers defined by the different SSPs, as well as incorporating assumptions on other key driving factors described in the qualitative narratives. In this paper, we present forecasts for additional quantitative indicators based upon the implementation of the SSP development pathways in IFs. These results will be of value to many researchers.

Change Ahead: Transient Scenarios for Long-term Water Management

NASA Astrophysics Data System (ADS)

Haasnoot, Marjolijn; Beersma, Jules; Schellekens, Jaap

2013-04-01

While the use of an ensemble of transient scenarios is common in climate change studies, they are rarely used in water management studies. Present planning studies on long-term water management often use a few plausible futures for one or two projection years, ignoring the dynamic aspect of adaptation through the interaction between the water system and society. Over the course of time society experiences, learns and adapts to changes and events, making policy responses part of a plausible future, and thus the success of a water management strategy. Exploring transient scenarios and policy options over time can support decision making on water management strategies in an uncertain and changing environment. We have developed and applied such a method, called exploring adaptation pathways (Haasnoot et al., 2012; Haasnoot et al., 2011). This method uses multiple realisations of transient scenarios to assess the efficacy of policy actions over time. In case specified objectives are not achieved anymore, an adaptation tipping point (Kwadijk et al., 2010) is reached. After reaching a tipping point, additional actions are needed to reach the objectives. As a result, a pathway emerges. In this presentation we describe the development of transient scenarios for long term water management, and how these scenarios can be used for long term water management under uncertainty. We illustrate this with thought experiments, and results from computational modeling experiment for exploring adaptation pathways in the lower Rhine delta. The results and the thought experiments show, among others, that climate variability is at least just as important as climate change for taking decisions in water management. References Haasnoot, M., Middelkoop, H., Offermans, A., Beek, E., Deursen, W.A.v. (2012) Exploring pathways for sustainable water management in river deltas in a changing environment. Climatic Change 115, 795-819. Haasnoot, M., Middelkoop, H., van Beek, E., van Deursen, W.P.A. (2011) A Method to Develop Sustainable Water Management Strategies for an Uncertain Future. Sustainable Development 19, 369-381. Kwadijk, J.C.J., Haasnoot, M., Mulder, J.P.M., Hoogvliet, M.M.C., Jeuken, A.B.M., van der Krogt, R.A.A., van Oostrom, N.G.C., Schelfhout, H.A., van Velzen, E.H., van Waveren, H., de Wit, M.J.M. (2010) Using adaptation tipping points to prepare for climate change and sea level rise: a case study in the Netherlands. Wiley Interdisciplinary Reviews: Climate Change 1, 729-740.

Analysis of JAK-STAT signaling pathway genes and their microRNAs in the intestinal mucosa of genetically disparate chicken lines induced with necrotic enteritis.

PubMed

Truong, Anh Duc; Rengaraj, Deivendran; Hong, Yeojin; Hoang, Cong Thanh; Hong, Yeong Ho; Lillehoj, Hyun S

2017-05-01

The JAK-STAT signaling pathway plays a key role in cytokine and growth factor activation and is involved in several cellular functions and diseases. The main objective of this study was to investigate the expression of candidate JAK-STAT pathway genes and their regulators and interactors in the intestinal mucosal layer of two genetically disparate chicken lines [Marek's disease (MD)-resistant line 6.3 and MD-susceptible line 7.2] induced with necrotic enteritis (NE). Through RNA-sequencing, we investigated 116 JAK-STAT signaling pathway-related genes that were significant and differentially expressed between the intestinal mucosa of the two lines compared with respective uninfected controls. About 15 JAK-STAT pathway genes were further verified by qRT-PCR, and the results were in agreement with our sequencing data. All the identified 116 genes were annotated through Gene Ontology and mapped to the KEGG chicken JAK-STAT signaling pathway. To the best of our knowledge, this is the first study to represent the transcriptional analysis of a large number of candidate genes, regulators, and potential interactors in the JAK-STAT pathway of the two chicken lines induced with NE. Several key genes of the interactome, namely, STAT1/3/4, STAT5B, JAK1-3, TYK2, AKT1/3, SOCS1-5, PIAS1/2/4, PTPN6/11, and PIK3, were determined to be differentially expressed in the two lines. Moreover, we detected 68 known miRNAs variably targeting JAK-STAT pathway genes and differentially expressed in the two lines induced with NE. The RNA-sequencing and bioinformatics analyses in this study provided an abundance of data that will be useful for future studies on JAK-STAT pathways associated with the functions of two genetically disparate chicken lines induced with NE. Copyright © 2017 Elsevier B.V. All rights reserved.

Development of Future Scenario Emission Inventories for East Asia in Support of Multiple Modeling Studies

NASA Astrophysics Data System (ADS)

Kim, Y.; Woo, J. H.; Choi, K. C.; Lee, J. B.; Song, C. K.; Kim, S. K.; Hong, J.; Hong, S. C.; Zhang, Q.; Hong, C.; Tong, D.

2015-12-01

Future emission scenarios based on up-to-date regional socio-economic and control policy information were developed in support of climate-air quality integrated modeling research over East Asia. Two IPCC-participated Integrated Assessment Models(IAMs) were used to developed those scenario pathways. The two emission processing systems, KU-EPS and SMOKE-Asia, were used to convert these future scenario emissions to comprehensive chemical transport model-ready form. The NIER/KU-CREATE (Comprehensive Regional Emissions inventory for Atmospheric Transport Experiment) served as the regional base-year emission inventory. For anthropogenic emissions, it has 54 fuel classes, 201 sub-sectors and 13 pollutants, including CO2, CH4, N2O, SO2, NOx, CO, NMVOC, NH3, OC, BC, PM10, PM2.5, and mercury. Fast energy growth and aggressive penetration of the control measures make emissions projection very active for East Asia. Despite of more stringent air pollution control policies by the governments, however, air quality over the region seems not been improved as much - even worse in many cases. The needs of more scientific understanding of inter-relationship among emissions, transport, chemistry over the region are very high to effectively protect public health and ecosystems against ozone, fine particles, and other toxic pollutants in the air. After developing these long-term future emissions, therefore, we also tried to apply our future scenarios to develop the present emissions inventory for chemical weather forecasting and aircraft field campaign. On site, we will present; 1) the future scenario development framework and process methodologies, 2) initial development results of the future emission pathways, 3) present emission inventories from short-term projection, and 4) air quality modeling performance improvements over the region.

Adolescents' Changing Future Expectations Predict the Timing of Adult Role Transitions

ERIC Educational Resources Information Center

Beal, Sarah J.; Crockett, Lisa J.; Peugh, James

2016-01-01

Individual differences in the transition to adulthood are well established. This study examines the extent to which heterogeneity in pathways to adulthood that have been observed in the broader U.S. population are mirrored in adolescents' expectations regarding when they will experience key adult role transitions (e.g., marriage). Patterns of…

Proceedings from the 2011 American Association of Oral and Maxillofacial Surgeons Research Summit

DTIC Science & Technology

2012-01-01

technetium-99m sulfur colloid) that is then detect- able on nuclear imaging. The tracer enters the inter- stitial space, flows to lymphatic capillaries, and be... cochlear function. The focus of future studies is to further characterize the TGF- signaling pathway and its effects on bone extracellular matrix quality

Integrated pathway-based approach identifies association between genomic regions at CTCF and CACNB2 and schizophrenia.

PubMed

Juraeva, Dilafruz; Haenisch, Britta; Zapatka, Marc; Frank, Josef; Witt, Stephanie H; Mühleisen, Thomas W; Treutlein, Jens; Strohmaier, Jana; Meier, Sandra; Degenhardt, Franziska; Giegling, Ina; Ripke, Stephan; Leber, Markus; Lange, Christoph; Schulze, Thomas G; Mössner, Rainald; Nenadic, Igor; Sauer, Heinrich; Rujescu, Dan; Maier, Wolfgang; Børglum, Anders; Ophoff, Roel; Cichon, Sven; Nöthen, Markus M; Rietschel, Marcella; Mattheisen, Manuel; Brors, Benedikt

2014-06-01

In the present study, an integrated hierarchical approach was applied to: (1) identify pathways associated with susceptibility to schizophrenia; (2) detect genes that may be potentially affected in these pathways since they contain an associated polymorphism; and (3) annotate the functional consequences of such single-nucleotide polymorphisms (SNPs) in the affected genes or their regulatory regions. The Global Test was applied to detect schizophrenia-associated pathways using discovery and replication datasets comprising 5,040 and 5,082 individuals of European ancestry, respectively. Information concerning functional gene-sets was retrieved from the Kyoto Encyclopedia of Genes and Genomes, Gene Ontology, and the Molecular Signatures Database. Fourteen of the gene-sets or pathways identified in the discovery dataset were confirmed in the replication dataset. These include functional processes involved in transcriptional regulation and gene expression, synapse organization, cell adhesion, and apoptosis. For two genes, i.e. CTCF and CACNB2, evidence for association with schizophrenia was available (at the gene-level) in both the discovery study and published data from the Psychiatric Genomics Consortium schizophrenia study. Furthermore, these genes mapped to four of the 14 presently identified pathways. Several of the SNPs assigned to CTCF and CACNB2 have potential functional consequences, and a gene in close proximity to CACNB2, i.e. ARL5B, was identified as a potential gene of interest. Application of the present hierarchical approach thus allowed: (1) identification of novel biological gene-sets or pathways with potential involvement in the etiology of schizophrenia, as well as replication of these findings in an independent cohort; (2) detection of genes of interest for future follow-up studies; and (3) the highlighting of novel genes in previously reported candidate regions for schizophrenia.

Thoughts on the Teaching of Metabolism

ERIC Educational Resources Information Center

Metzger, Robert P.

2006-01-01

Systems biology, metabolomics, metabolic engineering, and other recent developments in biochemistry suggest that future biochemists will require a detailed familiarity with the compounds and pathways of intermediary metabolism and their biochemical control. The challenge to the biochemistry instructor is the presentation of metabolic pathways in a…

Metabolic Engineering of the Shikimate Pathway for Production of Aromatics and Derived Compounds—Present and Future Strain Construction Strategies

PubMed Central

Averesch, Nils J. H.; Krömer, Jens O.

2018-01-01

The aromatic nature of shikimate pathway intermediates gives rise to a wealth of potential bio-replacements for commonly fossil fuel-derived aromatics, as well as naturally produced secondary metabolites. Through metabolic engineering, the abundance of certain intermediates may be increased, while draining flux from other branches off the pathway. Often targets for genetic engineering lie beyond the shikimate pathway, altering flux deep in central metabolism. This has been extensively used to develop microbial production systems for a variety of compounds valuable in chemical industry, including aromatic and non-aromatic acids like muconic acid, para-hydroxybenzoic acid, and para-coumaric acid, as well as aminobenzoic acids and aromatic α-amino acids. Further, many natural products and secondary metabolites that are valuable in food- and pharma-industry are formed outgoing from shikimate pathway intermediates. (Re)construction of such routes has been shown by de novo production of resveratrol, reticuline, opioids, and vanillin. In this review, strain construction strategies are compared across organisms and put into perspective with requirements by industry for commercial viability. Focus is put on enhancing flux to and through shikimate pathway, and engineering strategies are assessed in order to provide a guideline for future optimizations. PMID:29632862

Allorecognition pathways in transplant rejection and tolerance.

PubMed

Ali, Jason M; Bolton, Eleanor M; Bradley, J Andrew; Pettigrew, Gavin J

2013-10-27

With the advent of cellular therapies, it has become clear that the success of future therapies in prolonging allograft survival will require an intimate understanding of the allorecognition pathways and effector mechanisms that are responsible for chronic rejection and late graft loss.Here, we consider current understanding of T-cell allorecognition pathways and discuss the most likely mechanisms by which these pathways collaborate with other effector mechanisms to cause allograft rejection. We also consider how this knowledge may inform development of future strategies to prevent allograft rejection.Although both direct and indirect pathway CD4 T cells appear active immediately after transplantation, it has emerged that indirect pathway CD4 T cells are likely to be the dominant alloreactive T-cell population late after transplantation. Their ability to provide help for generating long-lived alloantibody is likely one of the main mechanisms responsible for the progression of allograft vasculopathy and chronic rejection.Recent work has suggested that regulatory T cells may be an effective cellular therapy in transplantation. Given the above, adoptive therapy with CD4 regulatory T cells with indirect allospecificity is a rational first choice in attempting to attenuate the development and progression of chronic rejection; those with additional properties that enable inhibition of germinal center alloantibody responses hold particular appeal.

Overexpression of hypoxia-inducible factor and metabolic pathways: possible targets of cancer.

PubMed

Singh, Davinder; Arora, Rohit; Kaur, Pardeep; Singh, Balbir; Mannan, Rahul; Arora, Saroj

2017-01-01

Cancer, the main cause of human deaths in the modern world is a group of diseases. Anticancer drug discovery is a challenge for scientists because of involvement of multiple survival pathways of cancer cells. An extensive study on the regulation of each step of these pathways may help find a potential cancer target. Up-regulated HIF-1 expression and altered metabolic pathways are two classical characteristics of cancer. Oxygen-dependent (through pVHL, PHDs, calcium-mediated) and independent (through growth factor signaling pathway, mdm2 pathway, HSP90) regulation of HIF-1α leads to angiogenesis, metastasis, and cell survival. The two subunits of HIF-1 regulates in the same fashion through different mechanisms. HIF-1α translation upregulates via mammalian target of rapamycin and mitogen-activated protein kinase signaling pathways, whereas HIF-1β through calmodulin kinase. Further, the stabilized interactions of these two subunits are important for proper functioning. Also, metabolic pathways crucial for the formation of building blocks (pentose phosphate pathway) and energy generation (glycolysis, TCA cycle and catabolism of glutamine) are altered in cancer cells to protect them from oxidative stress and to meet the reduced oxygen and nutrient supply. Up-regulated anaerobic metabolism occurs through enhanced expression of hexokinase, phosphofructokinase, triosephosphate isomerase, glucose 6-phosphate dehydrogenase and down-regulation of aerobic metabolism via pyruvate dehydrogenase kinase and lactate dehydrogenase which compensate energy requirements along with high glucose intake. Controlled expression of these two pathways through their common intermediate may serve as potent cancer target in future.

Assessing the utility of the willingness/prototype model in predicting help-seeking decisions.

PubMed

Hammer, Joseph H; Vogel, David L

2013-01-01

Prior research on professional psychological help-seeking behavior has operated on the assumption that the decision to seek help is based on intentional and reasoned processes. However, research on the dual-process prototype/willingness model (PWM; Gerrard, Gibbons, Houlihan, Stock, & Pomery, 2008) suggests health-related decisions may also involve social reaction processes that influence one's spontaneous willingness (rather than planned intention) to seek help, given conducive circumstances. The present study used structural equation modeling to evaluate the ability of these 2 information-processing pathways (i.e., the reasoned pathway and the social reaction pathway) to predict help-seeking decisions among 182 college students currently experiencing clinical levels of psychological distress. Results indicated that when both pathways were modeled simultaneously, only the social reaction pathway independently accounted for significant variance in help-seeking decisions. These findings argue for the utility of the PWM framework in the context of professional psychological help seeking and hold implications for future counseling psychology research, prevention, and practice. PsycINFO Database Record (c) 2013 APA, all rights reserved.

Connectome imaging for mapping human brain pathways

PubMed Central

Shi, Y; Toga, A W

2017-01-01

With the fast advance of connectome imaging techniques, we have the opportunity of mapping the human brain pathways in vivo at unprecedented resolution. In this article we review the current developments of diffusion magnetic resonance imaging (MRI) for the reconstruction of anatomical pathways in connectome studies. We first introduce the background of diffusion MRI with an emphasis on the technical advances and challenges in state-of-the-art multi-shell acquisition schemes used in the Human Connectome Project. Characterization of the microstructural environment in the human brain is discussed from the tensor model to the general fiber orientation distribution (FOD) models that can resolve crossing fibers in each voxel of the image. Using FOD-based tractography, we describe novel methods for fiber bundle reconstruction and graph-based connectivity analysis. Building upon these novel developments, there have already been successful applications of connectome imaging techniques in reconstructing challenging brain pathways. Examples including retinofugal and brainstem pathways will be reviewed. Finally, we discuss future directions in connectome imaging and its interaction with other aspects of brain imaging research. PMID:28461700

The Nrf2/Keap1/ARE Pathway and Oxidative Stress as a Therapeutic Target in Type II Diabetes Mellitus

PubMed Central

2017-01-01

Despite improvements in awareness and treatment of type II diabetes mellitus (TIIDM), this disease remains a major source of morbidity and mortality worldwide, and prevalence continues to rise. Oxidative damage caused by free radicals has long been known to contribute to the pathogenesis and progression of TIIDM and its complications. Only recently, however, has the role of the Nrf2/Keap1/ARE master antioxidant pathway in diabetic dysfunction begun to be elucidated. There is accumulating evidence that this pathway is implicated in diabetic damage to the pancreas, heart, and skin, among other cell types and tissues. Animal studies and clinical trials have shown promising results suggesting that activation of this pathway can delay or reverse some of these impairments in TIIDM. In this review, we outline the role of oxidative damage and the Nrf2/Keap1/ARE pathway in TIIDM, focusing on current and future efforts to utilize this relationship as a therapeutic target for prevention, prognosis, and treatment of TIID. PMID:28913364

Physician Confidence in Dental Trauma Treatment and the Introduction of a Dental Trauma Decision-Making Pathway for the Pediatric Emergency Department.

PubMed

Cully, Matthew; Cully, Jennifer; Nietert, Paul J; Titus, M Olivia

2018-04-24

The objectives of this study were to (1) survey and report the awareness and confidence of pediatric emergency medicine physicians in the management of dental trauma and (2) determine the prevalence of dental trauma decision-making pathway utilization in the pediatric emergency department. A survey was distributed through e-mail to the pediatric emergency medicine discussion list via Brown University LISTSERV. The survey study included 10 questions and was multiple-choice. The survey contained questions about physician confidence and their use of a dental trauma decision-making pathway. A total of 285 individuals responded to the survey. Somewhat confident was the most common response (61%) followed by not confident (20%) and confident (19%) by respondents in treating dental trauma. Forty-one percent of respondents felt comfortable, 39% somewhat comfortable, 19% not comfortable, and 1% not sure in replanting an avulsed tooth. Only 6% of respondents reported that their pediatric emergency department always or sometimes uses a dental trauma decision-making pathway, whereas 78% of pediatric emergency departments do not. We believe that the adoption of a decision-making pathway will provide timely management, improve emergency physician comfort, and enhance outcomes for pediatric patients presenting with a dental trauma. A future multicenter review will aim to evaluate these goals based on the utilization of our dental trauma decision-making pathway.

Time course of gene expression during mouse skeletal muscle hypertrophy

PubMed Central

Lee, Jonah D.; England, Jonathan H.; Esser, Karyn A.; McCarthy, John J.

2013-01-01

The purpose of this study was to perform a comprehensive transcriptome analysis during skeletal muscle hypertrophy to identify signaling pathways that are operative throughout the hypertrophic response. Global gene expression patterns were determined from microarray results on days 1, 3, 5, 7, 10, and 14 during plantaris muscle hypertrophy induced by synergist ablation in adult mice. Principal component analysis and the number of differentially expressed genes (cutoffs ≥2-fold increase or ≥50% decrease compared with control muscle) revealed three gene expression patterns during overload-induced hypertrophy: early (1 day), intermediate (3, 5, and 7 days), and late (10 and 14 days) patterns. Based on the robust changes in total RNA content and in the number of differentially expressed genes, we focused our attention on the intermediate gene expression pattern. Ingenuity Pathway Analysis revealed a downregulation of genes encoding components of the branched-chain amino acid degradation pathway during hypertrophy. Among these genes, five were predicted by Ingenuity Pathway Analysis or previously shown to be regulated by the transcription factor Kruppel-like factor-15, which was also downregulated during hypertrophy. Moreover, the integrin-linked kinase signaling pathway was activated during hypertrophy, and the downregulation of muscle-specific micro-RNA-1 correlated with the upregulation of five predicted targets associated with the integrin-linked kinase pathway. In conclusion, we identified two novel pathways that may be involved in muscle hypertrophy, as well as two upstream regulators (Kruppel-like factor-15 and micro-RNA-1) that provide targets for future studies investigating the importance of these pathways in muscle hypertrophy. PMID:23869057

Time course of gene expression during mouse skeletal muscle hypertrophy.

PubMed

Chaillou, Thomas; Lee, Jonah D; England, Jonathan H; Esser, Karyn A; McCarthy, John J

2013-10-01

The purpose of this study was to perform a comprehensive transcriptome analysis during skeletal muscle hypertrophy to identify signaling pathways that are operative throughout the hypertrophic response. Global gene expression patterns were determined from microarray results on days 1, 3, 5, 7, 10, and 14 during plantaris muscle hypertrophy induced by synergist ablation in adult mice. Principal component analysis and the number of differentially expressed genes (cutoffs ≥2-fold increase or ≥50% decrease compared with control muscle) revealed three gene expression patterns during overload-induced hypertrophy: early (1 day), intermediate (3, 5, and 7 days), and late (10 and 14 days) patterns. Based on the robust changes in total RNA content and in the number of differentially expressed genes, we focused our attention on the intermediate gene expression pattern. Ingenuity Pathway Analysis revealed a downregulation of genes encoding components of the branched-chain amino acid degradation pathway during hypertrophy. Among these genes, five were predicted by Ingenuity Pathway Analysis or previously shown to be regulated by the transcription factor Kruppel-like factor-15, which was also downregulated during hypertrophy. Moreover, the integrin-linked kinase signaling pathway was activated during hypertrophy, and the downregulation of muscle-specific micro-RNA-1 correlated with the upregulation of five predicted targets associated with the integrin-linked kinase pathway. In conclusion, we identified two novel pathways that may be involved in muscle hypertrophy, as well as two upstream regulators (Kruppel-like factor-15 and micro-RNA-1) that provide targets for future studies investigating the importance of these pathways in muscle hypertrophy.

Regulation of Survival Motor Neuron Protein by the Nuclear Factor-Kappa B Pathway in Mouse Spinal Cord Motoneurons.

PubMed

Arumugam, Saravanan; Mincheva-Tasheva, Stefka; Periyakaruppiah, Ambika; de la Fuente, Sandra; Soler, Rosa M; Garcera, Ana

2018-06-01

Survival motor neuron (SMN) protein deficiency causes the genetic neuromuscular disorder spinal muscular atrophy (SMA), characterized by spinal cord motoneuron degeneration. Since SMN protein level is critical to disease onset and severity, analysis of the mechanisms involved in SMN stability is one of the central goals of SMA research. Here, we describe the role of several members of the NF-κB pathway in regulating SMN in motoneurons. NF-κB is one of the main regulators of motoneuron survival and pharmacological inhibition of NF-κB pathway activity also induces mouse survival motor neuron (Smn) protein decrease. Using a lentiviral-based shRNA approach to reduce the expression of several members of NF-κB pathway, we observed that IKK and RelA knockdown caused Smn reduction in mouse-cultured motoneurons whereas IKK or RelB knockdown did not. Moreover, isolated motoneurons obtained from the severe SMA mouse model showed reduced protein levels of several NF-κB members and RelA phosphorylation. We describe the alteration of NF-κB pathway in SMA cells. In the context of recent studies suggesting regulation of altered intracellular pathways as a future pharmacological treatment of SMA, we propose the NF-κB pathway as a candidate in this new therapeutic approach.

Critical Roles of the Direct GABAergic Pallido-cortical Pathway in Controlling Absence Seizures

PubMed Central

Li, Min; Ma, Tao; Wu, Shengdun; Ma, Jingling; Cui, Yan; Xia, Yang; Xu, Peng; Yao, Dezhong

2015-01-01

The basal ganglia (BG), serving as an intermediate bridge between the cerebral cortex and thalamus, are believed to play crucial roles in controlling absence seizure activities generated by the pathological corticothalamic system. Inspired by recent experiments, here we systematically investigate the contribution of a novel identified GABAergic pallido-cortical pathway, projecting from the globus pallidus externa (GPe) in the BG to the cerebral cortex, to the control of absence seizures. By computational modelling, we find that both increasing the activation of GPe neurons and enhancing the coupling strength of the inhibitory pallido-cortical pathway can suppress the bilaterally synchronous 2–4 Hz spike and wave discharges (SWDs) during absence seizures. Appropriate tuning of several GPe-related pathways may also trigger the SWD suppression, through modulating the activation level of GPe neurons. Furthermore, we show that the previously discovered bidirectional control of absence seizures due to the competition between other two BG output pathways also exists in our established model. Importantly, such bidirectional control is shaped by the coupling strength of this direct GABAergic pallido-cortical pathway. Our work suggests that the novel identified pallido-cortical pathway has a functional role in controlling absence seizures and the presented results might provide testable hypotheses for future experimental studies. PMID:26496656

Relative Contributions of Agricultural Drift, Para-Occupational ...

EPA Pesticide Factsheets

Background: Increased pesticide concentrations in house dust in agricultural areas have been attributed to several exposure pathways, including agricultural drift, para-occupational, and residential use. Objective: To guide future exposure assessment efforts, we quantified relative contributions of these pathways using meta-regression models of published data on dust pesticide concentrations. Methods: From studies in North American agricultural areas published from 1995-2015, we abstracted dust pesticide concentrations reported as summary statistics (e.g., geometric means (GM)). We analyzed these data using mixed-effects meta-regression models that weighted each summary statistic by its inverse variance. Dependent variables were either the log-transformed GM (drift) or the log-transformed ratio of GMs from two groups (para-occupational, residential use). Results: For the drift pathway, predicted GMs decreased sharply and nonlinearly, with GMs 64% lower in homes 250 m versus 23 m from fields (inter-quartile range of published data) based on 52 statistics from 7 studies. For the para-occupational pathway, GMs were 2.3 times higher (95% confidence interval [CI]: 1.5-3.3; 15 statistics, 5 studies) in homes of farmers who applied pesticides more versus less recently or frequently. For the residential use pathway, GMs were 1.3 (95%CI: 1.1-1.4) and 1.5 (95%CI: 1.2-1.9) times higher in treated versus untreated homes, when the probability that a pesticide was used for

Harnessing pain heterogeneity and RNA transcriptome to identify blood-based pain biomarkers: a novel correlational study design and bioinformatics approach in a graded chronic constriction injury model.

PubMed

Grace, Peter M; Hurley, Daniel; Barratt, Daniel T; Tsykin, Anna; Watkins, Linda R; Rolan, Paul E; Hutchinson, Mark R

2012-09-01

A quantitative, peripherally accessible biomarker for neuropathic pain has great potential to improve clinical outcomes. Based on the premise that peripheral and central immunity contribute to neuropathic pain mechanisms, we hypothesized that biomarkers could be identified from the whole blood of adult male rats, by integrating graded chronic constriction injury (CCI), ipsilateral lumbar dorsal quadrant (iLDQ) and whole blood transcriptomes, and pathway analysis with pain behavior. Correlational bioinformatics identified a range of putative biomarker genes for allodynia intensity, many encoding for proteins with a recognized role in immune/nociceptive mechanisms. A selection of these genes was validated in a separate replication study. Pathway analysis of the iLDQ transcriptome identified Fcγ and Fcε signaling pathways, among others. This study is the first to employ the whole blood transcriptome to identify pain biomarker panels. The novel correlational bioinformatics, developed here, selected such putative biomarkers based on a correlation with pain behavior and formation of signaling pathways with iLDQ genes. Future studies may demonstrate the predictive ability of these biomarker genes across other models and additional variables. © 2012 The Authors. Journal of Neurochemistry © 2012 International Society for Neurochemistry.

Oxytocin: its role in benign prostatic hyperplasia via the ERK pathway.

PubMed

Xu, Huan; Fu, Shi; Chen, Yanbo; Chen, Qi; Gu, Meng; Liu, Chong; Qiao, Zhiguang; Zhou, Juan; Wang, Zhong

2017-04-01

The aim of the present study was to evaluate oxytocin and benign prostatic hyperplasia (BPH), and study the cell signalling mechanism. Investigation was performed in patients about the correlation between oxytocin level and BPH. Mice were injected with oxytocin or oxytocin antagonist for 2 weeks and the prostate morphology was studied after their sacrifice. Furthermore, in vitro experiments were performed to evaluate the oxytocin effect through the MEK/ERK/RSK pathway. Oxytocin was significantly elevated in the serum and prostate tissue of patients with BPH, and a positive correlation with prostate volume indicated. In the animal experiments, prostate enlargement was observed in the oxytocin-treated group, whereas oxytocin antagonist reduced prostate hyperplasia. The in vitro study confirmed this result and also revealed activation of the MEK/ERK/RSK pathway. Oxytocin is highly expressed in the serum and prostate tissue of patients with BPH. In addition, oxytocin aggravates BPH and the oxytocin-induced proliferative effect on prostatic cells is mediated through the MEK/ERK/RSK pathway, at least partly. Thus, the hypothalamic regulation may be involved in development of BPH, which may open a new door to more medications for BPH in the future. © 2017 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

Quantifying Uncertainty in Projections of Stratospheric Ozone Over the 21st Century

NASA Technical Reports Server (NTRS)

Charlton-Perez, A. J.; Hawkins, E.; Eyring, V.; Cionni, I.; Bodeker, G. E.; Kinnison, D. E.; Akiyoshi, H.; Frith, S. M.; Garcia, R.; Gettelman, A.;

Cross-sectional evidence for a stress-negative affect pathway to substance use among sexual minority girls.

PubMed

Marshal, Michael P; Burton, Chad M; Chisolm, Deena J; Sucato, Gina S; Friedman, Mark S

2013-08-01

Sexual minority girls (SMGs) are four times more likely to engage in substance use than are heterosexual girls. A better understanding of the explanatory mechanisms of this disparity is needed to inform prevention and intervention programs. The goal of this study was to conduct a preliminary test of a "stress-negative affect" pathway by examining gay-related victimization and depression as mediators of substance use among SMGs. Adolescent girls (N = 156, 41% SMGs) were recruited from two urban adolescent medicine clinics to participate in an NIH-funded study of adolescent substance use. The average age was 17.0 years old and 57% were nonwhite. Mediation analyses were conducted in a multiple regression framework using SPSS and a mediation macro utilizing bias-corrected bootstrapping. Four models were estimated to test mediated pathways from sexual orientation to gay-related victimization (Mediator 1), to depression symptoms (Mediator 2), and then to each of four substance use variables: cigarettes, marijuana, alcohol, and heavy alcohol use. Significant mediated pathways (mediation tests with 95% CIs) were found for cigarette, alcohol and heavy alcohol use outcome variables. Results provide preliminary support for the minority stress hypothesis and the stress-negative affect pathway, and may inform the development of future prevention and intervention programs. © 2013 Wiley Periodicals, Inc.

Methotrexate Induces Apoptosis in Organ-Cultured Nasal Polyps Via the Fas Pathway.

PubMed

Heo, Kyung Wook; Park, Seong Kook; Lee, Yeo Myeong; Choe, Si Hong; Gu, Pyung Mo; Hong, Tae Ui; Hur, Dae Young

2017-05-01

Methotrexate (MTX) is very effective when used to treat chronic inflammatory diseases, and also induces apoptosis in nasal polyps (NPs). Increasing evidence suggests that Fas-Fas ligand (FasL) interactions activate multiple pathways involved in the regulation of immune and inflammatory cell functions. The aim of the present study was to identify pathways activated by Fas signaling when NPs were treated with MTX. Nasal polyps tissues were cultured using an air-liquid interface organ culture method. Cultures were maintained in the absence or presence of MTX (10 or 100 μM) for 24 hours. The authors used the reverse transcription-polymerase chain reaction method and Western blotting to identify pathways activated by Fas when NPs were treated with MTX. The Fas mRNA expression ratio was unchanged upon MTX treatment, but the FasL mRNA expression ratio was significantly higher in MTX-treated than nontreated polyps. In addition, the expression levels of the Fas and FasL proteins were significantly higher in polyps treated with both 10 and 100 μM MTX compared with nontreated polyps. Methotrexate induces apoptosis in NPs via the Fas pathway. Future studies should explore the topical use of MTX for NP control. Methotrexate may be a useful alternative steroid-sparing agent for the treatment of NPs.

Next generation of immune checkpoint therapy in cancer: new developments and challenges.

PubMed

Marin-Acevedo, Julian A; Dholaria, Bhagirathbhai; Soyano, Aixa E; Knutson, Keith L; Chumsri, Saranya; Lou, Yanyan

2018-03-15

Immune checkpoints consist of inhibitory and stimulatory pathways that maintain self-tolerance and assist with immune response. In cancer, immune checkpoint pathways are often activated to inhibit the nascent anti-tumor immune response. Immune checkpoint therapies act by blocking or stimulating these pathways and enhance the body's immunological activity against tumors. Cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), programmed cell death receptor-1 (PD-1), and programmed cell death ligand-1(PD-L1) are the most widely studied and recognized inhibitory checkpoint pathways. Drugs blocking these pathways are currently utilized for a wide variety of malignancies and have demonstrated durable clinical activities in a subset of cancer patients. This approach is rapidly extending beyond CTLA-4 and PD-1/PD-L1. New inhibitory pathways are under investigation, and drugs blocking LAG-3, TIM-3, TIGIT, VISTA, or B7/H3 are being investigated. Furthermore, agonists of stimulatory checkpoint pathways such as OX40, ICOS, GITR, 4-1BB, CD40, or molecules targeting tumor microenvironment components like IDO or TLR are under investigation. In this article, we have provided a comprehensive review of immune checkpoint pathways involved in cancer immunotherapy, and discuss their mechanisms and the therapeutic interventions currently under investigation in phase I/II clinical trials. We also reviewed the limitations, toxicities, and challenges and outline the possible future research directions.

The Regulation of Filamentous Growth in Yeast

PubMed Central

Cullen, Paul J.; Sprague, George F.

2012-01-01

Filamentous growth is a nutrient-regulated growth response that occurs in many fungal species. In pathogens, filamentous growth is critical for host–cell attachment, invasion into tissues, and virulence. The budding yeast Saccharomyces cerevisiae undergoes filamentous growth, which provides a genetically tractable system to study the molecular basis of the response. Filamentous growth is regulated by evolutionarily conserved signaling pathways. One of these pathways is a mitogen activated protein kinase (MAPK) pathway. A remarkable feature of the filamentous growth MAPK pathway is that it is composed of factors that also function in other pathways. An intriguing challenge therefore has been to understand how pathways that share components establish and maintain their identity. Other canonical signaling pathways—rat sarcoma/protein kinase A (RAS/PKA), sucrose nonfermentable (SNF), and target of rapamycin (TOR)—also regulate filamentous growth, which raises the question of how signals from multiple pathways become integrated into a coordinated response. Together, these pathways regulate cell differentiation to the filamentous type, which is characterized by changes in cell adhesion, cell polarity, and cell shape. How these changes are accomplished is also discussed. High-throughput genomics approaches have recently uncovered new connections to filamentous growth regulation. These connections suggest that filamentous growth is a more complex and globally regulated behavior than is currently appreciated, which may help to pave the way for future investigations into this eukaryotic cell differentiation behavior. PMID:22219507

Pathways to anxiety-depression comorbidity: A longitudinal examination of childhood anxiety disorders.

PubMed

Wolk, Courtney Benjamin; Carper, Matthew M; Kendall, Philip C; Olino, Thomas M; Marcus, Steven C; Beidas, Rinad S

2016-10-01

Anxiety disorders are prevalent in youth and associated with later depressive disorders. A recent model posits three distinct anxiety-depression pathways. Pathway 1 represents youth with a diathesis to anxiety that increases risk for depressive disorders; Pathway 2 describes youth with a shared anxiety-depression diathesis; and Pathway 3 consists of youth with a diathesis for depression who develop anxiety as a consequence of depression impairment. This is the first partial test of this model following cognitive-behavioral treatment (CBT) for child anxiety. The present study included individuals (N = 66; M age = 27.23 years, SD = 3.54) treated with CBT for childhood anxiety disorders 7-19 years (M = 16.24; SD = 3.56) earlier. Information regarding anxiety (i.e., social phobia (SoP), separation anxiety disorder (SAD), generalized anxiety disorder (GAD)) and mood disorders (i.e., major depressive disorder (MDD) and dysthymic disorders) was obtained at pretreatment, posttreatment, and one or more follow-up intervals via interviews and self-reports. Evidence of pathways from SoP, SAD, and GAD to later depressive disorders was not observed. Treatment responders evidenced reduced GAD and SoP over time, although SoP was observed to have a more chronic and enduring pattern. Evidence for typically observed pathways from childhood anxiety disorders was not observed. Future research should prospectively examine if CBT treatment response disrupts commonly observed pathways. © 2016 Wiley Periodicals, Inc.

Imaging of size-dependent uptake and identification of novel pathways in mouse Peyer's patches using fluorescent organosilica particles.

PubMed

Awaad, Aziz; Nakamura, Michihiro; Ishimura, Kazunori

2012-07-01

We investigated size-dependent uptake of fluorescent thiol-organosilica particles by Peyer's patches (PPs). We performed an oral single-particle administration (95, 130, 200, 340, 695 and 1050 nm) and a simultaneous dual-particle administration using 2 kinds of particles. Histological imaging and quantitative analysis revealed that particles taken up by the PP subepithelial dome were size dependent, and there was an optimal size range for higher uptake. Quantitative analysis of simultaneous dual-particle administration revealed that the percentage of fluorescence areas for 95, 130, 200, 340, 695 and 1050 nm with respect to 110 nm area was 124.0, 89.1, 73.8, 20.2, 9.2 and 0.5%, respectively. Additionally, imaging using fluorescent thiol-organosilica particles could detect 2 novel pathways through mouse PP epithelium: the transcellular pathway and the paracellular pathway. The uptake of nanoparticles based on an optimal size range and 2 novel pathways could indicate a new approach for vaccine delivery and nanomedicine development. Studying various sizes of fluorescent organosilica particles and their uptake in Peyer's patches, this team of authors determined the optimal size range of administration. Two novel pathways through mouse Peyer's patch epithelium were detected, i.e., the transcellular pathway and the paracellular pathway. This observation may have important applications in future vaccine delivery and nano-drug delivery. Copyright © 2012 Elsevier Inc. All rights reserved.

Pathways for Off-site Corporate PV Procurement

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

Heeter, Jenny S

Through July 2017, corporate customers contracted for more than 2,300 MW of utility-scale solar. This paper examines the benefits, challenges, and outlooks for large-scale off-site solar purchasing through four pathways: power purchase agreements, retail choice, utility partnerships (green tariffs and bilateral contracts with utilities), and by becoming a licensed wholesale seller of electricity. Each pathway differs based on where in the United States it is available, the value provided to a corporate off-taker, and the ease of implementation. The paper concludes with a discussion of future pathway comparison, noting that to deploy more corporate off-site solar, new procurement pathways aremore » needed.« less

[Interdisciplinary clinical pathway for colorectal cancer].

PubMed

Fischbach, W; Engemann, R

2006-07-01

Limited financial resources in public health care have led to the introduction of clinical pathways as a means to a better effectivity and efficacy. Colorectal cancer met the requirements for establishing such a pathway in a distinguished way: high patient volume, high costs, interdisciplinary multi-modal treatment concepts in a relevant frequency, and existing evidence based guidelines. This article gives an example of a clinical pathway for colorectal cancer as established in our hospital. The potential of such pathways to save costs as well as their implications on treatment results and patients' satisfaction will have to be critically analyzed in the future before their value can be definitely estimated.

Climate change impacts on human health over Europe through its effect on air quality.

PubMed

Doherty, Ruth M; Heal, Mathew R; O'Connor, Fiona M

2017-12-05

This review examines the current literature on the effects of future emissions and climate change on particulate matter (PM) and O 3 air quality and on the consequent health impacts, with a focus on Europe. There is considerable literature on the effects of climate change on O 3 but fewer studies on the effects of climate change on PM concentrations. Under the latest Intergovernmental Panel on Climate Change (IPCC) 5th assessment report (AR5) Representative Concentration Pathways (RCPs), background O 3 entering Europe is expected to decrease under most scenarios due to higher water vapour concentrations in a warmer climate. However, under the extreme pathway RCP8.5 higher (more than double) methane (CH 4 ) abundances lead to increases in background O 3 that offset the O 3 decrease due to climate change especially for the 2100 period. Regionally, in polluted areas with high levels of nitrogen oxides (NO x ), elevated surface temperatures and humidities yield increases in surface O 3 - termed the O 3 climate penalty - especially in southern Europe. The O 3 response is larger for metrics that represent the higher end of the O 3 distribution, such as daily maximum O 3 . Future changes in PM concentrations due to climate change are much less certain, although several recent studies also suggest a PM climate penalty due to high temperatures and humidity and reduced precipitation in northern mid-latitude land regions in 2100.A larger number of studies have examined both future climate and emissions changes under the RCP scenarios. Under these pathways the impact of emission changes on air quality out to the 2050s will be larger than that due to climate change, because of large reductions in emissions of O 3 and PM pollutant precursor emissions and the more limited climate change response itself. Climate change will also affect climate extreme events such as heatwaves. Air pollution episodes are associated with stagnation events and sometimes heat waves. Air quality during the 2003 heatwave over Europe has been examined in numerous studies and mechanisms for enhancing O 3 have been identified.There are few studies on health effects associated with climate change impacts alone on air quality, but these report higher O 3 -related health burdens in polluted populated regions and greater PM 2.5 health burdens in these emission regions. Studies that examine the combined impacts of climate change and anthropogenic emissions change under the RCP scenarios report reductions in global and European premature O 3 -respiratory related and PM mortalities arising from the large decreases in precursor emissions. Under RCP 8.5 the large increase in CH 4 leads to global and European excess O 3 -respiratory related mortalities in 2100. For future health effects, besides uncertainty in future O 3 and particularly PM concentrations, there is also uncertainty in risk estimates such as effect modification by temperature on pollutant-response relationships and potential future adaptation that would alter exposure risk.

A taxonomy of visualization tasks for the analysis of biological pathway data.

PubMed

Murray, Paul; McGee, Fintan; Forbes, Angus G

2017-02-15

Understanding complicated networks of interactions and chemical components is essential to solving contemporary problems in modern biology, especially in domains such as cancer and systems research. In these domains, biological pathway data is used to represent chains of interactions that occur within a given biological process. Visual representations can help researchers understand, interact with, and reason about these complex pathways in a number of ways. At the same time, these datasets offer unique challenges for visualization, due to their complexity and heterogeneity. Here, we present taxonomy of tasks that are regularly performed by researchers who work with biological pathway data. The generation of these tasks was done in conjunction with interviews with several domain experts in biology. These tasks require further classification than is provided by existing taxonomies. We also examine existing visualization techniques that support each task, and we discuss gaps in the existing visualization space revealed by our taxonomy. Our taxonomy is designed to support the development and design of future biological pathway visualization applications. We conclude by suggesting future research directions based on our taxonomy and motivated by the comments received by our domain experts.

Mapping letters from the future: exploring narrative processes of imagining the future.

PubMed

Sools, Anneke M; Tromp, Thijs; Mooren, Jan H

2015-03-01

This article uses Letters from the Future (a health promotion instrument) to explore the human capacity of imagining the future. From a narrative perspective, letters from the future are considered to be indicative of a variety of forms through which human beings construct and understand their future selves and worlds. This is consistent with an interpretive approach to understanding the human mind, which offers an alternative for the current dominant causal-explanatory approach in psychology. On the basis of qualitative analysis of 480 letters from the future, collected online from a diverse group of Dutch and German persons, we first identified five narrative processes operating in the letters: imagining, evaluating, orienting, expressing emotions and engaging in dialogue. Second, using comparative analysis, we identified six types of how these processes are organized in the letters as a whole. These types differ regarding functionality (which of the five processes was dominant); temporality (prospective, retrospective and present-oriented); the extent to which a path between present and future was described; and the vividness of the imagination. We suggest that these types can be used in narrative health practice as 'pathways' to locate where letter writers are on their path to imagine the future, rather than as a normative taxonomy. Future research should focus on how these pathways can be used to navigate to health and well-being. © The Author(s) 2015.

Genetic Alterations in Glioma

PubMed Central

Bralten, Linda B. C.; French, Pim J.

2011-01-01

Gliomas are the most common type of primary brain tumor and have a dismal prognosis. Understanding the genetic alterations that drive glioma formation and progression may help improve patient prognosis by identification of novel treatment targets. Recently, two major studies have performed in-depth mutation analysis of glioblastomas (the most common and aggressive subtype of glioma). This systematic approach revealed three major pathways that are affected in glioblastomas: The receptor tyrosine kinase signaling pathway, the TP53 pathway and the pRB pathway. Apart from frequent mutations in the IDH1/2 gene, much less is known about the causal genetic changes of grade II and III (anaplastic) gliomas. Exceptions include TP53 mutations and fusion genes involving the BRAF gene in astrocytic and pilocytic glioma subtypes, respectively. In this review, we provide an update on all common events involved in the initiation and/or progression across the different subtypes of glioma and provide future directions for research into the genetic changes. PMID:24212656

Design principles for enhancing phase sensitivity and suppressing phase fluctuations simultaneously in biochemical oscillatory systems.

PubMed

Fei, Chenyi; Cao, Yuansheng; Ouyang, Qi; Tu, Yuhai

2018-04-12

Biological systems need to function accurately in the presence of strong noise and at the same time respond sensitively to subtle external cues. Here we study design principles in biochemical oscillatory circuits to achieve these two seemingly incompatible goals. We show that energy dissipation can enhance phase sensitivity linearly by driving the phase-amplitude coupling and increase timing accuracy by suppressing phase diffusion. Two general design principles in the key underlying reaction loop formed by two antiparallel pathways are found to optimize oscillation performance with a given energy budget: balancing the forward-to-backward flux ratio between the two pathways to reduce phase diffusion and maximizing the net flux of the phase-advancing pathway relative to that of the phase-retreating pathway to enhance phase sensitivity. Experimental evidences consistent with these design principles are found in the circadian clock of cyanobacteria. Future experiments to test the predicted dependence of phase sensitivity on energy dissipation are proposed.

Production of C2-C4 diols from renewable bioresources: new metabolic pathways and metabolic engineering strategies.

PubMed

Zhang, Ye; Liu, Dehua; Chen, Zhen

2017-01-01

C2-C4 diols classically derived from fossil resource are very important bulk chemicals which have been used in a wide range of areas, including solvents, fuels, polymers, cosmetics, and pharmaceuticals. Production of C2-C4 diols from renewable resources has received significant interest in consideration of the reducing fossil resource and the increasing environmental issues. While bioproduction of certain diols like 1,3-propanediol has been commercialized in recent years, biosynthesis of many other important C2-C4 diol isomers is highly challenging due to the lack of natural synthesis pathways. Recent advances in synthetic biology have enabled the de novo design of completely new pathways to non-natural molecules from renewable feedstocks. In this study, we review recent advances in bioproduction of C2-C4 diols, focusing on new metabolic pathways and metabolic engineering strategies being developed. We also discuss the challenges and future trends toward the development of economically competitive processes for bio-based diol production.

Use of a bovine genome chip to identify new biological pathways for beef quality in cattle.

PubMed

Guifen, Liu; Xiaomu, Liu; Fachun, Wan; Xiuwen, Tan; Haijian, Cheng; Enliang, Song

2012-12-01

The accumulation of muscle is largely influenced by the genetic background of cattle. Muscle tissue was collected from the longissimus muscle of Lilu beef cattle at 12, 18, 24 and 30 months old. Using meat quality analysis, we found that the Lilu beef cattle have good production and slaughter performance, the performance meets the criterion of beef cattle. Microarray analysis was able to identify a total of 4,219 genes that are differentially expressed (P ≤ 0.01) between the two groups of cattle (12 vs 18; 18 vs 24; 24 vs 30). Bioinformatics analysis results suggested that most of the differentially expressed genes are involved in the metabolic pathways and neuroactive ligand-receptor interaction pathways. In the future study that aims to look for genes relating to growth and meat quality, we will focus on the genes that have been shown to have a significant variation between groups and are involved in the two pathways.

ACTP: A webserver for predicting potential targets and relevant pathways of autophagy-modulating compounds

PubMed Central

Ouyang, Liang; Cai, Haoyang; Liu, Bo

2016-01-01

Autophagy (macroautophagy) is well known as an evolutionarily conserved lysosomal degradation process for long-lived proteins and damaged organelles. Recently, accumulating evidence has revealed a series of small-molecule compounds that may activate or inhibit autophagy for therapeutic potential on human diseases. However, targeting autophagy for drug discovery still remains in its infancy. In this study, we developed a webserver called Autophagic Compound-Target Prediction (ACTP) (http://actp.liu-lab.com/) that could predict autophagic targets and relevant pathways for a given compound. The flexible docking of submitted small-molecule compound (s) to potential autophagic targets could be performed by backend reverse docking. The webpage would return structure-based scores and relevant pathways for each predicted target. Thus, these results provide a basis for the rapid prediction of potential targets/pathways of possible autophagy-activating or autophagy-inhibiting compounds without labor-intensive experiments. Moreover, ACTP will be helpful to shed light on identifying more novel autophagy-activating or autophagy-inhibiting compounds for future therapeutic implications. PMID:26824420

Personalized identification of differentially expressed pathways in pediatric sepsis.

PubMed

Li, Binjie; Zeng, Qiyi

2017-10-01

Sepsis is a leading killer of children worldwide with numerous differentially expressed genes reported to be associated with sepsis. Identifying core pathways in an individual is important for understanding septic mechanisms and for the future application of custom therapeutic decisions. Samples used in the study were from a control group (n=18) and pediatric sepsis group (n=52). Based on Kauffman's attractor theory, differentially expressed pathways associated with pediatric sepsis were detected as attractors. When the distribution results of attractors are consistent with the distribution of total data assessed using support vector machine, the individualized pathway aberrance score (iPAS) was calculated to distinguish differences. Through attractor and Kyoto Encyclopedia of Genes and Genomes functional analysis, 277 enriched pathways were identified as attractors. There were 81 pathways with P<0.05 and 59 pathways with P<0.01. Distribution outcomes of screened attractors were mostly consistent with the total data demonstrated by the six classifying parameters, which suggested the efficiency of attractors. Cluster analysis of pediatric sepsis using the iPAS method identified seven pathway clusters and four sample clusters. Thus, in the majority pediatric sepsis samples, core pathways can be detected as different from accumulated normal samples. In conclusion, a novel procedure that identified the dysregulated attractors in individuals with pediatric sepsis was constructed. Attractors can be markers to identify pathways involved in pediatric sepsis. iPAS may provide a correlation score for each of the signaling pathways present in an individual patient. This process may improve the personalized interpretation of disease mechanisms and may be useful in the forthcoming era of personalized medicine.

Genomics and expression profiles of the Hedgehog and Notch signaling pathways in sea urchin development.

PubMed

Walton, Katherine D; Croce, Jenifer C; Glenn, Thomas D; Wu, Shu-Yu; McClay, David R

2006-12-01

The Hedgehog (Hh) and Notch signal transduction pathways control a variety of developmental processes including cell fate choice, differentiation, proliferation, patterning and boundary formation. Because many components of these pathways are conserved, it was predicted and confirmed that pathway components are largely intact in the sea urchin genome. Spatial and temporal location of these pathways in the embryo, and their function in development offer added insight into their mechanistic contributions. Accordingly, all major components of both pathways were identified and annotated in the sea urchin Strongylocentrotus purpuratus genome and the embryonic expression of key components was explored. Relationships of the pathway components, and modifiers predicted from the annotation of S. purpuratus, were compared against cnidarians, arthropods, urochordates, and vertebrates. These analyses support the prediction that the pathways are highly conserved through metazoan evolution. Further, the location of these two pathways appears to be conserved among deuterostomes, and in the case of Notch at least, display similar capacities in endomesoderm gene regulatory networks. RNA expression profiles by quantitative PCR and RNA in situ hybridization reveal that Hedgehog is produced by the endoderm beginning just prior to invagination, and signals to the secondary mesenchyme-derived tissues at least until the pluteus larva stage. RNA in situ hybridization of Notch pathway members confirms that Notch functions sequentially in the vegetal-most secondary mesenchyme cells and later in the endoderm. Functional analyses in future studies will embed these pathways into the growing knowledge of gene regulatory networks that govern early specification and morphogenesis.

Carbon emission limits required to satisfy future representative concentration pathways of greenhouse gases

NASA Astrophysics Data System (ADS)

Arora, V. K.; Scinocca, J. F.; Boer, G. J.; Christian, J. R.; Denman, K. L.; Flato, G. M.; Kharin, V. V.; Lee, W. G.; Merryfield, W. J.

2011-03-01

The response of the second-generation Canadian earth system model (CanESM2) to historical (1850-2005) and future (2006-2100) natural and anthropogenic forcing is assessed using the newly-developed representative concentration pathways (RCPs) of greenhouse gases (GHGs) and aerosols. Allowable emissions required to achieve the future atmospheric CO2 concentration pathways, are reported for the RCP 2.6, 4.5 and 8.5 scenarios. For the historical 1850-2005 period, cumulative land plus ocean carbon uptake and, consequently, cumulative diagnosed emissions compare well with observation-based estimates. The simulated historical carbon uptake is somewhat weaker for the ocean and stronger for the land relative to their observation-based estimates. The simulated historical warming of 0.9°C compares well with the observation-based estimate of 0.76 ± 0.19°C. The RCP 2.6, 4.5 and 8.5 scenarios respectively yield warmings of 1.4, 2.3, and 4.9°C and cumulative diagnosed fossil fuel emissions of 182, 643 and 1617 Pg C over the 2006-2100 period. The simulated warming of 2.3°C over the 1850-2100 period in the RCP 2.6 scenario, with the lowest concentration of GHGs, is slightly larger than the 2°C warming target set to avoid dangerous climate change by the 2009 UN Copenhagen Accord. The results of this study suggest that limiting warming to roughly 2°C by the end of this century is unlikely since it requires an immediate ramp down of emissions followed by ongoing carbon sequestration in the second half of this century.

Asymmetric response of tropical cyclone activity to global warming over the North Atlantic and western North Pacific from CMIP5 model projections

NASA Astrophysics Data System (ADS)

Park, Doo-Sun R.; Ho, Chang-Hoi; Chan, Johnny C. L.; Ha, Kyung-Ja; Kim, Hyeong-Seog; Kim, Jinwon; Kim, Joo-Hong

2017-01-01

Recent improvements in the theoretical understanding of the relationship between tropical cyclones (TCs) and their large-scale environments have resulted in significant improvements in the skill for forecasting TC activity at daily and seasonal time-scales. However, future changes in TC activity under a warmer climate remain uncertain, particularly in terms of TC genesis locations and subsequent pathways. Applying a track-pattern-based statistical model to 22 Coupled Model Intercomparison Project Phase 5 (CMIP5) model runs for the historical period and the future period corresponding to the Representative Concentration Pathway 8.5 emissions scenarios, this study shows that in future climate conditions, TC passage frequency will decrease over the North Atlantic, particularly in the Gulf of Mexico, but will increase over the western North Pacific, especially that hits Korea and Japan. Unlike previous studies based on fine-resolution models, an ensemble mean of CMIP5 models projects an increase in TC activity in the western North Pacific, which is owing to enhanced subtropical deep convection and favorable dynamic conditions therein in conjunction with the expansion of the tropics and vice versa for the North Atlantic. Our results suggest that North America will experience less TC landfalls, while northeast Asia will experience more TCs than in the present-day climate.

Asymmetric response of tropical cyclone activity to global warming over the North Atlantic and western North Pacific from CMIP5 model projections.

PubMed

Park, Doo-Sun R; Ho, Chang-Hoi; Chan, Johnny C L; Ha, Kyung-Ja; Kim, Hyeong-Seog; Kim, Jinwon; Kim, Joo-Hong

2017-01-30

Recent improvements in the theoretical understanding of the relationship between tropical cyclones (TCs) and their large-scale environments have resulted in significant improvements in the skill for forecasting TC activity at daily and seasonal time-scales. However, future changes in TC activity under a warmer climate remain uncertain, particularly in terms of TC genesis locations and subsequent pathways. Applying a track-pattern-based statistical model to 22 Coupled Model Intercomparison Project Phase 5 (CMIP5) model runs for the historical period and the future period corresponding to the Representative Concentration Pathway 8.5 emissions scenarios, this study shows that in future climate conditions, TC passage frequency will decrease over the North Atlantic, particularly in the Gulf of Mexico, but will increase over the western North Pacific, especially that hits Korea and Japan. Unlike previous studies based on fine-resolution models, an ensemble mean of CMIP5 models projects an increase in TC activity in the western North Pacific, which is owing to enhanced subtropical deep convection and favorable dynamic conditions therein in conjunction with the expansion of the tropics and vice versa for the North Atlantic. Our results suggest that North America will experience less TC landfalls, while northeast Asia will experience more TCs than in the present-day climate.

Rainfall and temperatures changes have confounding impacts on Phytophthora cinnamomi occurrence risk in the southwestern USA under climate change scenarios.

PubMed

Thompson, Sally E; Levin, Simon; Rodriguez-Iturbe, Ignacio

2014-04-01

Global change will simultaneously impact many aspects of climate, with the potential to exacerbate the risks posed by plant pathogens to agriculture and the natural environment; yet, most studies that explore climate impacts on plant pathogen ranges consider individual climatic factors separately. In this study, we adopt a stochastic modeling approach to address multiple pathways by which climate can constrain the range of the generalist plant pathogen Phytophthora cinnamomi (Pc): through changing winter soil temperatures affecting pathogen survival; spring soil temperatures and thus pathogen metabolic rates; and changing spring soil moisture conditions and thus pathogen growth rates through host root systems. We apply this model to the southwestern USA for contemporary and plausible future climate scenarios and evaluate the changes in the potential range of Pc. The results indicate that the plausible range of this pathogen in the southwestern USA extends over approximately 200,000 km(2) under contemporary conditions. While warming temperatures as projected by the IPCC A2 and B1 emissions scenarios greatly expand the range over which the pathogen can survive winter, projected reductions in spring rainfall reduce its feasible habitat, leading to spatially complex patterns of changing risk. The study demonstrates that temperature and rainfall changes associated with possible climate futures in the southwestern USA have confounding impacts on the range of Pc, suggesting that projections of future pathogen dynamics and ranges should account for multiple pathways of climate-pathogen interaction. © 2014 John Wiley & Sons Ltd.

Molecular chaperones in Parkinson's disease--present and future.

PubMed

Ebrahimi-Fakhari, Darius; Wahlster, Lara; McLean, Pamela J

2011-01-01

Parkinson's disease, like many other neurodegenerative disorders, is characterized by the progressive accumulation of pathogenic protein species and the formation of intracellular inclusion bodies. The cascade by which the small synaptic protein α-synuclein misfolds to form distinctive protein aggregates, termed Lewy bodies and Lewy neurites, has been the subject of intensive research for more than a decade. Genetic and pathological studies in Parkinson's disease patients as well as experimental studies in disease models have clearly established altered protein metabolism as a key element in the pathogenesis of Parkinson's disease. Alterations in protein metabolism include misfolding and aggregation, post-translational modification and dysfunctional degradation of cytotoxic protein species. Protein folding and re-folding are both mediated by a highly conserved network of molecules, called molecular chaperones and co-chaperones. In addition to the regulatory role in protein folding, molecular chaperone function is intimately associated with pathways of protein degradation, such as the ubiquitin-proteasome system and the autophagy-lysosomal pathway, to effectively remove irreversibly misfolded proteins. Because of the central role of molecular chaperones in maintaining protein homeostasis, we herein review our current knowledge on the involvement of molecular chaperones and co-chaperones in Parkinson's disease. We further discuss the capacity of molecular chaperones to prevent or modulate neurodegeneration, an important concept for future neuroprotective strategies and summarize the current progress in preclinical studies in models of Parkinson's disease and other neurodegenerative disorders. Finally we include a discussion on the future potential of using molecular chaperones as a disease modifying therapy.

The neurobiology of adaptation to seasons: Relevance and correlations in bipolar disorders.

PubMed

Maruani, Julia; Anderson, George; Etain, Bruno; Lejoyeux, Michel; Bellivier, Frank; Geoffroy, Pierre A

2018-06-25

Bipolar disorders (BDs) are severe and common psychiatric disorders. BD pathogenesis, clinical manifestations and relapses are associated with numerous circadian rhythm abnormalities. In addition, infradian fluctuations of mood, social activity, weight and sleep patterns are very frequent in BD. Disease course with a seasonal pattern (SP) occurs in approximately 25% of depressive and 15% of manic episodes, which is coupled to a more severe disease symptomatology. The pathophysiological mechanisms of seasonal effects in BD await clarification, with likely important clinical consequences. This review aims at synthesizing available data regarding the underlying pathophysiological mechanisms of seasonality in BD patients, with implications for future research directions in the study of seasonality in BD. Three factors are suggested to play significant roles in BD with SP, namely the suprachiasmatic nuclei, as well as the melatonergic and photoperiodism systems. It is proposed that BD with SP may be considered as a complex disorder resulting from the interaction of clock gene vulnerabilities and biological clock neuroplasticity, with environmental factors, such as the response to light. Light seems to play a key role in BD with SP, mainly due to two seasonal signaling pathways: a light to cortex serotonin transporter pathway, as well as a pathway connecting light to melatonin synthesis. This provides a theoretical framework for BD with SP, including for future research and clinical management. The review proposes that future research should explore markers of seasonality in BD, such as plasma melatonin, sleep-wake rhythms (with actigraphy) and genetic or epigenetic variants within the melatonin synthesis pathway. The role of light in driving BD with SP is an active area of research. Seasonality may also be intimately linked to wider aspects of BD, including via interactions with the gut microbiome, the gut-liver axis, cholesterol regulation, aspects of metabolic syndrome, vitamin D, decreased longevity, suicide risk and medication treatment targets. Further research on the role of seasonality in BD is likely to clarify the etiology, course and treatment of BD more widely.

A framework to analyze emissions implications of manufacturing shifts in the industrial sector through integrating bottom-up energy models and economic input-output environmental life cycle assessment models

EPA Science Inventory

Future year emissions depend highly on the evolution of the economy, technology and current and future regulatory drivers. A scenario framework was adopted to analyze various technology development pathways and societal change while considering existing regulations and future unc...

The Observed Longitudinal Relationship between Future Orientation and Substance Use Among a Cohort of Youth with Serious Criminal Offenses.

PubMed

Brooks, Merrian; Miller, Elizabeth; Abebe, Kaleab; Mulvey, Edward

2018-03-06

Future orientation (FO), an essential construct in youth development, encompassing goals, expectations for life, and ability to plan for the future. This study uses a multidimensional measure of future orientation to assess the relationship between change in future orientation and change in substance use over time. Data were from the Pathways to Desistence study. Justice involved youth (n = 1,354), ages 14 to 18 at time of recruitment, completed interviews every six months for three years. Multiple measures were chosen a priori as elements of future orientation. After evaluating the psychometrics of a new measure for future orientation, we ran mixed effects cross-lagged panel models to assess the relationship between changes in future orientation and substance use (tobacco, marijuana, hard drugs, and alcohol). There was a significant bidirectional relationship between future orientation and all substance use outcomes. Adjusted models accounted for different sites, sex, age, ethnicity, parental education, and proportion of time spent in a facility. In adjusted models, higher levels of future orientation resulted in smaller increases in substance use at future time points. Future orientation and substance use influence each other in this sample of adolescent offenders. Treating substance use disorders is also likely to increase future orientation, promoting positive youth development more generally. This study expands our understanding of the longitudinal relationship between changes in future orientation and changes in levels of substance use in a sample of justice involved youth with high levels of substance use, a group of considerable clinical and policy interest.

Molecular biology of anal squamous cell carcinoma: implications for future research and clinical intervention.

PubMed

Bernardi, Maria-Pia; Ngan, Samuel Y; Michael, Michael; Lynch, A Craig; Heriot, Alexander G; Ramsay, Robert G; Phillips, Wayne A

2015-12-01

Anal squamous cell carcinoma is a human papillomavirus-related disease, in which no substantial advances in treatment have been made in over 40 years, especially for those patients who develop disease relapse and for whom no surgical options exist. HPV can evade the immune system and its role in disease progression can be exploited in novel immunotherapy platforms. Although several studies have investigated the expression and inactivation (through loss of heterozygosity) of tumour suppressor genes in the pathways to cancer, no clinically valuable biomarkers have emerged. Regulators of apoptosis, including survivin, and agents targeting the PI3K/AKT pathway, offer opportunities for targeted therapy, although robust data are scarce. Additionally, antibody therapy targeting EGFR may prove effective, although its safety profile in combination with standard chemoradiotherapy has proven to be suboptimal. Finally, progress in the treatment of anal cancer has remained stagnant due to a lack of preclinical models, including cell lines and mouse models. In this Review, we discuss the molecular biology of anal squamous cell carcinoma, clinical trials in progress, and implications for novel therapeutic targets. Future work should focus on preclinical models to provide a resource for investigation of new molecular pathways and for testing novel targets. Copyright © 2015 Elsevier Ltd. All rights reserved.

Screening and analyzing genes associated with Amur tiger placental development.

PubMed

Li, Q; Lu, T F; Liu, D; Hu, P F; Sun, B; Ma, J Z; Wang, W J; Wang, K F; Zhang, W X; Chen, J; Guan, W J; Ma, Y H; Zhang, M H

2014-09-26

The Amur tiger is a unique endangered species in the world, and thus, protection of its genetic resources is extremely important. In this study, an Amur tiger placenta cDNA library was constructed using the SMART cDNA Library Construction kit. A total of 508 colonies were sequenced, in which 205 (76%) genes were annotated and mapped to 74 KEGG pathways, including 29 metabolism, 29 genetic information processing, 4 environmental information processing, 7 cell motility, and 5 organismal system pathways. Additionally, PLAC8, PEG10 and IGF-II were identified after screening genes from the expressed sequence tags, and they were associated with placental development. These findings could lay the foundation for future functional genomic studies of the Amur tiger.

Methods Used in Economic Evaluations of Testing and Diagnosis for Ovarian Cancer: A Systematic Review.

PubMed

Sharma, Vishal; Sundar, Sudha S; Breheny, Katie; Monahan, Mark; Sutton, Andrew John

2016-06-01

There are multiple tests available that can help diagnose ovarian cancer, and the cost-effective analysis of these diagnostic interventions is essential for making well-informed decisions regarding resource allocation. There are multiple factors that can impact on the conclusions drawn from economic evaluations including test accuracy, the impact of the testing pathway on patient costs and outcomes, and delays along the ovarian cancer test-treat pathway. The objective of this study was to evaluate how test accuracy, the choice of perspective, and delays along the testing and diagnostic pathway have been incorporated in economic evaluations of testing for ovarian cancer. A systematic review of published literature was undertaken to identify economic evaluations (eg, cost-effectiveness, cost-utility analysis) focused on testing and diagnosis for ovarian cancer. Seven studies met the inclusion criteria. Six studies incorporated test accuracy and its impact on patients to some extent. Four studies adopted a societal perspective, but only one considered the costs incurred by patients on the testing and diagnosis pathway. Where delays on the testing pathway were incorporated into the analysis, these were frequently due to false-negative test results leading to delays in patients accessing treatment. Any anxiety that patients might experience as a result of a positive test was not considered in these studies. The impact on patients of receiving a positive test in terms of anxiety and the costs incurred by patients having to attend for testing and diagnosis are rarely considered. Delays along the testing and diagnosis pathway can have a major effect on patient outcomes, and it is important that these are acknowledged in economic evaluations focused on testing. Future economic analysis should incorporate these key determinants in order that diagnostic tests for ovarian cancer can be robustly evaluated.

Relative Contributions of Agricultural Drift, Para-Occupational, and Residential Use Exposure Pathways to House Dust Pesticide Concentrations: Meta-Regression of Published Data

EPA Science Inventory

Background: Increased pesticide concentrations in house dust in agricultural areas have been attributed to several exposure pathways, including agricultural drift, para-occupational, and residential use. Objective: To guide future exposure assessment efforts, we quantified rel...

EDC testing in the future: Exploring roles of pathway-based in silico, in vitro and in vivo methods

EPA Science Inventory

Many thoroughly validated, robust tests with both mammalian and non-mammalian models have been developed to identify chemicals with the potential to impact endocrine pathways associated with the hypothalamic-pituitary-gonadal (HPG) and thyroidal axes. In the US, for example, the...

The future trajectory of adverse outcome pathways: a commentary.

PubMed

Sewell, Fiona; Gellatly, Nichola; Beaumont, Maria; Burden, Natalie; Currie, Richard; de Haan, Lolke; Hutchinson, Thomas H; Jacobs, Miriam; Mahony, Catherine; Malcomber, Ian; Mehta, Jyotigna; Whale, Graham; Kimber, Ian

2018-04-01

The advent of adverse outcome pathways (AOPs) has provided a new lexicon for description of mechanistic toxicology, and a renewed enthusiasm for exploring modes of action resulting in adverse health and environmental effects. In addition, AOPs have been used successfully as a framework for the design and development of non-animal approaches to toxicity testing. Although the value of AOPs is widely recognised, there remain challenges and opportunities associated with their use in practise. The purpose of this article is to consider specifically how the future trajectory of AOPs may provide a basis for addressing some of those challenges and opportunities.

Time Perspective and Identity Formation: Short-Term Longitudinal Dynamics in College Students

ERIC Educational Resources Information Center

Luyckx, Koen; Lens, Willy; Smits, Ilse; Goossens, Luc

2010-01-01

Planning for the future and developing a personalized identity are conceived of as important developmental tasks that adolescents and emerging adults are confronted with on the pathway to adulthood. The present study set out to examine whether both tasks develop in tandem by using a short-term longitudinal dataset consisting of 371 college…

How Neighborhoods Influence Child Maltreatment: A Review of the Literature and Alternative Pathways

ERIC Educational Resources Information Center

Coulton, Claudia J.; Crampton, David S.; Irwin, Molly; Spilsbury, James C.; Korbin, Jill E.

2007-01-01

Objective: To review the literature on the relationships between neighborhoods and child maltreatment and identify future directions for research in this area. Method: A search of electronic databases and a survey of experts yielded a list of 25 studies on the influence of geographically defined neighborhoods on child maltreatment. These studies…

Viewing clinical research career development through the lens of social cognitive career theory.

PubMed

Bakken, Lori L; Byars-Winston, Angela; Wang, Min-Fen

2006-02-01

Issues such as, over commitment, insufficient time, and lack of funding, threaten physicians' entry and sustainability in a research career pathway. Social cognitive career theory is presented as a conceptual framework to critically examine the limitations of the National Institutes of Health's (NIH) efforts to promote the career development of physician-scientists. Special attention is given to the unique challenges of promoting this career pathway for women and underrepresented minorities. The authors propose enhanced recommendations for the career development of physician-scientists and research questions for future studies and program development aimed at advancing the nation's efforts to promote clinical research.

Hawaii natural compounds are promising to reduce ovarian cancer deaths.

PubMed

Fei-Zhang, David J; Li, Chunshun; Cao, Shugeng

2016-07-02

The low survival rate of patients with ovarian cancer largely results from the advanced ovarian tumors as well as tumor resistance to chemotherapy, leading to metastasis and recurrence. However, it is missing as to an effective therapeutic approach that focuses on these aspects to prolong progression-free survival and to decrease mortality in ovarian cancer patients. Here, based on our cancer drug discovery studies, we provide prospective insights into the development of a future line of drugs to effectively reduce ovarian cancer deaths. Pathways that increase the probability of cancer, such as the defective Fanconi anemia (FA) pathway, may render cancer cells more sensitive to new drug targeting.

Dynamic transcriptomic analysis in hircine longissimus dorsi muscle from fetal to neonatal development stages.

PubMed

Zhan, Siyuan; Zhao, Wei; Song, Tianzeng; Dong, Yao; Guo, Jiazhong; Cao, Jiaxue; Zhong, Tao; Wang, Linjie; Li, Li; Zhang, Hongping

2018-01-01

Muscle growth and development from fetal to neonatal stages consist of a series of delicately regulated and orchestrated changes in expression of genes. In this study, we performed whole transcriptome profiling based on RNA-Seq of caprine longissimus dorsi muscle tissue obtained from prenatal stages (days 45, 60, and 105 of gestation) and neonatal stage (the 3-day-old newborn) to identify genes that are differentially expressed and investigate their temporal expression profiles. A total of 3276 differentially expressed genes (DEGs) were identified (Q value < 0.01). Time-series expression profile clustering analysis indicated that DEGs were significantly clustered into eight clusters which can be divided into two classes (Q value < 0.05), class I profiles with downregulated patterns and class II profiles with upregulated patterns. Based on cluster analysis, GO enrichment analysis found that 75, 25, and 8 terms to be significantly enriched in biological process (BP), cellular component (CC), and molecular function (MF) categories in class I profiles, while 35, 21, and 8 terms to be significantly enriched in BP, CC, and MF in class II profiles. KEGG pathway analysis revealed that DEGs from class I profiles were significantly enriched in 22 pathways and the most enriched pathway was Rap1 signaling pathway. DEGs from class II profiles were significantly enriched in 17 pathways and the mainly enriched pathway was AMPK signaling pathway. Finally, six selected DEGs from our sequencing results were confirmed by qPCR. Our study provides a comprehensive understanding of the molecular mechanisms during goat skeletal muscle development from fetal to neonatal stages and valuable information for future studies of muscle development in goats.

The immune signaling pathways of Manduca sexta

PubMed Central

Cao, Xiaolong; He, Yan; Hu, Yingxia; Wang, Yang; Chen, Yun-Ru; Bryant, Bart; Clem, Rollie J.; Schwartz, Lawrence M.; Blissard, Gary; Jiang, Haobo

2015-01-01

Signal transduction pathways and their coordination are critically important for proper functioning of animal immune systems. Our knowledge of the constituents of the intracellular signaling network in insects mainly comes from genetic analyses in Drosophila melanogaster. To facilitate future studies of similar systems in the tobacco hornworm and other lepidopteran insects, we have identified and examined the homologous genes in the genome of Manduca sexta. Based on 1:1 orthologous relationships in most cases, we hypothesize that the Toll, Imd, MAPK-JNK-p38 and JAK-STAT pathways are intact and operative in this species, as are most of the regulatory mechanisms. Similarly, cellular processes such as autophagy, apoptosis and RNA interference probably function in similar ways, because their mediators and modulators are mostly conserved in this lepidopteran species. We have annotated a total of 186 genes encoding 199 proteins, studied their domain structures and evolution, and examined their mRNA levels in tissues at different life stages. Such information provides a genomic perspective of the intricate signaling system in a non-drosophiline insect. PMID:25858029

Expanding the View of Proton Pumping in Cytochrome c Oxidase through Computer Simulation

PubMed Central

Peng, Yuxing; Voth, Gregory A.

2011-01-01

In cytochrome c oxidase (CcO), a redox-driven proton pump, protons are transported by the Grotthuss shuttling via hydrogen-bonded water molecules and protonatable residues. Proton transport through the D-pathway is a complicated process that is highly sensitive to alterations in the amino acids or the solvation structure in the channel, both of which can inhibit proton pumping and enzymatic activity. Simulations of proton transport in the hydrophobic cavity showed a clear redox state dependence. To study the mechanism of proton pumping in CcO, multi-state empirical valence bond (MS-EVB) simulations have been conducted, focusing on the proton transport through the D-pathway and the hydrophobic cavity next to the binuclear center. The hydration structures, transport pathways, effects of residues, and free energy surfaces of proton transport were revealed in these MS-EVB simulations. The mechanistic insight gained from them is herein reviewed and placed in context for future studies. PMID:22178790

New pathways in the evaluation of programmes for men who perpetrate violence against their female partners.

PubMed

Wojnicka, Katarzyna; Scambor, Christian; Kraus, Heinrich

2016-08-01

Today, evaluation research in the field of intervention programmes for men who perpetrate violence against their female partners still makes a fragmentary impression. Across Europe various evaluation studies have been performed. However, the methodologies applied are too heterogeneous to allow the combination of the results in a meta-analytical way. In this paper we propose a future pathway for organising outcome evaluation studies of domestic violence perpetrator programmes in community settings, so that today's problems in this field can be overcome. In a pragmatic framework that acknowledges the limited pre-conditions for evaluation studies in the area of domestic violence perpetrator programmes as it is today, feasible approaches for outcome evaluation are outlined, with recent developments in the field taken as starting points. The framework for organising future evaluation studies of work with perpetrators of domestic violence is presented together with a strategy to promote this framework. International networks of practitioners and researchers play a central role in this strategy through upskilling the area of practical work, preparing the ground for evaluation research and improving cooperation between practitioners and researchers. This paper is based on the results of the European funded project IMPACT (under the Daphne-III-funding programme of the European Commission). Copyright © 2016 Elsevier Ltd. All rights reserved.

Bacterial pathogenesis of plants: future challenges from a microbial perspective: Challenges in Bacterial Molecular Plant Pathology.

PubMed

Pfeilmeier, Sebastian; Caly, Delphine L; Malone, Jacob G

2016-10-01

Plant infection is a complicated process. On encountering a plant, pathogenic microorganisms must first adapt to life on the epiphytic surface, and survive long enough to initiate an infection. Responsiveness to the environment is critical throughout infection, with intracellular and community-level signal transduction pathways integrating environmental signals and triggering appropriate responses in the bacterial population. Ultimately, phytopathogens must migrate from the epiphytic surface into the plant tissue using motility and chemotaxis pathways. This migration is coupled with overcoming the physical and chemical barriers to entry into the plant apoplast. Once inside the plant, bacteria use an array of secretion systems to release phytotoxins and protein effectors that fulfil diverse pathogenic functions (Fig. ) (Melotto and Kunkel, ; Phan Tran et al., ). As our understanding of the pathways and mechanisms underpinning plant pathogenicity increases, a number of central research challenges are emerging that will profoundly shape the direction of research in the future. We need to understand the bacterial phenotypes that promote epiphytic survival and surface adaptation in pathogenic bacteria. How do these pathways function in the context of the plant-associated microbiome, and what impact does this complex microbial community have on the onset and severity of plant infections? The huge importance of bacterial signal transduction to every stage of plant infection is becoming increasingly clear. However, there is a great deal to learn about how these signalling pathways function in phytopathogenic bacteria, and the contribution they make to various aspects of plant pathogenicity. We are increasingly able to explore the structural and functional diversity of small-molecule natural products from plant pathogens. We need to acquire a much better understanding of the production, deployment, functional redundancy and physiological roles of these molecules. Type III secretion systems (T3SSs) are important and well-studied contributors to bacterial disease. Several key unanswered questions will shape future investigations of these systems. We need to define the mechanism of hierarchical and temporal control of effector secretion. For successful infection, effectors need to interact with host components to exert their function. Advanced biochemical, proteomic and cell biological techniques will enable us to study the function of effectors inside the host cell in more detail and on a broader scale. Population genomics analyses provide insight into evolutionary adaptation processes of phytopathogens. The determination of the diversity and distribution of type III effectors (T3Es) and other virulence genes within and across pathogenic species, pathovars and strains will allow us to understand how pathogens adapt to specific hosts, the evolutionary pathways available to them, and the possible future directions of the evolutionary arms race between effectors and molecular plant targets. Although pathogenic bacteria employ a host of different virulence and proliferation strategies, as a result of the space constraints, this review focuses mainly on the hemibiotrophic pathogens. We discuss the process of plant infection from the perspective of these important phytopathogens, and highlight new approaches to address the outstanding challenges in this important and fast-moving field. © 2016 The Authors. Molecular Plant Pathology Published by British Society for Plant Pathology and John Wiley & Sons Ltd.

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

PubMed

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

2014-01-01

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

Genome-wide pathway analysis of memory impairment in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort implicates gene candidates, canonical pathways, and networks.

PubMed

Ramanan, Vijay K; Kim, Sungeun; Holohan, Kelly; Shen, Li; Nho, Kwangsik; Risacher, Shannon L; Foroud, Tatiana M; Mukherjee, Shubhabrata; Crane, Paul K; Aisen, Paul S; Petersen, Ronald C; Weiner, Michael W; Saykin, Andrew J

2012-12-01

Memory deficits are prominent features of mild cognitive impairment (MCI) and Alzheimer's disease (AD). The genetic architecture underlying these memory deficits likely involves the combined effects of multiple genetic variants operative within numerous biological pathways. In order to identify functional pathways associated with memory impairment, we performed a pathway enrichment analysis on genome-wide association data from 742 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants. A composite measure of memory was generated as the phenotype for this analysis by applying modern psychometric theory to item-level data from the ADNI neuropsychological test battery. Using the GSA-SNP software tool, we identified 27 canonical, expertly-curated pathways with enrichment (FDR-corrected p-value < 0.05) against this composite memory score. Processes classically understood to be involved in memory consolidation, such as neurotransmitter receptor-mediated calcium signaling and long-term potentiation, were highly represented among the enriched pathways. In addition, pathways related to cell adhesion, neuronal differentiation and guided outgrowth, and glucose- and inflammation-related signaling were also enriched. Among genes that were highly-represented in these enriched pathways, we found indications of coordinated relationships, including one large gene set that is subject to regulation by the SP1 transcription factor, and another set that displays co-localized expression in normal brain tissue along with known AD risk genes. These results 1) demonstrate that psychometrically-derived composite memory scores are an effective phenotype for genetic investigations of memory impairment and 2) highlight the promise of pathway analysis in elucidating key mechanistic targets for future studies and for therapeutic interventions.

Cross-talk between EGFR and IL-6 drives oncogenic signaling and offers therapeutic opportunities in cancer.

PubMed

Ray, Kriti; Ujvari, Beata; Ramana, Venkata; Donald, John

2018-04-07

Epidermal growth factor receptor (EGFR) is a known target in cancer therapy and targeting the receptor has proven to be extremely successful in treating cancers that are dependent on EGFR signaling. To that effect, targeted therapies to EGFR such as Cetuximab, Panitumumab-monoclonal antibodies and Gefitinib, Erlotinib-tyrosine kinase inhibitors have had success in therapeutic scenarios. However, the development of resistance to these drugs makes it necessary to combine anti- EGFR therapies with other inhibitors, so that resistance can be overcome by the targeting of alternate signaling pathways. On the other hand, components of the inflammatory pathway, within and around a tumor, provide a conducive environment for tumor growth by supplying numerous cytokines and chemokines that foster carcinogenesis. Interleukin 6 (IL-6) is one such cytokine that is found to be associated with inflammation-driven cancers and which also plays a crucial role in acquired resistance to anti-EGFR drugs. The EGFR and IL-6 signaling pathways crosstalk in multiple ways, through various mediators and downstream signaling pathways driving resistance and hence co-targeting them has potential for future cancer treatments. Here we provide an overview on the crosstalk between the EGFR and IL-6 pathways, and discuss how co-targeting these two pathways could be a promising combination therapy of the future. Copyright © 2018 Elsevier Ltd. All rights reserved.

Transcriptome analysis reveals candidate genes involved in luciferin metabolism in Luciola aquatilis (Coleoptera: Lampyridae)

PubMed Central

Vongsangnak, Wanwipa; Chumnanpuen, Pramote

2016-01-01

Bioluminescence, which living organisms such as fireflies emit light, has been studied extensively for over half a century. This intriguing reaction, having its origins in nature where glowing insects can signal things such as attraction or defense, is now widely used in biotechnology with applications of bioluminescence and chemiluminescence. Luciferase, a key enzyme in this reaction, has been well characterized; however, the enzymes involved in the biosynthetic pathway of its substrate, luciferin, remains unsolved at present. To elucidate the luciferin metabolism, we performed a de novo transcriptome analysis using larvae of the firefly species, Luciola aquatilis. Here, a comparative analysis is performed with the model coleopteran insect Tribolium casteneum to elucidate the metabolic pathways in L. aquatilis. Based on a template luciferin biosynthetic pathway, combined with a range of protein and pathway databases, and various prediction tools for functional annotation, the candidate genes, enzymes, and biochemical reactions involved in luciferin metabolism are proposed for L. aquatilis. The candidate gene expression is validated in the adult L. aquatilis using reverse transcription PCR (RT-PCR). This study provides useful information on the bio-production of luciferin in the firefly and will benefit to future applications of the valuable firefly bioluminescence system. PMID:27761329

Future Water Scarcity and Potential Effects on Food Production under Climate Change in the Yellow River Basin

NASA Astrophysics Data System (ADS)

Tang, Q.; Yin, Y. Y.; Liu, X.; Zhang, X.

2016-12-01

Increasing population and socio-economic development have put great pressure on water resources of the Yellow River Basin. The anticipated climate and socio-economic changes may further increase water stress. In this study, we assess water scarcity under climate change and various socio-economic pathways with an emphasis on the impact of water shortages on food production. The water demands in the 21st century are projected under the new developed Shared Socio-economic Pathways (SSPs). The renewable water supply is estimated from the climate projections under the Representative Concentration Pathways (RCP) 8.5. The agricultural water use is assumed to have the lowest priority of all water consumers when water shortage occurs. The results show that the water demands in domestic and industrial sectors would grow rapidly. As more water resources would be occupied by domestic and industrial sectors, a portion of irrigated land would have to be converted to rain-fed agriculture which would lead to more than a reduction in food production under various socio-economic pathways. This study highlights the links between water, food and ecosystems in a changing environment and suggests that trade-offs should be considered when developing regional adaptation strategies.

Gene expression profiles in liver of mouse after chronic exposure to drinking water.

PubMed

Wu, Bing; Zhang, Yan; Zhao, Dayong; Zhang, Xuxiang; Kong, Zhiming; Cheng, Shupei

2009-10-01

cDNA micorarray approach was applied to hepatic transcriptional profile analysis in male mouse (Mus musculus, ICR) to assess the potential health effects of drinking water in Nanjing, China. Mice were treated with continuous exposure to drinking water for 90 days. Hepatic gene expression was analyzed with Affymetrix Mouse Genome 430A 2.0 arrays, and pathway analysis was carried out by Molecule Annotation System 2.0 and KEGG pathway database. A total of 836 genes were found to be significantly altered (1.5-fold, P < or = 0.05), including 294 up-regulated genes and 542 down-regulated genes. According to biological pathway analysis, drinking water exposure resulted in aberration of gene expression and biological pathways linked to xenobiotic metabolism, signal transduction, cell cycle and oxidative stress response. Further, deregulation of several genes associated with carcinogenesis or tumor progression including Ccnd1, Egfr, Map2k3, Mcm2, Orc2l and Smad2 was observed. Although transcription changes in identified genes are unlikely to be used as a sole indicator of adverse health effects, the results of this study could enhance our understanding of early toxic effects of drinking water exposure and support future studies on drinking water safety.

Current available therapies and future directions in the treatment of malignant gliomas

PubMed Central

Desjardins, Annick; Reardon, David A; Vredenburgh, James J

2009-01-01

The prognosis of patients diagnosed with malignant glioma (MG) remains poor. However, recent advances in neuro-oncology allowing a better understanding of this particular disease have allowed the development of new therapeutics. Many molecular genetic and signal transduction pathway targets have been identified that are now being investigated. Novel locoregional treatments, as well as strategies to improve regional delivery, are being evaluated. Studies of combinations of these approaches are also underway. In this review, we will discuss the current and future therapies under evaluation for the treatment of malignant gliomas. PMID:19707392

Exposure to Community Violence and Sexual Behaviors Among African American Youth: Testing Multiple Pathways.

PubMed

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

2018-01-01

African American youth bear a disproportionate burden of sexually transmitted infections. A growing number of studies document that youth exposure to community violence and sexual behaviors are highly correlated. Despite such growing evidence, only a few studies have empirically tested conceptually driven pathways that may account for such relationships. This study seeks to address that gap by exploring multiple pathways linking exposure to community violence and youth sexual behaviors. Using an existing sample of 563 African American youth attending high school, we examined whether possible links between exposure to community violence and sexual activity, sexual risk behaviors were mediated by aggression, low student-teacher connectedness, and negative peer norms. Major findings indicated indirect relationships between exposures to community violence and both sexual activity and risky sex, mediated by aggression and negative peer norms with no significant differences based on gender or socioeconomic status. Overall findings also indicated a significant indirect effect of aggression to risky sex via negative peer norms and from community violence to risky peer norms via aggression. By illuminating ways that community violence, aggression, peer norms, and sexual behaviors are dynamically interrelated, these findings have significant implications for future research and intervention initiatives aimed at addressing the different pathways.

Programmed Cell Death-1/Programmed Death-ligand 1 Pathway: A New Target for Sepsis.

PubMed

Liu, Qiang; Li, Chun-Sheng

2017-04-20

Sepsis remains a leading cause of death in many Intensive Care Units worldwide. Immunosuppression has been a primary focus of sepsis research as a key pathophysiological mechanism. Given the important role of the negative costimulatory molecules programmed cell death-1 (PD-1) and programmed death-ligand 1 (PD-L1) in the occurrence of immunosuppression during sepsis, we reviewed literatures related to the PD-1/PD-L1 pathway to examine its potential as a new target for sepsis treatment. Studies of the association between PD-1/PD-L1 and sepsis published up to January 31, 2017, were obtained by searching the PubMed database. English language studies, including those based on animal models, clinical research, and reviews, with data related to PD-1/PD-L1 and sepsis, were evaluated. Immunomodulatory therapeutics could reverse the deactivation of immune cells caused by sepsis and restore immune cell activation and function. Blockade of the PD-1/PD-L1 pathway could reduce the exhaustion of T-cells and enhance the proliferation and activation of T-cells. The anti-PD-1/PD-L1 pathway shows promise as a new target for sepsis treatment. This review provides a basis for clinical trials and future studies aimed at revaluating the efficacy and safety of this targeted approach.

Perspectives on the Use of Clinical Pathways in Oncology Care.

PubMed

Chiang, Anne C; Ellis, Peter; Zon, Robin

2017-01-01

Pathways and guidelines are valuable tools to provide evidence-based care in oncology. Pathways may be more restrictive than guidelines because they attempt (where possible) to reduce cost, add efficiency, and remove unwarranted variability. Pathways offer an opportunity to measure, report, and improve quality of care; they can drive to evidence-based targeted therapy where appropriate; they can enhance efficiency through standardization; and, finally, they can be a vehicle to enhance participation in clinical trials. Pathway implementation requires understanding and commitment on the part of the physician and leadership as they may initially disrupt workflow, but ultimately have the ability to enhance patient care. ASCO criteria have been published for the development and implementation of high-quality oncology pathway programs. Future challenges for pathways include incorporation of molecular testing and appropriate targeted care in a real-time precision oncology approach.

In Delaware, Creating Pathways and Opportunities for Youth

ERIC Educational Resources Information Center

Rothman, Robert

2017-01-01

Launched in 2011 by the Harvard Graduate School of Education and Jobs for the Future, the Pathways to Prosperity initiative is helping states create seamless transitions from high school to college and the workforce. Inspired by youth development systems that have long been in place in other high-performing nations--such as Australia, Switzerland,…

Stories of Learning and Their Significance to Future Pathways and Aspirations

ERIC Educational Resources Information Center

Barnes, Sally-Anne; Brown, Alan

2016-01-01

This explores the narratives from three individuals in low-skilled employment in the UK. The interviewees reflected upon their experiences of learning from compulsory education and beyond and their pathways through education to employment. The narratives illustrate how with the support of significant others, resilience and proactivity, they can…

Career Pathways: Education with a Purpose

ERIC Educational Resources Information Center

Hull, Dan M.

2004-01-01

Hot off the press comes the guide to the next generation of education reform. Dan Hull and some of the nation's leading practitioners and educational leaders show how to remake high schools to improve academic outcomes, prepare students for today's high-skills workplace, and motivate them to learn because they see a pathway to their future.…

The Pathway Program: How a Collaborative, Distributed Learning Program Showed Us the Future of Social Work Education

ERIC Educational Resources Information Center

Morris, Teresa; Mathias, Christine; Swartz, Ronnie; Jones, Celeste A; Klungtvet-Morano, Meka

2013-01-01

This paper describes a three-campus collaborative, distributed learning program that delivers social work education to remote rural and desert communities in California via distance learning modalities. This "Pathway Program" provides accredited social work education for a career ladder beginning with advising and developing an academic…

Education for Sustainability: Assessing Pathways to the Future

ERIC Educational Resources Information Center

Huckle, John

2014-01-01

In this paper John Huckle reflects on the outlook of environmental education based on conferences in 1972 and 1992 regarding the lack of sustainable development being realized. Huckle points "education for sustainability" along a pathway provided by critical theory and pedagogy and uses theory to examine the nature of ecological crisis,…

Building an Adverse Outcome Pathway Framework through HTS Data and Literature Mining Integration (FutureToxII)

EPA Science Inventory

Interpreting EPA’s ToxCast in vitro assay data in the context of Adverse Outcome Pathway (AOP) development is a significant challenge. While chemical activation in these assays may shed light on the molecular initiating event, the downstream effect of these activities at higher ...

Building Integrated Pathways to Sustainable Careers: An Introduction to the Accelerated Opportunity Initiative

ERIC Educational Resources Information Center

Pleasants, Rachel

2011-01-01

"Accelerating Opportunity" responds to the nation's growing need for improved pathways from Adult Basic Education (ABE) to credentials of value in the labor market. It builds on promising practices developed in "Breaking Through," an initiative of Jobs for the Future and the National Council for Workforce Education, and…

Social Identities as Pathways into and out of Addiction.

PubMed

Dingle, Genevieve A; Cruwys, Tegan; Frings, Daniel

2015-01-01

There exists a predominant identity loss and "redemption" narrative in the addiction literature describing how individuals move from a "substance user" identity to a "recovery" identity. However, other identity related pathways influencing onset, treatment seeking and recovery may exist, and the process through which social identities unrelated to substance use change over time is not well understood. This study was designed to provide a richer understanding of such social identities processes. Semi-structured interviews were conducted with 21 adults residing in a drug and alcohol therapeutic community (TC) and thematic analysis revealed two distinct identity-related pathways leading into and out of addiction. Some individuals experienced a loss of valued identities during addiction onset that were later renewed during recovery (consistent with the existing redemption narrative). However, a distinct identity gain pathway emerged for socially isolated individuals, who described the onset of their addiction in terms of a new valued social identity. Almost all participants described their TC experience in terms of belonging to a recovery community. Participants on the identity loss pathway aimed to renew their pre-addiction identities after treatment while those on the identity gain pathway aimed to build aspirational new identities involving study, work, or family roles. These findings help to explain how social factors are implicated in the course of addiction, and may act as either motivations for or barriers to recovery. The qualitative analysis yielded a testable model for future research in other samples and settings.

Social Identities as Pathways into and out of Addiction

PubMed Central

Dingle, Genevieve A.; Cruwys, Tegan; Frings, Daniel

2015-01-01

There exists a predominant identity loss and “redemption” narrative in the addiction literature describing how individuals move from a “substance user” identity to a “recovery” identity. However, other identity related pathways influencing onset, treatment seeking and recovery may exist, and the process through which social identities unrelated to substance use change over time is not well understood. This study was designed to provide a richer understanding of such social identities processes. Semi-structured interviews were conducted with 21 adults residing in a drug and alcohol therapeutic community (TC) and thematic analysis revealed two distinct identity-related pathways leading into and out of addiction. Some individuals experienced a loss of valued identities during addiction onset that were later renewed during recovery (consistent with the existing redemption narrative). However, a distinct identity gain pathway emerged for socially isolated individuals, who described the onset of their addiction in terms of a new valued social identity. Almost all participants described their TC experience in terms of belonging to a recovery community. Participants on the identity loss pathway aimed to renew their pre-addiction identities after treatment while those on the identity gain pathway aimed to build aspirational new identities involving study, work, or family roles. These findings help to explain how social factors are implicated in the course of addiction, and may act as either motivations for or barriers to recovery. The qualitative analysis yielded a testable model for future research in other samples and settings. PMID:26648882

Toll-like receptor-4 signaling pathway in aorta aging and diseases: "its double nature".

PubMed

Balistreri, Carmela Rita; Ruvolo, Giovanni; Lio, Domenico; Madonna, Rosalinda

2017-09-01

Recent advances in the field of innate immunity have revealed a complex role of innate immune signaling pathways in both tissue homeostasis and disease. Among them, the Toll-like receptor 4 (TLR-4) pathways has been linked to various pathophysiological conditions, such as cardiovascular diseases (CVDs). This has been interrogated by developing multiple laboratory tools that have shown in animal models and clinical conditions, the involvement of the TLR-4 signaling pathway in the pathophysiology of different CVDs, such as atherosclerosis, ischemic heart disease, heart failure, ischemia-reperfusion injury and aorta aneurysm. Among these, aorta aneurysm, a very complex pathological condition with uncertain etiology and fatal complications (i.e. dissection and rupture), has been associated with the occurrence of high risk cardiovascular conditions, including thrombosis and embolism. In this review, we discuss the possible role of TLR-4 signaling pathway in the development of aorta aneurysm, considering the emerging evidence from ongoing investigations. Our message is that emphasizing the role of TLR-4 signaling pathway in aorta aneurysm may serve as a starting point for future studies, leading to a better understanding of the pathophysiological basis and perhaps the effective treatment of this difficult human disease. Copyright © 2017 Elsevier Ltd. All rights reserved.

Recent trends in metabolic engineering of microorganisms for the production of advanced biofuels.

PubMed

Cheon, Seungwoo; Kim, Hye Mi; Gustavsson, Martin; Lee, Sang Yup

2016-12-01

As climate change has become one of the major global risks, our heavy dependence on petroleum-derived fuels has received much public attention. To solve such problems, production of sustainable fuels has been intensively studied over the past years. Thanks to recent advances in synthetic biology and metabolic engineering technologies, bio-based platforms for advanced biofuels production have been developed using various microorganisms. The strategies for production of advanced biofuels have converged upon four major metabolic routes: the 2-ketoacid pathway, the fatty acid synthesis (FAS) pathway, the isoprenoid pathway, and the reverse β-oxidation pathway. Additionally, the polyketide synthesis pathway has recently been attracting interest as a promising alternative biofuel production route. In this article, recent trends in advanced biofuels production are reviewed by categorizing them into three types of advanced biofuels: alcohols, biodiesel and jet fuel, and gasoline. Focus is given on the strategies of employing synthetic biology and metabolic engineering for the development of microbial strains producing advanced fuels. Finally, the prospects for future advances needed to achieve much more efficient bio-based production of advanced biofuels are discussed, focusing on designing advanced biofuel production pathways coupled with screening, modifying, and creating novel enzymes. Copyright © 2016 Elsevier Ltd. All rights reserved.

Training in metabolomics research. II. Processing and statistical analysis of metabolomics data, metabolite identification, pathway analysis, applications of metabolomics and its future

PubMed Central

Barnes, Stephen; Benton, H. Paul; Casazza, Krista; Cooper, Sara; Cui, Xiangqin; Du, Xiuxia; Engler, Jeffrey; Kabarowski, Janusz H.; Li, Shuzhao; Pathmasiri, Wimal; Prasain, Jeevan K.; Renfrow, Matthew B.; Tiwari, Hemant K.

2017-01-01

Metabolomics, a systems biology discipline representing analysis of known and unknown pathways of metabolism, has grown tremendously over the past 20 years. Because of its comprehensive nature, metabolomics requires careful consideration of the question(s) being asked, the scale needed to answer the question(s), collection and storage of the sample specimens, methods for extraction of the metabolites from biological matrices, the analytical method(s) to be employed and the quality control of the analyses, how collected data are correlated, the statistical methods to determine metabolites undergoing significant change, putative identification of metabolites, and the use of stable isotopes to aid in verifying metabolite identity and establishing pathway connections and fluxes. This second part of a comprehensive description of the methods of metabolomics focuses on data analysis, emerging methods in metabolomics and the future of this discipline. PMID:28239968

Controlling cell-free metabolism through physiochemical perturbations.

PubMed

Karim, Ashty S; Heggestad, Jacob T; Crowe, Samantha A; Jewett, Michael C

2018-01-01

Building biosynthetic pathways and engineering metabolic reactions in cells can be time-consuming due to complexities in cellular metabolism. These complexities often convolute the combinatorial testing of biosynthetic pathway designs needed to define an optimal biosynthetic system. To simplify the optimization of biosynthetic systems, we recently reported a new cell-free framework for pathway construction and testing. In this framework, multiple crude-cell extracts are selectively enriched with individual pathway enzymes, which are then mixed to construct full biosynthetic pathways on the time scale of a day. This rapid approach to building pathways aids in the study of metabolic pathway performance by providing a unique freedom of design to modify and control biological systems for both fundamental and applied biotechnology. The goal of this work was to demonstrate the ability to probe biosynthetic pathway performance in our cell-free framework by perturbing physiochemical conditions, using n-butanol synthesis as a model. We carried out three unique case studies. First, we demonstrated the power of our cell-free approach to maximize biosynthesis yields by mapping physiochemical landscapes using a robotic liquid-handler. This allowed us to determine that NAD and CoA are the most important factors that govern cell-free n-butanol metabolism. Second, we compared metabolic profile differences between two different approaches for building pathways from enriched lysates, heterologous expression and cell-free protein synthesis. We discover that phosphate from PEP utilization, along with other physiochemical reagents, during cell-free protein synthesis-coupled, crude-lysate metabolic system operation inhibits optimal cell-free n-butanol metabolism. Third, we show that non-phosphorylated secondary energy substrates can be used to fuel cell-free protein synthesis and n-butanol biosynthesis. Taken together, our work highlights the ease of using cell-free systems to explore physiochemical perturbations and suggests the need for a more controllable, multi-step, separated cell-free framework for future pathway prototyping and enzyme discovery efforts. Copyright © 2017 International Metabolic Engineering Society. Published by Elsevier Inc. All rights reserved.

Climate and human intervention effects on future fire activity and consequences for air pollution across the 21st century

NASA Astrophysics Data System (ADS)

Val Martin, M.; Pierce, J. R.; Heald, C. L.; Li, F.; Lawrence, D. M.; Wiedinmyer, C.; Tilmes, S.; Vitt, F.

2016-12-01

Emissions of aerosols and gases from fires have been shown to adversely affect air quality across the world. Fire activity is strongly related to climate and anthropogenic activities. Current fire projections for the 21st century seem very uncertain, ranging from increasing to declining depending on the climate, land cover change and population growth scenarios used. Here we present an analysis of the changes in future wildfire activity and consequences on air quality, with focus on PM2.5 and surface O3 over regions vulnerable to fire. We use the global Community Earth System Model (CESM) with a process-based fire model to simulate emissions from agriculture, peatland, deforestation and landscape fires for present-day and throughout the current century. We consider two future Representative Concentration Pathways climate scenarios combined with population density changes predicted from Shared Socio-economic Pathways to project climate and demographic effects on fire activity and further consequences for future air quality.

Defocused low-energy shock wave activates adipose tissue-derived stem cells in vitro via multiple signaling pathways.

PubMed

Xu, Lina; Zhao, Yong; Wang, Muwen; Song, Wei; Li, Bo; Liu, Wei; Jin, Xunbo; Zhang, Haiyang

2016-12-01

We found defocused low-energy shock wave (DLSW) could be applied in regenerative medicine by activating mesenchymal stromal cells. However, the possible signaling pathways that participated in this process remain unknown. In the present study, DLSW was applied in cultured rat adipose tissue-derived stem cells (ADSCs) to explore its effect on ADSCs and the activated signaling pathways. After treating with DLSW, the cellular morphology and cytoskeleton of ADSCs were observed. The secretions of ADSCs were detected. The expressions of ADSC surface antigens were analyzed using flow cytometry. The expressions of proliferating cell nuclear antigen and Ki67 were analyzed using western blot. The expression of CXCR2 and the migrations of ADSCs in vitro and in vivo were detected. The phosphorylation of selected signaling pathways with or without inhibitors was also detected. DLSW did not change the morphology and phenotype of ADSCs, and could promote the secretion, proliferation and migration of ADSCs. The phosphorylation levels were significantly higher in mitogen-activated protein kinases (MAPK) pathway, phosphoinositide 3-kinase (PI-3K)/AKT pathway and nuclear factor-kappa B (NF-κB) signaling pathway but not in Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. Furthermore, ADSCs were not activated by DLSW after adding the inhibitors of these pathways simultaneously. Our results demonstrated for the first time that DLSW could activate ADSCs through MAPK, PI-3K/AKT and NF-κB signaling pathways. Combination of DLSW and agonists targeting these pathways might improve the efficacy of ADSCs in regenerative medicine in the future. Copyright © 2016 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

An Epidemiologic Study of Genetic Variation in Hormonal Pathways in Relation to the Effect of Hormone Replacement Therapy on Breast Cancer Risk

DTIC Science & Technology

2007-04-01

active learning techniques in Introduction to Epidemiology Ongoing5 W81XWH-06-1-0312 Reding, Kerryn 7 TASK STATUS of FUTURE TASKS Task 3...Apply for and obtain IRB renewal Ongoing task Task 4: Training-related Work (Months 13-36) a. Present research findings on active learning at

Overcoming reprogramming resistance of Fanconi anemia cells

PubMed Central

Müller, Lars U. W.; Milsom, Michael D.; Harris, Chad E.; Vyas, Rutesh; Brumme, Kristina M.; Parmar, Kalindi; Moreau, Lisa A.; Schambach, Axel; Park, In-Hyun; London, Wendy B.; Strait, Kelly; Schlaeger, Thorsten; DeVine, Alexander L.; Grassman, Elke; D'Andrea, Alan; Daley, George Q.

2012-01-01

Fanconi anemia (FA) is a recessive syndrome characterized by progressive fatal BM failure and chromosomal instability. FA cells have inactivating mutations in a signaling pathway that is critical for maintaining genomic integrity and protecting cells from the DNA damage caused by cross-linking agents. Transgenic expression of the implicated genes corrects the phenotype of hematopoietic cells, but previous attempts at gene therapy have failed largely because of inadequate numbers of hematopoietic stem cells available for gene correction. Induced pluripotent stem cells (iPSCs) constitute an alternate source of autologous cells that are amenable to ex vivo expansion, genetic correction, and molecular characterization. In the present study, we demonstrate that reprogramming leads to activation of the FA pathway, increased DNA double-strand breaks, and senescence. We also demonstrate that defects in the FA DNA-repair pathway decrease the reprogramming efficiency of murine and human primary cells. FA pathway complementation reduces senescence and restores the reprogramming efficiency of somatic FA cells to normal levels. Disease-specific iPSCs derived in this fashion maintain a normal karyotype and are capable of hematopoietic differentiation. These data define the role of the FA pathway in reprogramming and provide a strategy for future translational applications of patient-specific FA iPSCs. PMID:22371882

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

PubMed

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

2015-11-01

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

Forecasting civil conflict along the shared socioeconomic pathways

NASA Astrophysics Data System (ADS)

Hegre, Håvard; Buhaug, Halvard; Calvin, Katherine V.; Nordkvelle, Jonas; Waldhoff, Stephanie T.; Gilmore, Elisabeth

2016-05-01

Climate change and armed civil conflict are both linked to socioeconomic development, although conditions that facilitate peace may not necessarily facilitate mitigation and adaptation to climate change. While economic growth lowers the risk of conflict, it is generally associated with increased greenhouse gas emissions and costs of climate mitigation policies. This study investigates the links between growth, climate change, and conflict by simulating future civil conflict using new scenario data for five alternative socioeconomic pathways with different mitigation and adaptation assumptions, known as the shared socioeconomic pathways (SSPs). We develop a statistical model of the historical effect of key socioeconomic variables on country-specific conflict incidence, 1960-2013. We then forecast the annual incidence of conflict, 2014-2100, along the five SSPs. We find that SSPs with high investments in broad societal development are associated with the largest reduction in conflict risk. This is most pronounced for the least developed countries—poverty alleviation and human capital investments in poor countries are much more effective instruments to attain global peace and stability than further improvements to wealthier economies. Moreover, the SSP that describes a sustainability pathway, which poses the lowest climate change challenges, is as conducive to global peace as the conventional development pathway.

Pathophysiologic mechanisms of biomedical nanomaterials

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

Wang, Liming, E-mail: wangliming@ihep.ac.cn; Chen, Chunying, E-mail: chenchy@nanoctr.cn

Nanomaterials (NMs) have been widespread used in biomedical fields, daily consuming, and even food industry. It is crucial to understand the safety and biomedical efficacy of NMs. In this review, we summarized the recent progress about the physiological and pathological effects of NMs from several levels: protein-nano interface, NM-subcellular structures, and cell–cell interaction. We focused on the detailed information of nano-bio interaction, especially about protein adsorption, intracellular trafficking, biological barriers, and signaling pathways as well as the associated mechanism mediated by nanomaterials. We also introduced related analytical methods that are meaningful and helpful for biomedical effect studies in the future.more » We believe that knowledge about pathophysiologic effects of NMs is not only significant for rational design of medical NMs but also helps predict their safety and further improve their applications in the future. - Highlights: • Rapid protein adsorption onto nanomaterials that affects biomedical effects • Nanomaterials and their interaction with biological membrane, intracellular trafficking and specific cellular effects • Nanomaterials and their interaction with biological barriers • The signaling pathways mediated by nanomaterials and related biomedical effects • Novel techniques for studying translocation and biomedical effects of NMs.« less

cGMP signaling as a target for the prevention and treatment of breast cancer.

PubMed

Windham, Perrin F; Tinsley, Heather N

2015-04-01

One in eight women in the United States will be diagnosed with invasive breast cancer in her lifetime. Advances in therapeutic strategies, diagnosis, and improved awareness have resulted in a significant reduction in breast cancer related mortality. However, there is a continued need for more effective and less toxic drugs for both the prevention and the treatment of breast cancer in order to see a continued decline in the morbidity and mortality associated with this disease. Recent studies suggest that the cGMP signaling pathway may be aberrantly regulated in breast cancer. As such, this pathway may serve as a source of novel targets for future breast cancer drug discovery efforts. This review provides an overview of cGMP signaling in normal physiology and in breast cancer as well as current strategies being investigated for targeting this pathway in breast cancer. Copyright © 2014 Elsevier Ltd. All rights reserved.

Vascular endothelial growth factor inhibitor-induced hypertension: from pathophysiology to prevention and treatment based on long-acting nitric oxide donors.

PubMed

Kruzliak, Peter; Novák, Jan; Novák, Miroslav

2014-01-01

Hypertension is the most common adverse effect of the inhibitors of vascular endothelial growth factor (VEGF) pathway-based therapy (VEGF pathway inhibitors therapy, VPI therapy) in cancer patients. VPI includes monoclonal antibodies against VEGF, tyrosine kinase inhibitors, VEGF Traps, and so-called aptamers that may become clinically relevant in the future. All of these substances inhibit the VEGF pathway, which in turn causes a decrease in nitric oxide (NO) and an increase in blood pressure, with the consequent development of hypertension and its final events (e.g., myocardial infarction or stroke). To our knowledge, there is no current study on how to provide an optimal therapy for patients on VPI therapy with hypertension. This review summarizes the roles of VEGF and NO in vessel biology, provides an overview of VPI agents, and suggests a potential treatment procedure for patients with VPI-induced hypertension.

Assessing cost-effectiveness of bioretention on stormwater in response to climate change and urbanization for future scenarios

NASA Astrophysics Data System (ADS)

Wang, Mo; Zhang, Dongqing; Adhityan, Appan; Ng, Wun Jern; Dong, Jianwen; Tan, Soon Keat

2016-12-01

Bioretention, as a popular low impact development practice, has become more important to mitigate adverse impacts on urban stormwater. However, there is very limited information regarding ensuring the effectiveness of bioretention response to uncertain future challenges, especially when taking into consideration climate change and urbanization. The main objective of this paper is to identify the cost-effectiveness of bioretention by assessing the hydrology performance under future scenarios modeling. First, the hydrology model was used to obtain peak runoff and TSS loads of bioretention with variable scales under different scenarios, i.e., different Representative Concentration Pathways (RCPs) and Shared Socio-economic reference Pathways (SSPs) for 2-year and 10-year design storms in Singapore. Then, life cycle costing (LCC) and life cycle assessment (LCA) were estimated for bioretention, and the cost-effectiveness was identified under different scenarios. Our finding showed that there were different degree of responses to 2-year and 10-year design storms but the general patterns and insights deduced were similar. The performance of bioretenion was more sensitive to urbanization than that for climate change in the urban catchment. In addition, it was noted that the methodology used in this study was generic and the findings could be useful as reference for other LID practices in response to climate change and urbanization.

Water within the Shared Socioeconomic Pathways: Constraints and the Impact on Future Global Change Scenarios

NASA Astrophysics Data System (ADS)

Graham, N. T.; Hejazi, M. I.; Davies, E. G.; Calvin, K. V.; Kim, S. H.; Miralles-Wilhelm, F.

2017-12-01

The Shared Socioeconomic Pathways (SSPs) represent the next generation of future global change scenarios and their inclusion in the Coupled Model Intercomparison Project Phase 6 (CMIP6) scenarios reinforces the importance of a complete understanding of the SSPs. This study uses the Global Change Assessment Model (GCAM) to investigate the effects of limited water supplies on future withdrawals at regional and water basin scales across all SSPs in combination with various climate mitigation scenarios. Water supply is calculated using a global hydrologic model and water data from five ISI-MIP models across the four RCP scenarios. When water constraints are incorporated, our results show that water withdrawals are reduced by as much as 40% across all SSP scenarios without climate policies. As climate policies are imposed and become more stringent, water withdrawals increase in regions already affected by water stress in order to allow for greater biomass production. The results of this research show the importance of including water resource constraints within the SSP scenarios for establishing water withdrawal scenarios under a wide range of scenarios including different climate policies. The results will also provide data products - such as gridded land use and water demand estimates - of potential interest to the impact, adaptation, and vulnerability community following the SSP scenarios.

The impact of genetics on future drug discovery in schizophrenia.

PubMed

Matsumoto, Mitsuyuki; Walton, Noah M; Yamada, Hiroshi; Kondo, Yuji; Marek, Gerard J; Tajinda, Katsunori

2017-07-01

Failures of investigational new drugs (INDs) for schizophrenia have left huge unmet medical needs for patients. Given the recent lackluster results, it is imperative that new drug discovery approaches (and resultant drug candidates) target pathophysiological alterations that are shared in specific, stratified patient populations that are selected based on pre-identified biological signatures. One path to implementing this paradigm is achievable by leveraging recent advances in genetic information and technologies. Genome-wide exome sequencing and meta-analysis of single nucleotide polymorphism (SNP)-based association studies have already revealed rare deleterious variants and SNPs in patient populations. Areas covered: Herein, the authors review the impact that genetics have on the future of schizophrenia drug discovery. The high polygenicity of schizophrenia strongly indicates that this disease is biologically heterogeneous so the identification of unique subgroups (by patient stratification) is becoming increasingly necessary for future investigational new drugs. Expert opinion: The authors propose a pathophysiology-based stratification of genetically-defined subgroups that share deficits in particular biological pathways. Existing tools, including lower-cost genomic sequencing and advanced gene-editing technology render this strategy ever more feasible. Genetically complex psychiatric disorders such as schizophrenia may also benefit from synergistic research with simpler monogenic disorders that share perturbations in similar biological pathways.

Comparison of Channel Catfish and Blue Catfish Gut Microbiota Assemblages Shows Minimal Effects of Host Genetics on Microbial Structure and Inferred Function.

PubMed

Bledsoe, Jacob W; Waldbieser, Geoffrey C; Swanson, Kelly S; Peterson, Brian C; Small, Brian C

2018-01-01

The microbiota of teleost fish has gained a great deal of research attention within the past decade, with experiments suggesting that both host-genetics and environment are strong ecological forces shaping the bacterial assemblages of fish microbiomes. Despite representing great commercial and scientific importance, the catfish within the family Ictaluridae , specifically the blue and channel catfish, have received very little research attention directed toward their gut-associated microbiota using 16S rRNA gene sequencing. Within this study we utilize multiple genetically distinct strains of blue and channel catfish, verified via microsatellite genotyping, to further quantify the role of host-genetics in shaping the bacterial communities in the fish gut, while maintaining environmental and husbandry parameters constant. Comparisons of the gut microbiota among the two catfish species showed no differences in bacterial species richness (observed and Chao1) or overall composition (weighted and unweighted UniFrac) and UniFrac distances showed no correlation with host genetic distances (Rst) according to Mantel tests. The microbiota of environmental samples (diet and water) were found to be significantly more diverse than that of the catfish gut associated samples, suggesting that factors within the host were further regulating the bacterial communities, despite the lack of a clear connection between microbiota composition and host genotype. The catfish gut communities were dominated by the phyla Fusobacteria, Proteobacteria, and Firmicutes; however, differential abundance analysis between the two catfish species using analysis of composition of microbiomes detected two differential genera, Cetobacterium and Clostridium XI . The metagenomic pathway features inferred from our dataset suggests the catfish gut bacterial communities possess pathways beneficial to their host such as those involved in nutrient metabolism and antimicrobial biosynthesis, while also containing pathways involved in virulence factors of pathogens. Testing of the inferred KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways by DESeq2 revealed minor difference in microbiota function, with only two metagenomic pathways detected as differentially abundant between the two catfish species. As the first study to characterize the gut microbiota of blue catfish, our study results have direct implications on future ictalurid catfish research. Additionally, our insight into the intrinsic factors driving microbiota structure has basic implications for the future study of fish gut microbiota.

Exploring differentially expressed genes related to metabolism by RNA-Seq in goat liver after dexamethasone treatment.

PubMed

Chen, Qu; Hua, Canfeng; Niu, Liqiong; Geng, Yali; Cai, Liuping; Tao, Shiyu; Ni, Yingdong; Zhao, Ruqian

2018-06-15

Chronic stress severely threatens the welfare and health of animals and humans. In order to study the effects of chronic stress on metabolism, de novo transcriptome sequencing was used to generate the expressed sequence tag dataset for the goat, using nextgeneration sequencing technology. For this study, consecutive dexamethasone (Dex) injection was used in 10 healthy male goats (body weight 25 ± 1.0 kg) to mimic chronic stress. Ten male goats were randomly assigned into two groups, one group was injected intramuscularly with the same volume of saline as control (Con) group, and another (Dex) group was injected intramuscularly with 0.2 mg/kg Dex for 21 days. To elucidate the resulting changes in genes, transcriptome profiling of liver was conducted by analysing samples from three goats of each group using RNA-Seq. A total of 137 differentially expressed genes (DEGs) were identified between Con group and Dex group. GO classification showed rhythmic process and hormone secretion in term cellular, and chemoattractant activity in term molecular function had noticeable differences in the proportion between DEGs and all genes. By mapping the DEGs to the COG database, we found that general function prediction only, energy production and conversion, and amino acid transport and metabolism were the most frequently represented functional clusters. We mapped the unigenes to the KEGG pathway database and found most annotated genes were involved in the AMPK signalling pathway as well as pathways in cancer and insulin signalling pathway. Via KEGG enrichment analysis, we found the DEGs were significantly enriched in insulin signalling pathway, AMPK signalling pathway and adipocytokine signalling pathway. In addition, these pathways have close relationship with metabolism, which resulted in metabolic changes in which the identified DEGs may play important roles. These results provide valuable information for further research on the complex molecular mechanisms of dexamethasone in goats and will provide a foundation for future studies. Copyright © 2018 Elsevier B.V. All rights reserved.

Natural Products Version 2.0: Connecting Genes to Molecules

PubMed Central

Walsh, Christopher T.; Fischbach, Michael A.

2009-01-01

Natural products have played a prominent role in the history of organic chemistry, and they continue to be important as drugs, biological probes, and targets of study for synthetic and analytical chemists. In this perspective, we explore how connecting Nature’s small molecules to the genes that encode them has sparked a renaissance in natural product research, focusing primarily on the biosynthesis of polyketides and nonribosomal peptides. We survey monomer biogenesis, coupling chemistries from templated and non-templated pathways, and the broad set of tailoring reactions and hybrid pathways that give rise to the diverse scaffolds and functionalization patterns of natural products. We conclude by considering two questions: What would it take to find all natural product scaffolds? What kind of scientists will be studying natural products in the future? PMID:20121095

Leveraging algal omics to reveal potential targets for augmenting TAG accumulation

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

Arora, Neha; Pienkos, Philip T.; Pruthi, Vikas

Ongoing global efforts to commercialize microalgal biofuels have expedited the use of multi-omics techniques to gain insights into lipid biosynthetic pathways. Functional genomics analyses have recently been employed to complement existing sequence-level omics studies, shedding light on the dynamics of lipid synthesis and its interplay with other cellular metabolic pathways, thus revealing possible targets for metabolic engineering. Here, we review the current status of algal omics studies to reveal potential targets to augment TAG accumulation in various microalgae. Here, this review specifically aims to examine and catalog systems level data related to stress-induced TAG accumulation in oleaginous microalgae and informmore » future metabolic engineering strategies to develop strains with enhanced bioproductivity, which could pave a path for sustainable green energy.« less

A Causal and Mediation Analysis of the Comorbidity Between Attention Deficit Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD).

PubMed

Sokolova, Elena; Oerlemans, Anoek M; Rommelse, Nanda N; Groot, Perry; Hartman, Catharina A; Glennon, Jeffrey C; Claassen, Tom; Heskes, Tom; Buitelaar, Jan K

2017-06-01

Autism spectrum disorder (ASD) and Attention-deficit/hyperactivity disorder (ADHD) are often comorbid. The purpose of this study is to explore the relationships between ASD and ADHD symptoms by applying causal modeling. We used a large phenotypic data set of 417 children with ASD and/or ADHD, 562 affected and unaffected siblings, and 414 controls, to infer a structural equation model using a causal discovery algorithm. Three distinct pathways between ASD and ADHD were identified: (1) from impulsivity to difficulties with understanding social information, (2) from hyperactivity to stereotypic, repetitive behavior, (3) a pairwise pathway between inattention, difficulties with understanding social information, and verbal IQ. These findings may inform future studies on understanding the pathophysiological mechanisms behind the overlap between ASD and ADHD.

Leveraging algal omics to reveal potential targets for augmenting TAG accumulation

DOE PAGES

Arora, Neha; Pienkos, Philip T.; Pruthi, Vikas; ...

2018-04-18

Ongoing global efforts to commercialize microalgal biofuels have expedited the use of multi-omics techniques to gain insights into lipid biosynthetic pathways. Functional genomics analyses have recently been employed to complement existing sequence-level omics studies, shedding light on the dynamics of lipid synthesis and its interplay with other cellular metabolic pathways, thus revealing possible targets for metabolic engineering. Here, we review the current status of algal omics studies to reveal potential targets to augment TAG accumulation in various microalgae. Here, this review specifically aims to examine and catalog systems level data related to stress-induced TAG accumulation in oleaginous microalgae and informmore » future metabolic engineering strategies to develop strains with enhanced bioproductivity, which could pave a path for sustainable green energy.« less

Leveraging algal omics to reveal potential targets for augmenting TAG accumulation.

PubMed

Arora, Neha; Pienkos, Philip T; Pruthi, Vikas; Poluri, Krishna Mohan; Guarnieri, Michael T

2018-04-18

Ongoing global efforts to commercialize microalgal biofuels have expedited the use of multi-omics techniques to gain insights into lipid biosynthetic pathways. Functional genomics analyses have recently been employed to complement existing sequence-level omics studies, shedding light on the dynamics of lipid synthesis and its interplay with other cellular metabolic pathways, thus revealing possible targets for metabolic engineering. Here, we review the current status of algal omics studies to reveal potential targets to augment TAG accumulation in various microalgae. This review specifically aims to examine and catalog systems level data related to stress-induced TAG accumulation in oleaginous microalgae and inform future metabolic engineering strategies to develop strains with enhanced bioproductivity, which could pave a path for sustainable green energy. Copyright © 2018. Published by Elsevier Inc.

Inhibition of Fatty Acid Synthase in Prostate Cancer by Olristat, a Novel Therapeutic

DTIC Science & Technology

2006-11-01

previous crystallography studies by solving the crystal structure of FAS bound to a cleaved orlistat . These data will provide valuable insight into...timeline of XBP-1 15 processing following orlistat treatment (Figure 3A). Previous studies have demonstrated that inhibition of protein translation with...future drug discovery and design within the FAS pathway. In total, we have made great strides toward understanding the anti-tumor effects of orlistat

Molecular signature of pancreatic adenocarcinoma: an insight from genotype to phenotype and challenges for targeted therapy

PubMed Central

Sahin, Ibrahim H; Iacobuzio-Donahue, Christine A; O’Reilly, Eileen M

2016-01-01

Introduction Pancreatic adenocarcinoma remains one of the most clinically challenging cancers despite an in-depth characterization of the molecular underpinnings and biology of this disease. Recent whole-genome-wide studies have elucidated the diverse and complex genetic alterations which generate a unique oncogenic signature for an individual pancreatic cancer patient and which may explain diverse disease behavior in a clinical setting. Areas covered In this review article, we discuss the key oncogenic pathways of pancreatic cancer including RAS-MAPK, PI3KCA and TGF-β signaling, as well as the impact of these pathways on the disease behavior and their potential targetability. The role of tumor suppressors particularly BRCA1 and BRCA2 genes and their role in pancreatic cancer treatment are elaborated upon. We further review recent genomic studies and their impact on future pancreatic cancer treatment. Expert opinion Targeted therapies inhibiting pro-survival pathways have limited impact on pancreatic cancer outcomes. Activation of pro-apoptotic pathways along with suppression of cancer-stem-related pathways may reverse treatment resistance in pancreatic cancer. While targeted therapy or a ‘precision medicine’ approach in pancreatic adenocarcinoma remains an elusive challenge for the majority of patients, there is a real sense of optimism that the strides made in understanding the molecular underpinnings of this disease will translate into improved outcomes. PMID:26439702

Transition and protective agency of early childhood learning behaviors as portents of later school attendance and adjustment.

PubMed

McDermott, Paul A; Rikoon, Samuel H; Fantuzzo, John W

2016-02-01

This article reports on the study of differential change trajectories for early childhood learning behaviors as they relate to future classroom adjustment and school attendance. A large sample (N=2152) of Head Start children was followed through prekindergarten, kindergarten, and 1st grade. Classroom learning behaviors were assessed twice each year by teachers who observed gradual declines in Competence Motivation and Attentional Persistence as children transitioned through schooling. Cross-classified multilevel growth models revealed distinct transitional pathways for future adjustment versus maladjustment and sporadic versus chronic absenteeism. Generalized multilevel logistic modeling and receiver operating characteristic curve analyses showed that teachers' earliest assessments were substantially predictive of eventual good classroom adjustment and school attendance, with increasing accuracy for prediction of future sociobehavioral adjustment as time progressed. Copyright © 2015 Society for the Study of School Psychology. Published by Elsevier Ltd. All rights reserved.

The Burn Wound Microenvironment

PubMed Central

Rose, Lloyd F.; Chan, Rodney K.

2016-01-01

Significance: While the survival rate of the severely burned patient has improved significantly, relatively little progress has been made in treatment or prevention of burn-induced long-term sequelae, such as contraction and fibrosis. Recent Advances: Our knowledge of the molecular pathways involved in burn wounds has increased dramatically, and technological advances now allow large-scale genomic studies, providing a global view of wound healing processes. Critical Issues: Translating findings from a large number of in vitro and preclinical animal studies into clinical practice represents a gap in our understanding, and the failures of a number of clinical trials suggest that targeting single pathways or cytokines may not be the best approach. Significant opportunities for improvement exist. Future Directions: Study of the underlying molecular influences of burn wound healing progression will undoubtedly continue as an active research focus. Increasing our knowledge of these processes will identify additional therapeutic targets, supporting informed clinical studies that translate into clinical relevance and practice. PMID:26989577

Physical Activity Measurements: Lessons Learned from the Pathways Study

PubMed Central

Going, Scott B.

2015-01-01

High obesity rates in American Indian children led to Pathways, a randomized school and community-based childhood prevention study. Seven tribes, five universities, the NIH/NHLBI, and four elementary schools partnered. Increasing physical activity (PA) was an important intervention target. PA assessment was based on study objectives, feasibility, and tribal acceptance. A time-segmented analysis was also desired. Two methods were developed during pilot testing, a new PA questionnaire and accelerometry. Together, the methods provided qualitative and quantitative information and showed 3 of 4 sites were able to increase average daily PA, although overall the control versus intervention difference was not significant. The main limitation was inability to distinguish PA among individuals. Accelerometer size and some community concerns led to a protocol based on a single day of wearing time. Newer model triaxial accelerometers which are much smaller and allow sampling of multiple days of activity are recommended for future studies. PMID:20689391

Development of Nested Socioeconomic Storylines for Climate Change IAV Applications (Invited)

NASA Astrophysics Data System (ADS)

Preston, B. L.; Absar, M.

2013-12-01

Socioeconomic scenarios are important for understanding future societal consequences of climate and weather. The global shared socioeconomic pathways (SSPs) represent a new opportunity for coordinated development and application of such scenarios to improve the representation of alternative societal development pathways within climate change consequence analysis. However, capitalizing on this opportunity necessitates bridging the scale disparity between the global SSPs and the regional/local context for which many impact, adaptation and vulnerability (IAV) studies are conducted. To this end, we adopted the Factor, Actor, and Sector methodology to develop a set of qualitative national and sub-national socioeconomic storylines for the United States and U.S. Southeast using the global SSPs as boundary conditions. In particular, our study sought to develop storylines to explore alternative socioeconomic futures for the U.S. Southeast and their implications for adaptive capacity of the region's energy, water, and agricultural sectors. These storylines subsequently serve as the foundation for a range of downstream IAV applications. These include qualitative vulnerability analysis to explore interactions between energy, water, and agriculture in a changing climate; as well as quantitative impact assessment where regional storylines are used to establish modeling parameters within a biophysical crop model. Such methods and applications illustrate potentially useful opportunities for routinizing the use of SSP-based storylines in IAV studies.

Relative Contributions of Agricultural Drift, Para-Occupational, and Residential Use Exposure Pathways to House Dust Pesticide Concentrations: Meta-Regression of Published Data.

PubMed

Deziel, Nicole C; Freeman, Laura E Beane; Graubard, Barry I; Jones, Rena R; Hoppin, Jane A; Thomas, Kent; Hines, Cynthia J; Blair, Aaron; Sandler, Dale P; Chen, Honglei; Lubin, Jay H; Andreotti, Gabriella; Alavanja, Michael C R; Friesen, Melissa C

2017-03-01

Increased pesticide concentrations in house dust in agricultural areas have been attributed to several exposure pathways, including agricultural drift, para-occupational, and residential use. To guide future exposure assessment efforts, we quantified relative contributions of these pathways using meta-regression models of published data on dust pesticide concentrations. From studies in North American agricultural areas published from 1995 to 2015, we abstracted dust pesticide concentrations reported as summary statistics [e.g., geometric means (GM)]. We analyzed these data using mixed-effects meta-regression models that weighted each summary statistic by its inverse variance. Dependent variables were either the log-transformed GM (drift) or the log-transformed ratio of GMs from two groups (para-occupational, residential use). For the drift pathway, predicted GMs decreased sharply and nonlinearly, with GMs 64% lower in homes 250 m versus 23 m from fields (interquartile range of published data) based on 52 statistics from seven studies. For the para-occupational pathway, GMs were 2.3 times higher [95% confidence interval (CI): 1.5, 3.3; 15 statistics, five studies] in homes of farmers who applied pesticides more recently or frequently versus less recently or frequently. For the residential use pathway, GMs were 1.3 (95% CI: 1.1, 1.4) and 1.5 (95% CI: 1.2, 1.9) times higher in treated versus untreated homes, when the probability that a pesticide was used for the pest treatment was 1-19% and ≥ 20%, respectively (88 statistics, five studies). Our quantification of the relative contributions of pesticide exposure pathways in agricultural populations could improve exposure assessments in epidemiologic studies. The meta-regression models can be updated when additional data become available. Citation: Deziel NC, Beane Freeman LE, Graubard BI, Jones RR, Hoppin JA, Thomas K, Hines CJ, Blair A, Sandler DP, Chen H, Lubin JH, Andreotti G, Alavanja MC, Friesen MC. 2017. Relative contributions of agricultural drift, para-occupational, and residential use exposure pathways to house dust pesticide concentrations: meta-regression of published data. Environ Health Perspect 125:296-305; http://dx.doi.org/10.1289/EHP426.

Relative Contributions of Agricultural Drift, Para-Occupational, and Residential Use Exposure Pathways to House Dust Pesticide Concentrations: Meta-Regression of Published Data

PubMed Central

Deziel, Nicole C.; Freeman, Laura E. Beane; Graubard, Barry I.; Jones, Rena R.; Hoppin, Jane A.; Thomas, Kent; Hines, Cynthia J.; Blair, Aaron; Sandler, Dale P.; Chen, Honglei; Lubin, Jay H.; Andreotti, Gabriella; Alavanja, Michael C. R.; Friesen, Melissa C.

2016-01-01

Background: Increased pesticide concentrations in house dust in agricultural areas have been attributed to several exposure pathways, including agricultural drift, para-occupational, and residential use. Objective: To guide future exposure assessment efforts, we quantified relative contributions of these pathways using meta-regression models of published data on dust pesticide concentrations. Methods: From studies in North American agricultural areas published from 1995 to 2015, we abstracted dust pesticide concentrations reported as summary statistics [e.g., geometric means (GM)]. We analyzed these data using mixed-effects meta-regression models that weighted each summary statistic by its inverse variance. Dependent variables were either the log-transformed GM (drift) or the log-transformed ratio of GMs from two groups (para-occupational, residential use). Results: For the drift pathway, predicted GMs decreased sharply and nonlinearly, with GMs 64% lower in homes 250 m versus 23 m from fields (interquartile range of published data) based on 52 statistics from seven studies. For the para-occupational pathway, GMs were 2.3 times higher [95% confidence interval (CI): 1.5, 3.3; 15 statistics, five studies] in homes of farmers who applied pesticides more recently or frequently versus less recently or frequently. For the residential use pathway, GMs were 1.3 (95% CI: 1.1, 1.4) and 1.5 (95% CI: 1.2, 1.9) times higher in treated versus untreated homes, when the probability that a pesticide was used for the pest treatment was 1–19% and ≥ 20%, respectively (88 statistics, five studies). Conclusion: Our quantification of the relative contributions of pesticide exposure pathways in agricultural populations could improve exposure assessments in epidemiologic studies. The meta-regression models can be updated when additional data become available. Citation: Deziel NC, Beane Freeman LE, Graubard BI, Jones RR, Hoppin JA, Thomas K, Hines CJ, Blair A, Sandler DP, Chen H, Lubin JH, Andreotti G, Alavanja MC, Friesen MC. 2017. Relative contributions of agricultural drift, para-occupational, and residential use exposure pathways to house dust pesticide concentrations: meta-regression of published data. Environ Health Perspect 125:296–305; http://dx.doi.org/10.1289/EHP426 PMID:27458779

Understanding the Effectiveness of Carbon Dioxide Removal to Reduce the Impacts of Climate Change.

NASA Astrophysics Data System (ADS)

Scott, V.; Tett, S. F.; Brander, M.

2017-12-01

The current Nationally Determined Contributions to the Paris Agreement suggest exceeding the emissions budgets corresponding to the below 2°C and 1.5°C temperature targets. To address this the future application of Carbon Dioxide Removal (CDR) is proposed to recapture excess emissions at a later time, so keeping the total net emissions within budget. This assumes that the climate change impact of CO2 emitted now can be fully compensated by a matched CO2 removal in the future. However, the impacts from this pathway of emissions budget overshoot and subsequent recapture may differ from those resulting from a pathway where emissions are held within budget with no temporary overshoot. These pathway dependent impacts could give rise to different climatic and societal futures despite the total net emissions being the same. Using a low resolution fully coupled Earth System Model with an interactive carbon cycle, we present an investigation into the pathway dependence of climate change impacts and how these relate to the scale and duration of the emissions budget overshoot and subsequent recapture. From this we discuss the effectiveness of CDR in avoiding climate change impacts relative to more immediate emissions reductions. We consider how this relative effectiveness might be reflected in GHG accounting methods and national GHG accounts, and explore the implications for Article 2 of the Paris Agreement, where holding temperatures to the targets is recognised to "significantly reduce the risks and impacts of climate change".

Advances in the treatment of erectile dysfunction: what’s new and upcoming?

PubMed Central

Patel, Chintan K.; Bennett, Nelson

2016-01-01

Erectile dysfunction adversely affects up to 20% of all men and is the most commonly treated sexual disorder. The public health implications of this condition are significant and represent a challenge for our healthcare system. The physiological pathways responsible for erections have been extensively studied, and much advancement has been made since the introduction of phosphodiesterase 5 inhibitors. Newer agents, such as dopaminergic and melanocortin receptor agonists, which target central erectogenic pathways, are under investigation. Newer formulations and delivery methods of existing medications such as alprostadil will also be introduced in the near future. Furthermore, low-intensity shockwave lithotripsy and stem cell regenerative techniques are innovative approaches to the treatment of erectile dysfunction. PMID:27516878

Use of genomic data in risk assessment case study: II. Evaluation of the dibutyl phthalate toxicogenomic data set

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

Euling, Susan Y., E-mail: euling.susan@epa.gov; White, Lori D.; Kim, Andrea S.

An evaluation of the toxicogenomic data set for dibutyl phthalate (DBP) and male reproductive developmental effects was performed as part of a larger case study to test an approach for incorporating genomic data in risk assessment. The DBP toxicogenomic data set is composed of nine in vivo studies from the published literature that exposed rats to DBP during gestation and evaluated gene expression changes in testes or Wolffian ducts of male fetuses. The exercise focused on qualitative evaluation, based on a lack of available dose–response data, of the DBP toxicogenomic data set to postulate modes and mechanisms of action formore » the male reproductive developmental outcomes, which occur in the lower dose range. A weight-of-evidence evaluation was performed on the eight DBP toxicogenomic studies of the rat testis at the gene and pathway levels. The results showed relatively strong evidence of DBP-induced downregulation of genes in the steroidogenesis pathway and lipid/sterol/cholesterol transport pathway as well as effects on immediate early gene/growth/differentiation, transcription, peroxisome proliferator-activated receptor signaling and apoptosis pathways in the testis. Since two established modes of action (MOAs), reduced fetal testicular testosterone production and Insl3 gene expression, explain some but not all of the testis effects observed in rats after in utero DBP exposure, other MOAs are likely to be operative. A reanalysis of one DBP microarray study identified additional pathways within cell signaling, metabolism, hormone, disease, and cell adhesion biological processes. These putative new pathways may be associated with DBP effects on the testes that are currently unexplained. This case study on DBP identified data gaps and research needs for the use of toxicogenomic data in risk assessment. Furthermore, this study demonstrated an approach for evaluating toxicogenomic data in human health risk assessment that could be applied to future chemicals. - Highlights: ► We evaluate the dibutyl phthalate toxicogenomic data for use in risk assessment. ► We focus on information about the mechanism of action for the developing testis. ► Multiple studies report effects on testosterone and insl3-related pathways. ► We identify additional affected pathways that may explain some testis effects. ► The case study is a template for evaluating toxicogenomic data in risk assessment.« less

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.

Ethylene signaling renders the jasmonate response of Arabidopsis insensitive to future suppression by salicylic Acid.

PubMed

Leon-Reyes, Antonio; Du, Yujuan; Koornneef, Annemart; Proietti, Silvia; Körbes, Ana P; Memelink, Johan; Pieterse, Corné M J; Ritsema, Tita

2010-02-01

Cross-talk between jasmonate (JA), ethylene (ET), and Salicylic acid (SA) signaling is thought to operate as a mechanism to fine-tune induced defenses that are activated in response to multiple attackers. Here, 43 Arabidopsis genotypes impaired in hormone signaling or defense-related processes were screened for their ability to express SA-mediated suppression of JA-responsive gene expression. Mutant cev1, which displays constitutive expression of JA and ET responses, appeared to be insensitive to SA-mediated suppression of the JA-responsive marker genes PDF1.2 and VSP2. Accordingly, strong activation of JA and ET responses by the necrotrophic pathogens Botrytis cinerea and Alternaria brassicicola prior to SA treatment counteracted the ability of SA to suppress the JA response. Pharmacological assays, mutant analysis, and studies with the ET-signaling inhibitor 1-methylcyclopropene revealed that ET signaling renders the JA response insensitive to subsequent suppression by SA. The APETALA2/ETHYLENE RESPONSE FACTOR transcription factor ORA59, which regulates JA/ET-responsive genes such as PDF1.2, emerged as a potential mediator in this process. Collectively, our results point to a model in which simultaneous induction of the JA and ET pathway renders the plant insensitive to future SA-mediated suppression of JA-dependent defenses, which may prioritize the JA/ET pathway over the SA pathway during multi-attacker interactions.

Evaluation of a setting reaction pathway in the novel composite TiHA-CSD bone cement by FT-Raman and FT-IR spectroscopy

NASA Astrophysics Data System (ADS)

Paluszkiewicz, Czesława; Czechowska, Joanna; Ślósarczyk, Anna; Paszkiewicz, Zofia

2013-02-01

The aim of this study was to determine a setting reaction pathway in a novel, surgically handy implant material, based on calcium sulfate hemihydrate (CSH) and titanium doped hydroxyapatite (TiHA). The previous studies confirmed superior biological properties of TiHA in comparison to the undoped hydroxyapatite (HA) what makes it highly attractive for future medical applications. In this study the three types of titanium modified HA powders: untreated, calcined at 800 °C, sintered at 1250 °C and CSH were used to produce bone cements. The Fourier Transform-InfraRed (FT-IR) spectroscopy and Raman spectroscopy were applied to evaluate processes taking place during the setting of the studied materials. Our results undoubtedly confirmed that the reaction pathways and the phase compositions differed significantly for set cements and were dependent on the initial heat treatment of TiHA powder. Final materials were multiphase composites consisting of calcium sulfate dihydrate, bassanite, tricalcium phosphate, hydroxyapatite and calcium titanate (perovskite). The FT-IR and Scanning Electron Microscopy (SEM) measurements performed after the incubation of the cement samples in the simulated body fluid (SBF), indicate on high bioactive potential of the obtained bone cements.

Charting the Emergence of Corporate Procurement of Utility-Scale PV

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

Heeter, Jenny S.; Cook, Jeffrey J.; Bird, Lori A.

Through July 2017, corporate customers contracted for more than 2,300 MW of utility-scale solar. This paper examines the benefits, challenges, and outlooks for large-scale off-site solar purchasing through four pathways: PPAs, retail choice, utility partnerships (green tariffs and bilateral contracts with utilities), and by becoming a licensed wholesale seller of electricity. Each pathway differs based on where in the United States it is available, the value provided to a corporate off-taker, and the ease of implementation. The paper concludes with a discussion of future pathway comparison, noting that to deploy more corporate off-site solar, new procurement pathways are needed.

Flexible Pedagogies: New Pedagogical Ideas. Flexible Pedagogies: Preparing for the Future Series

ERIC Educational Resources Information Center

Ryan, Alex; Tilbury, Daniella

2014-01-01

This publication is part of our five-strand research project "Flexible Pedagogies: preparing for the future". It identifies six "new pedagogical ideas" offering new pathways for learning. These include: (1) actively involving students in learning development and processes of "co-creation" thereby challenging existing…

Building the Workforce of the Future

ERIC Educational Resources Information Center

González-Rivera, Christian

2016-01-01

"Building the Workforce of the Future" is an in-depth, independent report on the first eighteen months of Career Pathways, New York City's sweeping new strategy for workforce development. In November 2014, Mayor de Blasio launched a sweeping new approach to workforce development in New York City. Unlike the previous model, which…

How Do Future Life Perspective and Present Action Work in Japanese Youth Development?

ERIC Educational Resources Information Center

Kawai, Toru; Moran, Seana

2017-01-01

"Future life perspective" and "present action," whose interaction affects how one's current activity affects later life, offer a critical crossroads for young adults in Japan as stable career paths have become more uncertain. Past generations benefited from stable institutional pathways, but recent generations must forge their…

Piper betle leaf extracts induced human hepatocellular carcinoma Hep3B cell death via MAPKs regulating the p73 pathway in vitro and in vivo.

PubMed

Wu, Pei-Fang; Tseng, Hsien-Chun; Chyau, Charng-Cherng; Chen, Jing-Hsien; Chou, Fen-Pi

2014-12-01

Extracts of Piper betle leaf (PBLs) are rich in bioactive compounds with potential chemopreventive ability. In this study, Hep3B cells which are p53 null were used to investigate the anti-tumor effect of PBLs in the cell and in the xenograft model. The results revealed that PBLs (0.1 to 1 mg mL(-1)) induced a dose- and time-dependent increase of cell toxicity. The underlying mechanisms as evidenced by flow cytometry and western blot analysis showed that PBLs triggered ATM, cAbl, and p73 expressions and activated JNK and p38 pathways that subsequently led to cell cycle arrest and mitochondria-dependent apoptosis. PBLs also inhibited tumor growth in Hep3B-bearing mice via inducing the MAPK-p73 pathway. Our results demonstrated the in vitro and in vivo anti-tumor potential of PBLs, supporting their application as a novel chemopreventive agent for the treatment of human hepatocellular carcinoma (HCC) in the future via targeting the p73 pathway.

Effect of climate change on sowing and harvest dates of spring barley and maize in Poland

NASA Astrophysics Data System (ADS)

Marcinkowski, Paweł; Piniewski, Mikołaj

2018-04-01

Climate change and projected temperature increase is recognised to have significant impact on agricultural production and crop phenology. This study evaluated the climate change impact on sowing and harvest dates of spring barley and maize in the boundaries of two largest catchments in Poland - the Vistula and the Odra. For this purpose, an agro-hydrological Soil and Water Assessment Tool has been used, driven by climate forcing data provided within the Coordinated Downscaling Experiment - European Domain experiment projected to the year 2100 under two representative concentration pathways: 4.5 and 8.5. The projected warmer climate significantly affected the potential scheduling of agricultural practices, accelerating the occurrence of sowing and harvest dates. The rate of acceleration was dependent on the time horizon and representative concentration pathways scenario. In general, the rate of sowing/harvest advance was accelerating in time and, also from representative concentration pathways 4.5 to 8.5, reaching 23 days for spring barley and 30 days for maize (ensemble mean for the far future under representative concentration pathways 8.5).

Discovery and molecular characterization of a Bcl-2-regulated cell death pathway in schistosomes.

PubMed

Lee, Erinna F; Clarke, Oliver B; Evangelista, Marco; Feng, Zhiping; Speed, Terence P; Tchoubrieva, Elissaveta B; Strasser, Andreas; Kalinna, Bernd H; Colman, Peter M; Fairlie, W Douglas

2011-04-26

Schistosomiasis is an infectious disease caused by parasites of the phylum platyhelminthe. Here, we describe the identification and characterization of a Bcl-2-regulated apoptosis pathway in Schistosoma japonicum and S. mansoni. Genomic, biochemical, and cell-based mechanistic studies provide evidence for a tripartite pathway, similar to that in humans including BH3-only proteins that are inhibited by prosurvival Bcl-2-like molecules, and Bax/Bak-like proteins that facilitate mitochondrial outer-membrane permeabilization. Because Bcl-2 proteins have been successfully targeted with "BH3 mimetic" drugs, particularly in the treatment of cancer, we investigated whether schistosome apoptosis pathways could provide targets for future antischistosomal drug discovery efforts. Accordingly, we showed that a schistosome prosurvival protein, sjA, binds ABT-737, a well-characterized BH3 mimetic. A crystal structure of sjA bound to a BH3 peptide provides direct evidence for the feasibility of developing BH3 mimetics to target Bcl-2 prosurvival proteins in schistosomes, suggesting an alternative application for this class of drugs beyond cancer treatment.

Discovery and molecular characterization of a Bcl-2–regulated cell death pathway in schistosomes

PubMed Central

Lee, Erinna F.; Clarke, Oliver B.; Evangelista, Marco; Feng, Zhiping; Speed, Terence P.; Tchoubrieva, Elissaveta B.; Strasser, Andreas; Kalinna, Bernd H.; Colman, Peter M.; Fairlie, W. Douglas

2011-01-01

Schistosomiasis is an infectious disease caused by parasites of the phylum platyhelminthe. Here, we describe the identification and characterization of a Bcl-2–regulated apoptosis pathway in Schistosoma japonicum and S. mansoni. Genomic, biochemical, and cell-based mechanistic studies provide evidence for a tripartite pathway, similar to that in humans including BH3-only proteins that are inhibited by prosurvival Bcl-2–like molecules, and Bax/Bak-like proteins that facilitate mitochondrial outer-membrane permeabilization. Because Bcl-2 proteins have been successfully targeted with “BH3 mimetic” drugs, particularly in the treatment of cancer, we investigated whether schistosome apoptosis pathways could provide targets for future antischistosomal drug discovery efforts. Accordingly, we showed that a schistosome prosurvival protein, sjA, binds ABT-737, a well-characterized BH3 mimetic. A crystal structure of sjA bound to a BH3 peptide provides direct evidence for the feasibility of developing BH3 mimetics to target Bcl-2 prosurvival proteins in schistosomes, suggesting an alternative application for this class of drugs beyond cancer treatment. PMID:21444803

The PD-1 pathway as a therapeutic target to overcome immune escape mechanisms in cancer.

PubMed

Henick, Brian S; Herbst, Roy S; Goldberg, Sarah B

2014-12-01

Immunotherapy is emerging as a powerful approach in cancer treatment. Preclinical data predicted the antineoplastic effects seen in clinical trials of programmed death-1 (PD-1) pathway inhibitors, as well as their observed toxicities. The results of early clinical trials are extraordinarily promising in several cancer types and have shaped the direction of ongoing and future studies. This review describes the biological rationale for targeting the PD-1 pathway with monoclonal antibodies for the treatment of cancer as a context for examining the results of early clinical trials. It also surveys the landscape of ongoing clinical trials and discusses their anticipated strengths and limitations. PD-1 pathway inhibition represents a new frontier in cancer immunotherapy, which shows clear evidence of activity in various tumor types including NSCLC and melanoma. Ongoing and upcoming trials will examine optimal combinations of these agents, which should further define their role across tumor types. Current limitations include the absence of a reliable companion diagnostic to predict likely responders, as well as lack of data in early-stage cancer when treatment has the potential to increase cure rates.

Targeting G protein coupled receptor-related pathways as emerging molecular therapies

PubMed Central

Ghanemi, Abdelaziz

2013-01-01

G protein coupled receptors (GPCRs) represent the most important targets in modern pharmacology because of the different functions they mediate, especially within brain and peripheral nervous system, and also because of their functional and stereochemical properties. In this paper, we illustrate, via a variety of examples, novel advances about the GPCR-related molecules that have been shown to play diverse roles in GPCR pathways and in pathophysiological phenomena. We have exemplified how those GPCRs’ pathways are, or might constitute, potential targets for different drugs either to stimulate, modify, regulate or inhibit the cellular mechanisms that are hypothesized to govern some pathologic, physiologic, biologic and cellular or molecular aspects both in vivo and in vitro. Therefore, influencing such pathways will, undoubtedly, lead to different therapeutical applications based on the related pharmacological implications. Furthermore, such new properties can be applied in different fields. In addition to offering fruitful directions for future researches, we hope the reviewed data, together with the elements found within the cited references, will inspire clinicians and researchers devoted to the studies on GPCR’s properties. PMID:25972730

PUFA diets alter the microRNA expression profiles in an inflammation rat model

PubMed Central

ZHENG, ZHENG; GE, YINLIN; ZHANG, JINYU; XUE, MEILAN; LI, QUAN; LIN, DONGLIANG; MA, WENHUI

2015-01-01

Omega-3 and -6 polyunsaturated fatty acids (PUFAs) can directly or indirectly regulate immune homeostasis via inflammatory pathways, and components of these pathways are crucial targets of microRNAs (miRNAs). However, no study has examined the changes in the miRNA transcriptome during PUFA-regulated inflammatory processes. Here, we established PUFA diet-induced autoimmune-prone (AP) and autoimmune-averse (AA) rat models, and studied their physical characteristics and immune status. Additionally, miRNA expression patterns in the rat models were compared using microarray assays and bioinformatic methods. A total of 54 miRNAs were differentially expressed in common between the AP and the AA rats, and the changes in rno-miR-19b-3p, -146b-5p and -183-5p expression were validated using stem-loop reverse transcription-quantitative polymerase chain reaction. To better understand the mechanisms underlying PUFA-regulated miRNA changes during inflammation, computational algorithms and biological databases were used to identify the target genes of the three validated miRNAs. Furthermore, Gene Ontology (GO) term annotation and KEGG pathway analyses of the miRNA targets further allowed to explore the potential implication of the miRNAs in inflammatory pathways. The predicted PUFA-regulated inflammatory pathways included the Toll-like receptor (TLR), T cell receptor (TCR), NOD-like receptor (NLR), RIG-I-like receptor (RLR), mitogen-activated protein kinase (MAPK) and the transforming growth factor-β (TGF-β) pathway. This study is the first report, to the best of our knowledge, on in vivo comparative profiling of miRNA transcriptomes in PUFA diet-induced inflammatory rat models using a microarray approach. The results provide a useful resource for future investigation of the role of PUFA-regulated miRNAs in immune homeostasis. PMID:25672643

How high school students envision their STEM career pathways

NASA Astrophysics Data System (ADS)

Zhang, Lin; Barnett, Michael

2015-09-01

Given that many urban students exclude Science, Technology, Engineering, and Mathematics careers from their career choices, the present study focuses on urban high school students and adopts the social-cultural approach to understand the following questions: how do students envision their careers? What are the experiences that shape students' self-reflections? And how do students' self-reflections influence the way they envision their future careers? Five students were interviewed and data were coded in two ways: by topic domains and confidence levels. The research findings indicate that: first, a lack of information about future careers limits students from developing effective strategic plans; second, students' perceived ability to handle situations of potential barriers and communications with their parents might contribute to their certainty about and confidence in future careers.

FREQUENT SUBGRAPH MINING OF PERSONALIZED SIGNALING PATHWAY NETWORKS GROUPS PATIENTS WITH FREQUENTLY DYSREGULATED DISEASE PATHWAYS AND PREDICTS PROGNOSIS.

PubMed

Durmaz, Arda; Henderson, Tim A D; Brubaker, Douglas; Bebek, Gurkan

2017-01-01

Large scale genomics studies have generated comprehensive molecular characterization of numerous cancer types. Subtypes for many tumor types have been established; however, these classifications are based on molecular characteristics of a small gene sets with limited power to detect dysregulation at the patient level. We hypothesize that frequent graph mining of pathways to gather pathways functionally relevant to tumors can characterize tumor types and provide opportunities for personalized therapies. In this study we present an integrative omics approach to group patients based on their altered pathway characteristics and show prognostic differences within breast cancer (p < 9:57E - 10) and glioblastoma multiforme (p < 0:05) patients. We were able validate this approach in secondary RNA-Seq datasets with p < 0:05 and p < 0:01 respectively. We also performed pathway enrichment analysis to further investigate the biological relevance of dysregulated pathways. We compared our approach with network-based classifier algorithms and showed that our unsupervised approach generates more robust and biologically relevant clustering whereas previous approaches failed to report specific functions for similar patient groups or classify patients into prognostic groups. These results could serve as a means to improve prognosis for future cancer patients, and to provide opportunities for improved treatment options and personalized interventions. The proposed novel graph mining approach is able to integrate PPI networks with gene expression in a biologically sound approach and cluster patients in to clinically distinct groups. We have utilized breast cancer and glioblastoma multiforme datasets from microarray and RNA-Seq platforms and identified disease mechanisms differentiating samples. Supplementary methods, figures, tables and code are available at https://github.com/bebeklab/dysprog.

Integrative pathway analysis of a genome-wide association study of V̇o2max response to exercise training

PubMed Central

Vivar, Juan C.; Sarzynski, Mark A.; Sung, Yun Ju; Timmons, James A.; Bouchard, Claude; Rankinen, Tuomo

2013-01-01

We previously reported the findings from a genome-wide association study of the response of maximal oxygen uptake (V̇o2max) to an exercise program. Here we follow up on these results to generate hypotheses on genes, pathways, and systems involved in the ability to respond to exercise training. A systems biology approach can help us better establish a comprehensive physiological description of what underlies V̇o2maxtrainability. The primary material for this exploration was the individual single-nucleotide polymorphism (SNP), SNP-gene mapping, and statistical significance levels. We aimed to generate novel hypotheses through analyses that go beyond statistical association of single-locus markers. This was accomplished through three complementary approaches: 1) building de novo evidence of gene candidacy through informatics-driven literature mining; 2) aggregating evidence from statistical associations to link variant enrichment in biological pathways to V̇o2max trainability; and 3) predicting possible consequences of variants residing in the pathways of interest. We started with candidate gene prioritization followed by pathway analysis focused on overrepresentation analysis and gene set enrichment analysis. Subsequently, leads were followed using in silico analysis of predicted SNP functions. Pathways related to cellular energetics (pantothenate and CoA biosynthesis; PPAR signaling) and immune functions (complement and coagulation cascades) had the highest levels of SNP burden. In particular, long-chain fatty acid transport and fatty acid oxidation genes and sequence variants were found to influence differences in V̇o2max trainability. Together, these methods allow for the hypothesis-driven ranking and prioritization of genes and pathways for future experimental testing and validation. PMID:23990238

Toward engineering E. coli with an autoregulatory system for lignin valorization

PubMed Central

Wu, Weihua; Liu, Fang; Singh, Seema

2018-01-01

Efficient lignin valorization could add more than 10-fold the value gained from burning it for energy and is critical for economic viability of future biorefineries. However, lignin-derived aromatics from biomass pretreatment are known to be potent fermentation inhibitors in microbial production of fuels and other value-added chemicals. In addition, isopropyl-β-d-1-thiogalactopyranoside and other inducers are routinely added into fermentation broth to induce the expression of pathway enzymes, which further adds to the overall process cost. An autoregulatory system that can diminish the aromatics’ toxicity as well as be substrate-inducible can be the key for successful integration of lignin valorization into future lignocellulosic biorefineries. Toward that goal, in this study an autoregulatory system is demonstrated that alleviates the toxicity issue and eliminates the cost of an external inducer. Specifically, this system is composed of a catechol biosynthesis pathway coexpressed with an active aromatic transporter CouP under induction by a vanillin self-inducible promoter, ADH7, to effectively convert the lignin-derived aromatics into value-added chemicals using Escherichia coli as a host. The constructed autoregulatory system can efficiently transport vanillin across the cell membrane and convert it to catechol. Compared with the system without CouP expression, the expression of catechol biosynthesis pathway with transporter CouP significantly improved the catechol yields about 30% and 40% under promoter pTrc and ADH7, respectively. This study demonstrated an aromatic-induced autoregulatory system that enabled conversion of lignin-derived aromatics into catechol without the addition of any costly, external inducers, providing a promising and economically viable route for lignin valorization. PMID:29500185

A systematic review of dynamics in climate risk and vulnerability assessments

NASA Astrophysics Data System (ADS)

Jurgilevich, Alexandra; Räsänen, Aleksi; Groundstroem, Fanny; Juhola, Sirkku

2017-01-01

Understanding climate risk is crucial for effective adaptation action, and a number of assessment methodologies have emerged. We argue that the dynamics of the individual components in climate risk and vulnerability assessments has received little attention. In order to highlight this, we systematically reviewed 42 sub-national climate risk and vulnerability assessments. We analysed the assessments using an analytical framework with which we evaluated (1) the conceptual approaches to vulnerability and exposure used, (2) if current or future risks were assessed, and (3) if and how changes over time (i.e. dynamics) were considered. Of the reviewed assessments, over half addressed future risks or vulnerability; and of these future-oriented studies, less than 1/3 considered both vulnerability and exposure dynamics. While the number of studies that include dynamics is growing, and while all studies included socio-economic aspects, often only biophysical dynamics was taken into account. We discuss the challenges of assessing socio-economic and spatial dynamics, particularly the poor availability of data and methods. We suggest that future-oriented studies assessing risk dynamics would benefit from larger stakeholder involvement, discussion of the assessment purpose, the use of multiple methods, inclusion of uncertainty/sensitivity analyses and pathway approaches.

The future of pharmacogenetics in the treatment of heart failure.

PubMed

Anwar, Mohamed Subhan; Iskandar, Muhammad Zaid; Parry, Helen M; Doney, Alex S; Palmer, Colin N; Lang, Chim C

2015-11-01

Heart failure is a common disease with high levels of morbidity and mortality. Current treatment comprises β-blockers, ACE inhibitors, aldosterone antagonists and diuretics. Variation in clinical response seen in patients begs the question of whether there is a pharmacogenetic component yet to be identified. To date, the genes most studied involve the β-1, β-2, α-2 adrenergic receptors and the renin-angiotensin-aldosterone pathway, mainly focusing on SNPs. However results have been inconsistent. Genome-wide association studies and next-generation sequencing are seen as alternative approaches to discovering genetic variations influencing drug response. Hopefully future research will lay the foundations for genotype-led drug management in these patients with the ultimate aim of improving their clinical outcome.

Pathways to the Future: A Longitudinal Study of Young Americans. Preliminary Report: Youth and the Labor Market--1979.

ERIC Educational Resources Information Center

Borus, Michael E.; And Others

This monograph presents preliminary cross-tabulation analyses of the 1979 National Longitudinal Survey of Youth Labor Market Experience of 12,693 youth of ages 14-21 who will be interviewed annually for at least five years. (Hispanic; non-Hispanic black; and non-Hispanic, non-black, poor youth were oversampled.) Each of the twenty-four topics…

Modeling global water use for the 21st century: the Water Futures and Solutions (WFaS) initiative and its approaches

NASA Astrophysics Data System (ADS)

Wada, Y.; Flörke, M.; Hanasaki, N.; Eisner, S.; Fischer, G.; Tramberend, S.; Satoh, Y.; van Vliet, M. T. H.; Yillia, P.; Ringler, C.; Burek, P.; Wiberg, D.

2016-01-01

To sustain growing food demand and increasing standard of living, global water use increased by nearly 6 times during the last 100 years, and continues to grow. As water demands get closer and closer to the water availability in many regions, each drop of water becomes increasingly valuable and water must be managed more efficiently and intensively. However, soaring water use worsens water scarcity conditions already prevalent in semi-arid and arid regions, increasing uncertainty for sustainable food production and economic development. Planning for future development and investments requires that we prepare water projections for the future. However, estimations are complicated because the future of the world's waters will be influenced by a combination of environmental, social, economic, and political factors, and there is only limited knowledge and data available about freshwater resources and how they are being used. The Water Futures and Solutions (WFaS) initiative coordinates its work with other ongoing scenario efforts for the sake of establishing a consistent set of new global water scenarios based on the shared socio-economic pathways (SSPs) and the representative concentration pathways (RCPs). The WFaS "fast-track" assessment uses three global water models, namely H08, PCR-GLOBWB, and WaterGAP. This study assesses the state of the art for estimating and projecting water use regionally and globally in a consistent manner. It provides an overview of different approaches, the uncertainty, strengths and weaknesses of the various estimation methods, types of management and policy decisions for which the current estimation methods are useful. We also discuss additional information most needed to be able to improve water use estimates and be able to assess a greater range of management options across the water-energy-climate nexus.

Modeling Global Water Use for the 21st Century: Water Futures and Solutions (WFaS) Initiative and Its Approaches

NASA Technical Reports Server (NTRS)

Wada, Y.; Florke, M.; Hanasaki, N.; Eisner, S.; Fischer, G.; Tramberend, S.; Satoh, Y.; van Vliet, M. T. H.; Yillia, P.; Ringler, C.;

Modeling global water use for the 21st century: Water Futures and Solutions (WFaS) initiative and its approaches

NASA Astrophysics Data System (ADS)

Wada, Y.; Flörke, M.; Hanasaki, N.; Eisner, S.; Fischer, G.; Tramberend, S.; Satoh, Y.; van Vliet, M. T. H.; Yillia, P.; Ringler, C.; Wiberg, D.

2015-08-01

To sustain growing food demand and increasing standard of living, global water use increased by nearly 6 times during the last 100 years and continues to grow. As water demands get closer and closer to the water availability in many regions, each drop of water becomes increasingly valuable and water must be managed more efficiently and intensively. However, soaring water use worsens water scarcity condition already prevalent in semi-arid and arid regions, increasing uncertainty for sustainable food production and economic development. Planning for future development and investments requires that we prepare water projections for the future. However, estimations are complicated because the future of world's waters will be influenced by a combination of environmental, social, economic, and political factors, and there is only limited knowledge and data available about freshwater resources and how they are being used. The Water Futures and Solutions initiative (WFaS) coordinates its work with other on-going scenario efforts for the sake of establishing a consistent set of new global water scenarios based on the Shared Socioeconomic Pathways (SSPs) and the Representative Concentration Pathways (RCPs). The WFaS "fast-track" assessment uses three global water models, namely H08, PCR-GLOBWB, and WaterGAP. This study assesses the state of the art for estimating and projecting water use regionally and globally in a consistent manner. It provides an overview of different approaches, the uncertainty, strengths and weaknesses of the various estimation methods, types of management and policy decisions for which the current estimation methods are useful. We also discuss additional information most needed to be able to improve water use estimates and be able to assess a greater range of management options across the water-energy-climate nexus.

Pathways to sustainable intensification through crop water management

NASA Astrophysics Data System (ADS)

MacDonald, Graham K.; D'Odorico, Paolo; Seekell, David A.

2016-09-01

How much could farm water management interventions increase global crop production? This is the central question posed in a global modelling study by Jägermeyr et al (2016 Environ. Res. Lett. 11 025002). They define the biophysical realm of possibility for future gains in crop production related to agricultural water practices—enhancing water availability to crops and expanding irrigation by reducing non-productive water consumption. The findings of Jägermeyr et al offer crucial insight on the potential for crop water management to sustainably intensify agriculture, but they also provide a benchmark to consider the broader role of sustainable intensification targets in the global food system. Here, we reflect on how the global crop water management simulations of Jägermeyr et al could interact with: (1) farm size at more local scales, (2) downstream water users at the river basin scale, as well as (3) food trade and (4) demand-side food system strategies at the global scale. Incorporating such cross-scale linkages in future research could highlight the diverse pathways needed to harness the potential of farm-level crop water management for a more productive and sustainable global food system.

Global implementation of two shared socioeconomic pathways for future sanitation and wastewater flows.

PubMed

van Puijenbroek, P J T M; Bouwman, A F; Beusen, A H W; Lucas, P L

2015-01-01

Households are an important source of nutrient loading to surface water. Sewage systems without or with only primary wastewater treatment are major polluters of surface water. Future emission levels will depend on population growth, urbanisation, increases in income and investments in sanitation, sewage systems and wastewater treatment plants. This study presents the results for two possible shared socioeconomic pathways (SSPs). SSP1 is a scenario that includes improvement of wastewater treatment and SSP3 does not include such improvement, with fewer investments and a higher population growth. The main drivers for the nutrient emission model are population growth, income growth and urbanisation. Under the SSP1 scenario, 5.7 billion people will be connected to a sewage system and for SSP3 this is 5 billion. Nitrogen and phosphorus emissions increase by about 70% under both SSP scenarios, with the largest increase in SSP1. South Asia and Africa have the largest emission increases, in the developed countries decrease the nutrient emissions. The higher emission level poses a risk to ecosystem services.

Reactive nitrogen losses from China's food system for the shared socioeconomic pathways (SSPs).

PubMed

Wang, Mengru; Kroeze, Carolien; Strokal, Maryna; Ma, Lin

2017-12-15

Food production in China has been changing fast as a result of socio-economic development. This resulted in an increased use of nitrogen (N) in food production, and also to increased reactive nitrogen (Nr) losses to the environment, causing nitrogen pollution. Our study is the first to quantify future Nr losses from China's food system for the Shared Socio-economic Pathways (SSPs). We show that Nr losses differ largely among SSPs. We first qualitatively described the five SSP storylines for China with a focus on food production and consumption. Next, we interpreted these SSP scenarios quantitatively for 2030 and 2050, using the NUFER (NUtrient Flows in Food chains, Environment and Resources use) model to project the Nr losses from China's food system. The results indicate that Nr losses from future food system in China are relatively low for SSP1 and SSP2, and relatively high for SSP3 and SSP4. In SSP5 Nr losses from China's food system are projected to be slightly lower than the level of today. Copyright © 2017 Elsevier B.V. All rights reserved.

Beyond Earth's boundaries: Human exploration of the Solar System in the 21st Century

NASA Technical Reports Server (NTRS)

1991-01-01

This is an annual report describing work accomplished in developing the knowledge base that will permit informed recommendations and decisions concerning national space policy and the goal of human expansion into the solar system. The following topics are presented: (1) pathways to human exploration; (2) human exploration case studies; (3) case study results and assessment; (4) exploration program implementation strategy; (5) approach to international cooperation; (6) recommendations; and (7) future horizons.

Ensuring the availability of the nursing workforce through philanthropy: a case study.

PubMed

Bolton, Linda Burnes; Swanson, Jane; Zamora, Elizabeth

2014-01-01

The Institute of Medicine report on the Future of Nursing identified the need to increase the preparation of nurses, create pathways for nurses to lead as partners to improve health by promoting interprofessional education and practice, and to remove barriers to full practice of nurses across the continuum. This case study shares the experience of large systems and their creativity using philanthropy in their quest to ensure the availability of a qualified nursing workforce.

Enhanced Recovery after Urological Surgery: A Contemporary Systematic Review of Outcomes, Key Elements, and Research Needs.

PubMed

Azhar, Raed A; Bochner, Bernard; Catto, James; Goh, Alvin C; Kelly, John; Patel, Hiten D; Pruthi, Raj S; Thalmann, George N; Desai, Mihir

2016-07-01

Enhanced Recovery after Surgery (ERAS) programs are multimodal care pathways that aim to decrease intra-operative blood loss, decrease postoperative complications, and reduce recovery times. To overview the use and key elements of ERAS pathways, and define needs for future clinical trials. A comprehensive systematic MEDLINE search was performed for English language reports published before May 2015 using the terms "postoperative period," "postoperative care," "enhanced recovery after surgery," "enhanced recovery," "accelerated recovery," "fast track recovery," "recovery program," "recovery pathway", "ERAS," and "urology" or "cystectomy" or "urologic surgery." We identified 18 eligible articles. Patient counseling, physical conditioning, avoiding excessive alcohol and smoking, and good nutrition appeared to protect against postoperative complications. Fasting from solid food for only 6h and perioperative liquid-carbohydrate loading up to 2h prior to surgery appeared to be safe and reduced recovery times. Restricted, balanced, and goal-directed fluid replacement is effective when individualized, depending on patient morbidity and surgical procedure. Decreased intraoperative blood loss may be achieved by several measures. Deep vein thrombosis prophylaxis, antibiotic prophylaxis, and thermoregulation were found to help reduce postsurgical complications, as was a multimodal approach to postoperative nausea, vomiting, and analgesia. Chewing gum, prokinetic agents, oral laxatives, and an early resumption to normal diet appear to aid faster return to normal bowel function. Further studies should compare anesthetic protocols, refine analgesia, and evaluate the importance of robot-assisted surgery and the need/timing for drains and catheters. ERAS regimens are multidisciplinary, multimodal pathways that optimize postoperative recovery. This review provides an overview of the use and key elements of Enhanced Recovery after Surgery programs, which are multimodal, multidisciplinary care pathways that aim to optimize postoperative recovery. Additional conclusions include identifying effective procedures within Enhanced Recovery after Surgery programs and defining needs for future clinical trials. Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.

An assessment of molecular pathways of obesity susceptible to nutrient, toxicant and genetically induced epigenetic perturbation

PubMed Central

Xue, Jing; Ideraabdullah, Folami Y.

2015-01-01

In recent years, the etiology of human disease has greatly improved with the inclusion of epigenetic mechanisms, in particular as a common link between environment and disease. However, for most diseases we lack a detailed interpretation of the epigenetic regulatory pathways perturbed by environment and causal mechanisms. Here, we focus on recent findings elucidating nutrient-related epigenetic changes linked to obesity. We highlight studies demonstrating that obesity is a complex disease linked to disruption of epigenetically regulated metabolic pathways in the brain, adipose tissue and liver. These pathways regulate (1) homeostatic and hedonic eating behaviors (2) adipocyte differentiation and fat accumulation, and (3) energy expenditure. By compiling these data we illustrate that obesity-related phenotypes are repeatedly linked to disruption of critical epigenetic mechanisms that regulate of key metabolic genes. These data are supported by genetic mutation of key epigenetic regulators and many of the diet induced epigenetic mechanisms of obesity are also perturbed by exposure to environmental toxicants. Identifying similarly perturbed epigenetic mechanisms in multiple experimental models of obesity strengthens the translational applications of these findings. We also discuss many of the ongoing challenges to understanding the role of environmentally-induced epigenetic pathways in obesity and suggest future studies to elucidate these roles. This assessment illustrates our current understanding of molecular pathways of obesity that are susceptible to environmental perturbation via epigenetic mechanisms. Thus, it lays the groundwork for dissecting the complex interactions between diet, genes, and toxicants that contribute to obesity and obesity-related phenotypes. PMID:27012616

A bottom-up robust optimization framework for identifying river basin development pathways under deep climate uncertainty

NASA Astrophysics Data System (ADS)

Taner, M. U.; Ray, P.; Brown, C.

2016-12-01

Hydroclimatic nonstationarity due to climate change poses challenges for long-term water infrastructure planning in river basin systems. While designing strategies that are flexible or adaptive hold intuitive appeal, development of well-performing strategies requires rigorous quantitative analysis that address uncertainties directly while making the best use of scientific information on the expected evolution of future climate. Multi-stage robust optimization (RO) offers a potentially effective and efficient technique for addressing the problem of staged basin-level planning under climate change, however the necessity of assigning probabilities to future climate states or scenarios is an obstacle to implementation, given that methods to reliably assign probabilities to future climate states are not well developed. We present a method that overcomes this challenge by creating a bottom-up RO-based framework that decreases the dependency on probability distributions of future climate and rather employs them after optimization to aid selection amongst competing alternatives. The iterative process yields a vector of `optimal' decision pathways each under the associated set of probabilistic assumptions. In the final phase, the vector of optimal decision pathways is evaluated to identify the solutions that are least sensitive to the scenario probabilities and are most-likely conditional on the climate information. The framework is illustrated for the planning of new dam and hydro-agricultural expansions projects in the Niger River Basin over a 45-year planning period from 2015 to 2060.

Uncovering the immune responses of Apis mellifera ligustica larval gut to Ascosphaera apis infection utilizing transcriptome sequencing.

PubMed

Chen, Dafu; Guo, Rui; Xu, Xijian; Xiong, Cuiling; Liang, Qin; Zheng, Yanzhen; Luo, Qun; Zhang, Zhaonan; Huang, Zhijian; Kumar, Dhiraj; Xi, Weijun; Zou, Xuan; Liu, Min

2017-07-20

Honeybees are susceptible to a variety of diseases, including chalkbrood, which is capable of causing huge losses of both the number of bees and colony productivity. This research is designed to characterize the transcriptome profiles of Ascosphaera apis-treated and un-treated larval guts of Apis mellifera ligustica in an attempt to unravel the molecular mechanism underlying the immune responses of western honeybee larval guts to mycosis. In this study, 24, 296 and 2157 genes were observed to be differentially expressed in A. apis-treated Apis mellifera (4-, 5- and 6-day-old) compared with un-treated larval guts. Moreover, the expression patterns of differentially expressed genes (DEGs) were examined via trend analysis, and subsequently, gene ontology analysis and KEGG pathway enrichment analysis were conducted for DEGs involved in up- and down-regulated profiles. Immunity-related pathways were selected for further analysis, and our results demonstrated that a total of 13 and 50 DEGs were annotated in the humoral immune-related and cellular immune-related pathways, respectively. Additionally, we observed that many DEGs up-regulated in treated guts were part of cellular immune pathways, such as the lysosome, ubiquitin mediated proteolysis, and insect hormone biosynthesis pathways and were induced by A. apis invasion. However, more down-regulated DEGs were restrained. Surprisingly, a majority of DEGs within the Toll-like receptor signaling pathway, and the MAPK signaling pathway were up-regulated in treated guts, while all but two genes involved in the NF-κB signaling pathway were down-regulated, which suggested that most genes involved in humoral immune-related pathways were activated in response to the invasive fungal pathogen. This study's findings provide valuable information regarding the investigation of the molecular mechanism of immunity defenses of A. m. ligustica larval guts to infection with A. apis. Furthermore, these studies lay the groundwork for future researches on key genes controlling the susceptibility of A. m. ligustica larvae to chalkbrood. Copyright © 2017 Elsevier B.V. All rights reserved.

Gene–environment interaction in tobacco-related cancers

PubMed Central

Taioli, Emanuela

2008-01-01

This review summarizes the carcinogenic effects of tobacco smoke and the basis for interaction between tobacco smoke and genetic factors. Examples of published papers on gene–tobacco interaction and cancer risk are presented. The assessment of gene–environment interaction in tobacco-related cancers has been more complex than originally expected for several reasons, including the multiplicity of genes involved in tobacco metabolism, the numerous substrates metabolized by the relevant genes and the interaction of smoking with other metabolic pathways. Future studies on gene–environment interaction and cancer risk should include biomarkers of smoking dose, along with markers of quantitative historical exposure to tobacco. Epigenetic studies should be added to classic genetic analyses, in order to better understand gene–environmental interaction and individual susceptibility. Other metabolic pathways in competition with tobacco genetic metabolism/repair should be incorporated in epidemiological studies to generate a more complete picture of individual cancer risk associated with environmental exposure to carcinogens. PMID:18550573

Epigenetic regulation in human melanoma: past and future.

PubMed

Sarkar, Debina; Leung, Euphemia Y; Baguley, Bruce C; Finlay, Graeme J; Askarian-Amiri, Marjan E

2015-01-01

The development and progression of melanoma have been attributed to independent or combined genetic and epigenetic events. There has been remarkable progress in understanding melanoma pathogenesis in terms of genetic alterations. However, recent studies have revealed a complex involvement of epigenetic mechanisms in the regulation of gene expression, including methylation, chromatin modification and remodeling, and the diverse activities of non-coding RNAs. The roles of gene methylation and miRNAs have been relatively well studied in melanoma, but other studies have shown that changes in chromatin status and in the differential expression of long non-coding RNAs can lead to altered regulation of key genes. Taken together, they affect the functioning of signaling pathways that influence each other, intersect, and form networks in which local perturbations disturb the activity of the whole system. Here, we focus on how epigenetic events intertwine with these pathways and contribute to the molecular pathogenesis of melanoma.

Natural mentors, racial identity, and educational attainment among african american adolescents: exploring pathways to success.

PubMed

Hurd, Noelle M; Sánchez, Bernadette; Zimmerman, Marc A; Caldwell, Cleopatra H

2012-01-01

The present study explored how relationships with natural mentors may contribute to African American adolescents' long-term educational attainment by influencing adolescents' racial identity and academic beliefs. This study included 541 academically at-risk African American adolescents transitioning into adulthood. The mean age of participants at Time 1 was 17.8 (SD = .64) and slightly over half (54%) of study participants were female. Results of the current study indicated that relationships with natural mentors promoted more positive long-term educational attainment among participants through increased private regard (a dimension of racial identity) and stronger beliefs in the importance of doing well in school for future success. Implications of these findings and directions for future research are discussed. © 2012 The Authors. Child Development © 2012 Society for Research in Child Development, Inc.

Neurology of Learning Disabilities: What Will the Future Bring? The Answer Comes from the Successes of the Recent Past

ERIC Educational Resources Information Center

Galaburda, Albert M.

2005-01-01

Dyslexia may represent the first example of a LD whereby a possible pathway may link the observed behavior to an underlying neurological substrate that has a neurodevelopmental history beginning with an abnormal gene. Similar efforts are being made to link other cognitive disorders of development to a molecular pathway involved in brain…

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.

Anti–PD-1/PD-L1 therapy of human cancer: past, present, and future

PubMed Central

Chen, Lieping; Han, Xue

2015-01-01

Major progress has been made toward our understanding of the programmed death-1/programmed death ligand-1 (PD-1/PD-L1) pathway (referred to as the PD pathway). mAbs are already being used to block the PD pathway to treat human cancers (anti-PD therapy), especially advanced solid tumors. This therapy is based on principles that were discovered through basic research more than a decade ago, but the great potential of this pathway to treat a broad spectrum of advanced human cancers is just now becoming apparent. In this Review, we will briefly review the history and development of anti-PD therapy, from the original benchwork to the most up-to-date clinical results. We will then focus the discussion on three basic principles that define this unique therapeutic approach and highlight how anti-PD therapy is distinct from other immunotherapeutic approaches, namely tumor site immune modulation, targeting tumor-induced immune defects, and repairing ongoing (rather than generating de novo) tumor immunity. We believe that these fundamental principles set the standard for future immunotherapies and will guide our efforts to develop more efficacious and less toxic immune therapeutics to treat human cancers. PMID:26325035

PATIKA: an integrated visual environment for collaborative construction and analysis of cellular pathways.

PubMed

Demir, E; Babur, O; Dogrusoz, U; Gursoy, A; Nisanci, G; Cetin-Atalay, R; Ozturk, M

2002-07-01

Availability of the sequences of entire genomes shifts the scientific curiosity towards the identification of function of the genomes in large scale as in genome studies. In the near future, data produced about cellular processes at molecular level will accumulate with an accelerating rate as a result of proteomics studies. In this regard, it is essential to develop tools for storing, integrating, accessing, and analyzing this data effectively. We define an ontology for a comprehensive representation of cellular events. The ontology presented here enables integration of fragmented or incomplete pathway information and supports manipulation and incorporation of the stored data, as well as multiple levels of abstraction. Based on this ontology, we present the architecture of an integrated environment named Patika (Pathway Analysis Tool for Integration and Knowledge Acquisition). Patika is composed of a server-side, scalable, object-oriented database and client-side editors to provide an integrated, multi-user environment for visualizing and manipulating network of cellular events. This tool features automated pathway layout, functional computation support, advanced querying and a user-friendly graphical interface. We expect that Patika will be a valuable tool for rapid knowledge acquisition, microarray generated large-scale data interpretation, disease gene identification, and drug development. A prototype of Patika is available upon request from the authors.

Modifying an Insect Cell N-Glycan Processing Pathway Using CRISPR-Cas Technology.

PubMed

Mabashi-Asazuma, Hideaki; Kuo, Chu-Wei; Khoo, Kay-Hooi; Jarvis, Donald L

2015-10-16

Fused lobes (FDL) is an enzyme that simultaneously catalyzes a key trimming reaction and antagonizes elongation reactions in the insect N-glycan processing pathway. Accordingly, FDL function accounts, at least in part, for major differences in the N-glycosylation patterns of glycoproteins produced by insect and mammalian cells. In this study, we used the CRISPR-Cas9 system to edit the fdl gene in Drosophila melanogaster S2 cells. CRISPR-Cas9 editing produced a high frequency of site-specific nucleotide insertions and deletions, reduced the production of insect-type, paucimannosidic products (Man3GlcNAc2), and led to the production of partially elongated, mammalian-type complex N-glycans (GlcNAc2Man3GlcNAc2) in S2 cells. As CRISPR-Cas9 has not been widely used to analyze or modify protein glycosylation pathways or edit insect cell genes, these results underscore its broad utility as a tool for these purposes. Our results also confirm the key role of FDL at the major branch point distinguishing insect and mammalian N-glycan processing pathways. Finally, the new FDL-deficient S2 cell derivative produced in this study will enable future bottom-up glycoengineering efforts designed to isolate insect cell lines that can efficiently produce recombinant glycoproteins with chemically predefined oligosaccharide side-chain structures.

Signaling Pathways of ESE-16, an Antimitotic and Anticarbonic Anhydrase Estradiol Analog, in Breast Cancer Cells

PubMed Central

Stander, Barend Andre; Joubert, Fourie; Tu, Chingkuang; Sippel, Katherine H.; McKenna, Robert; Joubert, Annie Margaretha

2013-01-01

The aim of this study was to characterize the in vitro action of 2-ethyl-3-O-sulphamoyl-estra-1,3,5(10)16-tetraene (ESE-16) on non-tumorigenic MCF-12A, tumorigenic MCF-7 and metastatic MDA-MB-231 breast cancer cells. ESE-16 is able to inhibit the activity of a carbonic anhydrase II and a mimic of carbonic anhydrase IX in the nanomolar range. Gene and protein expression studies using various techniques including gene and antibody microarrays and various flow cytometry assays yielded valuable information about the mechanism of action of ESE-16. The JNK pathway was identified as an important pathway mediating the effects of ESE-16 while the p38 stress-induced pathway is more important in MDA-MB-231 cells exposed to ESE-16. Lysosomal rupture and iron metabolism was identified as important mediators of mitochondrial membrane depolarization. Abrogation of Bcl-2 phosphorylation status as a result of ESE-16 also plays a role in inducing mitochondrial membrane depolarization. The study provides a basis for future research projects to develop the newly synthesized compound into a clinically usable anticancer agent either alone or in combination with other agents. Keywords: Antimitotic, anticarbonic anhydrase IX, apoptosis, autophagy, cell cycle arrest, Bcl-2, JNK, p38, mitochondrial membrane depolarization, flow cytometry, gene expression and protein microarray, anticancer. PMID:23382857

Microarray Analysis of Long Noncoding RNAs in Female Diabetic Peripheral Neuropathy Patients.

PubMed

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

2018-01-01

Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes mellitus (DM). Because of its controversial pathogenesis, DPN is still not diagnosed or managed properly in most patients. In this study, human lncRNA microarrays were used to identify the differentially expressed lncRNAs in DM and DPN patients, and some of the discovered lncRNAs were further validated in additional 78 samples by quantitative realtime PCR (qRT-PCR). The microarray analysis identified 446 and 1327 differentially expressed lncRNAs in DM and DPN, respectively. The KEGG pathway analysis further revealed that the differentially expressed lncRNA-coexpressed mRNAs between DPN and DM groups were significantly enriched in the MAPK signaling pathway. The lncRNA/mRNA coexpression network indicated that BDNF and TRAF2 correlated with 6 lncRNAs. The qRT-PCR confirmed the initial microarray results. These findings demonstrated that the interplay between lncRNAs and mRNA may be involved in the pathogenesis of DPN, especially the neurotrophin-MAPK signaling pathway, thus providing relevant information for future studies. © 2018 The Author(s). Published by S. Karger AG, Basel.

Atmospheric origins of perchlorate on Mars and in the Atacama

NASA Astrophysics Data System (ADS)

Catling, D. C.; Claire, M. W.; Zahnle, K. J.; Quinn, R. C.; Clark, B. C.; Hecht, M. H.; Kounaves, S.

2010-01-01

Isotopic studies indicate that natural perchlorate is produced on Earth in arid environments by the oxidation of chlorine species through pathways involving ozone or its photochemical products. With this analogy, we propose that the arid environment on Mars may have given rise to perchlorate through the action of atmospheric oxidants. A variety of hypothetical pathways can be proposed including photochemical reactions, electrostatic discharge, and gas-solid reactions. Because perchlorate-rich deposits in the Atacama desert are closest in abundance to perchlorate measured at NASA's Phoenix Lander site, we made a preliminary study of the means to produce Atacama perchlorate to help shed light on the origin of Martian perchlorate. We investigated gas phase pathways using a 1-D photochemical model. We found that perchlorate can be produced in sufficient quantities to explain the abundance of perchlorate in the Atacama from a proposed gas phase oxidation of chlorine volatiles to perchloric acid. The feasibility of gas phase production for the Atacama provides justification for future investigations of gas phase photochemistry as a possible source for Martian perchlorate.

Developmental pathways to autism: A review of prospective studies of infants at risk☆

PubMed Central

Jones, Emily J.H.; Gliga, Teodora; Bedford, Rachael; Charman, Tony; Johnson, Mark H.

2014-01-01

Autism Spectrum Disorders (ASDs) are neurodevelopmental disorders characterized by impairments in social interaction and communication, and the presence of restrictive and repetitive behaviors. Symptoms of ASD likely emerge from a complex interaction between pre-existing neurodevelopmental vulnerabilities and the child's environment, modified by compensatory skills and protective factors. Prospective studies of infants at high familial risk for ASD (who have an older sibling with a diagnosis) are beginning to characterize these developmental pathways to the emergence of clinical symptoms. Here, we review the range of behavioral and neurocognitive markers for later ASD that have been identified in high-risk infants in the first years of life. We discuss theoretical implications of emerging patterns, and identify key directions for future work, including potential resolutions to several methodological challenges for the field. Mapping how ASD unfolds from birth is critical to our understanding of the developmental mechanisms underlying this disorder. A more nuanced understanding of developmental pathways to ASD will help us not only to identify children who need early intervention, but also to improve the range of interventions available to them. PMID:24361967

Wellbeing in the aftermath of floods.

PubMed

Walker-Springett, Kate; Butler, Catherine; Adger, W Neil

2017-01-01

The interactions between flood events, their aftermath, and recovery leading to health and wellbeing outcomes for individuals are complex, and the pathways and mechanisms through which wellbeing is affected are often hidden and remain under-researched. This study analyses the diverse processes that explain changes in wellbeing for those experiencing flooding. It identifies key pathways to wellbeing outcomes that concern perceptions of lack of agency, dislocation from home, and disrupted futures inducing negative impacts, with offsetting positive effects through community networks and interactions. The mixed method study is based on data from repeated qualitative semi-structured interviews (n=60) and a structured survey (n=1000) with individuals that experienced flooding directly during winter 2013/14 in two UK regions. The results show for the first time the diversity and intersection of pathways to wellbeing outcomes in the aftermath of floods. The findings suggest that enhanced public health planning and interventions could focus on the precise practices and mechanisms that intersect to produce anxiety, stress, and their amelioration at individual and community levels. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Dimensions of Racism and their Impact on Partner Selection among Men who have Sex with Men of Colour: Understanding Pathways to Sexual Risk

PubMed Central

Ayala, George; Paul, Jay; Choi, Kyung-Hee

2013-01-01

While many studies have established the relationship between experiences of racism and sexual risk among men who have sex with men of colour, the pathways by which this occurs are underdeveloped. To address this gap, we must better investigate the lived realities of racism in the gay community. In this study, we had the unique opportunity to examine experiences of racism among African American, Latino and Asian/Pacific Islander men who have sex with men living in Los Angeles through focus groups and individual in-depth interviews. We found three themes of racism: exclusion from West Hollywood and the mainstream gay community, sexual rejection based on race/ethnicity, and sexual stereotypes. There were differences across the three racial groups in the experiences of each theme, however. We then considered how racism impacted partner selection and found that race played a salient role in determining power differentials within mixed-race partnerships. Finally, we discussed several future areas for research that can better establish pathways between racism and sexual risk. PMID:23659363

Dimensions of racism and their impact on partner selection among men of colour who have sex with men: understanding pathways to sexual risk.

PubMed

Ro, Annie; Ayala, George; Paul, Jay; Choi, Kyung-Hee

2013-01-01

While many studies have established the relationship between experiences of racism and sexual risk among men of colour who have sex with men, the pathways by which this occurs are underdeveloped. To address this gap, we must better investigate the lived realities of racism in the gay community. In this study, we had the unique opportunity to examine experiences of racism among African American, Asian/Pacific Islander and Latino men who have sex with men living in Los Angeles through focus groups and individual in-depth interviews. We found three themes of racism: exclusion from West Hollywood and the mainstream gay community, sexual rejection based on race/ethnicity and sexual stereotypes. There were differences across the three racial groups in the experiences of each theme, however. We then considered how racism impacted partner selection and found that race played a salient role in determining power differentials within mixed-race partnerships. Finally, we discussed several future areas for research that can better establish pathways between racism and sexual risk.

The potential of targeting Ras proteins in lung cancer.

PubMed

McCormick, Frank

2015-04-01

The Ras pathway is a major driver in lung adenocarcinoma: over 75% of all cases harbor mutations that activate this pathway. While spectacular clinical successes have been achieved by targeting activated receptor tyrosine kinases in this pathway, little, if any, significant progress has been achieved targeting Ras proteins themselves or cancers driven by oncogenic Ras mutants. New approaches to drug discovery, new insights into Ras function, new ways of attacking undruggable proteins through RNA interference and new ways of harnessing the immune system could change this landscape in the relatively near future.

Unconventional Aqueous Humor Outflow: A Review

PubMed Central

Johnson, Mark; McLaren, Jay W.; Overby, Darryl R.

2016-01-01

Aqueous humor flows out of the eye primarily through the conventional outflow pathway that includes the trabecular meshwork and Schlemm's canal. However, a fraction of aqueous humor passes through an alternative or ‘unconventional’ route that includes the ciliary muscle, supraciliary and suprachoroidal spaces. From there, unconventional outflow may drain through two pathways: a uveoscleral pathway where aqueous drains across the sclera to be resorbed by orbital vessels, and a uveovortex pathway where aqueous humor enters the choroid to drain through the vortex veins. We review the anatomy, physiology and pharmacology of these pathways. We also discuss methods to determine unconventional outflow rate, including direct techniques that use radioactive or fluorescent tracers recovered from tissues in the unconventional pathway and indirect methods that estimate unconventional outflow based on total outflow over a range of pressures. Indirect methods are subject to a number of assumptions and generally give poor agreement with tracer measurements. We review the variety of animal models that have been used to study conventional and unconventional outflow. The mouse appears to be a promising model because it captures several aspects of conventional and unconventional outflow dynamics common to humans, although questions remain regarding the magnitude of unconventional outflow in mice. Finally, we review future directions. There is a clear need to develop improved methods for measuring unconventional outflow in both animals and humans. PMID:26850315

The Arabidopsis endoplasmic reticulum associated degradation pathways are involved in the regulation of heat stress response

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

Li, Lin-Mao; University of Chinese Academy of Sciences, Beijing; Lü, Shi-You

Abstracts: The Cytosolic Protein Response (CPR) in the cytosol and the Unfolded Protein Response (UPR) and ER-associated degradation (ERAD) in the endoplasmic reticulum are major pathways of the cellular proteostasis network. However, despite years of effort, how these protein quality control systems coordinated in vivo remains largely unknown, particularly in plants. In this study, the roles of two evolutionarily conserved ERAD pathways (DOA10 and HRD1) in heat stress response were investigated through reverse genetic approaches in Arabidopsis. Phenotypic analysis of the mutants showed that the two ERAD pathways additively play negative roles in heat tolerance, which was demonstrated by higher survivalmore » rate and lower electrolyte leakage in the loss of function mutants compared to the wild type plants. Importantly, gene expression analysis revealed that the mutant plants showed elevated transcriptional regulation of several downstream genes, including those encoding CPR and UPR marker genes, under both basal and heat stress conditions. Finally, multiple components of ERAD genes exhibited rapid response to increasing temperature. Taken together, our data not only unravels key insights into the crosstalk between different protein quality control processes, but also provides candidate genes to genetically improve plant heat tolerance in the future. - Highlights: • ERAD pathways cooperatively regulate plant thermotolerance. • ERAD pathways cooperatively regulate UPR and CPR. • ERAD components gene expression are upregulated by heat stress.« less

Spatially resolved estimation of ozone-related mortality in the United States under two representative concentration pathways (RCPs) and their uncertainty

DOE PAGES

Kim, Young-Min; Zhou, Ying; Gao, Yang; ...

2014-11-16

We report that the spatial pattern of the uncertainty in air pollution-related health impacts due to climate change has rarely been studied due to the lack of high-resolution model simulations, especially under the Representative Concentration Pathways (RCPs), the latest greenhouse gas emission pathways. We estimated future tropospheric ozone (O 3) and related excess mortality and evaluated the associated uncertainties in the continental United States under RCPs. Based on dynamically downscaled climate model simulations, we calculated changes in O 3 level at 12 km resolution between the future (2057 and 2059) and base years (2001–2004) under a low-to-medium emission scenario (RCP4.5)more » and a fossil fuel intensive emission scenario (RCP8.5). We then estimated the excess mortality attributable to changes in O 3. Finally, we analyzed the sensitivity of the excess mortality estimates to the input variables and the uncertainty in the excess mortality estimation using Monte Carlo simulations. O 3-related premature deaths in the continental U.S. were estimated to be 1312 deaths/year under RCP8.5 (95 % confidence interval (CI): 427 to 2198) and ₋2118 deaths/year under RCP4.5 (95 % CI: ₋3021 to ₋1216), when allowing for climate change and emissions reduction. The uncertainty of O 3-related excess mortality estimates was mainly caused by RCP emissions pathways. Finally, excess mortality estimates attributable to the combined effect of climate and emission changes on O 3 as well as the associated uncertainties vary substantially in space and so do the most influential input variables. Spatially resolved data is crucial to develop effective community level mitigation and adaptation policy.« less

Spatially resolved estimation of ozone-related mortality in the United States under two representative concentration pathways (RCPs) and their uncertainty

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

Kim, Young-Min; Zhou, Ying; Gao, Yang

We report that the spatial pattern of the uncertainty in air pollution-related health impacts due to climate change has rarely been studied due to the lack of high-resolution model simulations, especially under the Representative Concentration Pathways (RCPs), the latest greenhouse gas emission pathways. We estimated future tropospheric ozone (O 3) and related excess mortality and evaluated the associated uncertainties in the continental United States under RCPs. Based on dynamically downscaled climate model simulations, we calculated changes in O 3 level at 12 km resolution between the future (2057 and 2059) and base years (2001–2004) under a low-to-medium emission scenario (RCP4.5)more » and a fossil fuel intensive emission scenario (RCP8.5). We then estimated the excess mortality attributable to changes in O 3. Finally, we analyzed the sensitivity of the excess mortality estimates to the input variables and the uncertainty in the excess mortality estimation using Monte Carlo simulations. O 3-related premature deaths in the continental U.S. were estimated to be 1312 deaths/year under RCP8.5 (95 % confidence interval (CI): 427 to 2198) and ₋2118 deaths/year under RCP4.5 (95 % CI: ₋3021 to ₋1216), when allowing for climate change and emissions reduction. The uncertainty of O 3-related excess mortality estimates was mainly caused by RCP emissions pathways. Finally, excess mortality estimates attributable to the combined effect of climate and emission changes on O 3 as well as the associated uncertainties vary substantially in space and so do the most influential input variables. Spatially resolved data is crucial to develop effective community level mitigation and adaptation policy.« less

Deregulation of the COP9 signalosome-cullin-RING ubiquitin-ligase pathway: mechanisms and roles in urological cancers.

PubMed

Gummlich, Linda; Rabien, Anja; Jung, Klaus; Dubiel, Wolfgang

2013-07-01

The COP9 signalosome (CSN)-cullin-RING ubiquitin (Ub)-ligase (CRL) pathway is a prominent segment of the Ub proteasome system (UPS). It specifically ubiquitinates proteins and targets them for proteolytic elimination. As part of the UPS it maintains essential cellular processes including cell cycle progression, DNA repair, antigen processing and signal transduction. The CSN-CRL pathway consists of the CSN possessing eight subunits (CSN1-CSN8) and one CRL consisting of a cullin, a RING-domain protein and a substrate recognition subunit (SRS). In human cells approximately 250 CRLs exist each of which interacting with a specific set of substrates and the CSN. The CSN-CRL interplay determines the activity and specificity of CRL ubiquitination. The removal of the Ub-like protein Nedd8 from the CRL component cullin by the CSN (deneddylation) reduces the ubiquitinating activity and at the same time enables reassembly of CRLs in order to adapt to substrate specificity requirements. On the other hand, CRLs as well as substrates negatively influence the deneddylating activity of the CSN. In recent years evidence accumulated that deregulation of the CSN-CRL pathway can cause cancer. Here we review current knowledge on modifications of CSN and CRL components including CSN subunits, SRSs and cullins causing tumorigenesis with emphasis on urological neoplasia. The CSN-CRL pathway is a target of tumor-viruses as well as of a multitude of miRNAs. Recently evaluated miRNAs altered in urological cancers might have impact on the CSN-CRL pathway which has to be analyzed in future experiments. We propose that the pathway is a suitable target for future tumor therapy. Copyright © 2013 Elsevier Ltd. All rights reserved.

Oral narrative skills: Explaining the language-emergent literacy link by race/ethnicity and SES.

PubMed

Gardner-Neblett, Nicole; Iruka, Iheoma U

2015-07-01

Although children's early language skills have been found to predict literacy outcomes, little is known about the role of preschool oral narrative skills in the pathway between language and emergent literacy or how these associations differ by race/ethnicity and socioeconomic status. The current study uses the Early Childhood Longitudinal Study to explore how language at age 2 is associated with narrative skills at age 4 and emergent literacy outcomes at age 5 for a nationally representative sample of children. Findings demonstrate that early language is associated with narrative skills for most children. Oral narrative skills were found to mediate the pathway between early language and kindergarten emergent literacy for poor and nonpoor African American children. Implications for children's literacy development and future research are discussed. (c) 2015 APA, all rights reserved).

Climate change and growth scenarios for California wildfire

Treesearch

A.L. Westerling; B.P. Bryant; H.K. Preisler; T.P. Holmes; H.G. Hildalgo; T. Das; S.R. Shrestha

2011-01-01

Large wildfire occurrence and burned area are modeled using hydroclimate and landsurface characteristics under a range of future climate and development scenarios. The range of uncertainty for future wildfire regimes is analyzed over two emissions pathways (the Special Report on Emissions Scenarios [SRES] A2 and B1 scenarios); three global climate models (Centre...

Impacts of climate changes on ocean surface gravity waves over the eastern Canadian shelf

NASA Astrophysics Data System (ADS)

Guo, Lanli; Sheng, Jinyu

2017-05-01

A numerical study is conducted to investigate the impact of climate changes on ocean surface gravity waves over the eastern Canadian shelf (ECS). The "business-as-usual" climate scenario known as Representative Concentration Pathway RCP8.5 is considered in this study. Changes in the ocean surface gravity waves over the study region for the period 1979-2100 are examined based on 3 hourly ocean waves simulated by the third-generation ocean wave model known as WAVEWATCHIII. The wave model is driven by surface winds and ice conditions produced by the Canadian Regional Climate Model (CanRCM4). The whole study period is divided into the present (1979-2008), near future (2021-2050) and far future (2071-2100) periods to quantify possible future changes of ocean waves over the ECS. In comparison with the present ocean wave conditions, the time-mean significant wave heights ( H s ) are expected to increase over most of the ECS in the near future and decrease over this region in the far future period. The time-means of the annual 5% largest H s are projected to increase over the ECS in both near and far future periods due mainly to the changes in surface winds. The future changes in the time-means of the annual 5% largest H s and 10-m wind speeds are projected to be twice as strong as the changes in annual means. An analysis of inverse wave ages suggests that the occurrence of wind seas is projected to increase over the southern Labrador and central Newfoundland Shelves in the near future period, and occurrence of swells is projected to increase over other areas of the ECS in both the near and far future periods.

Training in metabolomics research. II. Processing and statistical analysis of metabolomics data, metabolite identification, pathway analysis, applications of metabolomics and its future.

PubMed

Barnes, Stephen; Benton, H Paul; Casazza, Krista; Cooper, Sara J; Cui, Xiangqin; Du, Xiuxia; Engler, Jeffrey; Kabarowski, Janusz H; Li, Shuzhao; Pathmasiri, Wimal; Prasain, Jeevan K; Renfrow, Matthew B; Tiwari, Hemant K

2016-08-01

Metabolomics, a systems biology discipline representing analysis of known and unknown pathways of metabolism, has grown tremendously over the past 20 years. Because of its comprehensive nature, metabolomics requires careful consideration of the question(s) being asked, the scale needed to answer the question(s), collection and storage of the sample specimens, methods for extraction of the metabolites from biological matrices, the analytical method(s) to be employed and the quality control of the analyses, how collected data are correlated, the statistical methods to determine metabolites undergoing significant change, putative identification of metabolites and the use of stable isotopes to aid in verifying metabolite identity and establishing pathway connections and fluxes. This second part of a comprehensive description of the methods of metabolomics focuses on data analysis, emerging methods in metabolomics and the future of this discipline. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Exploring the Climate Change, Migration and Conflict Nexus.

PubMed

Burrows, Kate; Kinney, Patrick L

2016-04-22

The potential link between climate change, migration, and conflict has been widely discussed and is increasingly viewed by policy makers as a security issue. However, considerable uncertainty remains regarding the role that climate variability and change play among the many drivers of migration and conflict. The overall objective of this paper is to explore the potential pathways linking climate change, migration and increased risk of conflict. We review the existing literature surrounding this issue and break the problem into two components: the links between climate change and migration, and those between migration and conflict. We found a large range of views regarding the importance of climate change as a driver for increasing rates of migration and subsequently of conflict. We argue that future research should focus not only on the climate-migration-conflict pathway but also work to understand the other pathways by which climate variability and change might exacerbate conflict. We conclude by proposing five questions to help guide future research on the link between climate change, migration, and conflict.

Exploring the Climate Change, Migration and Conflict Nexus

PubMed Central

Burrows, Kate; Kinney, Patrick L.

2016-01-01

The potential link between climate change, migration, and conflict has been widely discussed and is increasingly viewed by policy makers as a security issue. However, considerable uncertainty remains regarding the role that climate variability and change play among the many drivers of migration and conflict. The overall objective of this paper is to explore the potential pathways linking climate change, migration and increased risk of conflict. We review the existing literature surrounding this issue and break the problem into two components: the links between climate change and migration, and those between migration and conflict. We found a large range of views regarding the importance of climate change as a driver for increasing rates of migration and subsequently of conflict. We argue that future research should focus not only on the climate-migration-conflict pathway but also work to understand the other pathways by which climate variability and change might exacerbate conflict. We conclude by proposing five questions to help guide future research on the link between climate change, migration, and conflict. PMID:27110806

TRWG developmental pathway for biospecimen-based assessment modalities

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

Translational Research Working Group; Srivastava, Sudhir; Gray, Joe W.

The Translational Research Working Group (TRWG) was created as a national initiative to evaluate the current status of NCI's investment in translational research and envision its future. The TRWG conceptualized translational research as a set of six developmental processes or pathways focused on various clinical goals. One of those pathways describes the development of biospecimen-based assays that utilize biomarkers for the detection, diagnosis, prognosis, and assessment of response to cancer treatment. The biospecimen-based assessment modality (BM) pathway was conceived not as comprehensive description of the corresponding real-world processes, but rather as a tool designed to facilitate movement of a candidatemore » assay through the translational process to the point where it can be handed off for definitive clinical testing. This paper introduces the pathway in the context of prior work and discusses key challenges associated with the biomarker development process in light of the pathway.« less

Projected changes of the southwest Australian wave climate under two atmospheric greenhouse gas concentration pathways

NASA Astrophysics Data System (ADS)

Wandres, Moritz; Pattiaratchi, Charitha; Hemer, Mark A.

2017-09-01

Incident wave energy flux is responsible for sediment transport and coastal erosion in wave-dominated regions such as the southwestern Australian (SWA) coastal zone. To evaluate future wave climates under increased greenhouse gas concentration scenarios, past studies have forced global wave simulations with wind data sourced from global climate model (GCM) simulations. However, due to the generally coarse spatial resolution of global climate and wave simulations, the effects of changing offshore wave conditions and sea level rise on the nearshore wave climate are still relatively unknown. To address this gap of knowledge, we investigated the projected SWA offshore, shelf, and nearshore wave climate under two potential future greenhouse gas concentration trajectories (representative concentration pathways RCP4.5 and RCP8.5). This was achieved by downscaling an ensemble of global wave simulations, forced with winds from GCMs participating in the Coupled Model Inter-comparison Project (CMIP5), into two regional domains, using the Simulating WAves Nearshore (SWAN) wave model. The wave climate is modeled for a historical 20-year time slice (1986-2005) and a projected future 20-year time-slice (2081-2100) for both scenarios. Furthermore, we compare these scenarios to the effects of considering sea-level rise (SLR) alone (stationary wave climate), and to the effects of combined SLR and projected wind-wave change. Results indicated that the SWA shelf and nearshore wave climate is more sensitive to changes in offshore mean wave direction than offshore wave heights. Nearshore, wave energy flux was projected to increase by ∼10% in exposed areas and decrease by ∼10% in sheltered areas under both climate scenarios due to a change in wave directions, compared to an overall increase of 2-4% in offshore wave heights. With SLR, the annual mean wave energy flux was projected to increase by up to 20% in shallow water (< 30 m) as a result of decreased wave dissipation. In winter months, the longshore wave energy flux, which is responsible for littoral drift, is expected to increase by up to 39% (62%) under the RCP4.5 (RCP8.5) greenhouse gas concentration pathway with SLR. The study highlights the importance of using high-resolution wave simulations to evaluate future regional wave climates, since the coastal wave climate is more responsive to changes in wave direction and sea level than offshore wave heights.

Synergy and Interactions Among Biological Pathways Leading to Preterm Premature Rupture of Membranes

PubMed Central

Lannon, Sophia M. R.; Vanderhoeven, Jeroen P.; Eschenbach, David A.; Gravett, Michael G.; Waldorf, Kristina M. Adams

2014-01-01

Preterm premature rupture of membranes (PPROM) occurs in 1% to 2% of births. Impact of PPROM is greatest in low- and middle-income countries where prematurity-related deaths are most common. Recent investigations identify cytokine and matrix metalloproteinase activation, oxidative stress, and apoptosis as primary pathways to PPROM. These biological processes are initiated by heterogeneous etiologies including infection/inflammation, placental bleeding, uterine overdistention, and genetic polymorphisms. We hypothesize that pathways to PPROM overlap and act synergistically to weaken membranes. We focus our discussion on membrane composition and strength, pathways linking risk factors to membrane weakening, and future research directions to reduce the global burden of PPROM. PMID:24840939

The suppression of apoptosis by α-herpesvirus

PubMed Central

You, Yu; Cheng, An-Chun; Wang, Ming-Shu; Jia, Ren-Yong; Sun, Kun-Feng; Yang, Qiao; Wu, Ying; Zhu, Dekang; Chen, Shun; Liu, Ma-Feng; Zhao, Xin-Xin; Chen, Xiao-Yue

2017-01-01

Apoptosis, an important innate immune mechanism that eliminates pathogen-infected cells, is primarily triggered by two signalling pathways: the death receptor pathway and the mitochondria-mediated pathway. However, many viruses have evolved various strategies to suppress apoptosis by encoding anti-apoptotic factors or regulating apoptotic signalling pathways, which promote viral propagation and evasion of the host defence. During its life cycle, α-herpesvirus utilizes an elegant multifarious anti-apoptotic strategy to suppress programmed cell death. This progress article primarily focuses on the current understanding of the apoptosis-inhibition mechanisms of α-herpesvirus anti-apoptotic genes and their expression products and discusses future directions, including how the anti-apoptotic function of herpesvirus could be targeted therapeutically. PMID:28406478

Role of the Wnt/β-catenin pathway in gastric cancer: An in-depth literature review

PubMed Central

Chiurillo, Miguel Angel

2015-01-01

Gastric cancer remains one of the most common cancers worldwide and one of the leading cause for cancer-related deaths. Gastric adenocarcinoma is a multifactorial disease that is genetically, cytologically and architecturally more heterogeneous than other gastrointestinal carcinomas. The aberrant activation of the Wnt/β-catenin signaling pathway is involved in the development and progression of a significant proportion of gastric cancer cases. This review focuses on the participation of the Wnt/β-catenin pathway in gastric cancer by offering an analysis of the relevant literature published in this field. Indeed, it is discussed the role of key factors in Wnt/β-catenin signaling and their downstream effectors regulating processes involved in tumor initiation, tumor growth, metastasis and resistance to therapy. Available data indicate that constitutive Wnt signalling resulting from Helicobacter pylori infection and inactivation of Wnt inhibitors (mainly by inactivating mutations and promoter hypermethylation) play an important role in gastric cancer. Moreover, a number of recent studies confirmed CTNNB1 and APC as driver genes in gastric cancer. The identification of specific membrane, intracellular, and extracellular components of the Wnt pathway has revealed potential targets for gastric cancer therapy. High-throughput “omics” approaches will help in the search for Wnt pathway antagonist in the near future. PMID:25992323

An examination of the divergent general, specific, and other criminogenic risk/needs across neuropathic and psychopathic pathways to homicide.

PubMed

Gilligan, D G; Lennings, C J

2011-08-01

The social learning theory underlying Andrews and Bonta's Psychology of Criminal Conduct model has generally been seen as guiding risk assessment, with good relevance to mentally ill as well as non-mentally ill offenders. The current study reports a novel approach to qualitative assessment of 26 murderers found not guilty by reason of insanity (NGRI), divided into two groups--neuropathic offenders characterised by frontal lobe deficits and psychosis and psychopathic murderers characterised by high scores on psychopathy and an absence of neuropathic factors. The findings of the present research support the notion that the two pathways are embedded in two diverging theoretical frameworks of psychopathology and social learning theory, with each corresponding to the neuropathic and psychopathic pathways, respectively. Models of social learning theory may have limited utility to the total mentally disordered offender population overall as they apply more specifically to offenders within special offender groups or perhaps more specifically to offenders with psychopathic characteristics. However, the significantly greater association of the other social, physical, and mental health risk/needs with the neuropathic pathway suggests that pathological models are important for understanding the neuropathic pathway in relation to homicide offence and risk of future violence in NGRI samples.

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

PubMed Central

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

2016-01-01

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

Review on Abyssomicins: Inhibitors of the Chorismate Pathway and Folate Biosynthesis.

PubMed

Sadaka, Carmen; Ellsworth, Edmund; Hansen, Paul Robert; Ewin, Richard; Damborg, Peter; Watts, Jeffrey L

2018-06-06

Antifolates targeting folate biosynthesis within the shikimate-chorismate-folate metabolic pathway are ideal and selective antimicrobials, since higher eukaryotes lack this pathway and rely on an exogenous source of folate. Resistance to the available antifolates, inhibiting the folate pathway, underlines the need for novel antibiotic scaffolds and molecular targets. While para-aminobenzoic acid synthesis within the chorismate pathway constitutes a novel molecular target for antifolates, abyssomicins are its first known natural inhibitors. This review describes the abyssomicin family, a novel spirotetronate polyketide Class I antimicrobial. It summarizes synthetic and biological studies, structural, biosynthetic, and biological properties of the abyssomicin family members. This paper aims to explain their molecular target, mechanism of action, structure⁻activity relationship, and to explore their biological and pharmacological potential. Thirty-two natural abyssomicins and numerous synthetic analogues have been reported. The biological activity of abyssomicins includes their antimicrobial activity against Gram-positive bacteria and mycobacteria, antitumor properties, latent human immunodeficiency virus (HIV) reactivator, anti-HIV and HIV replication inducer properties. Their antimalarial properties have not been explored yet. Future analoging programs using the structure⁻activity relationship data and synthetic approaches may provide a novel abyssomicin structure that is active and devoid of cytotoxicity. Abyssomicin J and atrop- o -benzyl-desmethylabyssomicin C constitute promising candidates for such programs.

Forecasting civil conflict along the shared socioeconomic pathways

DOE PAGES

Hegre, Håvard; Buhaug, Halvard; Calvin, Katherine V.; ...

2016-04-25

Climate change and armed civil conflict are both linked to socioeconomic development, although conditions that facilitate peace may not necessarily facilitate mitigation and adaptation to climate change. While economic growth lowers the risk of conflict, it is generally associated with increased greenhouse gas emissions and costs of climate mitigation policies. Here, this study investigates the links between growth, climate change, and conflict by simulating future civil conflict using new scenario data for five alternative socioeconomic pathways with different mitigation and adaptation assumptions, known as the shared socioeconomic pathways (SSPs). We develop a statistical model of the historical effect of keymore » socioeconomic variables on country-specific conflict incidence, 1960–2013. We then forecast the annual incidence of conflict, 2014–2100, along the five SSPs. We find that SSPs with high investments in broad societal development are associated with the largest reduction in conflict risk. This is most pronounced for the least developed countries—poverty alleviation and human capital investments in poor countries are much more effective instruments to attain global peace and stability than further improvements to wealthier economies. Moreover, the SSP that describes a sustainability pathway, which poses the lowest climate change challenges, is as conducive to global peace as the conventional development pathway.« less

Forecasting civil conflict along the shared socioeconomic pathways

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

Hegre, Håvard; Buhaug, Halvard; Calvin, Katherine V.

Climate change and armed civil conflict are both linked to socioeconomic development, although conditions that facilitate peace may not necessarily facilitate mitigation and adaptation to climate change. While economic growth lowers the risk of conflict, it is generally associated with increased greenhouse gas emissions and costs of climate mitigation policies. Here, this study investigates the links between growth, climate change, and conflict by simulating future civil conflict using new scenario data for five alternative socioeconomic pathways with different mitigation and adaptation assumptions, known as the shared socioeconomic pathways (SSPs). We develop a statistical model of the historical effect of keymore » socioeconomic variables on country-specific conflict incidence, 1960–2013. We then forecast the annual incidence of conflict, 2014–2100, along the five SSPs. We find that SSPs with high investments in broad societal development are associated with the largest reduction in conflict risk. This is most pronounced for the least developed countries—poverty alleviation and human capital investments in poor countries are much more effective instruments to attain global peace and stability than further improvements to wealthier economies. Moreover, the SSP that describes a sustainability pathway, which poses the lowest climate change challenges, is as conducive to global peace as the conventional development pathway.« less

Identifying viable regulatory and innovation pathways for regenerative medicine: a case study of cultured red blood cells.

PubMed

Mittra, J; Tait, J; Mastroeni, M; Turner, M L; Mountford, J C; Bruce, K

2015-01-25

The creation of red blood cells for the blood transfusion markets represents a highly innovative application of regenerative medicine with a medium term (5-10 year) prospect for first clinical studies. This article describes a case study analysis of a project to derive red blood cells from human embryonic stem cells, including the systemic challenges arising from (i) the selection of appropriate and viable regulatory protocols and (ii) technological constraints related to stem cell manufacture and scale up to clinical Good Manufacturing Practice (GMP) standard. The method used for case study analysis (Analysis of Life Science Innovation Systems (ALSIS)) is also innovative, demonstrating a new approach to social and natural science collaboration to foresight product development pathways. Issues arising along the development pathway include cell manufacture and scale-up challenges, affected by regulatory demands emerging from the innovation ecosystem (preclinical testing and clinical trials). Our discussion reflects on the efforts being made by regulators to adapt the current pharmaceuticals-based regulatory model to an allogeneic regenerative medicine product and the broader lessons from this case study for successful innovation and translation of regenerative medicine therapies, including the role of methodological and regulatory innovation in future development in the field. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.

Inhibition of PI3-kinase-Akt pathway enhances dexamethasone-induced apoptosis in a human follicular lymphoma cell line.

PubMed

Nuutinen, Ulla; Postila, Ville; Mättö, Mikko; Eeva, Jonna; Ropponen, Antti; Eray, Mine; Riikonen, Pekka; Pelkonen, Jukka

2006-02-01

Glucocorticoids are commonly used in the treatment of various lymphoid malignancies. In the present study, we show that dexamethasone (Dex) induced depolarization of mitochondrial membrane, release of cytochrome c and DNA fragmentation in a human follicular lymphoma cell line, HF28RA. New protein synthesis was required before Dex-induced mitochondrial changes, and the kinetics of the apoptotic events correlated with the upregulation of the Bim protein. Furthermore, we studied whether specific inhibitors of known survival pathways would potentiate Dex-induced apoptosis. Our results show that inhibition of PKC and ERK pathways had no effect on apoptosis. In contrast, inhibition of PI3-kinase or Akt markedly enhanced Dex-induced apoptosis. The enhancement was seen at the mitochondrial level, and the kinetics of apoptosis was notably accelerated. In addition, inhibition of PI3-kinase did not alter levels of Bax, Bcl-2, Bcl-X(L) or Bim proteins in mitochondria but caused translocation of the pro-apoptotic protein Bad to mitochondria. However, inhibition of PI3-kinase-Akt pathway and subsequent translocation of Bad to mitochondria did not induce apoptosis itself. Based on these results and our current understanding of Bim and Bad action, it seems that both proteins play a synergistic role in this process. Thus, these results indicate that inhibitors of PI3-kinase-Akt pathway might be combined in future with glucocorticoids to improve the treatment of lymphoid malignancies.

Phylogenetic Origin and Diversification of RNAi Pathway Genes in Insects.

PubMed

Dowling, Daniel; Pauli, Thomas; Donath, Alexander; Meusemann, Karen; Podsiadlowski, Lars; Petersen, Malte; Peters, Ralph S; Mayer, Christoph; Liu, Shanlin; Zhou, Xin; Misof, Bernhard; Niehuis, Oliver

2016-12-01

RNA interference (RNAi) refers to the set of molecular processes found in eukaryotic organisms in which small RNA molecules mediate the silencing or down-regulation of target genes. In insects, RNAi serves a number of functions, including regulation of endogenous genes, anti-viral defense, and defense against transposable elements. Despite being well studied in model organisms, such as Drosophila, the distribution of core RNAi pathway genes and their evolution in insects is not well understood. Here we present the most comprehensive overview of the distribution and diversity of core RNAi pathway genes across 100 insect species, encompassing all currently recognized insect orders. We inferred the phylogenetic origin of insect-specific RNAi pathway genes and also identified several hitherto unrecorded gene expansions using whole-body transcriptome data from the international 1KITE (1000 Insect Transcriptome Evolution) project as well as other resources such as i5K (5000 Insect Genome Project). Specifically, we traced the origin of the double stranded RNA binding protein R2D2 to the last common ancestor of winged insects (Pterygota), the loss of Sid-1/Tag-130 orthologs in Antliophora (fleas, flies and relatives, and scorpionflies in a broad sense), and confirm previous evidence for the splitting of the Argonaute proteins Aubergine and Piwi in Brachyceran flies (Diptera, Brachycera). Our study offers new reference points for future experimental research on RNAi-related pathway genes in insects. © The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Anticipatory UPR Activation: A Protective Pathway and Target in Cancer

PubMed Central

Shapiro, David J.; Livezey, Mara; Yu, Liqun; Zheng, Xiaobin; Andruska, Neal

2016-01-01

The endoplasmic reticulum (EnR) stress sensor, the unfolded protein response (UPR), plays a key role in regulating intracellular protein homeostasis. The extensively studied reactive mode of UPR activation is characterized by unfolded protein, or other EnR stress, triggering UPR activation. Here we focus on the emerging anticipatory mode of UPR activation in which mitogenic steroid and peptide hormones and other effectors pre-activate the UPR and anticipate a future need for increased protein folding capacity. Mild UPR activation in breast cancer can be protective and contributes to antiestrogen resistance. Hyperactivation of the anticipatory UPR pathway in cancer cells with a small molecule converts it from cytoprotective to cytotoxic, highlighting its potential as a therapeutic target in estrogen receptor positive breast cancer. PMID:27354311

Microfabrication of individual 200 microm diameter transdermal microconduits using high voltage pulsing in salicylic acid and benzoic acid.

PubMed

Ilic, L; Gowrishankar, T R; Vaughan, T E; Herndon, T O; Weaver, J C

2001-01-01

We describe an extension of semiconductor fabrication methods that creates individual approximately 200 microm diameter aqueous pathways through human stratum corneum at predetermined sites. Our hypothesis is that spatially localized electroporation of the multilamellar lipid bilayer membranes provides rapid delivery of salicylic acid to the keratin within corneocytes, leading to localized keratin disruption and then to a microconduit. A microconduit penetrating the isolated stratum corneum supports a volumetric flow of order 0.01 ml per s with a pressure difference of only 0.01 atm (about 10(2) Pa). This study provides a method for rapidly microengineering a pathway in the skin to interface future devices for transdermal drug delivery and sampling of biologically relevant fluids.

Recent Advances in Microbial Production of Aromatic Chemicals and Derivatives.

PubMed

Noda, Shuhei; Kondo, Akihiko

2017-08-01

Along with the development of metabolic engineering and synthetic biology tools, various microbes are being used to produce aromatic chemicals. In microbes, aromatics are mainly produced via a common important precursor, chorismate, in the shikimate pathway. Natural or non-natural aromatics have been produced by engineering metabolic pathways involving chorismate. In the past decade, novel approaches have appeared to produce various aromatics or to increase their productivity, whereas previously, the targets were mainly aromatic amino acids and the strategy was deregulating feedback inhibition. In this review, we summarize recent studies of microbial production of aromatics based on metabolic engineering approaches. In addition, future perspectives and challenges in this research area are discussed. Copyright © 2017 Elsevier Ltd. All rights reserved.

Genetic approaches to understanding post-traumatic stress disorder

PubMed Central

Almli, Lynn M.; Fani, Negar; Smith, Alicia K.; Ressler, Kerry J.

2015-01-01

Post-traumatic stress disorder (PTSD) is increasingly recognized as both a disorder of enormous mental health and societal burden, but also as an anxiety disorder that may be particularly understandable from a scientific perspective. Specifically, PTSD can be conceptualized as a disorder of fear and stress dysregulation, and the neural circuitry underlying these pathways in both animals and humans are becoming increasingly well understood. Furthermore, PTSD is the only disorder in psychiatry in which the initiating factor, the trauma exposure, can be identified. Thus, the pathophysiology of the fear and stress response underlying PTSD can be examined and potentially interrupted. Twin studies have shown that the development of PTSD following a trauma is heritable, and that genetic risk factors may account for up to 30–40% of this heritability. A current goal is to understand the gene pathways that are associated with PTSD, and how those genes act on the fear/stress circuitry to mediate risk vs. resilience for PTSD. This review will examine gene pathways that have recently been analysed, primarily through candidate gene studies (including neuroimaging studies of candidate genes), in addition to genome-wide associations and the epigenetic regulation of PTSD. Future and on-going studies are utilizing larger and collaborative cohorts to identify novel gene candidates through genome-wide association and other powerful genomic approaches. Identification of PTSD biological pathways strengthens the hope of progress in the mechanistic understanding of a model psychiatric disorder and allows for the development of targeted treatments and interventions. PMID:24103155

Functional correlates of the anterolateral processing hierarchy in human auditory cortex.

PubMed

Chevillet, Mark; Riesenhuber, Maximilian; Rauschecker, Josef P

2011-06-22

Converging evidence supports the hypothesis that an anterolateral processing pathway mediates sound identification in auditory cortex, analogous to the role of the ventral cortical pathway in visual object recognition. Studies in nonhuman primates have characterized the anterolateral auditory pathway as a processing hierarchy, composed of three anatomically and physiologically distinct initial stages: core, belt, and parabelt. In humans, potential homologs of these regions have been identified anatomically, but reliable and complete functional distinctions between them have yet to be established. Because the anatomical locations of these fields vary across subjects, investigations of potential homologs between monkeys and humans require these fields to be defined in single subjects. Using functional MRI, we presented three classes of sounds (tones, band-passed noise bursts, and conspecific vocalizations), equivalent to those used in previous monkey studies. In each individual subject, three regions showing functional similarities to macaque core, belt, and parabelt were readily identified. Furthermore, the relative sizes and locations of these regions were consistent with those reported in human anatomical studies. Our results demonstrate that the functional organization of the anterolateral processing pathway in humans is largely consistent with that of nonhuman primates. Because our scanning sessions last only 15 min/subject, they can be run in conjunction with other scans. This will enable future studies to characterize functional modules in human auditory cortex at a level of detail previously possible only in visual cortex. Furthermore, the approach of using identical schemes in both humans and monkeys will aid with establishing potential homologies between them.

Pathways into mental health care for UK veterans: a qualitative study.

PubMed

Mellotte, Harriet; Murphy, Dominic; Rafferty, Laura; Greenberg, Neil

2017-01-01

Background : It is well established that veterans suffering from mental health difficulties under use mental health services. Objective : This study aimed to understand more about the barriers that prevent veterans from seeking professional help and the enablers that assist veterans in seeking professional help. It also aimed to explore potential mechanisms to improve veterans' help-seeking and pathways to care. Method : The study employed a qualitative design whereby 17 veterans who had recently attended specialist veteran mental health services took part in semi-structured interviews. The resultant data were analysed using grounded theory. Results : Participants described two distinct stages to their help-seeking: initial help-seeking and pathways through treatment. Specific barriers and enablers to help-seeking were identified at each stage. Initial barriers included recognizing that there is a problem, self-stigma and anticipated public stigma. Initial enablers included being in crisis, social support, motivation and the media. Treatment pathway barriers included practical factors and negative beliefs about health services and professionals. Treatment pathway enablers included having a diagnosis, being seen in a veteran-specific service and establishing a good therapeutic relationship. Participants provided some suggestions for interventions to improve veterans' help-seeking in future; these focussed on enhancing both veterans and health professionals' knowledge regarding mental health difficulties. Conclusions : This study identified a number of barriers and enablers that may impact a veteran's journey in seeking help from professional services for mental health difficulties. Enablers such as reaching a crisis point, social support, the media, having a diagnosis of PTSD and veteran-specific mental health services appeared to be important in opposing stigma-related beliefs and in supporting veterans to engage in help-seeking behaviours.

Pathways into mental health care for UK veterans: a qualitative study

PubMed Central

Mellotte, Harriet; Murphy, Dominic; Rafferty, Laura; Greenberg, Neil

2017-01-01

ABSTRACT Background: It is well established that veterans suffering from mental health difficulties under use mental health services. Objective: This study aimed to understand more about the barriers that prevent veterans from seeking professional help and the enablers that assist veterans in seeking professional help. It also aimed to explore potential mechanisms to improve veterans’ help-seeking and pathways to care. Method: The study employed a qualitative design whereby 17 veterans who had recently attended specialist veteran mental health services took part in semi-structured interviews. The resultant data were analysed using grounded theory. Results: Participants described two distinct stages to their help-seeking: initial help-seeking and pathways through treatment. Specific barriers and enablers to help-seeking were identified at each stage. Initial barriers included recognizing that there is a problem, self-stigma and anticipated public stigma. Initial enablers included being in crisis, social support, motivation and the media. Treatment pathway barriers included practical factors and negative beliefs about health services and professionals. Treatment pathway enablers included having a diagnosis, being seen in a veteran-specific service and establishing a good therapeutic relationship. Participants provided some suggestions for interventions to improve veterans’ help-seeking in future; these focussed on enhancing both veterans and health professionals’ knowledge regarding mental health difficulties. Conclusions: This study identified a number of barriers and enablers that may impact a veteran’s journey in seeking help from professional services for mental health difficulties. Enablers such as reaching a crisis point, social support, the media, having a diagnosis of PTSD and veteran-specific mental health services appeared to be important in opposing stigma-related beliefs and in supporting veterans to engage in help-seeking behaviours. PMID:29163864

[New integrated care model for older people admitted to Intermediate Care Units in Catalonia: A quasi-experimental study protocol].

PubMed

Santaeugènia, Sebastià J; García-Lázaro, Manuela; Alventosa, Ana María; Gutiérrez-Benito, Alícia; Monterde, Albert; Cunill, Joan

To evaluate the clinical effectiveness of an intermediate care model based on a system of care focused on integrated care pathways compared to the traditional model of geriatric care (usual care) in Catalonia. The design is a quasi-experimental pre-post non-randomised study with non-synchronous control group. The intervention consists of the development and implementation of integrated care pathways and the creation of specialised interdisciplinary teams in each of the processes. The two groups will be compared for demographic, clinical variables on admission and discharge, geriatric syndromes, and use of resources. This quasi-experimental study, aims to assess the clinical impact of the transformation of a traditional model of geriatric care to an intermediate care model in an integrated healthcare organisation. It is believed that the results of this study may be useful for future randomised controlled studies. Copyright © 2016 SEGG. Publicado por Elsevier España, S.L.U. All rights reserved.

Integrated RNA-seq and sRNA-seq analysis reveals miRNA effects on secondary metabolism in Solanum tuberosum L.

PubMed

Qiao, Yan; Zhang, Jinjin; Zhang, Jinwen; Wang, Zhiwei; Ran, An; Guo, Haixia; Wang, Di; Zhang, Junlian

2017-02-01

Light is a major environmental factor that affects metabolic pathways and stimulates the production of secondary metabolites in potato. However, adaptive changes in potato metabolic pathways and physiological functions triggered by light are partly explained by gene expression changes. Regulation of secondary metabolic pathways in potato has been extensively studied at transcriptional level, but little is known about the mechanisms of post-transcriptional regulation by miRNAs. To identify light-responsive miRNAs/mRNAs and construct putative metabolism pathways regulated by the miRNA-mRNA pairs, an integrated omics (sRNAome and transcriptome) analysis was performed to potato under light stimulus. A total of 31 and 48 miRNAs were identified to be differentially expressed in the leaves and tubers, respectively. Among the DEGs, 1353 genes in the leaves and 1841 genes in the tubers were upregulated, while 1595 genes in the leaves and 897 genes in the tubers were downregulated by light. Mapman enrichment analyses showed that genes related to MVA pathway, alkaloids-like, phenylpropanoids, flavonoids, and carotenoids metabolism were significantly upregulated, while genes associated with major CHO metabolism were repressed in the leaves and tubers. Integrated miRNA and mRNA profiles revealed that light-responsive miRNAs are important regulators in alkaloids metabolism, UMP salvage, lipid biosynthesis, and cellulose catabolism. Moreover, several miRNAs may participate in glycoalkaloids metabolism via JA signaling pathway, UDP-glucose biosynthesis and hydroxylation reaction. This study provides a global view of miRNA and mRNA expression profiles in potato response to light, our results suggest that miRNAs might play important roles in secondary metabolic pathways, especially in glycoalkaloid biosynthesis. The findings will enlighten us on the genetic regulation of secondary metabolite pathways and pave the way for future application of genetically engineered potato.

Escher: A Web Application for Building, Sharing, and Embedding Data-Rich Visualizations of Biological Pathways

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

King, Zachary A.; Drager, Andreas; Ebrahim, Ali

Escher is a web application for visualizing data on biological pathways. Three key features make Escher a uniquely effective tool for pathway visualization. First, users can rapidly design new pathway maps. Escher provides pathway suggestions based on user data and genome-scale models, so users can draw pathways in a semi-automated way. Second, users can visualize data related to genes or proteins on the associated reactions and pathways, using rules that define which enzymes catalyze each reaction. Thus, users can identify trends in common genomic data types (e.g. RNA-Seq, proteomics, ChIP)—in conjunction with metabolite- and reaction-oriented data types (e.g. metabolomics, fluxomics).more » Third, Escher harnesses the strengths of web technologies (SVG, D3, developer tools) so that visualizations can be rapidly adapted, extended, shared, and embedded. This paper provides examples of each of these features and explains how the development approach used for Escher can be used to guide the development of future visualization tools.« less

Escher: A Web Application for Building, Sharing, and Embedding Data-Rich Visualizations of Biological Pathways

PubMed Central

King, Zachary A.; Dräger, Andreas; Ebrahim, Ali; Sonnenschein, Nikolaus; Lewis, Nathan E.; Palsson, Bernhard O.

2015-01-01

Escher is a web application for visualizing data on biological pathways. Three key features make Escher a uniquely effective tool for pathway visualization. First, users can rapidly design new pathway maps. Escher provides pathway suggestions based on user data and genome-scale models, so users can draw pathways in a semi-automated way. Second, users can visualize data related to genes or proteins on the associated reactions and pathways, using rules that define which enzymes catalyze each reaction. Thus, users can identify trends in common genomic data types (e.g. RNA-Seq, proteomics, ChIP)—in conjunction with metabolite- and reaction-oriented data types (e.g. metabolomics, fluxomics). Third, Escher harnesses the strengths of web technologies (SVG, D3, developer tools) so that visualizations can be rapidly adapted, extended, shared, and embedded. This paper provides examples of each of these features and explains how the development approach used for Escher can be used to guide the development of future visualization tools. PMID:26313928

Escher: A Web Application for Building, Sharing, and Embedding Data-Rich Visualizations of Biological Pathways

DOE PAGES

King, Zachary A.; Drager, Andreas; Ebrahim, Ali; ...

2015-08-27

Escher is a web application for visualizing data on biological pathways. Three key features make Escher a uniquely effective tool for pathway visualization. First, users can rapidly design new pathway maps. Escher provides pathway suggestions based on user data and genome-scale models, so users can draw pathways in a semi-automated way. Second, users can visualize data related to genes or proteins on the associated reactions and pathways, using rules that define which enzymes catalyze each reaction. Thus, users can identify trends in common genomic data types (e.g. RNA-Seq, proteomics, ChIP)—in conjunction with metabolite- and reaction-oriented data types (e.g. metabolomics, fluxomics).more » Third, Escher harnesses the strengths of web technologies (SVG, D3, developer tools) so that visualizations can be rapidly adapted, extended, shared, and embedded. This paper provides examples of each of these features and explains how the development approach used for Escher can be used to guide the development of future visualization tools.« less

Assessing recent and near-future changes in Southern California's groundwater storage from the perspective of regional climate modeling

NASA Astrophysics Data System (ADS)

De Sales, F.; Rother, D.

2017-12-01

Current climate change assessments project an increase in temperature throughout the western U.S. over the next century, while precipitation is projected to decrease in the Southwest. These assessments are based mainly on coarse spatial resolution general circulation model (GCM) simulations, which do not include groundwater (soil and aquifer) storage projections. However, water availability is a regionally variable resource and climate change impacts on groundwater distribution will probably differ regionally across the southwestern U.S. We have implemented a coupled atmosphere-biosphere-aquifer regional modelling system (WRF/SSiB2/SIMGM) to generate recent (2005-2017) and near-future (2018-2030) high-resolution groundwater projections for Southern California. These projections are obtained by dynamic downscaling data from the Global Operation Analysis (recent) and the NCAR Community Earth System Model CMIP5 global projections (near future), which supported the Intergovernmental Panel on Climate Change 5th Assessment Report. Near-future simulations include three representative concentration pathway (RCP) scenarios namely, RCP4.5, RCP6, and RCP8.5. The model can reasonably simulate the recent changes in Southern California's groundwater as indicated by a comparison to terrestrial water storage obtained from the Gravity Recovery and Climate Experiment dataset. In particular, the 2011-2017 drought is simulated well with total groundwater storages declining throughout the period, especially along the western portion of the domain, which includes the high-populated areas of western Los Angeles, San Diego, Ventura and Orange counties. In general, the near-future simulations show a decline in groundwater storage for the region. The largest changes are observed with the RCP8.5 emission pathway, towards to southeastern tier of the study area. In addition to groundwater, this downscaling experiment also generates high-resolution precipitation and temperature estimates, which can help policy makers in the development of strategies to alleviate potential water resource deficiencies in California in the near future.

Parents' Participation in a Work-Based Anti-Poverty Program Can Enhance Their Children's Future Orientation: Understanding Pathways of Influence

ERIC Educational Resources Information Center

Purtell, Kelly M.; McLoyd, Vonnie C.

2013-01-01

Planning and preparing for life after high school is a central developmental task of American adolescents, and may be even more critical for low-income youth who are less likely to attend a four year college. This study investigates factors that led to the effects of the New Hope Project, a work-based, anti-poverty program directed at parents on…

Independent Assessment of Technology Characterizations to Support the Biomass Program Annual State-of-Technology Assessments

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

Yeh, B.

2011-03-01

This report discusses an investigation that addressed two thermochemical conversion pathways for the production of liquid fuels and addressed the steps to the process, the technology providers, a method for determining the state of technology and a tool to continuously assess the state of technology. This report summarizes the findings of the investigation as well as recommendations for improvements for future studies.

Complement pathway biomarkers and age-related macular degeneration

PubMed Central

Gemenetzi, M; Lotery, A J

2016-01-01

In the age-related macular degeneration (AMD) ‘inflammation model', local inflammation plus complement activation contributes to the pathogenesis and progression of the disease. Multiple genetic associations have now been established correlating the risk of development or progression of AMD. Stratifying patients by their AMD genetic profile may facilitate future AMD therapeutic trials resulting in meaningful clinical trial end points with smaller sample sizes and study duration. PMID:26493033

Heat-related mortality in a warming climate: projections for 12 U.S. cities.

PubMed

Petkova, Elisaveta P; Bader, Daniel A; Anderson, G Brooke; Horton, Radley M; Knowlton, Kim; Kinney, Patrick L

2014-10-31

Heat is among the deadliest weather-related phenomena in the United States, and the number of heat-related deaths may increase under a changing climate, particularly in urban areas. Regional adaptation planning is unfortunately often limited by the lack of quantitative information on potential future health responses. This study presents an assessment of the future impacts of climate change on heat-related mortality in 12 cities using 16 global climate models, driven by two scenarios of greenhouse gas emissions. Although the magnitude of the projected heat effects was found to differ across time, cities, climate models and greenhouse pollution emissions scenarios, climate change was projected to result in increases in heat-related fatalities over time throughout the 21st century in all of the 12 cities included in this study. The increase was more substantial under the high emission pathway, highlighting the potential benefits to public health of reducing greenhouse gas emissions. Nearly 200,000 heat-related deaths are projected to occur in the 12 cities by the end of the century due to climate warming, over 22,000 of which could be avoided if we follow a low GHG emission pathway. The presented estimates can be of value to local decision makers and stakeholders interested in developing strategies to reduce these impacts and building climate change resilience.

Longitudinal associations between adult children's relations with parents and intimate partners.

PubMed

Johnson, Matthew D; Galovan, Adam M; Horne, Rebecca M; Min, Joohong; Walper, Sabine

2017-10-01

Drawing on 5 waves of multiple-informant data gathered from focal participants and their parents and intimate partners (n = 360 families) who completed annual surveys in the German Family Panel (pairfam) study, the present investigation examined bidirectional associations between the development of adults' conflictual and intimate interactions with their parents and intimate partners. Autoregressive cross-lagged latent change score modeling results revealed a robust pattern of coordinated development between parent-adult child and couple conflictual and intimate interactions: increases in conflict and intimacy in one relationship were contemporaneously intertwined with changes in the other relationship. Additionally, prior couple intimacy and conflict predicted future parent-adult child relations in 7 out of 14 cross-lagged pathways examined, but parent-adult child conflict and intimacy was only associated with future couple interactions in 1 pathway. These associations were not moderated by the gender of parents or the adult child or whether the adult child was a young adult or nearing midlife. Frequency of contact between parents and the adult child moderated some associations. Adults simultaneously juggle ties with parents and intimate partners, and this study provides strong evidence supporting the coordinated development of conflictual and intimate patterns of interaction in each relationship. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Heat-Related Mortality in a Warming Climate: Projections for 12 U.S. Cities

NASA Technical Reports Server (NTRS)

Petkova, Elisaveta P.; Bader, Daniel A.; Anderson, G. Brooke; Horton, Radley M.; Knowlton, Kim; Kinney, Patrick L.

2014-01-01

Heat is among the deadliest weather-related phenomena in the United States, and the number of heat-related deaths may increase under a changing climate, particularly in urban areas. Regional adaptation planning is unfortunately often limited by the lack of quantitative information on potential future health responses. This study presents an assessment of the future impacts of climate change on heat-related mortality in 12 cities using 16 global climate models, driven by two scenarios of greenhouse gas emissions. Although the magnitude of the projected heat effects was found to differ across time, cities, climate models and greenhouse pollution emissions scenarios, climate change was projected to result in increases in heat-related fatalities over time throughout the 21st century in all of the 12 cities included in this study. The increase was more substantial under the high emission pathway, highlighting the potential benefits to public health of reducing greenhouse gas emissions. Nearly 200,000 heat-related deaths are projected to occur in the 12 cities by the end of the century due to climate warming, over 22,000 of which could be avoided if we follow a low GHG emission pathway. The presented estimates can be of value to local decision makers and stakeholders interested in developing strategies to reduce these impacts and building climate change resilience.

Ecdysone receptor agonism leading to lethal molting ...

EPA Pesticide Factsheets

Molting is a key biological process in growth, development, reproduction and survival in arthropods. Complex neuroendocrine pathways are involved in the regulation of molting and may potentially become targets of environmental endocrine disrupting compounds (EDCs). For example, several classes of pesticides used in agriculture and aquaculture specifically target key endocrine regulators of the molting process. These chemicals may also pose hazards to non-target species by causing molting defects, thus affecting the health of the ecosystems. The present review summarized the available knowledge on molting-related endocrine regulation and disruption in arthropods (with special focus on insects and crustaceans), in order to identify research gaps and develop a toxicity mechanism-based model for environmental hazard and risk assessment. Based on the review, multiple targets in the molting processes that EDCs can interact with were characterized to inform future studies. An adverse outcome pathway (AOP) describing ecdysone receptor agonism leading to incomplete ecdysis associated mortality was developed according to the OECD guideline and evaluated for weight of evidence using the Evolved Bradford Hill Criteria. This review proposed the first invertebrate endocrine disruption AOP and may serve as a knowledge foundation for future environmental studies and AOP development. Development of high throughput toxicology (HTT) programs (e.g., ToxCast, Tox21) and potential a

The Development of a Clinical Nurse Scholar in Baccalaureate Education.

PubMed

Beal, Judy A; Riley, Joan M

2015-01-01

The purpose of this national study was to explore the vision of chief academic officers for baccalaureate nursing education. We invited chief academic nursing officers, randomly selected from a representative sample of accredited baccalaureate nursing programs to participate in the study. Audiotaped interviews were conducted in focus groups at professional meetings or by telephone and were transcribed verbatim. Data collection continued until thematic saturation was reached (N = 29). Analysis of the findings revealed themes that described future vision for baccalaureate education that provides guidance to faculty as they develop curriculum. An overarching theme "We are all Stewards of the Profession" and three supporting themes emerged: "Learning Pathways are Varied," "Faculty Need to Grow," and "New Pedagogies Need to Focus on the Development of 'Who I Am' as a Clinical Scholar." Findings point to a future where diverse learning pathways are integrated throughout the curriculum. The curriculum of tomorrow will place greater emphasis on the development of professional identity as a nurse and calls for expanded stewardship for nursing education. Deans recommended that investing time and resources into well-designed faculty development programs will help all faculty, regardless of appointment, to adapt to changing student needs and rapidly evolving practice environments. Copyright © 2015 Elsevier Inc. All rights reserved.

The Role of Bacillithiol in Gram-Positive Firmicutes

PubMed Central

Chandrangsu, Pete; Loi, Vu Van

2018-01-01

Abstract Significance: Since the discovery and structural characterization of bacillithiol (BSH), the biochemical functions of BSH-biosynthesis enzymes (BshA/B/C) and BSH-dependent detoxification enzymes (FosB, Bst, GlxA/B) have been explored in Bacillus and Staphylococcus species. It was shown that BSH plays an important role in detoxification of reactive oxygen and electrophilic species, alkylating agents, toxins, and antibiotics. Recent Advances: More recently, new functions of BSH were discovered in metal homeostasis (Zn buffering, Fe-sulfur cluster, and copper homeostasis) and virulence control in Staphylococcus aureus. Unexpectedly, strains of the S. aureus NCTC8325 lineage were identified as natural BSH-deficient mutants. Modern mass spectrometry-based approaches have revealed the global reach of protein S-bacillithiolation in Firmicutes as an important regulatory redox modification under hypochlorite stress. S-bacillithiolation of OhrR, MetE, and glyceraldehyde-3-phosphate dehydrogenase (Gap) functions, analogous to S-glutathionylation, as both a redox-regulatory device and in thiol protection under oxidative stress. Critical Issues: Although the functions of the bacilliredoxin (Brx) pathways in the reversal of S-bacillithiolations have been recently addressed, significantly more work is needed to establish the complete Brx reduction pathway, including the major enzyme(s), for reduction of oxidized BSH (BSSB) and the targets of Brx action in vivo. Future Directions: Despite the large number of identified S-bacillithiolated proteins, the physiological relevance of this redox modification was shown for only selected targets and should be a subject of future studies. In addition, many more BSH-dependent detoxification enzymes are evident from previous studies, although their roles and biochemical mechanisms require further study. This review of BSH research also pin-points these missing gaps for future research. Antioxid. Redox Signal. 28, 445–462. PMID:28301954

Undoing climate warming by atmospheric carbon-dioxide removal: can a holocene-like climate be restored?

NASA Astrophysics Data System (ADS)

MacDougall, Andrew

2013-04-01

Understandably, most climate modelling studies of future climate have focused on the affects of carbon emissions in the present century or the long-term fate of anthropogenically emitted carbon. These studies make an assumption: that once net anthropogenic carbon emissions cease, that humanity will make no further effort to intervene in atmospheric composition. There is a case to be made, however, that there will be a desire to return to a "safe" atmospheric concentration of CO2. Realistically this implies synthetically removing CO2 from the atmosphere and storing it is some geologically stable form. For this study experiments were conducted using the University of Victoria Earth System Climate Model (UVic ESCM) forced with novel future atmospheric trace-gas concentration pathways to explore a gradual return to pre-industrial radiative forcing. The concentration pathways follow each RCP (2.6, 4.5, 6.0, and 8.5) exactly until the peak CO2 concentration of that RCP is reached, at which point atmospheric CO2 is reduced at the same rate it increased until the 1850 concentration of CO2 is reached. Non-CO2 greenhouse gas forcing follows the prescribed RCP path until the year of peak CO2, then is subsequently linearly reduced to pre-industrial forcing. Pasture and crop areas are also gradually reduced to their pre-industrial extent. Under the middle two concentration pathways (4.5 and 6.0) a climate resembling the 20th century climate can be restored by the 25th century, although surface temperature remains above the pre-industrial temperature until at least the 30th century. Due to carbon-cycle feedbacks the quantity of carbon that must be removed from the atmosphere is larger than the quantity that was originally emitted. For concentration pathways 2.6, 4.5, and 6.0 the sequestered CO2 is 115-190% of the original cumulative carbon emissions. These results suggest that even with monumental effort to remove CO2 from the atmosphere, humanity will be living with the consequences of fossil fuel emissions for a very long time.

MicroRNA and receptor mediated signaling pathways as potential therapeutic targets in heart failure.

PubMed

Tuttolomondo, Antonino; Simonetta, Irene; Pinto, Antonio

2016-11-01

Cardiac remodelling is a complex pathogenetic pathway involving genome expression, molecular, cellular, and interstitial changes that cause changes in size, shape and function of the heart after cardiac injury. Areas covered: We will review recent advances in understanding the role of several receptor-mediated signaling pathways and micro-RNAs, in addition to their potential as candidate target pathways in the pathogenesis of heart failure. The myocyte is the main target cell involved in the remodelling process via ischemia, cell necrosis and apoptosis (by means of various receptor pathways), and other mechanisms mediated by micro-RNAs. We will analyze the role of some receptor mediated signaling pathways such as natriuretic peptides, mediators of glycogen synthase kinase 3 and ERK1/2 pathways, beta-adrenergic receptor subtypes and relaxin receptor signaling mechanisms, TNF/TNF receptor family and TWEAK/Fn14 axis, and some micro-RNAs as candidate target pathways in pathogenesis of heart failure. These mediators of receptor-mediated pathways and micro-RNA are the most addressed targets of emerging therapies in modern heart failure treatment strategies. Expert opinion: Future treatment strategies should address mediators involved in multiple steps within heart failure pathogenetic pathways.

Perinatal exposure to high-fat diet programs energy balance, metabolism and behavior in adulthood.

PubMed

Sullivan, Elinor L; Smith, M Susan; Grove, Kevin L

2011-01-01

The perinatal environment plays an important role in programming many aspects of physiology and behavior including metabolism, body weight set point, energy balance regulation and predisposition to mental health-related disorders such as anxiety, depression and attention deficit hyperactivity disorder. Maternal health and nutritional status heavily influence the early environment and have a long-term impact on critical central pathways, including the melanocortinergic, serotonergic system and dopaminergic systems. Evidence from a variety of animal models including rodents and nonhuman primates indicates that exposure to maternal high-fat diet (HFD) consumption programs offspring for increased risk of adult obesity. Hyperphagia and increased preference for fatty and sugary foods are implicated as mechanisms for the increased obesity risk. The effects of maternal HFD consumption on energy expenditure are unclear, and future studies need to address the impact of perinatal HFD exposure on this important component of energy balance regulation. Recent evidence from animal models also indicates that maternal HFD consumption increases the risk of offspring developing mental health-related disorders such as anxiety. Potential mechanisms for perinatal HFD programming of neural pathways include circulating factors, such as hormones (leptin, insulin), nutrients (fatty acids, triglycerides and glucose) and inflammatory cytokines. As maternal HFD consumption and obesity are common and rapidly increasing, we speculate that future generations will be at increased risk for both metabolic and mental health disorders. Thus, it is critical that future studies identify therapeutic strategies that are effective at preventing maternal HFD-induced malprogramming. Copyright © 2010 S. Karger AG, Basel.

Application of the new scenario framework for climate change research: Future social vulnerability in large urban areas

NASA Astrophysics Data System (ADS)

Rohat, Guillaume; Flacke, Johannes; Dao, Hy

2016-04-01

It is by now widely acknowledged that future social vulnerability to climate change depends on both future climate state and future socio-economic conditions. Nevertheless, while most of the vulnerability assessments are using climate projections, the integration of socio-economic projections into the assessment of vulnerabilities has been very limited. Up to now, the vast majority of vulnerability assessments has been using current socio-economic conditions, hence has failed to consider the influence of socio-economic developments in the construction of vulnerability. To enhance the use of socio-economic projections into climate change impacts, adaptation and vulnerability assessments, the climate change research community has been recently involved in the development of a new model for creating scenarios that integrate future changes in climate as well as in society, known under the name of the new scenario framework for climate change research. This theoretical framework is made of a set of alternative futures of socio-economic developments (known as shared socio-economic pathways - SSPs), a set of hypothesis about future climate policies (known as shared policy assumptions - SPAs) and a set of greenhouse gas concentration trajectories (known as representative concentration pathways - RCPs), which are all combined into a scenario matrix architecture (SMA) whose aim is to facilitate the use of this framework. Despite calls by the climate change research community for the use of this conceptual framework in impacts, adaptation and vulnerability research, its use and its assessment has been very limited. Focusing on case-studies (i.e. specific cities as well as specific climate impacts and their associated human exposures and vulnerabilities), the study presented here will attempt to operationalize this theoretical framework for the assessment of future social vulnerability in large urban areas. A particular attention will be paid to less advanced and more vulnerable countries in the global south. We will discuss how this framework can be implemented for large urban agglomerations. To do so, we will examine: (i) by what means globally-developed SSPs can be extended into sector-specific and location-specific socio-economic development scenarios, (ii) in what manner the quantification of key socio-economic indicators (in accordance with the different SSPs), coupled with regional climate projections under different RCPs, can lead to a quantitative and reliable assessment of the evolution of future social vulnerability, and (iii) to which extent the SMA, i.e. the combination of extended SSPs, regional climate projections (under different RCPs) and various locally-developed SPAs, can answer some of the key questions regarding climate change adaptation policies, from a vulnerability perspective.

Dependence of future mortality changes on global CO2 concentrations: A review.

PubMed

Lee, Jae Young; Choi, Hayoung; Kim, Ho

2018-05-01

The heterogeneity among previous studies of future mortality projections due to climate change has often hindered comparisons and syntheses of resulting impacts. To address this challenge, the present study introduced a novel method to normalize the results from projection studies according to different baseline and projection periods and climate scenarios, thereby facilitating comparison and synthesis. This study reviewed the 15 previous studies involving projected climate change-related mortality under Representative Concentration Pathways. To synthesize their results, we first reviewed the important study design elements that affected the reported results in previous studies. Then, we normalized the reported results by CO 2 concentration in order to eliminate the effects of the baseline period, projection period, and climate scenario choices. For twenty-five locations worldwide, the normalized percentage changes in temperature-attributable mortality per 100 ppm increase in global CO 2 concentrations ranged between 41.9% and 330%, whereas those of total mortality ranged between 0.3% and 4.8%. The normalization methods presented in this work will guide future studies to provide their results in a normalized format and facilitate research synthesis to reinforce our understanding on the risk of climate change. Copyright © 2018 Elsevier Ltd. All rights reserved.

Enhancing a Person, Enhancing a Civilization: A Research Program at the Intersection of Bioethics, Future Studies, and Astrobiology.

PubMed

Ćirković, Milan M

2017-07-01

There are manifold intriguing issues located within largely unexplored borderlands of bioethics, future studies (including global risk analysis), and astrobiology. Human enhancement has for quite some time been among the foci of bioethical debates, but the same cannot be said about its global, transgenerational, and even cosmological consequences. In recent years, discussions of posthuman and, in general terms, postbiological civilization(s) have slowly gained a measure of academic respect, in parallel with the renewed interest in the entire field of future studies and the great strides made in understanding of the origin and evolution of life and intelligence in their widest, cosmic context. These developments promise much deeper synergic answers to questions regarding the long-term future of enhancement: how far can it go? Is human enhancement a further step toward building a true postbiological civilization? Should we actively participate and help shape this process? Is the future of humanity "typical" in the same Copernican sense as our location in space and time is typical in the galaxy, and if so, can we derive important insights about the evolutionary pathways of postbiological evolution from astrobiological and Search for ExtraTerrestrial Intelligence (SETI) studies? These and similar questions could be understood as parts of a possible unifying research program attempting to connect cultural and moral evolution with what we know and understand about their cosmological and biological counterparts.

Development and Performance of Alternative Electricity Sector Pathways Subject to Multiple Climate and Water Projections

NASA Astrophysics Data System (ADS)

Newmark, R. L.; Vorosmarty, C. J.; Miara, A.; Cohen, S.; Macknick, J.; Sun, Y.; Corsi, F.; Fekete, B. M.; Tidwell, V. C.

2017-12-01

Climate change impacts on air temperatures and water availability have the potential to alter future electricity sector investment decisions as well as the reliability and performance of the power sector. Different electricity sector configurations are more or less vulnerable to climate-induced changes. For example, once-through cooled thermal facilities are the most cost-effective and efficient technologies under cooler and wetter conditions, but can be substantially affected by and vulnerable to warmer and drier conditions. Non-thermal renewable technologies, such as PV and wind, are essentially "drought-proof" but have other integration and reliability challenges. Prior efforts have explored the impacts of climate change on electric sector development for a limited set of climate and electricity scenarios. Here, we provide a comprehensive suite of scenarios that evaluate how different electricity sector pathways could be affected by a range of climate and water resource conditions. We use four representative concentration pathway (RCP) scenarios under five global circulation models (GCM) as climate drivers to a Water Balance Model (WBM), to provide twenty separate future climate-water conditions. These climate-water conditions influence electricity sector development from present day to 2050 as determined using the Regional Energy Deployment Systems (ReEDS) model. Four unique electricity sector pathways will be considered, including business-as-usual, carbon cap, high renewable energy technology costs, and coal reliance scenarios. The combination of climate-water and electricity sector pathway scenarios leads to 80 potential future cases resulting in different national and regional electricity infrastructure configurations. The vulnerability of these configurations in relation to climate change (including in-stream thermal pollution impacts and environmental regulations) is evaluated using the Thermoelectric Power and Thermal Pollution (TP2M) model, providing quantitative estimates of the power sector's ability to meet loads, given changes in air temperature, water temperature, and water availability.

Pancreatic β-cell proliferation in obesity.

PubMed

Linnemann, Amelia K; Baan, Mieke; Davis, Dawn Belt

2014-05-01

Because obesity rates have increased dramatically over the past 3 decades, type 2 diabetes has become increasingly prevalent as well. Type 2 diabetes is associated with decreased pancreatic β-cell mass and function, resulting in inadequate insulin production. Conversely, in nondiabetic obesity, an expansion in β-cell mass occurs to provide sufficient insulin and to prevent hyperglycemia. This expansion is at least in part due to β-cell proliferation. This review focuses on the mechanisms regulating obesity-induced β-cell proliferation in humans and mice. Many factors have potential roles in the regulation of obesity-driven β-cell proliferation, including nutrients, insulin, incretins, hepatocyte growth factor, and recently identified liver-derived secreted factors. Much is still unknown about the regulation of β-cell replication, especially in humans. The extracellular signals that activate proliferative pathways in obesity, the relative importance of each of these pathways, and the extent of cross-talk between these pathways are important areas of future study. © 2014 American Society for Nutrition.

Combined blockade of vascular endothelial growth factor and programmed death 1 pathways in advanced kidney cancer.

PubMed

Einstein, David J; McDermott, David F

2017-06-01

Targeted and immune-based therapies have improved outcomes in advanced kidney cancer, yet novel strategies are needed to extend the duration of these benefits and expand them to more patients. Combined inhibition of vascular endothelial growth factor (VEGF) and the programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) pathways with therapeutic agents already in clinical use may offer such a strategy. Here, we describe the development and clinical evaluation of VEGF inhibitors and, separately, PD-1/PD-L1 inhibitors. We present preclinical evidence of interaction between these pathways and the rationale for combined blockade. Beyond well-known effects on pathologic angiogenesis, VEGF blockade also may decrease immune tolerance and enhance PD-1/PD-L1 blockade. We conclude with the results of several early trials of combined VEGF and PD-1/PD-L1 blockade, which demonstrate encouraging antitumor activity, and we pose questions for future study.

Tandem mass spectrometric analysis of cyclophosphamide, ifosfamide and their metabolites.

PubMed

Liu, Zhongfa; Chan, Kenneth K; Wang, Jeffrey J

2005-01-01

A detailed multi-stage (MSn) fragmentation study of cyclophosphamide (CP), ifosfamide (IF) and their major metabolites, using an ion-trap mass spectrometer and a Q-TOF mass spectrometer, was performed with the aid of specifically deuterium-labeled analogs. The analytes showed good responses in positive-ion electrospray mass spectrometry as [MH]+ ions. Tandem mass spectra revealed a wealth of structurally specific ions, allowing characterization of the fragmentation pathways of these analytes. The major fragmentation pathways of the protonated CP and IF are elimination of ethylene from C5 and C6 of 1,3,2-oxazaphosphorine-2-oxide via a McLafferty rearrangement, and cleavage of the P-N bond. However, their activated 4-OOH and 4-OH metabolites primarily underwent hydrogen peroxide elimination and dehydration, respectively, followed by fragmentation pathways similar to those of CP and IF. These results should prove useful in structural elucidation of future analogs of CP and IF, and/or of their metabolites. Copyright (c) 2005 John Wiley & Sons, Ltd.

Methane to bioproducts: the future of the bioeconomy?

PubMed

Pieja, Allison J; Morse, Molly C; Cal, Andrew J

2017-12-01

Methanotrophs have been studied since the 1970s, but interest has increased tremendously in recent years due to their potential to transform methane into valuable bioproducts. The vast quantity of available methane and the low price of methane as natural gas have helped to spur this interest. The most well-studied, biologically-derived products from methane include methanol, polyhydroxyalkanoates, and single cell protein. However, many other high-interest chemicals such as biofuels or high-value products such as ectoine could be made industrially relevant through metabolic engineering. Although challenges must be overcome to achieve commercialization of biologically manufactured methane-to-products, taking a holistic view of the production process or radically re-imagining pathways could lead to a future bioeconomy with methane as the primary feedstock. Copyright © 2017 Elsevier Ltd. All rights reserved.

Pathway concepts experiment for head-down synthetic vision displays

NASA Astrophysics Data System (ADS)

Prinzel, Lawrence J., III; Arthur, Jarvis J., III; Kramer, Lynda J.; Bailey, Randall E.

2004-08-01

Eight 757 commercial airline captains flew 22 approaches using the Reno Sparks 16R Visual Arrival under simulated Category I conditions. Approaches were flown using a head-down synthetic vision display to evaluate four tunnel ("minimal", "box", "dynamic pathway", "dynamic crow's feet") and three guidance ("ball", "tadpole", "follow-me aircraft") concepts and compare their efficacy to a baseline condition (i.e., no tunnel, ball guidance). The results showed that the tunnel concepts significantly improved pilot performance and situation awareness and lowered workload compared to the baseline condition. The dynamic crow's feet tunnel and follow-me aircraft guidance concepts were found to be the best candidates for future synthetic vision head-down displays. These results are discussed with implications for synthetic vision display design and future research.

The Impact of Urban US Policing Practices on Black Men Who Have Sex with Men's HIV Vulnerability: Ethnographic Findings and a Conceptual Model for Future Research.

PubMed

Parker, Caroline M; Parker, Richard G; Philbin, Morgan M; Hirsch, Jennifer S

2018-04-01

This paper advances research on racism and health by presenting a conceptual model that delineates pathways linking policing practices to HIV vulnerability among Black men who have sex with men in the urban USA. Pathways include perceived discrimination based on race, sexuality and gender performance, mental health, and condom-carrying behaviors. The model, intended to stimulate future empirical work, is based on a review of the literature and on ethnographic data collected in 2014 in New York City. This paper contributes to a growing body of work that examines policing practices as drivers of racial health disparities extending far beyond violence-related deaths.

Our Transforming Energy Economy: Pathways to a Decarbonized Future -

Science.gov Websites

a clean energy future. For example, JISEA's impacts can be seen in its growing natural gas research example, JISEA hosted the NG-RE 360 Degrees of Opportunity Forum, a series of workshops in different assets are one example, such as "smart" buildings that benefit both from solar photovoltaic

Meeting Report: FutureTox II: Contemporary Concepts in Toxicology “Pathways to Prediction: In Vitro and In Silico Models for Predictive Toxicology”

EPA Science Inventory

The Society of Toxicology (SOT) held avery successful FutureTox II Contemporary Concepts in Toxicology (CCT) Conference in Chapel Hill, North Carolina, on January 16th and 17th, 2014. There were over 291 attendees representing industry, government and academia; the sessions were ...

Lessons Learned through the Piedmont Futures Program: Why Career Education Is Important to Student Success

ERIC Educational Resources Information Center

Hughey-Commers, Erin

2011-01-01

Hands-on learning with business professionals is at the heart of the educators' approach with the Piedmont Futures program at Piedmont Virginia Community College. Too often educators provide the answers before students have asked the questions; they create career pathways without providing students with sufficient opportunities to explore which…

Harnessing system models of cell death signalling for cytotoxic chemotherapy: towards personalised medicine approaches?

PubMed

Huber, Heinrich J; McKiernan, Ross G; Prehn, Jochen H M

2014-03-01

Most cytotoxic chemotherapeutics are believed to kill cancer cells by inducing apoptosis. Understanding the factors that contribute to impairment of apoptosis in cancer cells is therefore critical for the development of novel therapies that circumvent the widespread chemoresistance. Apoptosis, however, is a complex and tightly controlled process that can be induced by different classes of chemotherapeutics targeting different signalling nodes and pathways. Moreover, apoptosis initiation and apoptosis execution strongly depend on patient-specific, genomic and proteomic signatures. Here, we will review recent translational studies that suggest a critical link between the sensitivity of cancer cells to initiate apoptosis and clinical outcome. Next we will discuss recent advances in the field of system modelling of apoptosis pathways for the prediction of treatment responses. We propose that initiation of mitochondrial apoptosis, defined as the process of mitochondrial outer membrane permeabilisation (MOMP), is a dose-dependent decision process that allows for a prediction of individual therapy responses and therapeutic windows. We provide evidence in contrast that apoptosis execution post-MOMP may be a binary decision that dictates whether apoptosis is executed or not. We will discuss the implications of this concept for the future use of novel adjuvant therapeutics that specifically target apoptosis signalling pathways or which may be used to reduce the impact of cell-to-cell heterogeneity on therapy responses. Finally, we will discuss the technical and regulatory requirements surrounding the use and implications of system-based patient stratification tools for the future of personalised oncology.

Brain evolution by brain pathway duplication

PubMed Central

Chakraborty, Mukta; Jarvis, Erich D.

2015-01-01

Understanding the mechanisms of evolution of brain pathways for complex behaviours is still in its infancy. Making further advances requires a deeper understanding of brain homologies, novelties and analogies. It also requires an understanding of how adaptive genetic modifications lead to restructuring of the brain. Recent advances in genomic and molecular biology techniques applied to brain research have provided exciting insights into how complex behaviours are shaped by selection of novel brain pathways and functions of the nervous system. Here, we review and further develop some insights to a new hypothesis on one mechanism that may contribute to nervous system evolution, in particular by brain pathway duplication. Like gene duplication, we propose that whole brain pathways can duplicate and the duplicated pathway diverge to take on new functions. We suggest that one mechanism of brain pathway duplication could be through gene duplication, although other mechanisms are possible. We focus on brain pathways for vocal learning and spoken language in song-learning birds and humans as example systems. This view presents a new framework for future research in our understanding of brain evolution and novel behavioural traits. PMID:26554045

Water Resource Planning Under Future Climate and Socioeconomic Uncertainty in the Cauvery River Basin in Karnataka, India

PubMed Central

Conway, Declan; Dessai, Suraje; Stainforth, David A.

2018-01-01

Abstract Decision‐Making Under Uncertainty (DMUU) approaches have been less utilized in developing countries than developed countries for water resources contexts. High climate vulnerability and rapid socioeconomic change often characterize developing country contexts, making DMUU approaches relevant. We develop an iterative multi‐method DMUU approach, including scenario generation, coproduction with stakeholders and water resources modeling. We apply this approach to explore the robustness of adaptation options and pathways against future climate and socioeconomic uncertainties in the Cauvery River Basin in Karnataka, India. A water resources model is calibrated and validated satisfactorily using observed streamflow. Plausible future changes in Indian Summer Monsoon (ISM) precipitation and water demand are used to drive simulations of water resources from 2021 to 2055. Two stakeholder‐identified decision‐critical metrics are examined: a basin‐wide metric comprising legal instream flow requirements for the downstream state of Tamil Nadu, and a local metric comprising water supply reliability to Bangalore city. In model simulations, the ability to satisfy these performance metrics without adaptation is reduced under almost all scenarios. Implementing adaptation options can partially offset the negative impacts of change. Sequencing of options according to stakeholder priorities into Adaptation Pathways affects metric satisfaction. Early focus on agricultural demand management improves the robustness of pathways but trade‐offs emerge between intrabasin and basin‐wide water availability. We demonstrate that the fine balance between water availability and demand is vulnerable to future changes and uncertainty. Despite current and long‐term planning challenges, stakeholders in developing countries may engage meaningfully in coproduction approaches for adaptation decision‐making under deep uncertainty. PMID:29706676

Water Resource Planning Under Future Climate and Socioeconomic Uncertainty in the Cauvery River Basin in Karnataka, India.

PubMed

Bhave, Ajay Gajanan; Conway, Declan; Dessai, Suraje; Stainforth, David A

2018-02-01

Decision-Making Under Uncertainty (DMUU) approaches have been less utilized in developing countries than developed countries for water resources contexts. High climate vulnerability and rapid socioeconomic change often characterize developing country contexts, making DMUU approaches relevant. We develop an iterative multi-method DMUU approach, including scenario generation, coproduction with stakeholders and water resources modeling. We apply this approach to explore the robustness of adaptation options and pathways against future climate and socioeconomic uncertainties in the Cauvery River Basin in Karnataka, India. A water resources model is calibrated and validated satisfactorily using observed streamflow. Plausible future changes in Indian Summer Monsoon (ISM) precipitation and water demand are used to drive simulations of water resources from 2021 to 2055. Two stakeholder-identified decision-critical metrics are examined: a basin-wide metric comprising legal instream flow requirements for the downstream state of Tamil Nadu, and a local metric comprising water supply reliability to Bangalore city. In model simulations, the ability to satisfy these performance metrics without adaptation is reduced under almost all scenarios. Implementing adaptation options can partially offset the negative impacts of change. Sequencing of options according to stakeholder priorities into Adaptation Pathways affects metric satisfaction. Early focus on agricultural demand management improves the robustness of pathways but trade-offs emerge between intrabasin and basin-wide water availability. We demonstrate that the fine balance between water availability and demand is vulnerable to future changes and uncertainty. Despite current and long-term planning challenges, stakeholders in developing countries may engage meaningfully in coproduction approaches for adaptation decision-making under deep uncertainty.

Water Resource Planning Under Future Climate and Socioeconomic Uncertainty in the Cauvery River Basin in Karnataka, India

NASA Astrophysics Data System (ADS)

Bhave, Ajay Gajanan; Conway, Declan; Dessai, Suraje; Stainforth, David A.

2018-02-01

Decision-Making Under Uncertainty (DMUU) approaches have been less utilized in developing countries than developed countries for water resources contexts. High climate vulnerability and rapid socioeconomic change often characterize developing country contexts, making DMUU approaches relevant. We develop an iterative multi-method DMUU approach, including scenario generation, coproduction with stakeholders and water resources modeling. We apply this approach to explore the robustness of adaptation options and pathways against future climate and socioeconomic uncertainties in the Cauvery River Basin in Karnataka, India. A water resources model is calibrated and validated satisfactorily using observed streamflow. Plausible future changes in Indian Summer Monsoon (ISM) precipitation and water demand are used to drive simulations of water resources from 2021 to 2055. Two stakeholder-identified decision-critical metrics are examined: a basin-wide metric comprising legal instream flow requirements for the downstream state of Tamil Nadu, and a local metric comprising water supply reliability to Bangalore city. In model simulations, the ability to satisfy these performance metrics without adaptation is reduced under almost all scenarios. Implementing adaptation options can partially offset the negative impacts of change. Sequencing of options according to stakeholder priorities into Adaptation Pathways affects metric satisfaction. Early focus on agricultural demand management improves the robustness of pathways but trade-offs emerge between intrabasin and basin-wide water availability. We demonstrate that the fine balance between water availability and demand is vulnerable to future changes and uncertainty. Despite current and long-term planning challenges, stakeholders in developing countries may engage meaningfully in coproduction approaches for adaptation decision-making under deep uncertainty.

Exploring the Housing and Household Energy Pathways to Stress: A Mixed Methods Study.

PubMed

Hernández, Diana; Phillips, Douglas; Siegel, Eva Laura

2016-09-14

Chronic stress, known to contribute to negative physical and mental health outcomes, is closely associated with broader issues of material hardship, poor neighborhood conditions, residential instability, and inadequate housing conditions. However, few studies have comprehensively explored pathways to stress in a low-income housing environment. A mixed-methods pilot study investigated the concept of energy insecurity by looking at the impacts of weatherization and energy efficiency interventions on low-income households in the South Bronx neighborhood of New York City. In-depth interviews were conducted with 20 low-income heads of household; participants also completed health, housing and budget assessments. Physical deficiencies, economic hardship, and health issues all interacted to directly and indirectly produce living conditions that contribute to chronic stress. Households with higher stress reported more health problems. Poor quality housing led to coping responses that increased expenses, which in turn increased stress around housing and energy affordability. This study provides further support for the connections between both health and the built environment and between low socio-economic status populations and net negative health outcomes. Energy insecurity is an important contributor to chronic stress in low-income households, and isolating pathways to stress where there is potential for interventions is important for future policy and housing-based strategies.

Exploring the Housing and Household Energy Pathways to Stress: A Mixed Methods Study

PubMed Central

Hernández, Diana; Phillips, Douglas; Siegel, Eva Laura

2016-01-01

Chronic stress, known to contribute to negative physical and mental health outcomes, is closely associated with broader issues of material hardship, poor neighborhood conditions, residential instability, and inadequate housing conditions. However, few studies have comprehensively explored pathways to stress in a low-income housing environment. A mixed-methods pilot study investigated the concept of energy insecurity by looking at the impacts of weatherization and energy efficiency interventions on low-income households in the South Bronx neighborhood of New York City. In-depth interviews were conducted with 20 low-income heads of household; participants also completed health, housing and budget assessments. Physical deficiencies, economic hardship, and health issues all interacted to directly and indirectly produce living conditions that contribute to chronic stress. Households with higher stress reported more health problems. Poor quality housing led to coping responses that increased expenses, which in turn increased stress around housing and energy affordability. This study provides further support for the connections between both health and the built environment and between low socio-economic status populations and net negative health outcomes. Energy insecurity is an important contributor to chronic stress in low-income households, and isolating pathways to stress where there is potential for interventions is important for future policy and housing-based strategies. PMID:27649222

Toward engineering E. coli with an autoregulatory system for lignin valorization.

PubMed

Wu, Weihua; Liu, Fang; Singh, Seema

2018-03-20

Efficient lignin valorization could add more than 10-fold the value gained from burning it for energy and is critical for economic viability of future biorefineries. However, lignin-derived aromatics from biomass pretreatment are known to be potent fermentation inhibitors in microbial production of fuels and other value-added chemicals. In addition, isopropyl-β-d-1-thiogalactopyranoside and other inducers are routinely added into fermentation broth to induce the expression of pathway enzymes, which further adds to the overall process cost. An autoregulatory system that can diminish the aromatics' toxicity as well as be substrate-inducible can be the key for successful integration of lignin valorization into future lignocellulosic biorefineries. Toward that goal, in this study an autoregulatory system is demonstrated that alleviates the toxicity issue and eliminates the cost of an external inducer. Specifically, this system is composed of a catechol biosynthesis pathway coexpressed with an active aromatic transporter CouP under induction by a vanillin self-inducible promoter, ADH7, to effectively convert the lignin-derived aromatics into value-added chemicals using Escherichia coli as a host. The constructed autoregulatory system can efficiently transport vanillin across the cell membrane and convert it to catechol. Compared with the system without CouP expression, the expression of catechol biosynthesis pathway with transporter CouP significantly improved the catechol yields about 30% and 40% under promoter pTrc and ADH7, respectively. This study demonstrated an aromatic-induced autoregulatory system that enabled conversion of lignin-derived aromatics into catechol without the addition of any costly, external inducers, providing a promising and economically viable route for lignin valorization. Copyright © 2018 the Author(s). Published by PNAS.

Causal Loop Analysis of coastal geomorphological systems

NASA Astrophysics Data System (ADS)

Payo, Andres; Hall, Jim W.; French, Jon; Sutherland, James; van Maanen, Barend; Nicholls, Robert J.; Reeve, Dominic E.

2016-03-01

As geomorphologists embrace ever more sophisticated theoretical frameworks that shift from simple notions of evolution towards single steady equilibria to recognise the possibility of multiple response pathways and outcomes, morphodynamic modellers are facing the problem of how to keep track of an ever-greater number of system feedbacks. Within coastal geomorphology, capturing these feedbacks is critically important, especially as the focus of activity shifts from reductionist models founded on sediment transport fundamentals to more synthesist ones intended to resolve emergent behaviours at decadal to centennial scales. This paper addresses the challenge of mapping the feedback structure of processes controlling geomorphic system behaviour with reference to illustrative applications of Causal Loop Analysis at two study cases: (1) the erosion-accretion behaviour of graded (mixed) sediment beds, and (2) the local alongshore sediment fluxes of sand-rich shorelines. These case study examples are chosen on account of their central role in the quantitative modelling of geomorphological futures and as they illustrate different types of causation. Causal loop diagrams, a form of directed graph, are used to distil the feedback structure to reveal, in advance of more quantitative modelling, multi-response pathways and multiple outcomes. In the case of graded sediment bed, up to three different outcomes (no response, and two disequilibrium states) can be derived from a simple qualitative stability analysis. For the sand-rich local shoreline behaviour case, two fundamentally different responses of the shoreline (diffusive and anti-diffusive), triggered by small changes of the shoreline cross-shore position, can be inferred purely through analysis of the causal pathways. Explicit depiction of feedback-structure diagrams is beneficial when developing numerical models to explore coastal morphological futures. By explicitly mapping the feedbacks included and neglected within a model, the modeller can readily assess if critical feedback loops are included.

[Status and future of natural resource for Chinese materia medica].

PubMed

Ma, Xiao-jing; Guo, Juan; Tang, Jin-fu; Ma, Xiao-hui; Ma, Ying; Dai, Zhu-bo; Guo, Lan-ping; Huang, Lu-qi

2015-05-01

For thousands of years, the natural resource for Chinese materiamedica has been the foundation of the traditional Chinese medicine industry, which provides abundant medicine for human. In recent years, increasing demands and irrational exploitation led to a lot of problems such as rapid decrease of traditional Chinese herbs reserves, low quality of medicine and dismishing traditional cultures. These restricted the development of the traditional Chinese medicine. To solve these problems, scientists have done much work on investigating traditional Chinese medicine resources, exploring the metabolic pathway of bioactive ingredients, cultivating new varieties, and carrying out synthetic biology. These studies provided a theoretical basis for sustainable utilizationand future developmentof traditional Chinese medicine resources.

Services for children with developmental co-ordination disorder: an evaluation against best practice principles.

PubMed

Pentland, Jacqueline; Maciver, Donald; Owen, Christine; Forsyth, Kirsty; Irvine, Linda; Walsh, Mike; Crowe, Miriam

2016-01-01

The National Health Service in Scotland published a best practice framework to support occupational therapists and physiotherapists to deliver effective services for children with developmental co-ordination disorder (DCD); however, adherence is variable. To highlight areas for development, this study compared the care pathway within a paediatric DCD service against the NHS Scotland framework. A partnership of researchers and clinicians based in the United Kingdom conducted a qualitative study with 37 participants (N = 13 interview participants, N = 24 workshop participants). In-depth interviews and/or workshops were used to map the DCD service against the NHS framework. Identified gaps were aligned with four key stages of the care pathway. Qualitative analysis software was used to analyse the data. Core principles to guide future development were identified for each phase of the pathway. These core principles related to the NHS framework and focused on issues such as involving the family, defining clear pathways and enhancing children's participation. Participants identified potential strategies for service improvement such as developing community-based interventions and information provision. Challenges when providing services for children with DCD include confusing service pathways and poor partnership working. It is, therefore, important that clinicians utilise collaborative working strategies that support children's participation. There are numerous challenges related to the implementation of best practice principles into the provision of therapy services for children with developmental coordination disorder (DCD). It is important that AHPs seek ways of engaging parents and educational professionals at all stages of the care pathway in order to ensure optimum service provision for the child. Addressing participation is an important aspect and community-based strategies may be particularly beneficial, both as a preventative activity and as an intervention approach.

Leucine Affects α-Amylase Synthesis through PI3K/Akt-mTOR Signaling Pathways in Pancreatic Acinar Cells of Dairy Calves.

PubMed

Guo, Long; Liang, Ziqi; Zheng, Chen; Liu, Baolong; Yin, Qingyan; Cao, Yangchun; Yao, Junhu

2018-05-23

Dietary nutrient utilization, particularly starch, is potentially limited by digestion in dairy cow small intestine because of shortage of α-amylase. Leucine acts as an effective signal molecular in the mTOR signaling pathway, which regulates a series of biological processes, especially protein synthesis. It has been reported that leucine could affect α-amylase synthesis and secretion in ruminant pancreas, but mechanisms have not been elaborated. In this study, pancreatic acinar (PA) cells were used as a model to determine the cellular signal of leucine influence on α-amylase synthesis. PA cells were isolated from newborn Holstein dairy bull calves and cultured in Dulbecco's modifed Eagle's medium/nutrient mixture F12 liquid media containing four leucine treatments (0, 0.23, 0.45, and 0.90 mM, respectively), following α-amylase activity, zymogen granule, and signal pathway factor expression detection. Rapamycin, a specific inhibitor of mTOR, was also applied to PA cells. Results showed that leucine increased ( p < 0.05) synthesis of α-amylase as well as phosphorylation of PI3K, Akt, mTOR, and S6K1 while reduced ( p < 0.05) GCN2 expression. Inhibition of mTOR signaling downregulated the α-amylase synthesis. In addition, the extracellular leucine dosage significantly influenced intracellular metabolism of isoleucine ( p < 0.05). Overall, leucine regulates α-amylase synthesis through promoting the PI3K/Akt-mTOR pathway and reducing the GCN2 pathway in PA cells of dairy calves. These pathways form the signaling network that controls the protein synthesis and metabolism. It would be of great interest in future studies to explore the function of leucine in ruminant nutrition.

Assessing uncertainties in global cropland futures using a conditional probabilistic modelling framework

NASA Astrophysics Data System (ADS)

Engström, Kerstin; Olin, Stefan; Rounsevell, Mark D. A.; Brogaard, Sara; van Vuuren, Detlef P.; Alexander, Peter; Murray-Rust, Dave; Arneth, Almut

2016-11-01

We present a modelling framework to simulate probabilistic futures of global cropland areas that are conditional on the SSP (shared socio-economic pathway) scenarios. Simulations are based on the Parsimonious Land Use Model (PLUM) linked with the global dynamic vegetation model LPJ-GUESS (Lund-Potsdam-Jena General Ecosystem Simulator) using socio-economic data from the SSPs and climate data from the RCPs (representative concentration pathways). The simulated range of global cropland is 893-2380 Mha in 2100 (± 1 standard deviation), with the main uncertainties arising from differences in the socio-economic conditions prescribed by the SSP scenarios and the assumptions that underpin the translation of qualitative SSP storylines into quantitative model input parameters. Uncertainties in the assumptions for population growth, technological change and cropland degradation were found to be the most important for global cropland, while uncertainty in food consumption had less influence on the results. The uncertainties arising from climate variability and the differences between climate change scenarios do not strongly affect the range of global cropland futures. Some overlap occurred across all of the conditional probabilistic futures, except for those based on SSP3. We conclude that completely different socio-economic and climate change futures, although sharing low to medium population development, can result in very similar cropland areas on the aggregated global scale.

Proteomic study of acute respiratory distress syndrome: current knowledge and implications for drug development

PubMed Central

Levitt, Joseph E.; Rogers, Angela J.

2017-01-01

The acute respiratory distress syndrome (ARDS) is a common cause of acute respiratory failure, and is associated with substantial mortality and morbidity. Dozens of clinical trials targeting ARDS have failed, with no drug specifically targeting lung injury in widespread clinical use. Thus, the need for drug development in ARDS is great. Targeted proteomic studies in ARDS have identified many key pathways in the disease, including inflammation, epithelial injury, endothelial injury or activation, and disordered coagulation and repair. Recent studies reveal the potential for proteomic changes to identify novel subphenotypes of ARDS patients who may be most likely to respond to therapy and could thus be targeted for enrollment in clinical trials. Nontargeted studies of proteomics in ARDS are just beginning and have the potential to identify novel drug targets and key pathways in the disease. Proteomics will play an important role in phenotyping of patients and developing novel therapies for ARDS in the future. PMID:27031735

Inhibition of ADAM-17 more effectively down-regulates the Notch pathway than that of γ-secretase in renal carcinoma.

PubMed

Guo, Zhen; Jin, Xunbo; Jia, Haiyan

2013-05-09

Our study is to research the effect of inhibited ADAM-17 expression through the Notch pathway in renal carcinoma. Immunohistochemistry and western blot were used to examine the expression of ADAM-17 protein in renal cancer tissues. Proliferation and cell invasion of 786-o cells, as well as OS-RC-2 cells, after treatment with two different inhibitors of the Notch pathway, were examined by CCK-8 assay and Transwell assay, respectively. 786-o cell apoptosis was measured using the FCM test. ADAM-17 was highly expressed in RCC tissues. Compared with blocking γ-secretase, a known mechanism of impairing Notch, blockade of ADAM-17 more effectively down-regulated the expressions of Notch1 and HES-1 proteins. Similarly, we found that the ADAM-17 inhibitor, Marimastat, could more efficiently reduce renal cell proliferation and invasive capacity in comparison with the γ-secretase inhibitor DAPT when used at the same dose. Similar results were obtained when apoptosis of 786-o was measured. Compared with γ-secretase, inhibition of ADAM-17 expression more effectively inhibits Notch pathway-mediated renal cancer cell proliferation and invasion. ADAM-17 may be a new target for future treatment of renal carcinoma.

WISP-3/CCN6 inhibits apoptosis by regulating caspase pathway after hyperoxia in lung epithelial cells.

PubMed

Wei, Shuquan; Wang, Kangwei; Zhao, Zhuxiang; Huang, Xiaomei; Tang, Wanna; Zhao, Ziwen

2018-06-16

Cell death is a normal phenomenon in the course of biological development, moreover, which is also a prominent feature in lung exposed to hyperoxia. Severe hypoxia occurs in ALI/ARDS patients, who generally require high concentration oxygen therapy assisted by mechanical ventilation. Nevertheless, high oxygen can cause excessive reactive oxygen species (ROS), leading to apoptosis in lung epithelial cells, which has been reported in our previous study. Herein, the correlation between increments of ROS and CCN6 expression was negative in CCN6-mediated the mitochondria dependent, intrinsic apoptotic pathway. Our latest research explained that CCN6 can inhibit caspase-8 mediated extrinsic apoptotic pathway to protect cells from hyperoxia-induced apoptosis. As demonstrated by Western Blot Analysis, Caspase 8 cleavage and Caspase 3 cleavage in CCN6-depleted cells exceeded the control group treated with high oxygen (48 h). And deletion of CCN6 enhanced caspase-8 activation after hyperoxia shown by Flow Cytometry. Although, it is unclear how CCN6 participated in the regulation of apoptotic pathways, the future targeted therapy drugs inhibiting CCN6 may be useful in the treatment of ALI/ARDS. Copyright © 2018. Published by Elsevier B.V.

The Pathways fertility preservation decision aid website for women with cancer: development and field testing.

PubMed

Woodard, Terri L; Hoffman, Aubri S; Covarrubias, Laura A; Holman, Deborah; Schover, Leslie; Bradford, Andrea; Hoffman, Derek B; Mathur, Aakrati; Thomas, Jerah; Volk, Robert J

2018-02-01

To improve survivors' awareness and knowledge of fertility preservation counseling and treatment options, this study engaged survivors and providers to design, develop, and field-test Pathways: a fertility preservation patient decision aid website for young women with cancer©. Using an adapted user-centered design process, our stakeholder advisory group and research team designed and optimized the Pathways patient decision aid website through four iterative cycles of review and revision with clinicians (n = 21) and survivors (n = 14). Field-testing (n = 20 survivors) assessed post-decision aid scores on the Fertility Preservation Knowledge Scale, feasibility of assessing women's decision-making values while using the website, and website usability/acceptability ratings. Iterative stakeholder engagement optimized the Pathways decision aid website to meet survivors' and providers' needs, including providing patient-friendly information and novel features such as interactive value clarification exercises, testimonials that model shared decision making, financial/referral resources, and a printable personal summary. Survivors scored an average of 8.2 out of 13 (SD 1.6) on the Fertility Preservation Knowledge Scale. They rated genetic screening and having a biological child as strong factors in their decision-making, and 71% indicated a preference for egg freezing. Most women (> 85%) rated Pathways favorably, and all women (100%) said they would recommend it to other women. The Pathways decision aid is a usable and acceptable tool to help women learn about fertility preservation. The Pathways decision aid may help women make well-informed values-based decisions and prevent future infertility-related distress.

Metabolomic analysis of pancreatic β-cell insulin release in response to glucose.

PubMed

Huang, Mei; Joseph, Jamie W

2012-01-01

Defining the key metabolic pathways that are important for fuel-regulated insulin secretion is critical to providing a complete picture of how nutrients regulate insulin secretion. We have performed a detailed metabolomics study of the clonal β-cell line 832/13 using a gas chromatography-mass spectrometer (GC-MS) to investigate potential coupling factors that link metabolic pathways to insulin secretion. Mid-polar and polar metabolites, extracted from the 832/13 β-cells, were derivatized and then run on a GC/MS to identify and quantify metabolite concentrations. Three hundred fifty-five out of 527 chromatographic peaks could be identified as metabolites by our metabolomic platform. These identified metabolites allowed us to perform a systematic analysis of key pathways involved in glucose-stimulated insulin secretion (GSIS). Of these metabolites, 41 were consistently identified as biomarker for GSIS by orthogonal partial least-squares (OPLS). Most of the identified metabolites are from common metabolic pathways including glycolytic, sorbitol-aldose reductase pathway, pentose phosphate pathway, and the TCA cycle suggesting these pathways play an important role in GSIS. Lipids and related products were also shown to contribute to the clustering of high glucose sample groups. Amino acids lysine, tyrosine, alanine and serine were upregulated by glucose whereas aspartic acid was downregulated by glucose suggesting these amino acids might play a key role in GSIS. In summary, a coordinated signaling cascade elicited by glucose metabolism in pancreatic β-cells is revealed by our metabolomics platform providing a new conceptual framework for future research and/or drug discovery.

Distribution and uptake pathways of organochlorine pesticides in greenhouse and conventional vegetables.

PubMed

Zhang, Anping; Luo, Wenxiu; Sun, Jianqiang; Xiao, Hang; Liu, Weiping

2015-02-01

The application of greenhouse vegetable cultivation has dramatically expanded worldwide during the last several decades. However, little information is available on the distribution and uptake of pesticides in greenhouse vegetables. To bridge this knowledge gap, the present study was initiated to investigate the distribution and uptake of organochlorine pesticides (OCPs) in vegetables from plastic greenhouse and conventional cultivation methods. The uptake pathways of OCPs were not significantly different between these two cultivation methods. The arithmetic means of OCP concentrations in greenhouse vegetables were higher than those in conventional vegetables, although there was no significant difference. This small difference raised the concern of whether the tiny difference could be magnified to a significant difference by bioaccumulation in the food chain. The issue should be addressed by a well-designed scheme in future studies. Copyright © 2014 Elsevier B.V. All rights reserved.

Recent Advances in Targeted Therapy for Glioma.

PubMed

Lin, Lin; Cai, Jinquan; Jiang, Chuanlu

2017-01-01

Gliomas are the most common primary malignant brain tumors, which have a universally fatal outcome. Current standard treatment for glioma patients is surgical removal followed by radiotherapy and adjuvant chemotherapy. Due to therapeutic resistance and tumor recurrence, efforts are ongoing to identify the molecules that are fundamental to regulate the tumor progression and provide additional methods for individual treatment of glioma patients. By studying the initiation and maintenance of glioma, studies focused on the targets of tyrosine kinase receptors including EGFR, PDGFR and other crucial signal pathways such as PI3K/AKT and RAS/RAF/MAPK pathway. Furthermore, recent advances in targeting immunotherapy and stem cell therapy also brought numerous strategies to glioma treatment. This article reviewed the researches focused on the advanced strategies of various target therapies for improving the glioma treatment efficacy, and discussed the challenges and future directions for glioma therapy. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

In search of antiepileptogenic treatments for post-traumatic epilepsy.

PubMed

Saletti, Patricia G; Ali, Idrish; Casillas-Espinosa, Pablo M; Semple, Bridgette D; Lisgaras, Christos; Moshé, Solomon L; Galanopoulou, Aristea S

2018-06-21

Post-traumatic epilepsy (PTE) occurs in 20% of individuals with acquired epilepsy, and can impact significantly the quality of life due to the seizures and other functional or cognitive and behavioral outcomes of the traumatic brain injury (TBI) and PTE. There is no available antiepileptogenic or disease modifying treatment for PTE. Animal models of TBI and PTE have been developed, offering useful insights on the value of inflammatory, neurodegenerative pathways, hemorrhages and iron accumulation, calcium channels and other target pathways that could be used for treatment development. Most of the existing preclinical studies test efficacy towards pathologies of functional recovery after TBI, while a few studies are emerging testing the effects towards induced or spontaneous seizures. Here we review the existing preclinical trials testing new candidate treatments for TBI sequelae and PTE, and discuss future directions for efforts aiming at developing antiepileptogenic and disease-modifying treatments. Copyright © 2018. Published by Elsevier Inc.

Kinetic Study of Acetone-Butanol-Ethanol Fermentation in Continuous Culture

PubMed Central

Buehler, Edward A.; Mesbah, Ali

2016-01-01

Acetone-butanol-ethanol (ABE) fermentation by clostridia has shown promise for industrial-scale production of biobutanol. However, the continuous ABE fermentation suffers from low product yield, titer, and productivity. Systems analysis of the continuous ABE fermentation will offer insights into its metabolic pathway as well as into optimal fermentation design and operation. For the ABE fermentation in continuous Clostridium acetobutylicum culture, this paper presents a kinetic model that includes the effects of key metabolic intermediates and enzymes as well as culture pH, product inhibition, and glucose inhibition. The kinetic model is used for elucidating the behavior of the ABE fermentation under the conditions that are most relevant to continuous cultures. To this end, dynamic sensitivity analysis is performed to systematically investigate the effects of culture conditions, reaction kinetics, and enzymes on the dynamics of the ABE production pathway. The analysis provides guidance for future metabolic engineering and fermentation optimization studies. PMID:27486663

Genetics of Age-Related Macular Degeneration: Current Concepts, Future Directions

PubMed Central

DeAngelis, Margaret M.; Silveira, Alexandra C.; Carr, Elizabeth A.; Kim, Ivana K.

2014-01-01

Age-related macular degeneration (AMD) is a progressive degenerative disease which leads to blindness, affecting the quality of life of millions of Americans. More than 1.75 million individuals in the United States are affected by the advanced form of AMD. The etiological pathway of AMD is not yet fully understood, but there is a clear genetic influence on disease risk. To date, the 1q32 (CFH) and 10q26 (PLEKHA1/ARMS2/HTRA1) loci are the most strongly associated with disease; however, the variation in these genomic regions alone is unable to predict disease development with high accuracy. Therefore, current genetic studies are aimed at identifying new genes associated with AMD and their modifiers, with the goal of discovering diagnostic or prognostic biomarkers. Moreover, these studies provide the foundation for further investigation into the pathophysiology of AMD by utilizing a systems-biology-based approach to elucidate underlying mechanistic pathways. PMID:21609220

Apigenin: A dietary flavonoid with diverse anticancer properties.

PubMed

Madunić, Josip; Madunić, Ivana Vrhovac; Gajski, Goran; Popić, Jelena; Garaj-Vrhovac, Vera

2018-01-28

Apigenin is a natural flavonoid found in several dietary plant foods such as vegetables and fruits. A large number of studies conducted over the past years have shown that this particular natural compound has potential antioxidant, anti-inflammatory, and anticancer properties. Therefore, apigenin has generated a great deal of interest as a possible chemotherapeutic modality due to its low intrinsic toxicity and remarkable effects on normal versus cancerous cells, compared with other structurally related flavonoids. Here, we review its role in anticancer research, as well as several cancer signalling pathways, including MAPK, PI3K/Akt and NF-κB pathways, and their specific role in different cancer types. Based on the available literature, the beneficial effects of apigenin as a future anticancer modality are promising but they require further in vitro and in vivo studies to enable its translation from bench to bedside. Copyright © 2017 Elsevier B.V. All rights reserved.

Zymomonas mobilis: a novel platform for future biorefineries.

PubMed

He, Ming Xiong; Wu, Bo; Qin, Han; Ruan, Zhi Yong; Tan, Fu Rong; Wang, Jing Li; Shui, Zong Xia; Dai, Li Chun; Zhu, Qi Li; Pan, Ke; Tang, Xiao Yu; Wang, Wen Guo; Hu, Qi Chun

2014-01-01

Biosynthesis of liquid fuels and biomass-based building block chemicals from microorganisms have been regarded as a competitive alternative route to traditional. Zymomonas mobilis possesses a number of desirable characteristics for its special Entner-Doudoroff pathway, which makes it an ideal platform for both metabolic engineering and commercial-scale production of desirable bio-products as the same as Escherichia coli and Saccharomyces cerevisiae based on consideration of future biomass biorefinery. Z. mobilis has been studied extensively on both fundamental and applied level, which will provide a basis for industrial biotechnology in the future. Furthermore, metabolic engineering of Z. mobilis for enhancing bio-ethanol production from biomass resources has been significantly promoted by different methods (i.e. mutagenesis, adaptive laboratory evolution, specific gene knock-out, and metabolic engineering). In addition, the feasibility of representative metabolites, i.e. sorbitol, bionic acid, levan, succinic acid, isobutanol, and isobutanol produced by Z. mobilis and the strategies for strain improvements are also discussed or highlighted in this paper. Moreover, this review will present some guidelines for future developments in the bio-based chemical production using Z. mobilis as a novel industrial platform for future biofineries.

Pathogenesis and treatment of psoriasis: exploiting pathophysiological pathways for precision medicine.

PubMed

Alwan, Wisam; Nestle, Frank O

2015-01-01

Psoriasis is a common, chronic inflammatory skin disease associated with multi-system manifestations including arthritis and obesity. Our knowledge of the aetiology of the condition, including the key genomic, immune and environmental factors, has led to the development of targeted, precision therapies that alleviate patient morbidity. This article reviews the key pathophysiological pathways and therapeutic targets and highlights future areas of interest in psoriasis research.

Electrophysiological experiments in microgravity: lessons learned and future challenges.

PubMed

Wuest, Simon L; Gantenbein, Benjamin; Ille, Fabian; Egli, Marcel

2018-01-01

Advances in electrophysiological experiments have led to the discovery of mechanosensitive ion channels (MSCs) and the identification of the physiological function of specific MSCs. They are believed to play important roles in mechanosensitive pathways by allowing for cells to sense their mechanical environment. However, the physiological function of many MSCs has not been conclusively identified. Therefore, experiments have been developed that expose cells to various mechanical loads, such as shear flow, membrane indentation, osmotic challenges and hydrostatic pressure. In line with these experiments, mechanical unloading, as experienced in microgravity, represents an interesting alternative condition, since exposure to microgravity leads to a series of physiological adaption processes. As outlined in this review, electrophysiological experiments performed in microgravity have shown an influence of gravity on biological functions depending on ion channels at all hierarchical levels, from the cellular level to organs. In this context, calcium signaling represents an interesting cellular pathway, as it involves the direct action of calcium-permeable ion channels, and specific gravitatic cells have linked graviperception to this pathway. Multiple key proteins in the graviperception pathways have been identified. However, measurements on vertebrae cells have revealed controversial results. In conclusion, electrophysiological experiments in microgravity have shown that ion-channel-dependent physiological processes are altered in mechanically unloaded conditions. Future experiments may provide a better understanding of the underlying mechanisms.

Dissecting Germ Cell Metabolism through Network Modeling.

PubMed

Whitmore, Leanne S; Ye, Ping

2015-01-01

Metabolic pathways are increasingly postulated to be vital in programming cell fate, including stemness, differentiation, proliferation, and apoptosis. The commitment to meiosis is a critical fate decision for mammalian germ cells, and requires a metabolic derivative of vitamin A, retinoic acid (RA). Recent evidence showed that a pulse of RA is generated in the testis of male mice thereby triggering meiotic commitment. However, enzymes and reactions that regulate this RA pulse have yet to be identified. We developed a mouse germ cell-specific metabolic network with a curated vitamin A pathway. Using this network, we implemented flux balance analysis throughout the initial wave of spermatogenesis to elucidate important reactions and enzymes for the generation and degradation of RA. Our results indicate that primary RA sources in the germ cell include RA import from the extracellular region, release of RA from binding proteins, and metabolism of retinal to RA. Further, in silico knockouts of genes and reactions in the vitamin A pathway predict that deletion of Lipe, hormone-sensitive lipase, disrupts the RA pulse thereby causing spermatogenic defects. Examination of other metabolic pathways reveals that the citric acid cycle is the most active pathway. In addition, we discover that fatty acid synthesis/oxidation are the primary energy sources in the germ cell. In summary, this study predicts enzymes, reactions, and pathways important for germ cell commitment to meiosis. These findings enhance our understanding of the metabolic control of germ cell differentiation and will help guide future experiments to improve reproductive health.

Conservation of the coding regions of the glycine N-acyltransferase gene further suggests that glycine conjugation is an essential detoxification pathway.

PubMed

van der Sluis, Rencia; Badenhorst, Christoffel P S; Erasmus, Elardus; van Dyk, Etresia; van der Westhuizen, Francois H; van Dijk, Alberdina A

2015-10-15

Thorough investigation of the glycine conjugation pathway has been neglected. No defect of the glycine conjugation pathway has been reported and this could reflect the essential role of glycine conjugation in hepatic metabolism. Therefore, we hypothesised that genetic variation in the open reading frame (ORF) of the GLYAT gene should be low and that deleterious alleles would be found at low frequencies. This hypothesis was investigated by analysing the genetic variation of the human GLYAT ORF using data available in public databases. We also sequenced the GLYAT ORF of a small cohort of South African Afrikaner Caucasian individuals. In total, data from 1537 individuals was analysed. The two most prominent GLYAT haplotypes in all populations analysed, were S156 (70%) and T17S156 (20%). The S156C199 and S156H131 haplotypes, which have a negative effect on the enzyme activity of a recombinant human GLYAT, were detected at very low frequencies. In the Afrikaner Caucasian cohort a novel Q61L SNP occurring at a high frequency (12%) was detected. The results of this study indicated that the GLYAT ORF is highly conserved and supported the hypothesis that the glycine conjugation pathway is an essential detoxification pathway. These findings emphasise the importance of future investigations to determine the in vivo capacity of the glycine conjugation pathway for the detoxification of benzoate and other xenobiotics. Copyright © 2015 Elsevier B.V. All rights reserved.

Quantifying the economic competitiveness of cellulosic biofuel pathways under uncertainty and regional sensitivity

NASA Astrophysics Data System (ADS)

Brown, Tristan R.

The revised Renewable Fuel Standard requires the annual blending of 16 billion gallons of cellulosic biofuel by 2022 from zero gallons in 2009. The necessary capacity investments have been underwhelming to date, however, and little is known about the likely composition of the future cellulosic biofuel industry as a result. This dissertation develops a framework for identifying and analyzing the industry's likely future composition while also providing a possible explanation for why investment in cellulosic biofuels capacity has been low to date. The results of this dissertation indicate that few cellulosic biofuel pathways will be economically competitive with petroleum on an unsubsidized basis. Of five cellulosic biofuel pathways considered under 20-year price forecasts with volatility, only two achieve positive mean 20-year net present value (NPV) probabilities. Furthermore, recent exploitation of U.S. shale gas reserves and the subsequent fall in U.S. natural gas prices have negatively impacted the economic competitiveness of all but two of the cellulosic biofuel pathways considered; only two of the five pathways achieve substantially higher 20-year NPVs under a post-shale gas economic scenario relative to a pre-shale gas scenario. The economic competitiveness of cellulosic biofuel pathways with petroleum is reduced further when considered under price uncertainty in combination with realistic financial assumptions. This dissertation calculates pathway-specific costs of capital for five cellulosic biofuel pathway scenarios. The analysis finds that the large majority of the scenarios incur costs of capital that are substantially higher than those commonly assumed in the literature. Employment of these costs of capital in a comparative TEA greatly reduces the mean 20-year NPVs for each pathway while increasing their 10-year probabilities of default to above 80% for all five scenarios. Finally, this dissertation quantifies the economic competitiveness of six cellulosic biofuel pathways being commercialized in eight different U.S. states under price uncertainty, utilization of pathway-specific costs of capital, and region-specific economic factors. 10-year probabilities of default in excess of 60% are calculated for all eight location scenarios considered, with default probabilities in excess of 98% calculated for seven of the eight. Negative mean 20-year NPVs are calculated for seven of the eight location scenarios.

The ROOTS study: a 10-year review of findings on adolescent depression, and recommendations for future longitudinal research.

PubMed

Lewis, Gemma; Jones, Peter B; Goodyer, Ian M

2016-02-01

The purpose of this study is to review longitudinal findings on adolescent mental health from the 'ROOTS study', and provide directions and recommendations for future longitudinal research. To do this, we discuss relevant findings from the ROOTS study, and review its strengths and limitations. We examined all publications from the ROOTS study up to July 2015, selected those examining adolescent mental health, and classified them as investigating (a) childhood risk factors for adolescent depression, (b) genetic and cognitive vulnerability to depression in adolescence, (c) genetic markers, childhood adversities, and neuroendophenotypes, (d) morning cortisol and depression, (e) physical activity and depression symptoms, and (f) the underlying structure of mental health in adolescence. We reviewed the strengths and limitations of the ROOTS study, and how they feed into recommendations for future longitudinal research. There was evidence supporting a putative hormonal biomarker for the emergence of depression in boys. Environmental pathways from child adversity to adolescent depression were confirmed in girls, partly accounted for by negative life events in early adolescence. The preceding role of automatic cognitive biases assessed using behavioural tasks was substantiated, with evidence for genetic susceptibility. Novel latent statistical models of child adversity, depression, anxiety, and psychotic experiences were produced, with concurrent and prospective validity. Our experiences conducting the ROOTS study resulted in a set of strengths, limitations, and recommendations for future longitudinal studies. The ROOTS study has advanced knowledge on the aetiology of adolescent depression by investigating environmental, genetic, hormonal, and neural risk factors. Findings provide a foundation for future research integrating cognitive neuroscience with epidemiology.

Basal cell nevus syndrome (Gorlin syndrome): genetic insights, diagnostic challenges, and unmet milestones.

PubMed

Akbari, Maryam; Chen, Harold; Guo, Grace; Legan, Zachary; Ghali, Ghali

2018-01-31

In this article, we present three clinical case reports on Basal Cell Nevus Syndrome (Gorlin Syndrome). Gorlin syndrome is an inherited medical condition with challenges that manifest in multiple body systems and complicate early diagnosis. We examine the epidemiology of the disease and benefits of genetic testing, molecular pathophysiology, and advancement in the molecular-based therapy of Basal Cell Nevus syndrome. The goal of this paper is to shed light on both unmet challenges and advancements in the management of Gorlin syndrome and to provide a new clinical perspective and guidance for future research. Furthermore, the FDA approved Hedgehog pathway inhibitors Vismodegib and Sonidegib designed for advanced basal cell carcinoma have opened a new door for treatment that may ultimately decrease the number of surgeries for a patient with Gorlin syndrome. The role of these agents in syndromic odontogenic keratocyst has not been studied extensively, but one study found that hedgehog pathway inhibitors decrease the size of syndromic odontogenic keratocyst. Ideal surgical treatment that balances low recurrence rates with low impact on one's quality of life for syndromic odontogenic keratocyst is another unanswered question for oral and maxillofacial surgeons. Per survey studies, treatment options practiced for syndromic odontogenic keratocyst range from marsupialization to segmental osteotomy. Future studies performed should take a comprehensive long-term approach with at least three years of follow-up in order to determine the most appropriate treatment. Copyright © 2018 Elsevier B.V. All rights reserved.

Histone methyltransferase SETDB1 maintains survival of mouse spermatogonial stem/progenitor cells via PTEN/AKT/FOXO1 pathway.

PubMed

Liu, Tiantian; Chen, Xiaoxu; Li, Tianjiao; Li, Xueliang; Lyu, Yinghua; Fan, Xiaoteng; Zhang, Pengfei; Zeng, Wenxian

2017-10-01

Spermatogonial stem cells (SSCs) possess the capacity of self-renewal and differentiation, which are the basis of spermatogenesis. In maintenance of SSC homeostasis, intrinsic/extrinsic factors and various signaling pathways tightly control the fate of SSCs. Methyltransferase SETDB1 (Set domain, bifurcated 1) catalyzes histone H3 lysine 9 (H3K9) trimethylation and represses gene expression. SETDB1 is required for maintaining the survival of spermatogonial stem cells in mice. However, the underlying molecular mechanism remains unclear. In the present study, we found that Setdb1 regulates PTEN/AKT/FOXO1 pathway to inhibit SSC apoptosis. Co-immunoprecipitation and reporter gene assay revealed that SETDB1 interacted and coordinated with AKT to regulate FOXO1 activity and expression of the downstream target genes Bim and Puma. Among the SETDB1-bound genes, the H3K9me3 levels on the promoter regions of Bim and Pten decreased in Setdb1-KD group; in contrast, H3K9me3 status on promoters of Bax and Puma remained unchanged. Therefore, SETDB1 was responsible for regulating the transcription activity of genes in the apoptotic pathway at least in part through modulating H3K9me3. This study replenishes the research on the epigenetic regulation of SSC survival, and provides a new insight for the future study of epigenetic regulation of spermatogenesis. Copyright © 2017 Elsevier B.V. All rights reserved.

Is systems pharmacology ready to impact upon therapy development? A study on the cholesterol biosynthesis pathway

PubMed Central

Benson, Helen E; Sharman, Joanna L; Mpamhanga, Chido P; Parton, Andrew; Southan, Christopher; Harmar, Anthony J; Ghazal, Peter

2017-01-01

Background and Purpose An ever‐growing wealth of information on current drugs and their pharmacological effects is available from online databases. As our understanding of systems biology increases, we have the opportunity to predict, model and quantify how drug combinations can be introduced that outperform conventional single‐drug therapies. Here, we explore the feasibility of such systems pharmacology approaches with an analysis of the mevalonate branch of the cholesterol biosynthesis pathway. Experimental Approach Using open online resources, we assembled a computational model of the mevalonate pathway and compiled a set of inhibitors directed against targets in this pathway. We used computational optimization to identify combination and dose options that show not only maximal efficacy of inhibition on the cholesterol producing branch but also minimal impact on the geranylation branch, known to mediate the side effects of pharmaceutical treatment. Key Results We describe serious impediments to systems pharmacology studies arising from limitations in the data, incomplete coverage and inconsistent reporting. By curating a more complete dataset, we demonstrate the utility of computational optimization for identifying multi‐drug treatments with high efficacy and minimal off‐target effects. Conclusion and Implications We suggest solutions that facilitate systems pharmacology studies, based on the introduction of standards for data capture that increase the power of experimental data. We propose a systems pharmacology workflow for the refinement of data and the generation of future therapeutic hypotheses. PMID:28910500

Metabolomics Analysis of the Toxic Effects of the Production of Lycopene and Its Precursors.

PubMed

Miguez, April M; McNerney, Monica P; Styczynski, Mark P

2018-01-01

Using cells as microbial factories enables highly specific production of chemicals with many advantages over chemical syntheses. A number of exciting new applications of this approach are in the area of precision metabolic engineering, which focuses on improving the specificity of target production. In recent work, we have used precision metabolic engineering to design lycopene-producing Escherichia coli for use as a low-cost diagnostic biosensor. To increase precursor availability and thus the rate of lycopene production, we heterologously expressed the mevalonate pathway. We found that simultaneous induction of these pathways increases lycopene production, but induction of the mevalonate pathway before induction of the lycopene pathway decreases both lycopene production and growth rate. Here, we aim to characterize the metabolic changes the cells may be undergoing during expression of either or both of these heterologous pathways. After establishing an improved method for quenching E. coli for metabolomics analysis, we used two-dimensional gas chromatography coupled to mass spectrometry (GCxGC-MS) to characterize the metabolomic profile of our lycopene-producing strains in growth conditions characteristic of our biosensor application. We found that the metabolic impacts of producing low, non-toxic levels of lycopene are of much smaller magnitude than the typical metabolic changes inherent to batch growth. We then used metabolomics to study differences in metabolism caused by the time of mevalonate pathway induction and the presence of the lycopene biosynthesis genes. We found that overnight induction of the mevalonate pathway was toxic to cells, but that the cells could recover if the lycopene pathway was not also heterologously expressed. The two pathways appeared to have an antagonistic metabolic effect that was clearly reflected in the cells' metabolic profiles. The metabolites homocysteine and homoserine exhibited particularly interesting behaviors and may be linked to the growth inhibition seen when the mevalonate pathway is induced overnight, suggesting potential future work that may be useful in engineering increased lycopene biosynthesis.

The Feasibility of Avoiding Future Climate Impacts: Results from the AVOID Programmes

NASA Astrophysics Data System (ADS)

Lowe, J. A.; Warren, R.; Arnell, N.; Buckle, S.

2014-12-01

The AVOID programme and its successor, AVOID2, have focused on answering three core questions: how do we characterise potentially dangerous climate change and impacts, which emissions pathways can avoid at least some of these impacts, and how feasible are the future reductions needed to significantly deviate from a business-as-usual future emissions pathway. The first AVOID project succeeded in providing the UK Government with evidence to inform its position on climate change. A key part of the work involved developing a range of global emissions pathways and estimating and understanding the corresponding global impacts. This made use of a combination of complex general circulation models, simple climate models, pattern-scaling and state-of-the art impacts models. The results characterise the range of avoidable impacts across the globe in several key sectors including river and coastal flooding, cooling and heating energy demand, crop productivity and aspects of biodiversity. The avoided impacts between a scenario compatible with a 4ºC global warming and one with a 2ºC global warming were found to be highly sector dependent and avoided fractions typically ranged between 20% and 70%. A further key aspect was characterising the magnitude of the uncertainty involved, which is found to be very large in some impact sectors although the avoided fraction appears a more robust metric. The AVOID2 programme began in 2014 and will provide results in the run up to the Paris CoP in 2015. This includes new post-IPCC 5th assessment evidence to inform the long-term climate goal, a more comprehensive assessment of the uncertainty ranges of feasible emission pathways compatible with the long-term goal and enhanced estimates of global impacts using the latest generation of impact models and scenarios.

A Translational Pathway Toward a Clinical Trial Using the Second-Generation AAV Micro Dystrophin Vector

DTIC Science & Technology

2017-09-01

future experimental therapeutic studies in the canine model such as CRISPR -mediated gene editing, stem cell therapy, dystrophin-independent disease...There is no scientific/budget overlap with the current proposal.) CRISPR /Cas9-based gene editing for the correction of Duchenne muscular dystrophy...lab will perform in vivo gene delivery and functional outcome measurements in mice treated by AAV- CRISPR gene repair vectors and if needed will also

Naturally occurring polyphenol, morin hydrate, inhibits enzymatic activity of N-methylpurine DNA glycosylase, a DNA repair enzyme with various roles in human disease

PubMed Central

Dixon, Monica; Woodrick, Jordan; Gupta, Suhani; Karmahapatra, Soumendra Krishna; Devito, Stephen; Vasudevan, Sona; Dakshanamurthy, Sivanesan; Adhikari, Sanjay; Yenugonda, Venkata M.; Roy, Rabindra

2015-01-01

Interest in the mechanisms of DNA repair pathways, including the base excision repair (BER) pathway specifically, has heightened since these pathways have been shown to modulate important aspects of human disease. Modulation of the expression or activity of a particular BER enzyme, N-methylpurine DNA glycosylase (MPG), has been demonstrated to play a role in carcinogenesis and resistance to chemotherapy as well as neurodegenerative diseases, which has intensified the focus on studying MPG-related mechanisms of repair. A specific small molecule inhibitor for MPG activity would be a valuable biochemical tool for understanding these repair mechanisms. By screening several small molecule chemical libraries, we identified a natural polyphenolic compound, morin hydrate, which inhibits MPG activity specifically (IC50 = 2.6 µM). Detailed mechanism analysis showed that morin hydrate inhibited substrate DNA binding of MPG, and eventually the enzymatic activity of MPG. Computational docking studies with an x-ray derived MPG structure as well as comparison studies with other structurally-related flavanoids offer a rationale for the inhibitory activity of morin hydrate observed. The results of this study suggest that the morin hydrate could be an effective tool for studying MPG function and it is possible that morin hydrate and its derivatives could be utilized in future studies focused on the role of MPG in human disease. PMID:25650313

Pathways for scaling up public health interventions.

PubMed

Indig, Devon; Lee, Karen; Grunseit, Anne; Milat, Andrew; Bauman, Adrian

2017-08-01

To achieve population-wide health improvement, public health interventions found effective in selected samples need to be 'scaled up' and implemented more widely. The pathways through which interventions are scaled up are not well characterised. The aim of this paper is to identify examples of public health interventions which have been scaled up and to develop a conceptual framework which quantifies and describes this process. A multi-stage international literature search was undertaken to identify examples of public health interventions in high income countries that have been scaled up or implemented at scale. Initial abstract review identified articles which met all the criteria of being a: 1) public health intervention; 2) chronic disease prevention focus; 3) program delivered at a wide geographical scale (state, national or international). Interventions were reviewed and coded into a conceptual framework pathway to document their scaling up process. For each program, an in-depth review of the identified articles was undertaken along with a broad internet based search to determine the outcomes of the dissemination process. A conceptual framework of scaling up pathways was developed that involved four stages (development, efficacy testing, real world trial and dissemination) to which the 40 programs were mapped. The search identified 40 public health interventions that showed evidence of being scaled up. Four pathways were identified to capture the different scaling up trajectories taken which included: 'Type I - Comprehensive' (55%) which passed through all four stages, 'Type II - Efficacy omitters' (5%) which did not conduct efficacy testing, 'Type III - Trial omitters' (25%) which did not conduct a real world trial, and 'Type IV - At scale dissemination' (15%) which skipped both efficacy testing and a real world trial. This is the first study to classify and quantify the potential pathways through which public health interventions in high income countries are scaled up to reach the broader population. Mapping these pathways not only demonstrates the different trajectories that occur in scaling up public health interventions, but also allows the variation across scaling up pathways to be classified. The policy and practice determinants leading to each pathway remain for future study, especially to identify the conditions under which efficacy and replication stages are missing.

Identification of potential genetic components involved in the deviant quorum-sensing signaling pathways of Burkholderia glumae through a functional genomics approach

PubMed Central

Chen, Ruoxi; Barphagha, Inderjit K.; Ham, Jong Hyun

2015-01-01

Burkholderia glumae is the chief causal agent for bacterial panicle blight of rice. The acyl-homoserine lactone (AHL)-mediated quorum-sensing (QS) system dependent on a pair of luxI and luxR homologs, tofI and tofR, is the primary cell-to-cell signaling mechanism determining the virulence of this bacterium. Production of toxoflavin, a major virulence factor of B. glumae, is known to be dependent on the tofI/tofR QS system. In our previous study, however, it was observed that B. glumae mutants defective in tofI or tofR produced toxoflavin if they grew on the surface of a solid medium, suggesting that alternative signaling pathways independent of tofI or tofR are activated in that growth condition for the production of toxoflavin. In this study, potential genetic components involved in the tofI- and tofR-independent signaling pathways for toxoflavin production were sought through screening random mini-Tn5 mutants of B. glumae to better understand the intercellular signaling pathways of this pathogen. Fifteen and three genes were initially identified as the potential genetic elements of the tofI- and tofR-independent pathways, respectively. Especially, the ORF (bglu_2g06320) divergently transcribed from toxJ, which encodes an orphan LuxR protein and controls toxoflavin biosynthesis, was newly identified in this study as a gene required for the tofR-independent toxoflavin production and named as toxK. Among those genes, flhD, dgcB, and wzyB were further studied to validate their functions in the tofI-independent toxoflavin production, and similar studies were also conducted with qsmR and toxK for their functions in the tofR-independent toxoflavin production. This work provides a foundation for future comprehensive studies of the intercellular signaling systems of B. glumae and other related pathogenic bacteria. PMID:25806356

Climate Risk Informed Decision Analysis: A Hypothetical Application to the Waas Region

NASA Astrophysics Data System (ADS)

Gilroy, Kristin; Mens, Marjolein; Haasnoot, Marjolijn; Jeuken, Ad

2016-04-01

More frequent and intense hydrologic events under climate change are expected to enhance water security and flood risk management challenges worldwide. Traditional planning approaches must be adapted to address climate change and develop solutions with an appropriate level of robustness and flexibility. The Climate Risk Informed Decision Analysis (CRIDA) method is a novel planning approach embodying a suite of complementary methods, including decision scaling and adaptation pathways. Decision scaling offers a bottom-up approach to assess risk and tailors the complexity of the analysis to the problem at hand and the available capacity. Through adaptation pathway,s an array of future strategies towards climate robustness are developed, ranging in flexibility and immediacy of investments. Flexible pathways include transfer points to other strategies to ensure that the system can be adapted if future conditions vary from those expected. CRIDA combines these two approaches in a stakeholder driven process which guides decision makers through the planning and decision process, taking into account how the confidence in the available science, the consequences in the system, and the capacity of institutions should influence strategy selection. In this presentation, we will explain the CRIDA method and compare it to existing planning processes, such as the US Army Corps of Engineers Principles and Guidelines as well as Integrated Water Resources Management Planning. Then, we will apply the approach to a hypothetical case study for the Waas Region, a large downstream river basin facing rapid development threatened by increased flood risks. Through the case study, we will demonstrate how a stakeholder driven process can be used to evaluate system robustness to climate change; develop adaptation pathways for multiple objectives and criteria; and illustrate how varying levels of confidence, consequences, and capacity would play a role in the decision making process, specifically in regards to the level of robustness and flexibility in the selected strategy. This work will equip practitioners and decision makers with an example of a structured process for decision making under climate uncertainty that can be scaled as needed to the problem at hand. This presentation builds further on another submitted abstract "Climate Risk Informed Decision Analysis (CRIDA): A novel practical guidance for Climate Resilient Investments and Planning" by Jeuken et al.

Pathways to suicide attempts among male offenders: the role of agency.

PubMed

Byng, Richard; Howerton, Amanda; Owens, Christabel V; Campbell, John

2015-07-01

Suicide is common among offenders, who are at increased risk of homelessness, unemployment and mental illness and are prone to impulsivity. Release from prison is a particularly vulnerable time. This qualitative study investigated the views of 35 offenders in South-West England prior to and after release from prison, enquiring into their previous suicide attempts and how they saw their future. Semi-structured interviews were analysed thematically, comparing individuals who had made one, more than one, and no suicide attempts. Multiple attempters were often in despair and enmeshed in substance misuse, with little control over their lives. Most of those with one-off or no previous attempts portrayed themselves as having more mastery. One-off attempters described using particularly violent means. The role of different types of agency in pathways to and from suicide is discussed. Iterational agency, the selective reactivation of past patterns of behaviour, appeared to dominate in individuals who were choosing between further suicide attempts and substance use. Projective agency, having a more future orientation, appeared more prominent in some single attempters and in those individuals with plans to escape crime and social exclusion. © 2015 Foundation for the Sociology of Health & Illness.

Designing Dynamic Adaptive Policy Pathways using Many-Objective Robust Decision Making

NASA Astrophysics Data System (ADS)

Kwakkel, Jan; Haasnoot, Marjolijn

2017-04-01

Dealing with climate risks in water management requires confronting a wide variety of deeply uncertain factors, while navigating a many dimensional space of trade-offs amongst objectives. There is an emerging body of literature on supporting this type of decision problem, under the label of decision making under deep uncertainty. Two approaches within this literature are Many-Objective Robust Decision Making, and Dynamic Adaptive Policy Pathways. In recent work, these approaches have been compared. One of the main conclusions of this comparison was that they are highly complementary. Many-Objective Robust Decision Making is a model based decision support approach, while Dynamic Adaptive Policy Pathways is primarily a conceptual framework for the design of flexible strategies that can be adapted over time in response to how the future is actually unfolding. In this research we explore this complementarity in more detail. Specifically, we demonstrate how Many-Objective Robust Decision Making can be used to design adaptation pathways. We demonstrate this combined approach using a water management problem, in the Netherlands. The water level of Lake IJselmeer, the main fresh water resource of the Netherlands, is currently managed through discharge by gravity. Due to climate change, this won't be possible in the future, unless water levels are changed. Changing the water level has undesirable flood risk and spatial planning consequences. The challenge is to find promising adaptation pathways that balance objectives related to fresh water supply, flood risk, and spatial issues, while accounting for uncertain climatic and land use change. We conclude that the combination of Many-Objective Robust Decision Making and Dynamic Adaptive Policy Pathways is particularly suited for dealing with deeply uncertain climate risks.

Concept mapping One-Carbon Metabolism to model future ontologies for nutrient-gene-phenotype interactions.

PubMed

Joslin, A C; Green, R; German, J B; Lange, M C

2014-09-01

Advances in the development of bioinformatic tools continue to improve investigators' ability to interrogate, organize, and derive knowledge from large amounts of heterogeneous information. These tools often require advanced technical skills not possessed by life scientists. User-friendly, low-barrier-to-entry methods of visualizing nutrigenomics information are yet to be developed. We utilized concept mapping software from the Institute for Human and Machine Cognition to create a conceptual model of diet and health-related data that provides a foundation for future nutrigenomics ontologies describing published nutrient-gene/polymorphism-phenotype data. In this model, maps containing phenotype, nutrient, gene product, and genetic polymorphism interactions are visualized as triples of two concepts linked together by a linking phrase. These triples, or "knowledge propositions," contextualize aggregated data and information into easy-to-read knowledge maps. Maps of these triples enable visualization of genes spanning the One-Carbon Metabolism (OCM) pathway, their sequence variants, and multiple literature-mined associations including concepts relevant to nutrition, phenotypes, and health. The concept map development process documents the incongruity of information derived from pathway databases versus literature resources. This conceptual model highlights the importance of incorporating information about genes in upstream pathways that provide substrates, as well as downstream pathways that utilize products of the pathway under investigation, in this case OCM. Other genes and their polymorphisms, such as TCN2 and FUT2, although not directly involved in OCM, potentially alter OCM pathway functionality. These upstream gene products regulate substrates such as B12. Constellations of polymorphisms affecting the functionality of genes along OCM, together with substrate and cofactor availability, may impact resultant phenotypes. These conceptual maps provide a foundational framework for development of nutrient-gene/polymorphism-phenotype ontologies and systems visualization.

21st Century Learning and Information Literacy

ERIC Educational Resources Information Center

Breivik, Patricia Senn

2005-01-01

The faces of immigrant children who had come through Ellis Island with their parents in search of better futures stare out at me from a set of black and white photographs near my desk. The children, frozen in time, are lined up for blocks, waiting for the doors of a public library to open. Access to information was their pathway to a future of…

Becoming Job-Ready: Collaborative Future Plans of Latina Adolescent Girls and Their Mothers in a Low-Income Urban Community

ERIC Educational Resources Information Center

Packard, Becky Wai-Ling; Babineau, Maureen E.; Machado, Haidee

2012-01-01

This article examined the future plans constructed by Latina adolescent girls and their mothers within a lower income urban community. Seventeen high school juniors and their mothers were interviewed about the girls' pursuit of a trade during high school and anticipated postsecondary pathways in the nursing field. Thematic content analyses…

Pathways of iron acquisition and utilization in Leishmania

PubMed Central

Flannery, Andrew R.; Renberg, Rebecca L.; Andrews, Norma W.

2013-01-01

Iron is essential for many metabolic pathways, but is toxic in excess. Recent identification of the ferric iron reductase LFR1, the ferrous iron transporter LIT1, and the heme transporter LHR1 greatly advanced our understanding of how Leishmania parasites acquire iron and regulate its uptake. LFR1 and LIT1 have close orthologs in plants, and are required for Leishmania virulence. Consistent with the lack of heme biosynthesis in trypanosomatids, LHR1 and LABCG5, a protein involved in heme salvage from hemoglobin, seem essential for Leishmania survival. LFR1, LIT1 and LHR1 are upregulated under low iron availability, in agreement with the need to prevent excessive iron uptake. Future studies should clarify how Leishmania interacts with the iron homeostasis machinery of its host cell, the macrophage. PMID:23962817

Stereotypic Movement Disorders.

PubMed

Katherine, Mackenzie

2018-04-01

This review summarizes motor stereotypies in terms of description, prevalence, pathophysiology, diagnosis and management. They are fixed and persistent movements. Stereotypies begin before 3 years of age and continue into adulthood. Primary motor stereotypies occur in children of normal intelligence, whereas secondary stereotypies ensue in the setting of an additional diagnosis such as autism spectrum disorder or other neurologic disorders. They are highly associated with comorbidities such as anxiety, obsessive-compulsive symptoms, inattention, and tics. The pathophysiology of stereotypies involves fronto-striatal overactive dopaminergic pathways, and underactive cholinergic and GABAergic inhibitory pathways. No genetic markers have been identified despite a clear genetic predisposition. Behavioral therapy is the principle treatment. Future studies will focus on identifying genetic markers, and on better understanding the functional and structural neurobiology of these movements. Copyright © 2018 Elsevier Inc. All rights reserved.

Morphoproteomic profiling of the mammalian target of rapamycin (mTOR) signaling pathway in desmoplastic small round cell tumor (EWS/WT1), Ewing's sarcoma (EWS/FLI1) and Wilms' tumor(WT1).

PubMed

Subbiah, Vivek; Brown, Robert E; Jiang, Yunyun; Buryanek, Jamie; Hayes-Jordan, Andrea; Kurzrock, Razelle; Anderson, Pete M

2013-01-01

Desmoplastic small round cell tumor (DSRCT) is a rare sarcoma in adolescents and young adults. The hallmark of this disease is a EWS-WT1 translocation resulting from apposition of the Ewing's sarcoma (EWS) gene with the Wilms' tumor (WT1) gene. We performed morphoproteomic profiling of DSRCT (EWS-WT1), Ewing's sarcoma (EWS-FLI1) and Wilms' tumor (WT1) to better understand the signaling pathways for selecting future targeted therapies. This pilot study assessed patients with DSRCT, Wilms' tumor and Ewing's sarcoma. Morphoproteomics and immunohistochemical probes were applied to detect: p-mTOR (Ser2448); p-Akt (Ser473); p-ERK1/2 (Thr202/Tyr204); p-STAT3 (Tyr 705); and cell cycle-related analytes along with their negative controls. In DSRCT the PI3K/Akt/mTOR pathway is constitutively activated by p-Akt (Ser 473) expression in the nuclear compartment of the tumor cells and p-mTOR phosphorylated on Ser 2448, suggesting mTORC2 (rictor+mTOR) as the dominant form. Ewing's sarcoma had upregulated p-Akt and p-mTOR, predominantly mTORC2. In Wilm's tumor, the mTOR pathway is also activated with most tumor cells moderately expressing p-mTOR (Ser 2448) in plasmalemmal and cytoplasmic compartments. This coincides with the constitutive activation of one of the downstream effectors of the mTORC1 signaling pathway, namely p-p70S6K (Thr 389). There was constitutive activation of the Ras/Raf/ERK pathway p-ERK 1/2 (Thr202/Tyr204) expression in the Wilms tumor and metastatic Ewing's sarcoma, but not in the DSRCT. MORPHOPROTEOMIC TUMOR ANALYSES REVEALED CONSTITUTIVE ACTIVATION OF THE MTOR PATHWAY AS EVIDENCED BY: (a) expression of phosphorylated (p)-mTOR, p-p70S6K; (b) mTORC 2 in EWS and DSRCT; (c) ERK signaling was seen in the advanced setting indicating these as resistance pathways to IGF1R related therapies. This is the first morphoproteomic study of such pathways in these rare malignancies and may have potential therapeutic implications. Further study using morphoproteomic assessments of these tumors are warranted.

Shared Socio-Economic Pathways of the Energy Sector – Quantifying the Narratives

DOE PAGES

Bauer, Nico; Calvin, Katherine; Emmerling, Johannes; ...

2016-08-23

Energy is crucial for supporting basic human needs, development and well-being. The future evolution of the scale and character of the energy system will be fundamentally shaped by socioeconomic conditions and drivers, available energy resources, technologies of energy supply and transformation, and end-use energy demand. However, because energy-related activities are significant sources of greenhouse gas (GHG) emissions and other environmental and social externalities, energy system development will also be influenced by social acceptance and strategic policy choices. All of these uncertainties have important implications for many aspects of economic and environmental sustainability, and climate change in particular. In the Shared-Socioeconomicmore » Pathway (SSP) framework these uncertainties are structured into five narratives, arranged according to the challenges to climate change mitigation and adaptation. In this study we explore future energy sector developments across the five SSPs using Integrated Assessment Models (IAMs), and we also provide summary output and analysis for selected scenarios of global emissions mitigation policies. The mitigation challenge strongly corresponds with global baseline energy sector growth over the 21st century, which varies between 40% and 230% depending on final energy consumer behavior, technological improvements, resource availability and policies. The future baseline CO 2-emission range is even larger, as the most energy-intensive SSP also incorporates a comparatively high share of carbon-intensive fossil fuels, and vice versa. Inter-regional disparities in the SSPs are consistent with the underlying socioeconomic assumptions; these differences are particularly strong in the SSPs with large adaptation challenges, which have little inter-regional convergence in long-term income and final energy demand levels. The scenarios presented do not include feedbacks of climate change on energy sector development. The energy sector SSPs with and without emissions mitigation policies are introduced and analyzed here in order to contribute to future research in climate sciences, mitigation analysis, and studies on impacts, adaptation and vulnerability.« less

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

Signaling Pathways in Cardiac Myocyte Apoptosis

PubMed Central

Xia, Peng; Liu, Yuening

2016-01-01

Cardiovascular diseases, the number 1 cause of death worldwide, are frequently associated with apoptotic death of cardiac myocytes. Since cardiomyocyte apoptosis is a highly regulated process, pharmacological intervention of apoptosis pathways may represent a promising therapeutic strategy for a number of cardiovascular diseases and disorders including myocardial infarction, ischemia/reperfusion injury, chemotherapy cardiotoxicity, and end-stage heart failure. Despite rapid growth of our knowledge in apoptosis signaling pathways, a clinically applicable treatment targeting this cellular process is currently unavailable. To help identify potential innovative directions for future research, it is necessary to have a full understanding of the apoptotic pathways currently known to be functional in cardiac myocytes. Here, we summarize recent progress in the regulation of cardiomyocyte apoptosis by multiple signaling molecules and pathways, with a focus on the involvement of these pathways in the pathogenesis of heart disease. In addition, we provide an update regarding bench to bedside translation of this knowledge and discuss unanswered questions that need further investigation. PMID:28101515

Renewable Electricity Futures for the United States

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

Mai, Trieu; Hand, Maureen; Baldwin, Sam F.

2014-04-14

This paper highlights the key results from the Renewable Electricity (RE) Futures Study. It is a detailed consideration of renewable electricity in the United States. The paper focuses on technical issues related to the operability of the U. S. electricity grid and provides initial answers to important questions about the integration of high penetrations of renewable electricity technologies from a national perspective. The results indicate that the future U. S. electricity system that is largely powered by renewable sources is possible and the further work is warranted to investigate this clean generation pathway. The central conclusion of the analysis ismore » that renewable electricity generation from technologies that are commercially available today, in combination with a more flexible electric system, is more than adequate to supply 80% of the total U. S. electricity generation in 2050 while meeting electricity demand on an hourly basis in every region of the United States.« less

Nanotoxicity prediction using computational modelling - review and future directions

NASA Astrophysics Data System (ADS)

Saini, Bhavna; Srivastava, Sumit

2018-04-01

Nanomaterials has stimulated various outlooks for future in a number of industries and scientific ventures. A number of applications such as cosmetics, medicines, and electronics are employing nanomaterials due to their various compelling properties. The unending growth of nanomaterials usage in our daily life has escalated the health and environmental risks. Early nanotoxicity recognition is a big challenge. Various researches are going on in the field of nanotoxicity, which comprised of several problems such as inadequacy of proper datasets, lack of appropriate rules and characterization of nanomaterials. Computational modelling would be beneficial asset for nanomaterials researchers because it can foresee the toxicity, rest on previous experimental data. In this study, we have reviewed sufficient work demonstrating a proper pathway to proceed with QSAR analysis of Nanomaterials for toxicity modelling. The paper aims at providing comprehensive insight of Nano QSAR, various theories, tools and approaches used, along with an outline for future research directions to work on.

Innate immune humoral factors, C1q and factor H, with differential pattern recognition properties, alter macrophage response to carbon nanotubes.

PubMed

Pondman, Kirsten M; Pednekar, Lina; Paudyal, Basudev; Tsolaki, Anthony G; Kouser, Lubna; Khan, Haseeb A; Shamji, Mohamed H; Ten Haken, Bennie; Stenbeck, Gudrun; Sim, Robert B; Kishore, Uday

2015-11-01

Interaction between the complement system and carbon nanotubes (CNTs) can modify their intended biomedical applications. Pristine and derivatised CNTs can activate complement primarily via the classical pathway which enhances uptake of CNTs and suppresses pro-inflammatory response by immune cells. Here, we report that the interaction of C1q, the classical pathway recognition molecule, with CNTs involves charge pattern and classical pathway activation that is partly inhibited by factor H, a complement regulator. C1q and its globular modules, but not factor H, enhanced uptake of CNTs by macrophages and modulated the pro-inflammatory immune response. Thus, soluble complement factors can interact differentially with CNTs and alter the immune response even without complement activation. Coating CNTs with recombinant C1q globular heads offers a novel way of controlling classical pathway activation in nanotherapeutics. Surprisingly, the globular heads also enhance clearance by phagocytes and down-regulate inflammation, suggesting unexpected complexity in receptor interaction. Carbon nanotubes (CNTs) maybe useful in the clinical setting as targeting drug carriers. However, it is also well known that they can interact and activate the complement system, which may have a negative impact on the applicability of CNTs. In this study, the authors functionalized multi-walled CNT (MWNT), and investigated the interaction with the complement pathway. These studies are important so as to gain further understanding of the underlying mechanism in preparation for future use of CNTs in the clinical setting. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Neuroproteomics approach and neurosystems biology analysis: ROCK inhibitors as promising therapeutic targets in neurodegeneration and neurotrauma.

PubMed

Raad, Mohamad; El Tal, Tala; Gul, Rukhsana; Mondello, Stefania; Zhang, Zhiqun; Boustany, Rose-Mary; Guingab, Joy; Wang, Kevin K; Kobeissy, Firas

2012-12-01

Several common degenerative mechanisms and mediators underlying the neuronal injury pathways characterize several neurodegenerative diseases including Alzheimer's, Parkinson's, and Huntington's disease, as well as brain neurotrauma. Such common ground invites the emergence of new approaches and tools to study the altered pathways involved in neural injury alongside with neuritogenesis, an intricate process that commences with neuronal differentiation. Achieving a greater understanding of the impaired pathways of neuritogenesis would significantly help in uncovering detailed mechanisms of axonal regeneration. Among the several agents involved in neuritogenesis are the Rho and Rho kinases (ROCKs), which constitute key integral points in the Rho/ROCK pathway that is known to be disrupted in multiple neuropathologies such as spinal cord injury, traumatic brain injury, and Alzheimer's disease. This in turn renders ROCK inhibition as a promising candidate for therapeutic targets for treatment of neurodegenerative diseases. Among the novel tools to investigate the mechanisms involved in a specific disorder is the use of neuroproteomics/systems biology approach, a growing subfield of bioinformatics aiming to study and establishing a global assessment of the entire neuronal proteome, addressing the dynamic protein changes and interactions. This review aims to examine recent updates regarding how neuroproteomics aids in the understanding of molecular mechanisms of activation and inhibition in the area of neurogenesis and how Rho/ROCK pathway/ROCK inhibitors, primarily Y-27632 and Fasudil compounds, are applied in biological settings, promoting neuronal survival and neuroprotection that has direct future implications in neurotrauma. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Propolis Augments Apoptosis Induced by Butyrate via Targeting Cell Survival Pathways

PubMed Central

Drago, Eric; Bordonaro, Michael; Lee, Seon; Atamna, Wafa; Lazarova, Darina L.

2013-01-01

Diet is one of the major lifestyle factors affecting incidence of colorectal cancer (CC), and despite accumulating evidence that numerous diet-derived compounds modulate CC incidence, definitive dietary recommendations are not available. We propose a strategy that could facilitate the design of dietary supplements with CC-preventive properties. Thus, nutrient combinations that are a source of apoptosis-inducers and inhibitors of compensatory cell proliferation pathways (e.g., AKT signaling) may produce high levels of programmed death in CC cells. Here we report the combined effect of butyrate, an apoptosis inducer that is produced through fermentation of fiber in the colon, and propolis, a honeybee product, on CC cells. We established that propolis increases the apoptosis of CC cells exposed to butyrate through suppression of cell survival pathways such as the AKT signaling. The programmed death of CC cells by combined exposure to butyrate and propolis is further augmented by inhibition of the JNK signaling pathway. Analyses on the contribution of the downstream targets of JNK signaling, c-JUN and JAK/STAT, to the apoptosis of butyrate/propolis-treated CC cells ascertained that JAK/STAT signaling has an anti-apoptotic role; whereas, the role of cJUN might be dependent upon regulatory cell factors. Thus, our studies ascertained that propolis augments apoptosis of butyrate-sensitive CC cells and re-sensitizes butyrate-resistant CC cells to apoptosis by suppressing AKT signaling and downregulating the JAK/STAT pathway. Future in vivo studies should evaluate the CC-preventive potential of a dietary supplement that produces high levels of colonic butyrate, propolis, and diet-derived JAK/STAT inhibitors. PMID:24023824

Willingness to Engage in Consensual Nonmonogamy Among Emerging Adults: A Structural Equation Analysis of Sexual Identity, Casual Sex Attitudes, and Gender.

PubMed

Sizemore, Kayla M; Olmstead, Spencer B

2017-01-01

Research on consensual nonmonogamy (CNM) has increased over the past decade. However, willingness to engage in CNM is an understudied phenomenon within this body of literature. Little research has examined the correlates of this aspect of CNM or focused on individuals in the developmental period of emerging adulthood. This study used multigroup structural equation modeling (SEM) to test a conceptual model of emerging adults' (ages 18 to 29; N = 890) willingness to engage in CNM. Results indicated that emerging adult experimentation/possibilities, sexual identity exploration, and permissive attitudes toward casual sex were all related to willingness to engage in CNM. Results also showed that the pathway from emerging adult experimentation/possibilities to willingness to engage in CNM was differentially mediated across gender. Specifically, for women there was an indirect (and positive) pathway from experimentation/possibilities to willingness to engage in CNM through sexual identity exploration. For men there was an indirect (and positive) pathway from experimentation/possibilities to willingness to engage in CNM through permissive attitudes toward casual sex. Implications for future studies on CNM among emerging adults are discussed.

Convergent evolution of caffeine in plants by co-option of exapted ancestral enzymes.

PubMed

Huang, Ruiqi; O'Donnell, Andrew J; Barboline, Jessica J; Barkman, Todd J

2016-09-20

Convergent evolution is a process that has occurred throughout the tree of life, but the historical genetic and biochemical context promoting the repeated independent origins of a trait is rarely understood. The well-known stimulant caffeine, and its xanthine alkaloid precursors, has evolved multiple times in flowering plant history for various roles in plant defense and pollination. We have shown that convergent caffeine production, surprisingly, has evolved by two previously unknown biochemical pathways in chocolate, citrus, and guaraná plants using either caffeine synthase- or xanthine methyltransferase-like enzymes. However, the pathway and enzyme lineage used by any given plant species is not predictable from phylogenetic relatedness alone. Ancestral sequence resurrection reveals that this convergence was facilitated by co-option of genes maintained over 100 million y for alternative biochemical roles. The ancient enzymes of the Citrus lineage were exapted for reactions currently used for various steps of caffeine biosynthesis and required very few mutations to acquire modern-day enzymatic characteristics, allowing for the evolution of a complete pathway. Future studies aimed at manipulating caffeine content of plants will require the use of different approaches given the metabolic and genetic diversity revealed by this study.

The possible interplay of synaptic and clock genes in autism spectrum disorders.

PubMed

Bourgeron, T

2007-01-01

Autism spectrum disorders (ASD) are complex neurodevelopmental conditions characterized by deficits in social communication, absence or delay in language, and stereotyped and repetitive behaviors. Results from genetic studies reveal one pathway associated with susceptibility to ASD, which includes the synaptic cell adhesion molecules NLGN3, NLGN4, and NRXN1 and a postsynaptic scaffolding protein SHANK3. This protein complex is crucial for the maintenance of functional synapses as well as the adequate balance between neuronal excitation and inhibition. Among the factors that could modulate this pathway are the genes controlling circadian rhythms. Indeed, sleep disorders and low melatonin levels are frequently observed in ASD. In this context, an alteration of both this synaptic pathway and the setting of the clock would greatly increase the risk of ASD. In this chapter, I report genetic and neurobiological findings that highlight the major role of synaptic and clock genes in the susceptibility to ASD. On the basis of these lines of evidence, I propose that future studies of ASD should investigate the circadian modulation of synaptic function as a focus for functional analyses and the development of new therapeutic strategies.

Convergent evolution of caffeine in plants by co-option of exapted ancestral enzymes

PubMed Central

Huang, Ruiqi; O’Donnell, Andrew J.; Barboline, Jessica J.; Barkman, Todd J.

2016-01-01

Convergent evolution is a process that has occurred throughout the tree of life, but the historical genetic and biochemical context promoting the repeated independent origins of a trait is rarely understood. The well-known stimulant caffeine, and its xanthine alkaloid precursors, has evolved multiple times in flowering plant history for various roles in plant defense and pollination. We have shown that convergent caffeine production, surprisingly, has evolved by two previously unknown biochemical pathways in chocolate, citrus, and guaraná plants using either caffeine synthase- or xanthine methyltransferase-like enzymes. However, the pathway and enzyme lineage used by any given plant species is not predictable from phylogenetic relatedness alone. Ancestral sequence resurrection reveals that this convergence was facilitated by co-option of genes maintained over 100 million y for alternative biochemical roles. The ancient enzymes of the Citrus lineage were exapted for reactions currently used for various steps of caffeine biosynthesis and required very few mutations to acquire modern-day enzymatic characteristics, allowing for the evolution of a complete pathway. Future studies aimed at manipulating caffeine content of plants will require the use of different approaches given the metabolic and genetic diversity revealed by this study. PMID:27638206

Genetic studies of Crohn's disease: Past, present and future

PubMed Central

Liu, Jimmy Z.; Anderson, Carl A.

2014-01-01

The exact aetiology of Crohn's disease is unknown, though it is clear from early epidemiological studies that a combination of genetic and environmental risk factors contributes to an individual's disease susceptibility. Here, we review the history of gene-mapping studies of Crohn's disease, from the linkage-based studies that first implicated the NOD2 locus, through to modern-day genome-wide association studies that have discovered over 140 loci associated with Crohn's disease and yielded novel insights into the biological pathways underlying pathogenesis. We describe on-going and future gene-mapping studies that utilise next generation sequencing technology to pinpoint causal variants and identify rare genetic variation underlying Crohn's disease risk. We comment on the utility of genetic markers for predicting an individual's disease risk and discuss their potential for identifying novel drug targets and influencing disease management. Finally, we describe how these studies have shaped and continue to shape our understanding of the genetic architecture of Crohn's disease. PMID:24913378

PUFA diets alter the microRNA expression profiles in an inflammation rat model.

PubMed

Zheng, Zheng; Ge, Yinlin; Zhang, Jinyu; Xue, Meilan; Li, Quan; Lin, Dongliang; Ma, Wenhui

2015-06-01

Omega‑3 and ‑6 polyunsaturated fatty acids (PUFAs) can directly or indirectly regulate immune homeostasis via inflammatory pathways, and components of these pathways are crucial targets of microRNAs (miRNAs). However, no study has examined the changes in the miRNA transcriptome during PUFA‑regulated inflammatory processes. Here, we established PUFA diet‑induced autoimmune‑prone (AP) and autoimmune‑averse (AA) rat models, and studied their physical characteristics and immune status. Additionally, miRNA expression patterns in the rat models were compared using microarray assays and bioinformatic methods. A total of 54 miRNAs were differentially expressed in common between the AP and the AA rats, and the changes in rno‑miR‑19b‑3p, ‑146b‑5p and ‑183‑5p expression were validated using stem‑loop reverse transcription‑quantitative polymerase chain reaction. To better understand the mechanisms underlying PUFA‑regulated miRNA changes during inflammation, computational algorithms and biological databases were used to identify the target genes of the three validated miRNAs. Furthermore, Gene Ontology (GO) term annotation and KEGG pathway analyses of the miRNA targets further allowed to explore the potential implication of the miRNAs in inflammatory pathways. The predicted PUFA‑regulated inflammatory pathways included the Toll‑like receptor (TLR), T cell receptor (TCR), NOD‑like receptor (NLR), RIG‑I‑like receptor (RLR), mitogen‑activated protein kinase (MAPK) and the transforming growth factor‑β (TGF‑β) pathway. This study is the first report, to the best of our knowledge, on in vivo comparative profiling of miRNA transcriptomes in PUFA diet‑induced inflammatory rat models using a microarray approach. The results provide a useful resource for future investigation of the role of PUFA‑regulated miRNAs in immune homeostasis.

Sulfur Radical-Induced Redox Modifications in Proteins: Analysis and Mechanistic Aspects.

PubMed

Schöneich, Christian

2017-03-10

The sulfur-containing amino acids cysteine (Cys) and methionine (Met) are prominent protein targets of redox modification during conditions of oxidative stress. Here, two-electron pathways have received widespread attention, in part due to their role in signaling processes. However, Cys and Met are equally prone to one-electron pathways, generating intermediary radicals and/or radial ions. These radicals/radical ions can generate various reaction products that are not commonly monitored in redox proteomic studies, but they may be relevant for the fate of proteins during oxidative stress. Recent Advances: Time-resolved kinetic studies and product analysis have expanded our mechanistic understanding of radical reaction pathways of sulfur-containing amino acids. These reactions are now studied in some detail for Met and Cys in proteins, and homocysteine (Hcy) chemically linked to proteins, and the role of protein radical reactions in physiological processes is evolving. Radical-derived products from Cys, Hcy, and Met can react with additional amino acids in proteins, leading to secondary protein modifications, which are potentially remote from initial points of radical attack. These products may contain intra- and intermolecular cross-links, which may lead to protein aggregation. Protein sequence and conformation will have a significant impact on the formation of such products, and a thorough understanding of reaction mechanisms and specifically how protein structure influences reaction pathways will be critical for identification and characterization of novel reaction products. Future studies must evaluate the biological significance of novel reaction products that are derived from radical reactions of sulfur-containing amino acids. Antioxid. Redox Signal. 26, 388-405.

Developmental Pathways Are Blueprints for Designing Successful Crops

PubMed Central

Trevaskis, Ben

2018-01-01

Genes controlling plant development have been studied in multiple plant systems. This has provided deep insights into conserved genetic pathways controlling core developmental processes including meristem identity, phase transitions, determinacy, stem elongation, and branching. These pathways control plant growth patterns and are fundamentally important to crop biology and agriculture. This review describes the conserved pathways that control plant development, using Arabidopsis as a model. Historical examples of how plant development has been altered through selection to improve crop performance are then presented. These examples, drawn from diverse crops, show how the genetic pathways controlling development have been modified to increase yield or tailor growth patterns to suit local growing environments or specialized crop management practices. Strategies to apply current progress in genomics and developmental biology to future crop improvement are then discussed within the broader context of emerging trends in plant breeding. The ways that knowledge of developmental processes and understanding of gene function can contribute to crop improvement, beyond what can be achieved by selection alone, are emphasized. These include using genome re-sequencing, mutagenesis, and gene editing to identify or generate novel variation in developmental genes. The expanding scope for comparative genomics, the possibility to engineer new developmental traits and new approaches to resolve gene–gene or gene–environment interactions are also discussed. Finally, opportunities to integrate fundamental research and crop breeding are highlighted. PMID:29922318

Developmental Pathways Are Blueprints for Designing Successful Crops.

PubMed

Trevaskis, Ben

2018-01-01

Genes controlling plant development have been studied in multiple plant systems. This has provided deep insights into conserved genetic pathways controlling core developmental processes including meristem identity, phase transitions, determinacy, stem elongation, and branching. These pathways control plant growth patterns and are fundamentally important to crop biology and agriculture. This review describes the conserved pathways that control plant development, using Arabidopsis as a model. Historical examples of how plant development has been altered through selection to improve crop performance are then presented. These examples, drawn from diverse crops, show how the genetic pathways controlling development have been modified to increase yield or tailor growth patterns to suit local growing environments or specialized crop management practices. Strategies to apply current progress in genomics and developmental biology to future crop improvement are then discussed within the broader context of emerging trends in plant breeding. The ways that knowledge of developmental processes and understanding of gene function can contribute to crop improvement, beyond what can be achieved by selection alone, are emphasized. These include using genome re-sequencing, mutagenesis, and gene editing to identify or generate novel variation in developmental genes. The expanding scope for comparative genomics, the possibility to engineer new developmental traits and new approaches to resolve gene-gene or gene-environment interactions are also discussed. Finally, opportunities to integrate fundamental research and crop breeding are highlighted.

Telling the Climate Change Story: Framing and Messaging

NASA Astrophysics Data System (ADS)

Hassol, S. J.

2011-12-01

Scientists have important roles to play in communicating climate change, yet most scientists are not well versed in important aspects of communication. Scientists can improve their communication by helping to develop and deliver effectively framed messages. Research suggests that effective messages about climate change should include science-based descriptions of the risks posed by human-induced warming as well as information about solutions for a better future. Thus, telling the climate change story effectively involves clearly stating that human-induced climate change is happening now and having impacts on society, while also showing that it is not too late to make a difference for the future. For example, framing and messaging should include the fact that lower emissions pathways lead to less severe climate change and fewer impacts than higher emissions pathways. It also involves communicating that there is much we can do to alter our emissions pathway, and that doing these things has other benefits, for example, for human health and the economy. Scientists telling the climate change story should make the threats tangible and the opportunities clear.

Implications of alternative assumptions regarding future air pollution control in scenarios similar to the Representative Concentration Pathways

NASA Astrophysics Data System (ADS)

Chuwah, Clifford; van Noije, Twan; van Vuuren, Detlef P.; Hazeleger, Wilco; Strunk, Achim; Deetman, Sebastiaan; Beltran, Angelica Mendoza; van Vliet, Jasper

2013-11-01

The uncertain, future development of emissions of short-lived trace gases and aerosols forms a key factor for future air quality and climate forcing. The Representative Concentration Pathways (RCPs) only explore part of this range as they all assume that worldwide ambitious air pollution control policies will be implemented. In this study, we explore how different assumptions on future air pollution policy and climate policy lead to different concentrations of air pollutants for a set of RCP-like scenarios developed using the IMAGE model. These scenarios combine low and high air pollution variants of the scenarios with radiative forcing targets in 2100 of 2.6 W m-2 and 6.0 W m-2. Simulations using the global atmospheric chemistry and transport model TM5 for the present-day climate show that both climate mitigation and air pollution control policies have large-scale effects on pollutant concentrations, often of similar magnitude. If no further air pollution policies would be implemented, pollution levels could be considerably higher than in the RCPs, especially in Asia. Air pollution control measures could significantly reduce the warming by tropospheric ozone and black carbon and the cooling by sulphate by 2020, and in the longer term contribute to enhanced warming by methane. These effects tend to cancel each other on a global scale. According to our estimates the effect of the worldwide implementation of air pollution control measures on the total global mean direct radiative forcing in 2050 is +0.09 W m-2 in the 6.0 W m-2 scenario and -0.16 W m-2 in the 2.6 W m-2 scenario.

Programmable genetic circuits for pathway engineering.

PubMed

Hoynes-O'Connor, Allison; Moon, Tae Seok

2015-12-01

Synthetic biology has the potential to provide decisive advances in genetic control of metabolic pathways. However, there are several challenges that synthetic biologists must overcome before this vision becomes a reality. First, a library of diverse and well-characterized sensors, such as metabolite-sensing or condition-sensing promoters, must be constructed. Second, robust programmable circuits that link input conditions with a specific gene regulation response must be developed. Finally, multi-gene targeting strategies must be integrated with metabolically relevant sensors and complex, robust logic. Achievements in each of these areas, which employ the CRISPR/Cas system, in silico modeling, and dynamic sensor-regulators, among other tools, provide a strong basis for future research. Overall, the future for synthetic biology approaches in metabolic engineering holds immense promise. Copyright © 2015 Elsevier Ltd. All rights reserved.

Pathway Concepts Experiment for Head-Down Synthetic Vision Displays

NASA Technical Reports Server (NTRS)

Prinzel, Lawrence J., III; Arthur, Jarvis J., III; Kramer, Lynda J.; Bailey, Randall E.

2004-01-01

Eight 757 commercial airline captains flew 22 approaches using the Reno Sparks 16R Visual Arrival under simulated Category I conditions. Approaches were flown using a head-down synthetic vision display to evaluate four tunnel ("minimal", "box", "dynamic pathway", "dynamic crow s feet") and three guidance ("ball", "tadpole", "follow-me aircraft") concepts and compare their efficacy to a baseline condition (i.e., no tunnel, ball guidance). The results showed that the tunnel concepts significantly improved pilot performance and situation awareness and lowered workload compared to the baseline condition. The dynamic crow s feet tunnel and follow-me aircraft guidance concepts were found to be the best candidates for future synthetic vision head-down displays. These results are discussed with implications for synthetic vision display design and future research.

Kynurenine Pathway Pathologies: do Nicotinamide and Other Pathway Co-Factors have a Therapeutic Role in Reduction of Symptom Severity, Including Chronic Fatigue Syndrome (CFS) and Fibromyalgia (FM)

PubMed Central

Blankfield, Adele

2013-01-01

The definition of dual tryptophan pathways has increased the understanding of the mind-body, body-mind dichotomy. The serotonergic pathway highlights the primary (endogenous) psychiatric disorders. The up-regulation of the kynurenine pathway by physical illnesses can cause neuropathic and immunological disorders1 associated with secondary neuropsychiatric symptoms. Tryptophan and nicotinamide deficiencies fall within the protein energy malnutrition (PEM) spectrum. They can arise if the kynurenine pathway is stressed by primary or secondary inflammatory conditions and the consequent imbalance of available catabolic/anabolic substrates may adversely influence convalescent phase efficiency. The replacement of depleted or reduced NAD+ levels and other cofactors can perhaps improve the clinical management of these disorders. Chronic fatigue syndrome (CFS) and fibromyalgia (FM) appear to meet the criteria of a tryptophan-kynurenine pathway disorder with potential neuroimmunological sequelae. Aspects of some of the putative precipitating factors have been previously outlined.2,3 An analysis of the areas of metabolic dysfunction will focus on future directions for research and management. PMID:23922501

Integrative pathway knowledge bases as a tool for systems molecular medicine.

PubMed

Liang, Mingyu

2007-08-20

There exists a sense of urgency to begin to generate a cohesive assembly of biomedical knowledge as the pace of knowledge accumulation accelerates. The urgency is in part driven by the emergence of systems molecular medicine that emphasizes the combination of systems analysis and molecular dissection in the future of medical practice and research. A potentially powerful approach is to build integrative pathway knowledge bases that link organ systems function with molecules.

Femara® and the future: tailoring treatment and combination therapies with Femara

PubMed Central

Ma, Cynthia

2007-01-01

Long-term estrogen deprivation treatment for breast cancer can, in some patients, lead to the activation of alternate cellular pathways, resulting in the re-emergence of the disease. This is a distressing scenario for oncologists and patients, but recent intensive molecular and biochemical studies are beginning to unravel these pathways, revealing opportunities for new targeted treatments. Far from making present therapies redundant, these new discoveries open the door to novel combination therapies that promise to provide enhanced efficacy or overcome treatment resistance. Letrozole, one of the most potent aromatase inhibitors, is the ideal candidate for combination therapy; indeed, it is one of the most intensively studied aromatase inhibitors in the evolving combinatorial setting. Complementary to the use of combination therapy is the development of molecular tools to identify patients who will benefit the most from these new treatments. Microarray gene profiling studies, designed to detect letrozole-responsive targets, are currently under way to understand how the use of the drug can be tailored more efficiently to specific patient needs. PMID:17912640

Stabilizing Off-pathway Oligomers by Polyphenol Nanoassemblies for IAPP Aggregation Inhibition

NASA Astrophysics Data System (ADS)

Nedumpully-Govindan, Praveen; Kakinen, Aleksandr; Pilkington, Emily H.; Davis, Thomas P.; Chun Ke, Pu; Ding, Feng

2016-01-01

Experimental studies have shown that many naturally occurring polyphenols have inhibitory effect on the aggregation of several proteins. Here, we use discrete molecular dynamics (DMD) simulations and high-throughput dynamic light scattering (DLS) experiments to study the anti-aggregation effects of two polyphenols, curcumin and resveratrol, on the aggregation of islet amyloid polypeptide (IAPP or amylin). Our DMD simulations suggest that the aggregation inhibition is caused by stabilization of small molecular weight IAPP off-pathway oligomers by the polyphenols. Our analysis indicates that IAPP-polyphenol hydrogen bonds and π-π stacking combined with hydrophobic interactions are responsible for the stabilization of oligomers. The presence of small oligomers is confirmed with DLS measurements in which nanometer-sized oligomers are found to be stable for up to 7.5 hours, the time frame within which IAPP aggregates in the absence of polyphenols. Our study offers a general anti-aggregation mechanism for polyphenols, and further provides a computational framework for the future design of anti-amyloid aggregation therapeutics.

Explanatory models concerning the effects of small-area characteristics on individual health.

PubMed

Voigtländer, Sven; Vogt, Verena; Mielck, Andreas; Razum, Oliver

2014-06-01

Material and social living conditions at the small-area level are assumed to have an effect on individual health. We review existing explanatory models concerning the effects of small-area characteristics on health and describe the gaps future research should try to fill. Systematic literature search for, and analysis of, studies that propose an explanatory model of the relationship between small-area characteristics and health. Fourteen studies met our inclusion criteria. Using various theoretical approaches, almost all of the models are based on a three-tier structure linking social inequalities (posited at the macro-level), small-area characteristics (posited at the meso-level) and individual health (micro-level). No study explicitly defines the geographical borders of the small-area context. The health impact of the small-area characteristics is explained by specific pathways involving mediating factors (psychological, behavioural, biological). These pathways tend to be seen as uni-directional; often, causality is implied. They may be modified by individual factors. A number of issues need more attention in research on explanatory models concerning small-area effects on health. Among them are the (geographical) definition of the small-area context; the systematic description of pathways comprising small-area contextual as well as compositional factors; questions of direction of association and causality; and the integration of a time dimension.

Asian water futures - Multi scenarios, models and criteria assessment -

NASA Astrophysics Data System (ADS)

Satoh, Yusuke; Burek, Peter; Wada, Yoshihide; Flrörke, Martina; Eisner, Stephanie; Hanasaki, Naota; Kahil, Taher; Tramberend, Sylvia; Fischer, Günther; Wiberg, David

2016-04-01

A better understanding of the current and future availability of water resources is essential for the implementation of the recently agreed Sustainable Development Goals (SDGs). Long-term/efficient strategies for coping with current and potential future water-related challenges are urgently required. Although Representative Concentration Pathways (RCPs) and Shared Socioeconomic Pathways (SSPs) were develop for the impact assessment of climate change, very few assessments have yet used the SSPs to assess water resources. Then the IIASA Water Futures and Solutions Initiative (WFaS), developed a set of water use scenarios consistent with RCPs and SSPs and applying the latest climate changes scenarios. Here this study focuses on results for Asian countries for the period 2010-2050. We present three conceivable future pathways of Asian water resources, determined by feasible combinations of two RCPs and three SSPs. Such a scenario approach provides valuable insights towards identifying appropriate strategies as gaps between a "scenario world" and reality. In addition, for the assessment of future water resources a multi-criteria analysis is applied. A classification system for countries and watershed that consists of two broad dimensions: (i) economic and institutional adaptive capacity, (ii) hydrological complexity. The latter is composed of several sub-indexes including total renewable water resources per capita, the ratio of water demand to renewable water resource, variability of runoff and dependency ratio to external. Furthermore, this analysis uses a multi-model approach to estimate runoff and discharge using 5 GCMs and 5 global hydrological models (GHMs). Three of these GHMs calculate water use based on a consistent set of scenarios in addition to water availability. As a result, we have projected hot spots of water scarcity in Asia and their spatial and temporal change. For example, in a scenario based on SSP2 and RCP6.0, by 2050, in total 2.1 billion people (46% of Asian population) are going to live in countries classified as high hydrological complexity. In particular, in Afghanistan, Azerbaijan and Pakistan, then home to 370 million people, hydrological complexity will be high while adaptation capacity is still low. On the other hand, a part of people however who live in countries with higher expected adaptive capacities may have better futures depending on policies and investment. Besides country scale, grid scale analyses clearly highlighted that a large part of population living under strong water stress in highly populated areas of Asia, such as east and coastal areas in China and large parts of India. Our preliminary results show that a significant impact of socioeconomic scenarios on each of the indexes which is comparable to that of climate scenarios. For instance, the least timing, trend and spatial distribution of water resource per capita are highly affected by projected population. This study shows that features of time series change in each indexes are also informative particularly for decision makers because they support in optimal timing of investment for countermeasures. In this presentation, we are showing our analysis framework and results of each integrated indexes.

Political and medical views on medical marijuana and its future.

PubMed

Rubens, Muni

2014-01-01

The policies, laws, politics, public opinions, and scientific inferences of medical marijuana are rapidly changing as the debate on medical use of marijuana has always been political, rather than scientific. Federal law has barred the use of medical marijuana though 18 state governments and Washington, DC, support the medical use of marijuana. Unfortunately, not many studies exist on medical marijuana to back these laws and policies. The judiciary, on the other hand, has elicited a diverse response to medical marijuana through its rulings over several decades. Some rulings favored the federal government's opinion, and others supported the larger public view and many state governments with legalized medical marijuana. Public opinion on legalizing medical marijuana has always favored the use of medical marijuana. The movement of scientific knowledge of medical marijuana follows an erratic, discontinuous pathway. The future place of medical marijuana in U.S. society remains unknown. The three forces-scientific knowledge, social-political acceptance, and laws-play a role in the direction that medical marijuana takes in society. Overcoming political-social forces requires a concerted effort from the scientific community and political leaders. The results of scientific research must guide the decisions for laws and medical use of marijuana. This article aims to trace the political dilemma and contradictory views shared by federal and state governments and predict the future of medical marijuana by tracing the past history of medical marijuana with its bumpy pathway in the social-political arena.

Future Scenario Development from Disruptive Exploration Technologies and Business Models in the U.S. Geothermal Industry

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

Wall, Anna

With recent trends toward intermittent renewable energy sources in the U.S., the geothermal industry in its current form faces a crossroad: adapt, disrupt, or be left behind. Strategic planning with scenario analysis offers a framework to characterize plausible views of the future given current trends - as well as disruptions to the status quo. To inform strategic planning in the Department of Energy's (DOE) Geothermal Technology Office (GTO), the Geothermal Vision Study is tasked with offering data-driven pathways for future geothermal development. Scenario analysis is a commonly used tool in private industry corporate strategic planning as a way to prioritizemore » and manage large investments in light of uncertainty and risk. Since much of the uncertainty and risk in a geothermal project is believed to occur within early stage exploration and drilling, this paper focuses on the levers (technical and financial) within the exploration process that can be pulled to affect change. Given these potential changes, this work first qualitatively explores potential shifts to the geothermal industry. Future work within the Geothermal Vision Study will incorporate these qualitative scenarios quantitatively, in competition with other renewable and conventional energy industries.« less

Impact of Climate Change on Potential Distribution of Chinese Caterpillar Fungus (Ophiocordyceps sinensis) in Nepal Himalaya

PubMed Central

Shrestha, Uttam Babu; Bawa, Kamaljit S.

2014-01-01

Climate change has already impacted ecosystems and species and substantial impacts of climate change in the future are expected. Species distribution modeling is widely used to map the current potential distribution of species as well as to model the impact of future climate change on distribution of species. Mapping current distribution is useful for conservation planning and understanding the change in distribution impacted by climate change is important for mitigation of future biodiversity losses. However, the current distribution of Chinese caterpillar fungus, a flagship species of the Himalaya with very high economic value, is unknown. Nor do we know the potential changes in suitable habitat of Chinese caterpillar fungus caused by future climate change. We used MaxEnt modeling to predict current distribution and changes in the future distributions of Chinese caterpillar fungus in three future climate change trajectories based on representative concentration pathways (RCPs: RCP 2.6, RCP 4.5, and RCP 6.0) in three different time periods (2030, 2050, and 2070) using species occurrence points, bioclimatic variables, and altitude. About 6.02% (8,989 km2) area of the Nepal Himalaya is suitable for Chinese caterpillar fungus habitat. Our model showed that across all future climate change trajectories over three different time periods, the area of predicted suitable habitat of Chinese caterpillar fungus would expand, with 0.11–4.87% expansion over current suitable habitat. Depending upon the representative concentration pathways, we observed both increase and decrease in average elevation of the suitable habitat range of the species. PMID:25180515

Impact of climate change on potential distribution of Chinese caterpillar fungus (Ophiocordyceps sinensis) in Nepal Himalaya.

PubMed

Shrestha, Uttam Babu; Bawa, Kamaljit S

2014-01-01

Climate change has already impacted ecosystems and species and substantial impacts of climate change in the future are expected. Species distribution modeling is widely used to map the current potential distribution of species as well as to model the impact of future climate change on distribution of species. Mapping current distribution is useful for conservation planning and understanding the change in distribution impacted by climate change is important for mitigation of future biodiversity losses. However, the current distribution of Chinese caterpillar fungus, a flagship species of the Himalaya with very high economic value, is unknown. Nor do we know the potential changes in suitable habitat of Chinese caterpillar fungus caused by future climate change. We used MaxEnt modeling to predict current distribution and changes in the future distributions of Chinese caterpillar fungus in three future climate change trajectories based on representative concentration pathways (RCPs: RCP 2.6, RCP 4.5, and RCP 6.0) in three different time periods (2030, 2050, and 2070) using species occurrence points, bioclimatic variables, and altitude. About 6.02% (8,989 km2) area of the Nepal Himalaya is suitable for Chinese caterpillar fungus habitat. Our model showed that across all future climate change trajectories over three different time periods, the area of predicted suitable habitat of Chinese caterpillar fungus would expand, with 0.11-4.87% expansion over current suitable habitat. Depending upon the representative concentration pathways, we observed both increase and decrease in average elevation of the suitable habitat range of the species.

Investigation of Proposed Ladderane Biosynthetic Genes from Anammox Bacteria by Heterologous Expression in E. coli

PubMed Central

Javidpour, Pouya; Deutsch, Samuel; Mutalik, Vivek K.; Hillson, Nathan J.; Petzold, Christopher J.; Keasling, Jay D.; Beller, Harry R.

2016-01-01

Ladderanes are hydrocarbon chains with three or five linearly concatenated cyclobutane rings that are uniquely produced as membrane lipid components by anammox (anaerobic ammonia-oxidizing) bacteria. By virtue of their angle and torsional strain, ladderanes are unusually energetic compounds, and if produced biochemically by engineered microbes, could serve as renewable, high-energy-density jet fuel components. The biochemistry and genetics underlying the ladderane biosynthetic pathway are unknown, however, previous studies have identified a pool of 34 candidate genes from the anammox bacterium, Kuenenia stuttgartiensis, some or all of which may be involved with ladderane fatty acid biosynthesis. The goal of the present study was to establish a systematic means of testing the candidate genes from K. stuttgartiensis for involvement in ladderane biosynthesis through heterologous expression in E. coli under anaerobic conditions. This study describes an efficient means of assembly of synthesized, codon-optimized candidate ladderane biosynthesis genes in synthetic operons that allows for changes to regulatory element sequences, as well as modular assembly of multiple operons for simultaneous heterologous expression in E. coli (or potentially other microbial hosts). We also describe in vivo functional tests of putative anammox homologs of the phytoene desaturase CrtI, which plays an important role in the hypothesized ladderane pathway, and a method for soluble purification of one of these enzymes. This study is, to our knowledge, the first experimental effort focusing on the role of specific anammox genes in the production of ladderanes, and lays the foundation for future efforts toward determination of the ladderane biosynthetic pathway. Our substantial, but far from comprehensive, efforts at elucidating the ladderane biosynthetic pathway were not successful. We invite the scientific community to take advantage of the considerable synthetic biology resources and experimental results developed in this study to elucidate the biosynthetic pathway that produces unique and intriguing ladderane lipids. PMID:26975050

PI3K pathway inhibitors: potential prospects as adjuncts to vaccine immunotherapy for glioblastoma.

PubMed

Oh, Taemin; Ivan, Michael E; Sun, Matthew Z; Safaee, Michael; Fakurnejad, Shayan; Clark, Aaron J; Sayegh, Eli T; Bloch, Orin; Parsa, Andrew T

2014-01-01

Constitutive activation of the PI3K pathway has been implicated in glioblastoma (GBM) pathogenesis. Pharmacologic inhibition can both inhibit tumor survival and downregulate expression of programmed death ligand-1, a protein highly expressed on glioma cells that strongly contributes to cancer immunosuppression. In that manner, PI3K pathway inhibitors can help optimize GBM vaccine immunotherapy. In this review, we describe and assess the potential integration of various classes of PI3K pathway inhibitors into GBM immunotherapy. While early-generation inhibitors have a wide range of immunosuppressive effects that could negate their antitumor potency, further work should better characterize how contemporary inhibitors affect the immune response. This will help determine if these inhibitors are truly a therapeutic avenue with a strong future in GBM immunotherapy.

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.

Peripheral inflammation and cognitive aging.

PubMed

Lim, Alvin; Krajina, Katarina; Marsland, Anna L

2013-01-01

Evidence suggests that inflammation, an innate immune response facilitating recovery from injury and pathogenic invasion, is positively associated with age-related cognitive decline and may play a role in risk for dementia. Physiological pathways linking the peripheral immune and central nervous systems are outlined, and studies linking inflammation with neurocognitive function are overviewed. We also present recent studies from our laboratory showing that midlife inflammation is related to cognitive function and brain morphology. Finally, potential implications for treatment, future directions, and limitations are discussed. Copyright © 2013 S. Karger AG, Basel.

Training the next generation of physician-executives: an innovative residency pathway in management and leadership.

PubMed

Ackerly, D Clay; Sangvai, Devdutta G; Udayakumar, Krishna; Shah, Bimal R; Kalman, Noah S; Cho, Alex H; Schulman, Kevin A; Fulkerson, William J; Dzau, Victor J

2011-05-01

The rapidly changing field of medicine demands that future physician-leaders excel not only in clinical medicine but also in the management of complex health care enterprises. However, many physicians have become leaders "by accident," and the active cultivation of future leaders is required. Addressing this need will require multiple approaches, targeting trainees at various stages of their careers, such as degree-granting programs, residency and fellowship training, and career and leadership development programs. Here, the authors describe a first-of-its-kind graduate medical education pathway at Duke Medicine, the Management and Leadership Pathway for Residents (MLPR). This program was developed for residents with both a medical degree and management training. Created in 2009, with its first cohort enrolled in the summer of 2010, the MLPR is intended to help catalyze the emergence of a new generation of physician-leaders. The program will provide physicians-in-training with rigorous clinical exposure along with mentorship and rotational opportunities in management to accelerate the development of critical leadership and management skills in all facets of medicine, including care delivery, research, and education. To achieve this, the MLPR includes 15 to 18 months of project-based rotations under the guidance of senior leaders in many disciplines including finance, patient safety, health system operations, strategy, and others. Developing both clinical and management skill sets during graduate medical education holds the promise of engaging future leaders of health care at an early career stage, keeping more MD-MBA graduates within health care, and creating a bench of talented future physician-executives. Copyright © by the Association of American medical Colleges.

Current and Future United States Light-Duty Vehicle Pathways: Cradle-to-Grave Lifecycle Greenhouse Gas Emissions and Economic Assessment

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

Elgowainy, Amgad; Han, Jeongwoo; Ward, Jacob

This article presents a cradle-to-grave (C2G) assessment of greenhouse gas (GHG) emissions and costs for current (2015) and future (2025-2030) light-duty vehicles. The analysis addressed both fuel cycle and vehicle manufacturing cycle for the following vehicle types: gasoline and diesel internal combustion engine vehicles (ICEVs), flex fuel vehicles, compressed natural gas (CNG) vehicles, hybrid electric vehicles (HEVs), hydrogen fuel cell electric vehicles (FCEVs), battery electric vehicles (BEVs), and plug-in hybrid electric vehicles (PHEVs). Gasoline ICEVs using current technology have C2G emissions of ~450 gCO2e/mi (grams of carbon dioxide equivalents per mile), while C2G emissions from HEVs, PHEVs, H2 FCEVs, andmore » BEVs range from 300-350 gCO2e/mi. Future vehicle efficiency gains are expected to reduce emissions to ~350 gCO2/mi for ICEVs and ~250 gCO2e/mi for HEVs, PHEVs, FCEVs, and BEVs. Utilizing low-carbon fuel pathways yields GHG reductions more than double those achieved by vehicle efficiency gains alone. Levelized costs of driving (LCDs) are in the range $0.25-$1.00/mi depending on time frame and vehicle-fuel technology. In all cases, vehicle cost represents the major (60-90%) contribution to LCDs. Currently, HEV and PHEV petroleum-fueled vehicles provide the most attractive cost in terms of avoided carbon emissions, although they offer lower potential GHG reductions. The ranges of LCD and cost of avoided carbon are narrower for the future technology pathways, reflecting the expected economic competitiveness of these alternative vehicles and fuels.« less

Current and Future United States Light-Duty Vehicle Pathways: Cradle-to-Grave Lifecycle Greenhouse Gas Emissions and Economic Assessment

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

Elgowainy, Amgad; Han, Jeongwoo; Ward, Jacob

This article presents a cradle-to-grave (C2G) assessment of greenhouse gas (GHG) emissions and costs for current (2015) and future (2025–2030) light-duty vehicles. The analysis addressed both fuel cycle and vehicle manufacturing cycle for the following vehicle types: gasoline and diesel internal combustion engine vehicles (ICEVs), flex fuel vehicles, compressed natural gas (CNG) vehicles, hybrid electric vehicles (HEVs), hydrogen fuel cell electric vehicles (FCEVs), battery electric vehicles (BEVs), and plug-in hybrid electric vehicles (PHEVs). Gasoline ICEVs using current technology have C2G emissions of ~450 gCO2e/mi (grams of carbon dioxide equivalents per mile), while C2G emissions from HEVs, PHEVs, H2 FCEVs, andmore » BEVs range from 300–350 gCO2e/mi. Future vehicle efficiency gains are expected to reduce emissions to ~350 gCO2/mi for ICEVs and ~250 gCO2e/mi for HEVs, PHEVs, FCEVs and BEVs. Utilizing low-carbon fuel pathways yields GHG reductions more than double those achieved by vehicle efficiency gains alone. Levelized costs of driving (LCDs) are in the range $0.25–$1.00/mi depending on timeframe and vehicle-fuel technology. In all cases, vehicle cost represents the major (60–90%) contribution to LCDs. Currently, HEV and PHEV petroleum-fueled vehicles provide the most attractive cost in terms of avoided carbon emissions, although they offer lower potential GHG reductions The ranges of LCD and cost of avoided carbon are narrower for the future technology pathways, reflecting the expected economic competitiveness of these alternative vehicles and fuels.« less

Current and Future United States Light-Duty Vehicle Pathways: Cradle-to-Grave Lifecycle Greenhouse Gas Emissions and Economic Assessment.

PubMed

Elgowainy, Amgad; Han, Jeongwoo; Ward, Jacob; Joseck, Fred; Gohlke, David; Lindauer, Alicia; Ramsden, Todd; Biddy, Mary; Alexander, Mark; Barnhart, Steven; Sutherland, Ian; Verduzco, Laura; Wallington, Timothy J

2018-02-20

This article presents a cradle-to-grave (C2G) assessment of greenhouse gas (GHG) emissions and costs for current (2015) and future (2025-2030) light-duty vehicles. The analysis addressed both fuel cycle and vehicle manufacturing cycle for the following vehicle types: gasoline and diesel internal combustion engine vehicles (ICEVs), flex fuel vehicles, compressed natural gas (CNG) vehicles, hybrid electric vehicles (HEVs), hydrogen fuel cell electric vehicles (FCEVs), battery electric vehicles (BEVs), and plug-in hybrid electric vehicles (PHEVs). Gasoline ICEVs using current technology have C2G emissions of ∼450 gCO 2 e/mi (grams of carbon dioxide equivalents per mile), while C2G emissions from HEVs, PHEVs, H 2 FCEVs, and BEVs range from 300-350 gCO 2 e/mi. Future vehicle efficiency gains are expected to reduce emissions to ∼350 gCO 2 /mi for ICEVs and ∼250 gCO 2e /mi for HEVs, PHEVs, FCEVs, and BEVs. Utilizing low-carbon fuel pathways yields GHG reductions more than double those achieved by vehicle efficiency gains alone. Levelized costs of driving (LCDs) are in the range $0.25-$1.00/mi depending on time frame and vehicle-fuel technology. In all cases, vehicle cost represents the major (60-90%) contribution to LCDs. Currently, HEV and PHEV petroleum-fueled vehicles provide the most attractive cost in terms of avoided carbon emissions, although they offer lower potential GHG reductions. The ranges of LCD and cost of avoided carbon are narrower for the future technology pathways, reflecting the expected economic competitiveness of these alternative vehicles and fuels.

Global wheat production potentials and management flexibility under the representative concentration pathways

NASA Astrophysics Data System (ADS)

Balkovič, Juraj; van der Velde, Marijn; Skalský, Rastislav; Xiong, Wei; Folberth, Christian; Khabarov, Nikolay; Smirnov, Alexey; Mueller, Nathaniel D.; Obersteiner, Michael

2014-11-01

Wheat is the third largest crop globally and an essential source of calories in human diets. Maintaining and increasing global wheat production is therefore strongly linked to food security. A large geographic variation in wheat yields across similar climates points to sizeable yield gaps in many nations, and indicates a regionally variable flexibility to increase wheat production. Wheat is particularly sensitive to a changing climate thus limiting management opportunities to enable (sustainable) intensification with potentially significant implications for future wheat production. We present a comprehensive global evaluation of future wheat yields and production under distinct Representative Concentration Pathways (RCPs) using the Environmental Policy Integrated Climate (EPIC) agro-ecosystem model. We project, in a geographically explicit manner, future wheat production pathways for rainfed and irrigated wheat systems. We explore agricultural management flexibility by quantifying the development of wheat yield potentials under current, rainfed, exploitable (given current irrigation infrastructure), and irrigated intensification levels. Globally, because of climate change, wheat production under conventional management (around the year 2000) would decrease across all RCPs by 37 to 52 and 54 to 103 Mt in the 2050s and 2090s, respectively. However, the exploitable and potential production gap will stay above 350 and 580 Mt, respectively, for all RCPs and time horizons, indicating that negative impacts of climate change can globally be offset by adequate intensification using currently existing irrigation infrastructure and nutrient additions. Future world wheat production on cropland already under cultivation can be increased by ~ 35% through intensified fertilization and ~ 50% through increased fertilization and extended irrigation, if sufficient water would be available. Significant potential can still be exploited, especially in rainfed wheat systems in Russia, Eastern Europe and North America.

Exploring midwifery students' views and experiences of caseload midwifery: A cross-sectional survey conducted in Victoria, Australia.

PubMed

Dawson, Kate; Newton, Michelle; Forster, Della; McLachlan, Helen

2015-02-01

in Australia, models of maternity care that offer women continuity of care with a known midwife have been promoted. Little is known about the intentions of the future midwifery workforce to work in such models. This study aimed to explore midwifery students' views and experiences of caseload midwifery and their work intentions in relation to the caseload model following graduation. cross-sectional survey. Victoria, Australia. 129 midwifery students representing all midwifery course pathways (Post Graduate Diploma, Bachelor of Midwifery, Bachelor of Nursing/Bachelor of Midwifery) in Victoria. midwifery students from all course pathways considered that continuity of care is important to women and indicated that exposure to continuity models during their course was very positive. Two-thirds of the students (67%) considered that the continuity experiences made them want to work in a caseload model; only 5% reported that their experiences had discouraged them from continuity of care work in the future. Most wanted a period of consolidation to gain experience as a midwife prior to commencing in the caseload model. Perceived barriers to caseload work were being on-call, and challenges in regard to work/life balance and family commitments. midwifery students in this study were very positive about caseload midwifery and most would consider working in caseload after a period of consolidation. Continuity of care experiences during students' midwifery education programmes appeared to provide students with insight and understanding of continuity of care for both women and midwives. Further research should explore what factors influence students' future midwifery work, whether or not their plans are fulfilled, and whether or not the caseload midwifery workforce can be sustained. Copyright © 2014 Elsevier Ltd. All rights reserved.

Projection of future temperature-related mortality due to climate and demographic changes.

PubMed

Lee, Jae Young; Kim, Ho

2016-09-01

Understanding the effects of global climate change from both environmental and human health perspectives has gained great importance. Particularly, studies on the direct effect of temperature increase on future mortality have been conducted. However, few of those studies considered population changes, and although the world population is rapidly aging, no previous study considered the effect of society aging. Here we present a projection of future temperature-related mortality due to both climate and demographic changes in seven major cities of South Korea, a fast aging country, until 2100; we used the HadGEM3-RA model under four Representative Concentration Pathway (RCP) scenarios (RCP 2.6, 4.5, 6.0, and 8.5) and the United Nations world population prospects under three fertility scenarios (high, medium, and low). The results showed markedly increased mortality in the elderly group, significantly increasing the overall future mortality. In 2090s, South Korea could experience a four- to six-time increase in temperature-related mortality compared to that during 1992-2010 under four different RCP scenarios and three different fertility variants, while the mortality is estimated to increase only by 0.5 to 1.5 times assuming no population aging. Therefore, not considering population aging may significantly underestimate temperature risks. Copyright © 2016 Elsevier Ltd. All rights reserved.

Response of a multi-stressed Mediterranean river to future climate and socio-economic scenarios.

PubMed

Stefanidis, Konstantinos; Panagopoulos, Yiannis; Mimikou, Maria

2018-06-15

Streams and rivers are among the most threatened ecosystems in Europe due to the combined effects of multiple pressures related to anthropogenic activities. Particularly in the Mediterranean region, changes in hydromorphology along with increased nutrient loadings are known to affect the ecological functions and ecosystem services of streams and rivers with the anticipated climate change being likely to further impair their functionality and structure. In this study, we investigated the combined effects of agricultural driven stressors on the ecology and delivered services of the Pinios river basin in Greece under three future world scenarios developed within the EU funded MARS project. Scenarios are based on combinations of Representative Concentration Pathways and Shared Socioeconomic Pathways and refer to early century (2030) and mid-century (2060) representing future climate worlds with particular socioeconomic characteristics. To assess the responses of ecological and ecosystem service indicators to the scenarios we first simulated hydrology and water quality in Pinios with a process-based model. Simulated abiotic stressor parameters (predictors) were linked to two biotic indicators, the macroinvertebrate indicators ASPT and EPT, with empirical modelling based on boosted regression trees and general linear models. Our results showed that the techno world scenario driven by fast economic growth and intensive exploitation of energy resources had the largest impact on both the abiotic status (nutrient loads and concentrations in water) and the biotic indicators. In contrast, the predicted changes under the other two future worlds, consensus and fragmented, were more diverse and were mostly dictated by the projected climate. This work showed that the future scenarios, especially the mid-century ones, had significant impact on both abiotic status and biotic responses underpinning the need for implementing catchment management practices able to mitigate the ecological threat on waters in the long-term. Copyright © 2018 Elsevier B.V. All rights reserved.

Future Climate Prediction of Urban Atmosphere in A Tropical Megacity: Utilization of RCP/SSP Scenarios with an Urban Growth Model

NASA Astrophysics Data System (ADS)

Darmanto, N. S.; Varquez, A. C. G.; Kanda, M.; Takakuwa, S.

2016-12-01

Economic development in Southeast Asia megacities leads to rapid transformation into more complicated urban configurations. These configurations, including building geometry, enhance aerodynamic drag thus reducing near-surface wind speeds. Roughness parameters representing building geometry, along with anthropogenic heat emissions, contribute to the formation of urban heat islands (UHI). All these have been reproduced successfully in the Weather Research and Forecasting (WRF) Model coupled with an improved single-layer urban canopy model incorporating a realistic distribution of urban parameters and anthropogenic heat emission in the Jakarta Greater Area. We apply this technology to climate change studies by introducing future urbanization defined by urban sprawl, vertical rise in buildings, and increase anthropogenic heat emission (AHE) due to population changes, into futuristic climate modelling. To simulate 2050s future climate, pseudo-global warming method was used which relied on current and ensembles of 5 CMIP5 GCMs for 2 representative concentration pathways (RCP), 2.6 and 8.5. To determine future urbanization level, 2050 population growth and energy consumption were estimated from shared socioeconomic pathways (SSP). This allows the estimation of future urban sprawl, building geometry, and AHE using the SLEUTH urban growth model and spatial growth assumptions. Two cases representing combinations of RCP and SSP were simulated in WRF: RCP2.6-SSP1 and RCP8.5-SSP3. Each case corresponds to best and worst-case scenarios of implementing adaptation and mitigation strategies, respectively. It was found that 2-m temperature of Jakarta will increase by 0.62°C (RCP2.6) and 1.44°C (RCP8.5) solely from background climate change; almost on the same magnitude as the background temperature increase of RCP2.6 (0.5°C) and RCP8.5 (1.2°C). Compared with previous studies, the result indicates that the effect of climate change on UHI in tropical cities may be lesser than cities located in the mid-latitudes. However, it is expected that the combined effect of urbanization and climate change will result to significant changes on future urban temperature. ACK: This research was supported by the Environment Research and Technology Development Fund (S-14) of the Ministry of the Environment, Japan.

A Generation of Challenge: Pathways to Success for Urban Youth. A Policy Study of the Levitan Youth Policy Network. Policy Issues Monograph 97-03.

ERIC Educational Resources Information Center

Sum, Andrew; Mangum, Stephen; deJesus, Edward; Walker, Gary; Gruber, David; Pines, Marion; Spring, William

This report refers to a generation under challenge, meaning the 18-to-24-year-olds who have recently come of age in the United States. A significant part of this generation has fallen victim to a neglected past and may be overwhelmed by its future. The report argues for an integrated and comprehensive service delivery system that can make a…

Teaching-as-Research Internships: A Model for the Development of Future Chemistry Faculty and the Improvement of Teaching in Science, Technology, Engineering, and Math

ERIC Educational Resources Information Center

Gillian-Daniel, Donald L.; Walz, Kenneth A.

2016-01-01

Over the past decade, the University of Wisconsin-Madison (UW-Madison) and Madison Area Technical College (Madison College) partnered to create an internship pathway for graduate students pursuing careers as future science, technology, engineering and math (STEM) faculty members. Since 2003, 10 doctoral students from the university completed…

Psychological Pathways Linking Social Support to Health Outcomes: A Visit with the “Ghosts” of Research Past, Present, and Future

PubMed Central

Uchino, Bert N.; Bowen, Kimberly; Carlisle, McKenzie; Birmingham, Wendy

2012-01-01

Contemporary models postulate the importance of psychological mechanisms linking perceived and received social support to physical health outcomes. In this review, we examine studies that directly tested the potential psychological mechanisms responsible for links between social support and health-relevant physiological processes (1980s to 2010). Inconsistent with existing theoretical models, no evidence was found that psychological mechanisms such as depression, perceived stress, and other affective processes are directly responsible for links between support and health. We discuss the importance of considering statistical/design issues, emerging conceptual perspectives, and limitations of our existing models for future research aimed at elucidating the psychological mechanisms responsible for links between social support and physical health outcomes. PMID:22326104

Land-use change may exacerbate climate change impacts on water resources in the Ganges basin

NASA Astrophysics Data System (ADS)

Tsarouchi, Gina; Buytaert, Wouter

2018-02-01

Quantifying how land-use change and climate change affect water resources is a challenge in hydrological science. This work aims to quantify how future projections of land-use and climate change might affect the hydrological response of the Upper Ganges river basin in northern India, which experiences monsoon flooding almost every year. Three different sets of modelling experiments were run using the Joint UK Land Environment Simulator (JULES) land surface model (LSM) and covering the period 2000-2035: in the first set, only climate change is taken into account, and JULES was driven by the CMIP5 (Coupled Model Intercomparison Project Phase 5) outputs of 21 models, under two representative concentration pathways (RCP4.5 and RCP8.5), whilst land use was held fixed at the year 2010. In the second set, only land-use change is taken into account, and JULES was driven by a time series of 15 future land-use pathways, based on Landsat satellite imagery and the Markov chain simulation, whilst the meteorological boundary conditions were held fixed at years 2000-2005. In the third set, both climate change and land-use change were taken into consideration, as the CMIP5 model outputs were used in conjunction with the 15 future land-use pathways to force JULES. Variations in hydrological variables (stream flow, evapotranspiration and soil moisture) are calculated during the simulation period. Significant changes in the near-future (years 2030-2035) hydrologic fluxes arise under future land-cover and climate change scenarios pointing towards a severe increase in high extremes of flow: the multi-model mean of the 95th percentile of streamflow (Q5) is projected to increase by 63 % under the combined land-use and climate change high emissions scenario (RCP8.5). The changes in all examined hydrological components are greater in the combined land-use and climate change experiment. Results are further presented in a water resources context, aiming to address potential implications of climate change and land-use change from a water demand perspective. We conclude that future water demands in the Upper Ganges region for winter months may not be met.

Representative Agricultural Pathways and Scenarios for Regional Integrated Assessment of Climate Change Impacts, Vulnerability, and Adaptation. 5; Chapter

NASA Technical Reports Server (NTRS)

Valdivia, Roberto O.; Antle, John M.; Rosenzweig, Cynthia; Ruane, Alexander C.; Vervoort, Joost; Ashfaq, Muhammad; Hathie, Ibrahima; Tui, Sabine Homann-Kee; Mulwa, Richard; Nhemachena, Charles;

MESSI: metabolic engineering target selection and best strain identification tool.

PubMed

Kang, Kang; Li, Jun; Lim, Boon Leong; Panagiotou, Gianni

2015-01-01

Metabolic engineering and synthetic biology are synergistically related fields for manipulating target pathways and designing microorganisms that can act as chemical factories. Saccharomyces cerevisiae's ideal bioprocessing traits make yeast a very attractive chemical factory for production of fuels, pharmaceuticals, nutraceuticals as well as a wide range of chemicals. However, future attempts of engineering S. cerevisiae's metabolism using synthetic biology need to move towards more integrative models that incorporate the high connectivity of metabolic pathways and regulatory processes and the interactions in genetic elements across those pathways and processes. To contribute in this direction, we have developed Metabolic Engineering target Selection and best Strain Identification tool (MESSI), a web server for predicting efficient chassis and regulatory components for yeast bio-based production. The server provides an integrative platform for users to analyse ready-to-use public high-throughput metabolomic data, which are transformed to metabolic pathway activities for identifying the most efficient S. cerevisiae strain for the production of a compound of interest. As input MESSI accepts metabolite KEGG IDs or pathway names. MESSI outputs a ranked list of S. cerevisiae strains based on aggregation algorithms. Furthermore, through a genome-wide association study of the metabolic pathway activities with the strains' natural variation, MESSI prioritizes genes and small variants as potential regulatory points and promising metabolic engineering targets. Users can choose various parameters in the whole process such as (i) weight and expectation of each metabolic pathway activity in the final ranking of the strains, (ii) Weighted AddScore Fuse or Weighted Borda Fuse aggregation algorithm, (iii) type of variants to be included, (iv) variant sets in different biological levels.Database URL: http://sbb.hku.hk/MESSI/. © The Author(s) 2015. Published by Oxford University Press.

The Anti-Oxidant and Antitumor Properties of Plant Polysaccharides.

PubMed

Jiao, Rui; Liu, Yingxia; Gao, Hao; Xiao, Jia; So, Kwok Fai

2016-01-01

Oxidative stress has been increasingly recognized as a major contributing factor in a variety of human diseases, from inflammation to cancer. Although certain parts of signaling pathways are still under investigation, detailed molecular mechanisms for the induction of diseases have been elucidated, especially the link between excessive oxygen reactive species (ROS) damage and tumorigenesis. Emerging evidence suggests anti-oxidant therapy can play a key role in treating those diseases. Among potential drug resources, plant polysaccharides are natural anti-oxidant constituents important for human health because of their long history in ethnopharmacology, wide availability and few side effects upon consumption. Plant polysaccharides have been shown to possess anti-oxidant, anti-inflammation, cell viability promotion, immune-regulation and antitumor functions in a number of disease models, both in laboratory studies and in the clinic. In this paper, we reviewed the research progress of signaling pathways involved in the initiation and progression of oxidative stress- and cancer-related diseases in humans. The natural sources, structural properties and biological actions of several common plant polysaccharides, including Lycium barbarum, Ginseng, Zizyphus Jujuba, Astragalus lentiginosus, and Ginkgo biloba are discussed in detail, with emphasis on their signaling pathways. All of the mentioned common plant polysaccharides have great potential to treat oxidative stress and cancinogenic disorders in cell models, animal disease models and clinical cases. ROS-centered pathways (e.g. mitochondrial autophagy, MAPK and JNK) and transcription factor-related pathways (e.g. NF-[Formula: see text]B and HIF) are frequently utilized by these polysaccharides with or without the further involvement of inflammatory and death receptor pathways. Some of the polysaccharides may also influence tumorigenic pathways, such as Wnt and p53 to play their anti-tumor roles. In addition, current problems and future directions for the application of those plant polysaccharides are also listed and discussed.

Pathways as a tool for the governance of sustainable management of soilsubsidence

NASA Astrophysics Data System (ADS)

Ellen, G. J.; Hommes, S.

2017-12-01

Subsidence is a physical, societal, economic and institutional challenge for the Netherlands. For urban areas because subsidence threatens the nearby future the liveability and touristic attractiveness of the historic cities. For the rural areas because it affects the - intensive - agricultural landuse which is an important pilar of the Dutch economy. Policy and decision-making concerning subsidence is suffering from `non-decision making'. Subsidence has been described and mapped based on (geological and geotechnical) scientific research, but the subject has only been marginally addressing in the national, regional and local policy arena's. To actually make it possible for subsidence to be discussed in the policy arena a method was designed which was used in two cases : the Dutch city of Gouda and a more rural area in the province of Flevoland in the middle of the Netherlands. The method used was based on three building blocks. First of all future perspectives - scenario planning methodology was used to create future perspectives on coping with land subsidence. For example for Gouda we created 4 future perspectives for 2060 distinguishing between allocation of responsibilities (public or private) and the strategic decision to cope with land subsidence (halt or continue to sink). The second building block was the use of pathways, were each pathway consisted of a cluster of land subsidence strategies covering the many dimensions of land subsidence, ranging from houses and their foundations for the city of Gouda towards different types of agricultural land use for the rural area in the province of Flevoland. The last building block was a governance design approach were for every pathway a governance arrangements were designed together with stakeholders. The method was evaluated and proved to be very useful. First, a better understanding of the unsustainability of subsidence was obtained. In addition, the different perspectives and strategies stimulated discussions within the policy arena's on what might be needed especially in terms of governance. Finally, after applying the described method a higher awareness has been gained on `non-decision making' and ways to move forward.

The mesenchymal stem cells in multiple sclerosis (MSCIMS) trial protocol and baseline cohort characteristics: an open-label pre-test: post-test study with blinded outcome assessments.

PubMed

Connick, Peter; Kolappan, Madhan; Patani, Rickie; Scott, Michael A; Crawley, Charles; He, Xiao-Ling; Richardson, Karen; Barber, Kelly; Webber, Daniel J; Wheeler-Kingshott, Claudia A M; Tozer, Daniel J; Samson, Rebecca S; Thomas, David L; Du, Ming-Qing; Luan, Shi L; Michell, Andrew W; Altmann, Daniel R; Thompson, Alan J; Miller, David H; Compston, Alastair; Chandran, Siddharthan

2011-03-02

No treatments are currently available that slow, stop, or reverse disease progression in established multiple sclerosis (MS). The Mesenchymal Stem Cells in Multiple Sclerosis (MSCIMS) trial tests the safety and feasibility of treatment with a candidate cell-based therapy, and will inform the wider challenge of designing early phase clinical trials to evaluate putative neuroprotective therapies in progressive MS. Illustrated by the MSCIMS trial protocol, we describe a novel methodology based on detailed assessment of the anterior visual pathway as a model of wider disease processes--the "sentinel lesion approach". MSCIMS is a phase IIA study of autologous mesenchymal stem cells (MSCs) in secondary progressive MS. A pre-test : post-test design is used with healthy controls providing normative data for inter-session variability. Complementary eligibility criteria and outcomes are used to select participants with disease affecting the anterior visual pathway. Ten participants with MS and eight healthy controls were recruited between October 2008 and March 2009. Mesenchymal stem cells were successfully isolated, expanded and characterised in vitro for all participants in the treatment arm. In addition to determining the safety and feasibility of the intervention and informing design of future studies to address efficacy, MSCIMS adopts a novel strategy for testing neuroprotective agents in MS--the sentinel lesion approach--serving as proof of principle for its future wider applicability. ClinicalTrials.gov (NCT00395200).

The mesenchymal stem cells in multiple sclerosis (MSCIMS) trial protocol and baseline cohort characteristics: an open-label pre-test: post-test study with blinded outcome assessments

PubMed Central

2011-01-01

Background No treatments are currently available that slow, stop, or reverse disease progression in established multiple sclerosis (MS). The Mesenchymal Stem Cells in Multiple Sclerosis (MSCIMS) trial tests the safety and feasibility of treatment with a candidate cell-based therapy, and will inform the wider challenge of designing early phase clinical trials to evaluate putative neuroprotective therapies in progressive MS. Illustrated by the MSCIMS trial protocol, we describe a novel methodology based on detailed assessment of the anterior visual pathway as a model of wider disease processes - the "sentinel lesion approach". Methods/design MSCIMS is a phase IIA study of autologous mesenchymal stem cells (MSCs) in secondary progressive MS. A pre-test : post-test design is used with healthy controls providing normative data for inter-session variability. Complementary eligibility criteria and outcomes are used to select participants with disease affecting the anterior visual pathway. Results Ten participants with MS and eight healthy controls were recruited between October 2008 and March 2009. Mesenchymal stem cells were successfully isolated, expanded and characterised in vitro for all participants in the treatment arm. Conclusions In addition to determining the safety and feasibility of the intervention and informing design of future studies to address efficacy, MSCIMS adopts a novel strategy for testing neuroprotective agents in MS - the sentinel lesion approach - serving as proof of principle for its future wider applicability. Trial registration ClinicalTrials.gov (NCT00395200). PMID:21366911

Acetaminophen and pregnancy: short- and long-term consequences for mother and child.

PubMed

Thiele, Kristin; Kessler, Timo; Arck, Petra; Erhardt, Annette; Tiegs, Gisa

2013-03-01

Counter-intuitively, over-the-counter medication is commonly taken by pregnant women. In this context, acetaminophen (APAP, e.g. Paracetamol, Tylenol) is generally recommended by physicians to treat fever and pain during pregnancy. Thus, APAP ranks at the top of the list of medications taken prenatally. Insights on an increased risk for pregnancy complications such as miscarriage, stillbirth, preterm birth or fetal malformations upon APAP exposure are rather ambiguous. However, emerging evidence arising from human trials clearly reveals a significant correlation between APAP use during pregnancy and an increased risk for the development of asthma in children later in life. Pathways through which APAP increases this risk are still elusive. APAP can be liver toxic and since APAP appears to freely cross the placenta, therapeutic and certainly toxic doses could not only affect maternal, but also fetal hepatocytes. It is noteworthy that during fetal development, the liver transiently functions as the main hematopoietic organ. We here review the effect of APAP on metabolic and immunological parameters in pregnant women and on fetal development and immune ontogeny in order to delineate novel, putative and to date underrated pathways through which APAP use during pregnancy can impair maternal, fetal and long term children's health. We conclude that future studies are urgently needed to reconsider the safety and dosage of APAP during pregnancy and - based on the advances made in the field of reproduction as well as APAP metabolism - we propose pathways, which should be addressed in future research and clinical endeavors. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Buildings of the Future Scoping Study: A Framework for Vision Development

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

Wang, Na; Goins, John D.

2015-02-01

The Buildings of the Future Scoping Study, funded by the U.S. Department of Energy (DOE) Building Technologies Office, seeks to develop a vision for what U.S. mainstream commercial and residential buildings could become in 100 years. This effort is not intended to predict the future or develop a specific building design solution. Rather, it will explore future building attributes and offer possible pathways of future development. Whether we achieve a more sustainable built environment depends not just on technologies themselves, but on how effectively we envision the future and integrate these technologies in a balanced way that generates economic, social,more » and environmental value. A clear, compelling vision of future buildings will attract the right strategies, inspire innovation, and motivate action. This project will create a cross-disciplinary forum of thought leaders to share their views. The collective views will be integrated into a future building vision and published in September 2015. This report presents a research framework for the vision development effort based on a literature survey and gap analysis. This document has four objectives. First, it defines the project scope. Next, it identifies gaps in the existing visions and goals for buildings and discusses the possible reasons why some visions did not work out as hoped. Third, it proposes a framework to address those gaps in the vision development. Finally, it presents a plan for a series of panel discussions and interviews to explore a vision that mitigates problems with past building paradigms while addressing key areas that will affect buildings going forward.« less

International Recommendations for Training Future Toxicologic Pathologists Participating in Regulatory-Type, Nonclinical Toxicity Studies*

PubMed Central

Bolon, Brad; Barale-Thomas, Erio; Bradley, Alys; Ettlin, Robert A.; Franchi, Carla A.S.; George, Catherine; Giusti, Anna Maria; Hall, Robert; Jacobsen, Matthew; Konishi, Yoichi; Ledieu, David; Morton, Daniel; Park, Jae-Hak; Scudamore, Cheryl L.; Tsuda, Hiroyuki; Vijayasarathi, S.K.; Wijnands, Marcel V.W.

2010-01-01

The International Federation of Societies of Toxicologic Pathologists (IFSTP) proposes a common global framework for training future toxicologic pathologists who will support regulatory-type nonclinical toxicology studies. Trainees optimally should undertake a scientific curriculum of at least 5 years at an accredited institution leading to a clinical degree (veterinary medicine or medicine). Trainees should then obtain 4 or more years of intensive pathology practice during a residency and/or on-the-job “apprenticeship,” at least 2 years of which must be focused on regulatory-type toxicologic pathology topics. Possession of a recognized pathology qualification (i.e., certification) is highly recommended. A non-clinical pathway (e.g., a graduate degree in medical biology or pathology) may be possible if medically trained pathologists are scarce, but this option is not optimal. Regular, lifelong continuing education (peer review of nonclinical studies, professional meetings, reading, short courses) will be necessary to maintain and enhance one’s understanding of current toxicologic pathology knowledge, skills, and tools. This framework should provide a rigorous yet flexible way to reliably train future toxicologic pathologists to generate, interpret, integrate, and communicate data in regulatory-type, nonclinical toxicology studies. PMID:22272030

Survival by self-destruction: A role for autophagy in the placenta?

PubMed Central

Bildirici, I; Longtine, MS; Chen, B; Nelson, DM

2012-01-01

Autophagy is a burgeoning area of research from yeast to humans. Although previously described as a death pathway, autophagy is now considered an important survival phenomenon in response to environmental stressors to which most organs are exposed. Despite an ever expanding literature in non-placental cells, studies of autophagy in the placenta are lagging. We review the regulation of autophagy, summarize available placental studies of autophagy, and highlight potential areas for future research. We believe that such studies will yield novel insights into how placentas protect the survival of the species by “self-eating”. PMID:22652048

Scenarios reveal pathways to sustain future ecosystem services in an agricultural landscape.

PubMed

Qiu, Jiangxiao; Carpenter, Stephen R; Booth, Eric G; Motew, Melissa; Zipper, Samuel C; Kucharik, Christopher J; Chen, Xi; Loheide, Steven P; Seifert, Jenny; Turner, Monica G

2018-01-01

Sustaining food production, water quality, soil retention, flood, and climate regulation in agricultural landscapes is a pressing global challenge given accelerating environmental changes. Scenarios are stories about plausible futures, and scenarios can be integrated with biophysical simulation models to explore quantitatively how the future might unfold. However, few studies have incorporated a wide range of drivers (e.g., climate, land-use, management, population, human diet) in spatially explicit, process-based models to investigate spatial-temporal dynamics and relationships of a portfolio of ecosystem services. Here, we simulated nine ecosystem services (three provisioning and six regulating services) at 220 × 220 m from 2010 to 2070 under four contrasting scenarios in the 1,345-km 2 Yahara Watershed (Wisconsin, USA) using Agro-IBIS, a dynamic model of terrestrial ecosystem processes, biogeochemistry, water, and energy balance. We asked (1) How does ecosystem service supply vary among alternative future scenarios? (2) Where on the landscape is the provision of ecosystem services most susceptible to future social-ecological changes? (3) Among alternative future scenarios, are relationships (i.e., trade-offs, synergies) among food production, water, and biogeochemical services consistent over time? Our results showed that food production varied substantially with future land-use choices and management, and its trade-offs with water quality and soil retention persisted under most scenarios. However, pathways to mitigate or even reverse such trade-offs through technological advances and sustainable agricultural practices were apparent. Consistent relationships among regulating services were identified across scenarios (e.g., trade-offs of freshwater supply vs. flood and climate regulation, and synergies among water quality, soil retention, and climate regulation), suggesting opportunities and challenges to sustaining these services. In particular, proactive land-use changes and management may buffer water quality against undesirable future climate changes, but changing climate may overwhelm management efforts to sustain freshwater supply and flood regulation. Spatially, changes in ecosystem services were heterogeneous across the landscape, underscoring the power of local actions and fine-scale management. Our research highlights the value of embracing spatial and temporal perspectives in managing ecosystem services and their complex interactions, and provides a system-level understanding for achieving sustainability of the food-water-climate nexus in agricultural landscapes. © 2017 by the Ecological Society of America.

The future of uveitis treatment.

PubMed

Lin, Phoebe; Suhler, Eric B; Rosenbaum, James T

2014-01-01

Uveitis is a heterogeneous collection of diseases with polygenic and environmental influences. This heterogeneity presents challenges in trial design and selection of end points. Despite the multitude of causes, therapeutics targeting common inflammatory pathways are effective in treating diverse forms of uveitis. These treatments, including corticosteroids and immunomodulatory agents, although often effective, can have untoward side effects, limiting their utility. The search for drugs with equal or improved efficacy that are safe is therefore paramount. A mechanism-based approach is most likely to yield the future breakthroughs in the treatment of uveitis. We review the literature and provide examples of the nuances of immune regulation and dysregulation that can be targeted for therapeutic benefit. As our understanding of the causes of uveitis grows we will learn how to better apply antibodies designed to block interaction between inflammatory cytokines and their receptors. T-lymphocyte activation can be targeted by blocking co-stimulatory pathways or inhibiting major histocompatibility complex protein interactions. Furthermore, intracellular downstream molecules from cytokine or other pathways can be inhibited using small molecule inhibitors, which have the benefit of being orally bioavailable. An emerging field is the lipid-mediated inflammatory and regulatory pathways. Alternatively, anti-inflammatory cytokines can be provided by administering recombinant protein, and intracellular "brakes" of inflammatory pathways can be introduced potentially by gene therapy. Novel approaches of delivering a therapeutic substance include, but are not limited to, the use of small interfering RNA, viral and nonviral gene therapy, and microparticle or viscous gel sustained-release drug-delivery platforms. Copyright © 2014. Published by Elsevier Inc.

Anti-obesity drugs: past, present and future

PubMed Central

Rodgers, R. John; Tschöp, Matthias H.; Wilding, John P. H.

2012-01-01

The ideal anti-obesity drug would produce sustained weight loss with minimal side effects. The mechanisms that regulate energy balance have substantial built-in redundancy, overlap considerably with other physiological functions, and are influenced by social, hedonic and psychological factors that limit the effectiveness of pharmacological interventions. It is therefore unsurprising that anti-obesity drug discovery programmes have been littered with false starts, failures in clinical development, and withdrawals due to adverse effects that were not fully appreciated at the time of launch. Drugs that target pathways in metabolic tissues, such as adipocytes, liver and skeletal muscle, have shown potential in preclinical studies but none has yet reached clinical development. Recent improvements in the understanding of peptidergic signalling of hunger and satiety from the gastrointestinal tract mediated by ghrelin, cholecystokinin (CCK), peptide YY (PYY) and glucagon-like peptide-1 (GLP-1), and of homeostatic mechanisms related to leptin and its upstream pathways in the hypothalamus, have opened up new possibilities. Although some have now reached clinical development, it is uncertain whether they will meet the strict regulatory hurdles required for licensing of an anti-obesity drug. However, GLP-1 receptor agonists have already succeeded in diabetes treatment and, owing to their attractive body-weight-lowering effects in humans, will perhaps also pave the way for other anti-obesity agents. To succeed in developing drugs that control body weight to the extent seen following surgical intervention, it seems obvious that a new paradigm is needed. In other therapeutic arenas, such as diabetes and hypertension, lower doses of multiple agents targeting different pathways often yield better results than strategies that modify one pathway alone. Some combination approaches using peptides and small molecules have now reached clinical trials, although recent regulatory experience suggests that large challenges lie ahead. In future, this polytherapeutic strategy could possibly rival surgery in terms of efficacy, safety and sustainability of weight loss. PMID:22915024

Exploration of Mechanisms behind Changes after Participation in a Parenting Intervention: A Qualitative Study in a Low-Resource Setting.

PubMed

Mejia, Anilena; Ulph, Fiona; Calam, Rachel

2016-03-01

Parenting interventions are effective for preventing psychological difficulties in children. However, their active ingredients have not been comprehensively explored. How do they work? What are the mechanisms operating behind changes? In 2012, a randomized controlled trial of a parenting intervention was conducted in low-resource communities of Panama. Effects on child behavioral difficulties, parental stress, and parenting practices were large in the short and long term. This was an ideal opportunity to explore potential mechanisms operating behind effects found in this low-resource setting. Twenty-five parents were interviewed. Data were analyzed through an inductive semantic thematic analysis. Three themes emerged from the data: (a) psychological mechanisms behind changes, (b) behavioral changes in parent, and (c) changes in the children. Parents described that the intervention triggered changes in emotion regulation, self-efficacy, and problem solving. Parents also reported behavioral changes such as praising their children more often, who in turn seemed more responsible and better at following instructions. The study offers participant-driven insight into potential pathways of change after participation in this parenting intervention, pathways that are often overlooked in quantitative studies. Future studies should further explore these pathways, through mediator and moderator analyses, and determine how much is shared across interventions and across different cultural settings. © Society for Community Research and Action 2016.

Gene network analysis shows immune-signaling and ERK1/2 as novel genetic markers for multiple addiction phenotypes: alcohol, smoking and opioid addiction.

PubMed

Reyes-Gibby, Cielito C; Yuan, Christine; Wang, Jian; Yeung, Sai-Ching J; Shete, Sanjay

2015-06-05

Addictions to alcohol and tobacco, known risk factors for cancer, are complex heritable disorders. Addictive behaviors have a bidirectional relationship with pain. We hypothesize that the associations between alcohol, smoking, and opioid addiction observed in cancer patients have a genetic basis. Therefore, using bioinformatics tools, we explored the underlying genetic basis and identified new candidate genes and common biological pathways for smoking, alcohol, and opioid addiction. Literature search showed 56 genes associated with alcohol, smoking and opioid addiction. Using Core Analysis function in Ingenuity Pathway Analysis software, we found that ERK1/2 was strongly interconnected across all three addiction networks. Genes involved in immune signaling pathways were shown across all three networks. Connect function from IPA My Pathway toolbox showed that DRD2 is the gene common to both the list of genetic variations associated with all three addiction phenotypes and the components of the brain neuronal signaling network involved in substance addiction. The top canonical pathways associated with the 56 genes were: 1) calcium signaling, 2) GPCR signaling, 3) cAMP-mediated signaling, 4) GABA receptor signaling, and 5) G-alpha i signaling. Cancer patients are often prescribed opioids for cancer pain thus increasing their risk for opioid abuse and addiction. Our findings provide candidate genes and biological pathways underlying addiction phenotypes, which may be future targets for treatment of addiction. Further study of the variations of the candidate genes could allow physicians to make more informed decisions when treating cancer pain with opioid analgesics.

Care pathway, towards the establishment of tailored funding: Reasons and criteria for success.

PubMed

Emery, Grégory; Le Fur, Camille; Epis-de-Fleurian, Anne-Aurélie; Josseran, Anne

2018-02-01

Care pathways are often at the forefront of political thinking about health care practices in France without ever finding a durable means for their extension. Closely linked to funding of healthcare system, they have, once again, been the object of so many economical discussions in 2017, as part of a more optimistic climate of governance which is therefore more open to change. Our changing system, the development and increasingly chronic nature of diseases, the scale of technological breakthroughs, these are all factors driving this topic forward. The object of this work, after a necessary study of the semantics of the term "pathway" and even "funding", was to identify all prerequisites and good practices for the stakeholders to develop a pilot pathway and then its relevant implementation in France. To do so, the members of the Round Table have relied on the presentation of examples of care pathways in order to identify triggers to a progressive, adapted extension to the whole territory. The group has identified key elements and priorities for the establishment of public funding beyond existing funding to incentive team work, particularly in the case of treatment rupture points and/or when they have diverging interests. Finally, creating a climate of confidence among patients, professionals, hospitals, the ARS, payers and manufacturers in handling change management will become the key challenges of the implementation of future pathways. Copyright © 2018 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.

Current status and future directions for in situ transmission electron microscopy

PubMed Central

Taheri, Mitra L.; Stach, Eric A.; Arslan, Ilke; Crozier, P.A.; Kabius, Bernd C.; LaGrange, Thomas; Minor, Andrew M.; Takeda, Seiji; Tanase, Mihaela; Wagner, Jakob B.; Sharma, Renu

2016-01-01

This review article discusses the current and future possibilities for the application of in situ transmission electron microscopy to reveal synthesis pathways and functional mechanisms in complex and nanoscale materials. The findings of a group of scientists, representing academia, government labs and private sector entities (predominantly commercial vendors) during a workshop, held at the Center for Nanoscale Science and Technology- National Institute of Science and Technology (CNST-NIST), are discussed. We provide a comprehensive review of the scientific needs and future instrument and technique developments required to meet them. PMID:27566048

Monitoring UV-induced signalling pathways in an ex vivo skin organ culture model using phospho-antibody array.

PubMed

Lenain, Christelle; Gamboa, Bastien; Perrin, Agnes; Séraïdaris, Alexia; Bertino, Béatrice; Rival, Yves; Bernardi, Mathieu; Piwnica, David; Méhul, Bruno

2018-05-01

We investigated UV-induced signalling in an ex vivo skin organ culture model using phospho-antibody array. Phosphorylation modulations were analysed in time-course experiments following exposure to solar-simulated UV and validated by Western blot analyses. We found that UV induced P-p38 and its substrates, P-ERK1/2 and P-AKT, which were previously shown to be upregulated by UV in cultured keratinocytes and in vivo human skin. This indicates that phospho-antibody array applied to ex vivo skin organ culture is a relevant experimental system to investigate signalling events following perturbations. As the identified proteins are components of pathways implicated in skin tumorigenesis, UV-exposed skin organ culture model could be used to investigate the effect on these pathways of NMSC cancer drug candidates. In addition, we found that phospho-HCK is induced upon UV exposure, producing a new candidate for future studies investigating its role in the skin response to UV and UV-induced carcinogenesis. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Neuroinflammatory targets and treatments for epilepsy validated in experimental models.

PubMed

Aronica, Eleonora; Bauer, Sebastian; Bozzi, Yuri; Caleo, Matteo; Dingledine, Raymond; Gorter, Jan A; Henshall, David C; Kaufer, Daniela; Koh, Sookyong; Löscher, Wolfgang; Louboutin, Jean-Pierre; Mishto, Michele; Norwood, Braxton A; Palma, Eleonora; Poulter, Michael O; Terrone, Gaetano; Vezzani, Annamaria; Kaminski, Rafal M

2017-07-01

A large body of evidence that has accumulated over the past decade strongly supports the role of inflammation in the pathophysiology of human epilepsy. Specific inflammatory molecules and pathways have been identified that influence various pathologic outcomes in different experimental models of epilepsy. Most importantly, the same inflammatory pathways have also been found in surgically resected brain tissue from patients with treatment-resistant epilepsy. New antiseizure therapies may be derived from these novel potential targets. An essential and crucial question is whether targeting these molecules and pathways may result in anti-ictogenesis, antiepileptogenesis, and/or disease-modification effects. Therefore, preclinical testing in models mimicking relevant aspects of epileptogenesis is needed to guide integrated experimental and clinical trial designs. We discuss the most recent preclinical proof-of-concept studies validating a number of therapeutic approaches against inflammatory mechanisms in animal models that could represent novel avenues for drug development in epilepsy. Finally, we suggest future directions to accelerate preclinical to clinical translation of these recent discoveries. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

Personal growth initiative and identity formation in adolescence through young adulthood: mediating processes on the pathway to well-being.

PubMed

Luyckx, Koen; Robitschek, Christine

2014-10-01

Developing a personal identity is a challenging task throughout adolescence and the transition to adulthood. The present study sampling 551 14-35 year olds (54.1% female) examined personal growth initiative (PGI) as a potential predictor of core identity processes and explored whether identity functioned as a mediator on the pathway from PGI to self-esteem and depressive symptoms. Path analyses from a structural equation modeling approach indicated that all four components of PGI (i.e., planfulness, readiness for change, intentional behavior, and using resources) predicted different commitment and exploration processes, with planfulness being the most consistent predictor. Important age differences linking PGI-components to identity exploration were found. Finally, especially the degree to which individuals identified themselves with their identity commitments and the degree to which they relied on ruminative or maladaptive forms of identity exploration mediated pathways from PGI to self-esteem and depressive symptoms. Implications and suggestions for future research are discussed. Copyright © 2014 The Foundation for Professionals in Services for Adolescents. Published by Elsevier Ltd. All rights reserved.

Bioinformatic perspectives on NRPS/PKS megasynthases: advances and challenges.

PubMed

Jenke-Kodama, Holger; Dittmann, Elke

2009-07-01

The increased understanding of both fundamental principles and mechanistic variations of NRPS/PKS megasynthases along with the unprecedented availability of microbial sequences has inspired a number of in silico studies of both enzyme families. The insights that can be extracted from these analyses go far beyond a rough classification of data and have turned bioinformatics into a frontier field of natural products research. As databases are flooded with NRPS/PKS gene sequence of microbial genomes and metagenomes, increasingly reliable structural prediction methods can help to uncover hidden treasures. Already, phylogenetic analyses have revealed that NRPS/PKS pathways should not simply be regarded as enzyme complexes, specifically evolved to product a selected natural product. Rather, they represent a collection of genetic opinions, allowing biosynthetic pathways to be shuffled in a process of perpetual chemical innovations and pathways diversification in nature can give impulses for specificities, protein interactions and genetic engineering of libraries of novel peptides and polyketides. The successful translation of the knowledge obtained from bioinformatic dissection of NRPS/PKS megasynthases into new techniques for drug discovery and design remain challenges for the future.

Bridging the Gap between Gut Microbial Dysbiosis and Cardiovascular Diseases.

PubMed

Lau, Kimberley; Srivatsav, Varun; Rizwan, Ayesha; Nashed, Andrew; Liu, Rui; Shen, Rui; Akhtar, Mahmood

2017-08-10

The human gut is heavily colonized by a community of microbiota, primarily bacteria, that exists in a symbiotic relationship with the host and plays a critical role in maintaining host homeostasis. The consumption of a high-fat (HF) diet has been shown to induce gut dysbiosis and reduce intestinal integrity. Recent studies have revealed that dysbiosis contributes to the progression of cardiovascular diseases (CVDs) by promoting two major CVD risk factors-atherosclerosis and hypertension. Imbalances in host-microbial interaction impair homeostatic mechanisms that regulate health and can activate multiple pathways leading to CVD risk factor progression. Dysbiosis has been implicated in the development of atherosclerosis through metabolism-independent and metabolite-dependent pathways. This review will illustrate how these pathways contribute to the various stages of atherosclerotic plaque progression. In addition, dysbiosis can promote hypertension through vascular fibrosis and an alteration of vascular tone. As CVD is the number one cause of death globally, investigating the gut microbiota as a locus of intervention presents a novel and clinically relevant avenue for future research, with vast therapeutic potential.

Bridging the Gap between Gut Microbial Dysbiosis and Cardiovascular Diseases

PubMed Central

Lau, Kimberley; Srivatsav, Varun; Rizwan, Ayesha; Nashed, Andrew; Liu, Rui; Shen, Rui; Akhtar, Mahmood

2017-01-01

The human gut is heavily colonized by a community of microbiota, primarily bacteria, that exists in a symbiotic relationship with the host and plays a critical role in maintaining host homeostasis. The consumption of a high-fat (HF) diet has been shown to induce gut dysbiosis and reduce intestinal integrity. Recent studies have revealed that dysbiosis contributes to the progression of cardiovascular diseases (CVDs) by promoting two major CVD risk factors—atherosclerosis and hypertension. Imbalances in host–microbial interaction impair homeostatic mechanisms that regulate health and can activate multiple pathways leading to CVD risk factor progression. Dysbiosis has been implicated in the development of atherosclerosis through metabolism-independent and metabolite-dependent pathways. This review will illustrate how these pathways contribute to the various stages of atherosclerotic plaque progression. In addition, dysbiosis can promote hypertension through vascular fibrosis and an alteration of vascular tone. As CVD is the number one cause of death globally, investigating the gut microbiota as a locus of intervention presents a novel and clinically relevant avenue for future research, with vast therapeutic potential. PMID:28796176

Recombinational Repair of DNA Damage in Escherichia coli and Bacteriophage λ

PubMed Central

Kuzminov, Andrei

1999-01-01

Although homologous recombination and DNA repair phenomena in bacteria were initially extensively studied without regard to any relationship between the two, it is now appreciated that DNA repair and homologous recombination are related through DNA replication. In Escherichia coli, two-strand DNA damage, generated mostly during replication on a template DNA containing one-strand damage, is repaired by recombination with a homologous intact duplex, usually the sister chromosome. The two major types of two-strand DNA lesions are channeled into two distinct pathways of recombinational repair: daughter-strand gaps are closed by the RecF pathway, while disintegrated replication forks are reestablished by the RecBCD pathway. The phage λ recombination system is simpler in that its major reaction is to link two double-stranded DNA ends by using overlapping homologous sequences. The remarkable progress in understanding the mechanisms of recombinational repair in E. coli over the last decade is due to the in vitro characterization of the activities of individual recombination proteins. Putting our knowledge about recombinational repair in the broader context of DNA replication will guide future experimentation. PMID:10585965

IL-1β, RAGE and FABP4: targeting the dynamic trio in metabolic inflammation and related pathologies

PubMed Central

Hardaway, Aimalie L; Podgorski, Izabela

2013-01-01

Within the past decade, inflammatory and lipid mediators, such as IL-1β, FABP4 and RAGE, have emerged as important contributors to metabolic dysfunction. As growing experimental and clinical evidence continues to tie obesity-induced chronic inflammation with dysregulated lipid, insulin signaling and related pathologies, IL-1β, FABP4 and RAGE each are being independently implicated as culprits in these events. There are also convincing data that molecular pathways driven by these molecules are interconnected in exacerbating metabolic consequences of obesity. This article highlights the roles of IL-1β, FABP4 and RAGE in normal physiology as well as focusing specifically on their contribution to inflammation, insulin resistance, atherosclerosis, Type 2 diabetes and cancer. Studies implicating the interconnection between these pathways, current and emerging therapeutics, and their use as potential biomarkers are also discussed. Evidence of impact of IL-1β, FABP4 and RAGE pathways on severity of metabolic dysfunction underlines the strong links between inflammatory events, lipid metabolism and insulin regulation, and offers new intriguing approaches for future therapies of obesity-driven pathologies. PMID:23795967

IL-1β, RAGE and FABP4: targeting the dynamic trio in metabolic inflammation and related pathologies.

PubMed

Hardaway, Aimalie L; Podgorski, Izabela

2013-06-01

Within the past decade, inflammatory and lipid mediators, such as IL-1β, FABP4 and RAGE, have emerged as important contributors to metabolic dysfunction. As growing experimental and clinical evidence continues to tie obesity-induced chronic inflammation with dysregulated lipid, insulin signaling and related pathologies, IL-1β, FABP4 and RAGE each are being independently implicated as culprits in these events. There are also convincing data that molecular pathways driven by these molecules are interconnected in exacerbating metabolic consequences of obesity. This article highlights the roles of IL-1β, FABP4 and RAGE in normal physiology as well as focusing specifically on their contribution to inflammation, insulin resistance, atherosclerosis, Type 2 diabetes and cancer. Studies implicating the interconnection between these pathways, current and emerging therapeutics, and their use as potential biomarkers are also discussed. Evidence of impact of IL-1β, FABP4 and RAGE pathways on severity of metabolic dysfunction underlines the strong links between inflammatory events, lipid metabolism and insulin regulation, and offers new intriguing approaches for future therapies of obesity-driven pathologies.

Targeting metabolic pathways for head and neck cancers therapeutics.

PubMed

Yamamoto, Masashi; Inohara, Hidenori; Nakagawa, Takashi

2017-09-01

Cancer cells have distinctive energy metabolism pathways that support their rapid cell division. The preference for anaerobic glycolysis under the normal oxygen condition is known as the Warburg effect and has been observed in head and neck cancers. These metabolic changes are controlled by cancer-related transcription factors, such as tumor suppressor gene and hypoxia inducible factor 1α. In addition, various metabolic enzymes also actively regulate cancer-specific metabolism including the switch between aerobic and anaerobic glycolysis. For a long time, these metabolic changes in cancer cells have been considered a consequence of transformation required to maintain the high rate of tumor cell replication. However, recent studies indicate that alteration of metabolism is sufficient to initiate tumor transformation. Indeed, oncogenic mutations in the metabolic enzymes, isocitrate dehydrogenase and succinate dehydrogenase, have been increasingly found in various cancers, including head and neck cancers. In the present review, we introduce recent findings regarding the cancer metabolism, including the molecular mechanisms of how they affect cancer pathogenesis and maintenance. We also discuss the current and future perspectives on therapeutics that target metabolic pathways, with an emphasis on head and neck cancer.

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.).

A systematic review of pathways to and processes associated with radicalization and extremism amongst Muslims in Western societies.

PubMed

McGilloway, Angela; Ghosh, Priyo; Bhui, Kamaldeep

2015-02-01

Following the terrorist attacks of 9/11 in the USA and 7/7 in the UK, academic interest in factors involved in radicalization and terrorism has increased dramatically. Many related social and psychological theories have been put forward, however terrorism literature still lacks empirical research. In particular, little is known about the early processes and pathways to radicalization. Our aim is to investigate original research on pathways and processes associated with radicalization and extremism amongst people of Muslim heritage living in Western societies, that is, the group prioritized by counter-terrorism policy. Studies included in the review were original qualitative or quantitative primary research published in peer-reviewed journals, identified by searching research databases. All disciplines of journals were included. No single cause or pathway was implicated in radicalization and violent extremism. Individuals may demonstrate vulnerabilities that increase exposure to radicalization; however, the only common characteristic determined that terrorists are generally well-integrated, 'normal' individuals. Engagement in such activity is dependent on a wide range of interacting variables influenced by personal, localized and externalized factors. Further research should examine broader determinants of radicalization in susceptible populations. Future policy should follow this public health approach rather than constructing from perpetrators already committed to engaging in terrorism.

Radiation activated CHK1/MEPE pathway may contribute to microgravity-induced bone density loss

NASA Astrophysics Data System (ADS)

Zhang, Xiangming; Wang, Ping; Wang, Ya

2015-11-01

Bone density loss in astronauts on long-term space missions is a chief medical concern. Microgravity in space is the major cause of bone density loss (osteopenia), and it is believed that high linear energy transfer (LET) radiation in space exacerbates microgravity-induced bone density loss; however, the mechanism remains unclear. It is known that acidic serine- and aspartate-rich motif (ASARM) as a small peptide released by matrix extracellular phosphoglycoprotein (MEPE) promotes osteopenia. We previously discovered that MEPE interacted with checkpoint kinase 1 (CHK1) to protect CHK1 from ionizing radiation promoted degradation. In this study, we addressed whether the CHK1-MEPE pathway activated by radiation contributes to the effects of microgravity on bone density loss. We examined the CHK1, MEPE and secreted MEPE/ASARM levels in irradiated (1 Gy of X-ray) and rotated cultured human osteoblast cells. The results showed that radiation activated CHK1, decreased the levels of CHK1 and MEPE in human osteoblast cells and increased the release of MEPE/ASARM. These results suggest that the radiation-activated CHK1/MEPE pathway exacerbates the effects of microgravity on bone density loss, which may provide a novel targeting factor/pathway for a future countermeasure design that could contribute to reducing osteopenia in astronauts.

Formal reasoning about systems biology using theorem proving

PubMed Central

Hasan, Osman; Siddique, Umair; Tahar, Sofiène

2017-01-01

System biology provides the basis to understand the behavioral properties of complex biological organisms at different levels of abstraction. Traditionally, analysing systems biology based models of various diseases have been carried out by paper-and-pencil based proofs and simulations. However, these methods cannot provide an accurate analysis, which is a serious drawback for the safety-critical domain of human medicine. In order to overcome these limitations, we propose a framework to formally analyze biological networks and pathways. In particular, we formalize the notion of reaction kinetics in higher-order logic and formally verify some of the commonly used reaction based models of biological networks using the HOL Light theorem prover. Furthermore, we have ported our earlier formalization of Zsyntax, i.e., a deductive language for reasoning about biological networks and pathways, from HOL4 to the HOL Light theorem prover to make it compatible with the above-mentioned formalization of reaction kinetics. To illustrate the usefulness of the proposed framework, we present the formal analysis of three case studies, i.e., the pathway leading to TP53 Phosphorylation, the pathway leading to the death of cancer stem cells and the tumor growth based on cancer stem cells, which is used for the prognosis and future drug designs to treat cancer patients. PMID:28671950