The burden of trisomy 21 disrupts the proteostasis network in Down syndrome

PubMed Central

Rauniyar, Abhishek K.; Jiang, Hua; Liggett, L. Alexander; Maclean, Kenneth N.

2017-01-01

Down syndrome (DS) is a genetic disorder caused by trisomy of chromosome 21. Abnormalities in chromosome number have the potential to lead to disruption of the proteostasis network (PN) and accumulation of misfolded proteins. DS individuals suffer from several comorbidities, and we hypothesized that disruption of proteostasis could contribute to the observed pathology and decreased cell viability in DS. Our results confirm the presence of a disrupted PN in DS, as several of its elements, including the unfolded protein response, chaperone system, and proteasomal degradation exhibited significant alterations compared to euploid controls in both cell and mouse models. Additionally, when cell models were treated with compounds that promote disrupted proteostasis, we observed diminished levels of cell viability in DS compared to controls. Collectively our findings provide a cellular-level characterization of PN dysfunction in DS and an improved understanding of the potential pathogenic mechanisms contributing to disrupted cellular physiology in DS. Lastly, this study highlights the future potential of designing therapeutic strategies that mitigate protein quality control dysfunction. PMID:28430800

A PQM-1-Mediated Response Triggers Transcellular Chaperone Signaling and Regulates Organismal Proteostasis.

PubMed

O'Brien, Daniel; Jones, Laura M; Good, Sarah; Miles, Jo; Vijayabaskar, M S; Aston, Rebecca; Smith, Catrin E; Westhead, David R; van Oosten-Hawle, Patricija

2018-06-26

In metazoans, tissues experiencing proteotoxic stress induce "transcellular chaperone signaling" (TCS) that activates molecular chaperones, such as hsp-90, in distal tissues. How this form of inter-tissue communication is mediated to upregulate systemic chaperone expression and whether it can be utilized to protect against protein misfolding diseases remain open questions. Using C. elegans, we identified key components of a systemic stress signaling pathway that links the innate immune response with proteostasis maintenance. We show that mild perturbation of proteostasis in the neurons or the intestine activates TCS via the GATA zinc-finger transcription factor PQM-1. PQM-1 coordinates neuron-activated TCS via the innate immunity-associated transmembrane protein CLEC-41, whereas intestine-activated TCS depends on the aspartic protease ASP-12. Both TCS pathways can induce hsp-90 in muscle cells and facilitate amelioration of Aβ 3-42 -associated toxicity. This may have powerful implications for the treatment of diseases related to proteostasis dysfunction. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity.

PubMed

Sorrentino, Vincenzo; Romani, Mario; Mouchiroud, Laurent; Beck, John S; Zhang, Hongbo; D'Amico, Davide; Moullan, Norman; Potenza, Francesca; Schmid, Adrien W; Rietsch, Solène; Counts, Scott E; Auwerx, Johan

2017-12-14

Alzheimer's disease is a common and devastating disease characterized by aggregation of the amyloid-β peptide. However, we know relatively little about the underlying molecular mechanisms or how to treat patients with Alzheimer's disease. Here we provide bioinformatic and experimental evidence of a conserved mitochondrial stress response signature present in diseases involving amyloid-β proteotoxicity in human, mouse and Caenorhabditis elegans that involves the mitochondrial unfolded protein response and mitophagy pathways. Using a worm model of amyloid-β proteotoxicity, GMC101, we recapitulated mitochondrial features and confirmed that the induction of this mitochondrial stress response was essential for the maintenance of mitochondrial proteostasis and health. Notably, increasing mitochondrial proteostasis by pharmacologically and genetically targeting mitochondrial translation and mitophagy increases the fitness and lifespan of GMC101 worms and reduces amyloid aggregation in cells, worms and in transgenic mouse models of Alzheimer's disease. Our data support the relevance of enhancing mitochondrial proteostasis to delay amyloid-β proteotoxic diseases, such as Alzheimer's disease.

Cranberry Extract Standardized for Proanthocyanidins Alleviates β-Amyloid Peptide Toxicity by Improving Proteostasis Through HSF-1 in Caenorhabditis elegans Model of Alzheimer's Disease.

PubMed

Guo, Hong; Cao, Min; Zou, Sige; Ye, Boping; Dong, Yuqing

2016-12-01

A growing body of evidence suggests that nutraceuticals with prolongevity properties may delay the onset of Alzheimer's disease (AD). We recently demonstrated that a proanthocyanidins-standardized cranberry extract has properties that prolong life span and promote innate immunity in Caenorhabditis elegans In this article, we report that supplementation of this cranberry extract delayed Aβ toxicity-triggered body paralysis in the C elegans AD model. Genetic analyses indicated that the cranberry-mediated Aβ toxicity alleviation required heat shock transcription factor (HSF)-1 rather than DAF-16 and SKN-1. Moreover, cranberry supplementation increased the transactivity of HSF-1 in an IIS-dependent manner. Further studies found that the cranberry extract relies on HSF-1 to significantly enhance the solubility of proteins in aged worms, implying an improved proteostasis in AD worms. Considering that HSF-1 plays a pivotal role in maintaining proteostasis, our results suggest that cranberry maintains the function of proteostasis through HSF-1, thereby protecting C elegans against Aβ toxicity. Together, our findings elucidated the mechanism whereby cranberry attenuated Aβ toxicity in C elegans and stressed the significance of proteostasis in the prevention of age-related diseases from a practical point of view. © The Author 2015. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

The plastid and mitochondrial peptidase network in Arabidopsis thaliana: a foundation for testing genetic interactions and functions in organellar proteostasis

USDA-ARS?s Scientific Manuscript database

Plant plastids and mitochondria have dynamic proteomes. To maintain their protein homeostasis, a proteostasis network containing protein chaperones, peptidases and their substrate recognition factors exists, but many peptidases, their functional connections and substrates are poorly characterized. T...

The measurement of Protein Synthesis for Assessing Proteostasis in Studies of Slowed Aging

PubMed Central

Miller, Benjamin F.; Drake, Joshua C.; Naylor, Bradley; Price, John C.; Hamilton, Karyn L.

2014-01-01

Slowing the aging process can reduce the risk for multiple chronic diseases simultaneously. It is increasingly recognized that maintaining protein homeostasis (or proteostasis) is important for slowing the aging process. Since proteostasis is a dynamic process, monitoring it is not a simple task and requires use of appropriate methods. This review will introduce methods to assess protein and DNA synthesis using deuterium oxide (D2O), and how protein and DNA synthesis outcomes provide insight into proteostatic mechanisms. Finally, we provide a discussion on how these assessments of protein and DNA synthesis are “mechanistic” investigations and provide an appropriate framework for the further development of slowed aging treatments. PMID:25283966

Small molecule proteostasis regulators that reprogram the ER to reduce extracellular protein aggregation

PubMed Central

Plate, Lars; Cooley, Christina B; Chen, John J; Paxman, Ryan J; Gallagher, Ciara M; Madoux, Franck; Genereux, Joseph C; Dobbs, Wesley; Garza, Dan; Spicer, Timothy P; Scampavia, Louis; Brown, Steven J; Rosen, Hugh; Powers, Evan T; Walter, Peter; Hodder, Peter; Wiseman, R Luke; Kelly, Jeffery W

2016-01-01

Imbalances in endoplasmic reticulum (ER) proteostasis are associated with etiologically-diverse degenerative diseases linked to excessive extracellular protein misfolding and aggregation. Reprogramming of the ER proteostasis environment through genetic activation of the Unfolded Protein Response (UPR)-associated transcription factor ATF6 attenuates secretion and extracellular aggregation of amyloidogenic proteins. Here, we employed a screening approach that included complementary arm-specific UPR reporters and medium-throughput transcriptional profiling to identify non-toxic small molecules that phenocopy the ATF6-mediated reprogramming of the ER proteostasis environment. The ER reprogramming afforded by our molecules requires activation of endogenous ATF6 and occurs independent of global ER stress. Furthermore, our molecules phenocopy the ability of genetic ATF6 activation to selectively reduce secretion and extracellular aggregation of amyloidogenic proteins. These results show that small molecule-dependent ER reprogramming, achieved through preferential activation of the ATF6 transcriptional program, is a promising strategy to ameliorate imbalances in ER function associated with degenerative protein aggregation diseases. DOI: http://dx.doi.org/10.7554/eLife.15550.001 PMID:27435961

Collapse of proteostasis represents an early molecular event in Caenorhabditis elegans aging.

PubMed

Ben-Zvi, Anat; Miller, Elizabeth A; Morimoto, Richard I

2009-09-01

Protein damage contributes prominently to cellular aging. To address whether this occurs at a specific period during aging or accumulates gradually, we monitored the biochemical, cellular, and physiological properties of folding sensors expressed in different tissues of C. elegans. We observed the age-dependent misfolding and loss of function of diverse proteins harboring temperature-sensitive missense mutations in all somatic tissues at the permissive condition. This widespread failure in proteostasis occurs rapidly at an early stage of adulthood, and coincides with a severely reduced activation of the cytoprotective heat shock response and the unfolded protein response. Enhancing stress responsive factors HSF-1 or DAF-16 suppresses misfolding of these metastable folding sensors and restores the ability of the cell to maintain a functional proteome. This suggests that a compromise in the regulation of proteostatic stress responses occurs early in adulthood and tips the balance between the load of damaged proteins and the proteostasis machinery. We propose that the collapse of proteostasis represents an early molecular event of aging that amplifies protein damage in age-associated diseases of protein conformation.

Individual and collective contributions of chaperoning and degradation to protein homeostasis in E. coli.

PubMed

Cho, Younhee; Zhang, Xin; Pobre, Kristine Faye R; Liu, Yu; Powers, David L; Kelly, Jeffery W; Gierasch, Lila M; Powers, Evan T

2015-04-14

The folding fate of a protein in vivo is determined by the interplay between a protein's folding energy landscape and the actions of the proteostasis network, including molecular chaperones and degradation enzymes. The mechanisms of individual components of the E. coli proteostasis network have been studied extensively, but much less is known about how they function as a system. We used an integrated experimental and computational approach to quantitatively analyze the folding outcomes (native folding versus aggregation versus degradation) of three test proteins biosynthesized in E. coli under a variety of conditions. Overexpression of the entire proteostasis network benefited all three test proteins, but the effect of upregulating individual chaperones or the major degradation enzyme, Lon, varied for proteins with different biophysical properties. In sum, the impact of the E. coli proteostasis network is a consequence of concerted action by the Hsp70 system (DnaK/DnaJ/GrpE), the Hsp60 system (GroEL/GroES), and Lon. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Proteostasis: bad news and good news from the endoplasmic reticulum.

PubMed

Noack, Julia; Brambilla Pisoni, Giorgia; Molinari, Maurizio

2014-01-01

The endoplasmic reticulum (ER) is an intracellular compartment dedicated to the synthesis and maturation of secretory and membrane proteins, totalling about 30% of the total eukaryotic cells proteome. The capacity to produce correctly folded polypeptides and to transport them to their correct intra- or extracellular destinations relies on proteostasis networks that regulate and balance the activity of protein folding, quality control, transport and degradation machineries. Nutrient and environmental changes, pathogen infection aging and, more relevant for the topics discussed in this review, mutations that impair attainment of the correct 3D structure of nascent polypeptide chains may compromise the activity of the proteostasis networks with devastating consequences on cells, organs and organisms' homeostasis. Here we present a review of mechanisms regulating folding and quality control of proteins expressed in the ER, and we describe the protein degradation and the ER stress pathways activated by the expression of misfolded proteins in the ER lumen. Finally, we highlight select examples of proteopathies (also known as conformational disorders or protein misfolding diseases) caused by protein misfolding in the ER and/or affecting cellular proteostasis and therapeutic interventions that might alleviate or cure the disease symptoms.

Proteostasis regulation by the ubiquitin system.

PubMed

Bett, John S

2016-10-15

Cells have developed an evolutionary obligation to survey and maintain proteome fidelity and avoid the possible toxic consequences of protein misfolding and aggregation. Disturbances to protein homoeostasis (proteostasis) can result in severe cellular phenotypes and are closely linked with the accumulation of microscopically visible deposits of aggregated proteins. These include inclusion bodies found in AD (Alzheimer's disease), HD (Huntington's disease) and ALS (amyotrophic lateral sclerosis) patient neurons. Protein aggregation is intimately linked with the ubiquitin and ubiquitin-like post-translational modifier system, which manages cellular protein folding stress and promotes the restoration of proteostasis. This is achieved in large part through the action of the UPS (ubiquitin-proteasome system), which is responsible for directing the proteasomal destruction of misfolded and damaged proteins tagged with ubiquitin chains. There are other less well understood ways in which ubiquitin family members can help to maintain proteostasis that complement, but are independent of, the UPS. This article discusses our current understanding of how the ubiquitin family regulates the protein misfolding pathways that threaten proteome fidelity, and how this is achieved by the key players in this process. © 2016 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Diversity in the origins of proteostasis networks- a driver for protein function in evolution

PubMed Central

Powers, Evan T.; Balch, William E.

2013-01-01

Although a protein’s primary sequence largely determines its function, proteins can adopt different folding states in response to changes in the environment, some of which may be deleterious to the organism. All organisms, including Bacteria, Archaea and Eukarya, have evolved a protein homeostasis network, or proteostasis network, that consists of chaperones and folding factors, degradation components, signalling pathways and specialized compartmentalized modules that manage protein folding in response to environmental stimuli and variation. Surveying the origins of proteostasis networks reveals that they have co-evolved with the proteome to regulate the physiological state of the cell, reflecting the unique stresses that different cells or organisms experience, and that they have a key role in driving evolution by closely managing the link between the phenotype and the genotype. PMID:23463216

The inhibition of IGF-1 signaling promotes proteostasis by enhancing protein aggregation and deposition.

PubMed

Moll, Lorna; Ben-Gedalya, Tziona; Reuveni, Hadas; Cohen, Ehud

2016-04-01

The discovery that the alteration of aging by reducing the activity of the insulin/IGF-1 signaling (IIS) cascade protects nematodes and mice from neurodegeneration-linked, toxic protein aggregation (proteotoxicity) raises the prospect that IIS inhibitors bear therapeutic potential to counter neurodegenerative diseases. Recently, we reported that NT219, a highly efficient IGF-1 signaling inhibitor, protects model worms from the aggregation of amyloid β peptide and polyglutamine peptides that are linked to the manifestation of Alzheimer's and Huntington's diseases, respectively. Here, we employed cultured cell systems to investigate whether NT219 promotes protein homeostasis (proteostasis) in mammalian cells and to explore its underlying mechanisms. We found that NT219 enhances the aggregation of misfolded prion protein and promotes its deposition in quality control compartments known as "aggresomes." NT219 also elevates the levels of certain molecular chaperones but, surprisingly, reduces proteasome activity and impairs autophagy. Our findings show that IGF-1 signaling inhibitors in general and NT219 in particular can promote proteostasis in mammalian cells by hyperaggregating hazardous proteins, thereby bearing the potential to postpone the onset and slow the progression of neurodegenerative illnesses in the elderly.-Moll, L., Ben-Gedalya, T., Reuveni, H., Cohen, E. The inhibition of IGF-1 signaling promotes proteostasis by enhancing protein aggregation and deposition. © FASEB.

Targeting mitochondrial function and proteostasis to mitigate dynapenia.

PubMed

Musci, Robert V; Hamilton, Karyn L; Miller, Benjamin F

2018-01-01

Traditionally, interventions to treat skeletal muscle aging have largely targeted sarcopenia-the age-related loss of skeletal muscle mass. Dynapenia refers to the age-related loss in skeletal muscle function due to factors outside of muscle mass, which helps to inform treatment strategies for aging skeletal muscle. There is evidence that mechanisms to maintain protein homeostasis and proteostasis, deteriorate with age. One key mechanism to maintain proteostasis is protein turnover, which is an energetically costly process. When there is a mismatch between cellular energy demands and energy provision, inelastic processes related to metabolism are maintained, but there is competition for the remaining energy between the elastic processes of somatic maintenance and growth. With aging, mitochondrial dysfunction reduces ATP generation capacity, constraining the instantaneous supply of energy, thus compromising growth and somatic maintenance processes. Further, with age the need for somatic maintenance increases because of the accumulation of protein damage. In this review, we highlight the significant role mitochondria have in maintaining skeletal muscle proteostasis through increased energy provision, protein turnover, and substrate flux. In addition, we provide evidence that improving mitochondrial function could promote a cellular environment that is conducive to somatic maintenance, and consequently for mitigating dynapenia. Finally, we highlight interventions, such as aerobic exercise, that could be used to improve mitochondrial function and improve outcomes related to dynapenia.

Thermal Shock Induces Host Proteostasis Disruption and Endoplasmic Reticulum Stress in the Model Symbiotic Cnidarian Aiptasia.

PubMed

Oakley, Clinton A; Durand, Elysanne; Wilkinson, Shaun P; Peng, Lifeng; Weis, Virginia M; Grossman, Arthur R; Davy, Simon K

2017-06-02

Coral bleaching has devastating effects on coral survival and reef ecosystem function, but many of the fundamental cellular effects of thermal stress on cnidarian physiology are unclear. We used label-free liquid chromatography-tandem mass spectrometry to compare the effects of rapidly (33.5 °C, 24 h) and gradually (30 and 33.5 °C, 12 days) elevated temperatures on the proteome of the model symbiotic anemone Aiptasia. We identified 2133 proteins in Aiptasia, 136 of which were differentially abundant between treatments. Thermal shock, but not acclimation, resulted in significant abundance changes in 104 proteins, including those involved in protein folding and synthesis, redox homeostasis, and central metabolism. Nineteen abundant structural proteins showed particularly reduced abundance, demonstrating proteostasis disruption and potential protein synthesis inhibition. Heat shock induced antioxidant mechanisms and proteins involved in stabilizing nascent proteins, preventing protein aggregation and degrading damaged proteins, which is indicative of endoplasmic reticulum stress. Host proteostasis disruption occurred before either bleaching or symbiont photoinhibition was detected, suggesting host-derived reactive oxygen species production as the proximate cause of thermal damage. The pronounced abundance changes in endoplasmic reticulum proteins associated with proteostasis and protein turnover indicate that these processes are essential in the cellular response of symbiotic cnidarians to severe thermal stress.

Modulation of proteostasis counteracts oxidative stress and affects DNA base excision repair capacity in ATM-deficient cells

PubMed Central

Yang, Di; Fletcher, Sally C.; Vendrell, Iolanda; Fischer, Roman; Legrand, Arnaud J.

2017-01-01

Abstract Ataxia telangiectasia (A-T) is a syndrome associated with loss of ATM protein function. Neurodegeneration and cancer predisposition, both hallmarks of A-T, are likely to emerge as a consequence of the persistent oxidative stress and DNA damage observed in this disease. Surprisingly however, despite these severe features, a lack of functional ATM is still compatible with early life, suggesting that adaptation mechanisms contributing to cell survival must be in place. Here we address this gap in our knowledge by analysing the process of human fibroblast adaptation to the lack of ATM. We identify profound rearrangement in cellular proteostasis occurring very early on after loss of ATM in order to counter protein damage originating from oxidative stress. Change in proteostasis, however, is not without repercussions. Modulating protein turnover in ATM-depleted cells also has an adverse effect on the DNA base excision repair pathway, the major DNA repair system that deals with oxidative DNA damage. As a consequence, the burden of unrepaired endogenous DNA lesions intensifies, progressively leading to genomic instability. Our study provides a glimpse at the cellular consequences of loss of ATM and highlights a previously overlooked role for proteostasis in maintaining cell survival in the absence of ATM function. PMID:28973444

Mitochondrial proteostasis as a shared characteristic of slowed aging: the importance of considering cell proliferation.

PubMed

Hamilton, Karyn L; Miller, Benjamin F

2017-10-15

Proteostasis is one of the seven "pillars of aging research" identified by the Trans-NIH Geroscience Initiative and loss of proteostasis is associated with aging and age-related chronic disease. Accumulated protein damage and resultant cellular dysfunction are consequences of limited protein repair systems and slowed protein turnover. When relatively high rates of protein turnover are maintained despite advancing age, damaged proteins are more quickly degraded and replaced, maintaining proteome fidelity. Therefore, maintenance of protein turnover represents an important proteostatic mechanism. However, measurement of protein synthesis without consideration for cell proliferation can result in an incomplete picture, devoid of information about how new proteins are being allocated. Simultaneous measurement of protein and DNA synthesis provides necessary mechanistic insight about proteins apportioned for newly proliferating cells versus for somatic maintenance. Using this approach with a number of murine models of slowed aging shows that, compared to controls, energetic resources are directed more toward somatic maintenance and proteostasis, and away from cell growth and proliferation. In particular, slowed aging models are associated with heightened mechanisms of mitochondrial proteostatic maintenance. Taking cell proliferation into account may explain the paradoxical findings that aging itself and slowed aging interventions can both be characterized by slower rates of protein synthesis. © 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.

Royal jelly promotes DAF-16-mediated proteostasis to tolerate β-amyloid toxicity in C. elegans model of Alzheimer's disease.

PubMed

Wang, Xiaoxia; Cao, Min; Dong, Yuqing

2016-08-23

Numerous studies have demonstrated that dietary intervention may promote health and help prevent Alzheimer's disease (AD). We recently reported that bee products of royal jelly (RJ) and enzyme-treated royal jelly (eRJ) were potent to promote healthy aging in C. elegans. Here, we examined whether RJ/eRJ consumption may benefit to mitigate the AD symptom in the disease model of C. elegans. Our results showed that RJ/eRJ supplementation significantly delayed the body paralysis in AD worms, suggesting the β-amyloid (Aβ) toxicity attenuation effects of RJ/eRJ. Genetic analyses suggested that RJ/eRJ-mediated alleviation of Aβ toxicity in AD worms required DAF-16, rather than HSF-1 and SKN-1, in an insulin/IGF signaling dependent manner. Moreover, RJ/eRJ modulated the transactivity of DAF-16 and dramatically improved the protein solubility in aged worms. Given protein solubility is a hallmark of healthy proteostasis, our findings demonstrated that RJ/eRJ supplementation improved proteostasis, and this promotion depended on the transactivity of DAF-16. Collectively, the present study not only elucidated the possible anti-AD mechanism of RJ/eRJ, but also provided evidence from a practical point of view to shed light on the extensive correlation of proteostasis and the prevention of neurodegenerative disorders.

Progressing neurobiological strategies against proteostasis failure: Challenges in neurodegeneration.

PubMed

Amanullah, Ayeman; Upadhyay, Arun; Joshi, Vibhuti; Mishra, Ribhav; Jana, Nihar Ranjan; Mishra, Amit

2017-12-01

Proteins are ordered useful cellular entities, required for normal health and organism's survival. The proteome is the absolute set of cellular expressed proteins, which regulates a wide range of physiological functions linked with all domains of life. In aging cells or under unfavorable cellular conditions, misfolding of proteins generates common pathological events linked with neurodegenerative diseases and aging. Current advances of proteome studies systematically generates some progress in our knowledge that how misfolding of proteins or their accumulation can contribute to the impairment or depletion of proteome functions. Still, the underlying causes of this unrecoverable loss are not clear that how such unsolved transitions give rise to multifactorial challengeable degenerative pathological conditions in neurodegeneration. In this review, we specifically focus and systematically summarize various molecular mechanisms of proteostasis maintenance, as well as discuss progressing neurobiological strategies, promising natural and pharmacological candidates, which can be useful to counteract the problem of proteopathies. Our article emphasizes an urgent need that now it is important for us to recognize the fundamentals of proteostasis to design a new molecular framework and fruitful strategies to uncover how the proteome defects are associated with aging and neurodegenerative diseases. A enhance understanding of progress link with proteome and neurobiological challenges may provide new basic concepts in the near future, based on pharmacological agents, linked with impaired proteostasis and neurodegenerative diseases. Copyright © 2017 Elsevier Ltd. All rights reserved.

Worming our way to novel drug discovery with the Caenorhabditis elegans proteostasis network, stress response and insulin-signaling pathways.

PubMed

O'Reilly, Linda P; Benson, Joshua A; Cummings, Erin E; Perlmutter, David H; Silverman, Gary A; Pak, Stephen C

2014-09-01

Many human diseases result from a failure of a single protein to achieve the correct folding and tertiary conformation. These so-called 'conformational diseases' involve diverse proteins and distinctive cellular pathologies. They all engage the proteostasis network (PN), to varying degrees in an attempt to mange cellular stress and restore protein homeostasis. The insulin/insulin-like growth factor signaling (IIS) pathway is a master regulator of cellular stress response, which is implicated in regulating components of the PN. This review focuses on novel approaches to target conformational diseases. The authors discuss the evidence supporting the involvement of the IIS pathway in modulating the PN and regulating proteostasis in Caenorhabditis elegans. Furthermore, they review previous PN and IIS drug screens and explore the possibility of using C. elegans for whole organism-based drug discovery for modulators of IIS-proteostasis pathways. An alternative approach to develop individualized therapy for each conformational disease is to modulate the global PN. The involvement of the IIS pathway in regulating longevity and response to a variety of stresses is well documented. Increasing data now provide evidence for the close association between the IIS and the PN pathways. The authors believe that high-throughput screening campaigns, which target the C. elegans IIS pathway, may identify drugs that are efficacious in treating numerous conformational diseases.

Modulation of proteostasis counteracts oxidative stress and affects DNA base excision repair capacity in ATM-deficient cells.

PubMed

Poletto, Mattia; Yang, Di; Fletcher, Sally C; Vendrell, Iolanda; Fischer, Roman; Legrand, Arnaud J; Dianov, Grigory L

2017-09-29

Ataxia telangiectasia (A-T) is a syndrome associated with loss of ATM protein function. Neurodegeneration and cancer predisposition, both hallmarks of A-T, are likely to emerge as a consequence of the persistent oxidative stress and DNA damage observed in this disease. Surprisingly however, despite these severe features, a lack of functional ATM is still compatible with early life, suggesting that adaptation mechanisms contributing to cell survival must be in place. Here we address this gap in our knowledge by analysing the process of human fibroblast adaptation to the lack of ATM. We identify profound rearrangement in cellular proteostasis occurring very early on after loss of ATM in order to counter protein damage originating from oxidative stress. Change in proteostasis, however, is not without repercussions. Modulating protein turnover in ATM-depleted cells also has an adverse effect on the DNA base excision repair pathway, the major DNA repair system that deals with oxidative DNA damage. As a consequence, the burden of unrepaired endogenous DNA lesions intensifies, progressively leading to genomic instability. Our study provides a glimpse at the cellular consequences of loss of ATM and highlights a previously overlooked role for proteostasis in maintaining cell survival in the absence of ATM function. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

Against the traffic: The first evidence for mitochondrial DNA transfer into the plastid genome

USDA-ARS?s Scientific Manuscript database

Transfer of DNA between different compartments of the plant cell, i.e. plastid, mitochondrion and nucleus, is a well-known phenomenon in plant evolution. Six directions of inter-compartmental DNA migration are possible in theory, however only four of them have been previously reported. These include...

Inter-compartmental transport of organophosphate and pyrethroid pesticides in South China: implications for a regional risk assessment.

PubMed

Li, Huizhen; Wei, Yanli; Lydy, Michael J; You, Jing

2014-07-01

The dynamic flux of an organophosphate and four pyrethroid pesticides was determined in an air-(soil)-water-sediment system based on monitoring data from Guangzhou, China. The total air-water flux, including air-water gaseous exchange and atmospheric deposition, showed deposition from air to water for chlorpyrifos, bifenthrin and cypermethrin, but volatilization for lambda-cyhalothrin and permethrin. The transport of the pesticides from overlying water to sediment suggested that sediment acted as a sink for the pesticides. Additionally, distinct annual atmospheric depositional fluxes between legacy and current-use pesticides suggested the role of consumer usage in their transport throughout the system. Finally, pesticide toxicity was estimated from annual air-water-sediment flux within an urban stream in Guangzhou. A dynamic flux-based risk assessment indicated that inter-compartmental transport of chlorpyrifos decreased its atmospheric exposure, but had little influence on its aquatic toxicity. Instead, water-to-sediment transport of pyrethroids increased their sediment toxicity, which was supported by previously reported toxicity data. Copyright © 2014 Elsevier Ltd. All rights reserved.

Small heat shock proteins mediate cell-autonomous and -nonautonomous protection in a Drosophila model for environmental-stress-induced degeneration.

PubMed

Kawasaki, Fumiko; Koonce, Noelle L; Guo, Linda; Fatima, Shahroz; Qiu, Catherine; Moon, Mackenzie T; Zheng, Yunzhen; Ordway, Richard W

2016-09-01

Cell and tissue degeneration, and the development of degenerative diseases, are influenced by genetic and environmental factors that affect protein misfolding and proteotoxicity. To better understand the role of the environment in degeneration, we developed a genetic model for heat shock (HS)-stress-induced degeneration in Drosophila This model exhibits a unique combination of features that enhance genetic analysis of degeneration and protection mechanisms involving environmental stress. These include cell-type-specific failure of proteostasis and degeneration in response to global stress, cell-nonautonomous interactions within a simple and accessible network of susceptible cell types, and precise temporal control over the induction of degeneration. In wild-type flies, HS stress causes selective loss of the flight ability and degeneration of three susceptible cell types comprising the flight motor: muscle, motor neurons and associated glia. Other motor behaviors persist and, accordingly, the corresponding cell types controlling leg motor function are resistant to degeneration. Flight motor degeneration was preceded by a failure of muscle proteostasis characterized by diffuse ubiquitinated protein aggregates. Moreover, muscle-specific overexpression of a small heat shock protein (HSP), HSP23, promoted proteostasis and protected muscle from HS stress. Notably, neurons and glia were protected as well, indicating that a small HSP can mediate cell-nonautonomous protection. Cell-autonomous protection of muscle was characterized by a distinct distribution of ubiquitinated proteins, including perinuclear localization and clearance of protein aggregates associated with the perinuclear microtubule network. This network was severely disrupted in wild-type preparations prior to degeneration, suggesting that it serves an important role in muscle proteostasis and protection. Finally, studies of resistant leg muscles revealed that they sustain proteostasis and the microtubule cytoskeleton after HS stress. These findings establish a model for genetic analysis of degeneration and protection mechanisms involving contributions of environmental factors, and advance our understanding of the protective functions and therapeutic potential of small HSPs. © 2016. Published by The Company of Biologists Ltd.

Morphological remodeling of C. elegans neurons during aging is modified by compromised protein homeostasis

PubMed Central

Vayndorf, Elena M; Scerbak, Courtney; Hunter, Skyler; Neuswanger, Jason R; Toth, Marton; Parker, J Alex; Neri, Christian; Driscoll, Monica; Taylor, Barbara E

2016-01-01

Understanding cellular outcomes, such as neuronal remodeling, that are common to both healthy and diseased aging brains is essential to the development of successful brain aging strategies. Here, we used Caenorhabdits elegans to investigate how the expression of proteotoxic triggers, such as polyglutamine (polyQ)-expanded huntingtin and silencing of proteostasis regulators, such as the ubiquitin–proteasome system (UPS) and protein clearance components, may impact the morphological remodeling of individual neurons as animals age. We examined the effects of disrupted proteostasis on the integrity of neuronal cytoarchitecture by imaging a transgenic C. elegans strain in which touch receptor neurons express the first 57 amino acids of the human huntingtin (Htt) gene with expanded polyQs (128Q) and by using neuron-targeted RNA interference in adult wild-type neurons to knockdown genes encoding proteins involved in proteostasis. We found that proteostatic challenges conferred by polyQ-expanded Htt and knockdown of specific genes involved in protein homeostasis can lead to morphological changes that are restricted to specific domains of specific neurons. The age-associated branching of PLM neurons is suppressed by N-ter polyQ-expanded Htt expression, whereas ALM neurons with polyQ-expanded Htt accumulate extended outgrowths and other soma abnormalities. Furthermore, knockdown of genes important for ubiquitin-mediated degradation, lysosomal function, and autophagy modulated these age-related morphological changes in otherwise normal neurons. Our results show that the expression of misfolded proteins in neurodegenerative disease such as Huntington’s disease modifies the morphological remodeling that is normally associated with neuronal aging. Our results also show that morphological remodeling of healthy neurons during aging can be regulated by the UPS and other proteostasis pathways. Collectively, our data highlight a model in which morphological remodeling during neuronal aging is strongly affected by disrupted proteostasis and expression of disease-associated, misfolded proteins such as human polyQ-Htt species. PMID:27347427

Loss of Ranbp2 in motoneurons causes disruption of nucleocytoplasmic and chemokine signaling, proteostasis of hnRNPH3 and Mmp28, and development of amyotrophic lateral sclerosis-like syndromes.

PubMed

Cho, Kyoung-In; Yoon, Dosuk; Qiu, Sunny; Danziger, Zachary; Grill, Warren M; Wetsel, William C; Ferreira, Paulo A

2017-05-01

The pathogenic drivers of sporadic and familial motor neuron disease (MND), such amyotrophic lateral sclerosis (ALS), are unknown. MND impairs the Ran GTPase cycle, which controls nucleocytoplasmic transport, ribostasis and proteostasis; however, cause-effect mechanisms of Ran GTPase modulators in motoneuron pathobiology have remained elusive. The cytosolic and peripheral nucleoporin Ranbp2 is a crucial regulator of the Ran GTPase cycle and of the proteostasis of neurological disease-prone substrates, but the roles of Ranbp2 in motoneuron biology and disease remain unknown. This study shows that conditional ablation of Ranbp2 in mouse Thy1 motoneurons causes ALS syndromes with hypoactivity followed by hindlimb paralysis, respiratory distress and, ultimately, death. These phenotypes are accompanied by: a decline in the nerve conduction velocity, free fatty acids and phophatidylcholine of the sciatic nerve; a reduction in the g-ratios of sciatic and phrenic nerves; and hypertrophy of motoneurons. Furthermore, Ranbp2 loss disrupts the nucleocytoplasmic partitioning of the import and export nuclear receptors importin β and exportin 1, respectively, Ran GTPase and histone deacetylase 4. Whole-transcriptome, proteomic and cellular analyses uncovered that the chemokine receptor Cxcr4, its antagonizing ligands Cxcl12 and Cxcl14, and effector, latent and activated Stat3 all undergo early autocrine and proteostatic deregulation, and intracellular sequestration and aggregation as a result of Ranbp2 loss in motoneurons. These effects were accompanied by paracrine and autocrine neuroglial deregulation of hnRNPH3 proteostasis in sciatic nerve and motoneurons, respectively, and post-transcriptional downregulation of metalloproteinase 28 in the sciatic nerve. Mechanistically, our results demonstrate that Ranbp2 controls nucleocytoplasmic, chemokine and metalloproteinase 28 signaling, and proteostasis of substrates that are crucial to motoneuronal homeostasis and whose impairments by loss of Ranbp2 drive ALS-like syndromes. © 2017. Published by The Company of Biologists Ltd.

An alternative graft fixation technique for scaphoid nonunions treated with vascular bone grafting.

PubMed

Korompilias, Anastasios V; Lykissas, Marios G; Kostas-Agnantis, Ioannis P; Gkiatas, Ioannis; Beris, Alexandros E

2014-07-01

To present our experience with vascularized bone grafting based on the 1,2-intercompartmental supraretinacular artery for the management of established scaphoid nonunion and to investigate the efficacy of graft immobilization with a combination of Kirschner wires and transarticular external fixation. A retrospective chart and radiographic review was conducted for patients with the diagnosis of scaphoid nonunion of the proximal pole or the waist treated with the 1,2-intercompartmental supraretinacular artery-based vascularized graft and fixed with a combination of Kirschner wires and transarticular external fixation between 2007 and 2011. We observed 23 consecutive patients for a mean of 34 ± 4 months. All patients were males with mean age of 25 ± 5 years. All patients had scaphoid nonunion and associated humpback deformity. The mean duration of nonunion was 7 ± 1 months. All scaphoid nonunions united after the index procedure at a mean of 10 ± 1 weeks. Two patients had avascular necrosis of the proximal pole based on the preoperative magnetic resonance imaging findings. After surgery, deformity correction was achieved in all patients, as recorded by the decrease in the lateral intrascaphoid angle and the increase in the dorsal scaphoid angle. At the last follow-up, no patients reported wrist pain. The mean Disabilities of the Arm, Shoulder, and Hand score improved significantly from 32 ± 12 before the operation to 5 ± 3 at the last postoperative visit. All patients showed statistically significant improvement in the range of motion and the grip strength of the involved wrist. The results of this study support the combined use of Kirschner wires and transarticular external fixation for fixation of a 1,2-intercompartmental supraretinacular artery-based vascular bone graft in the treatment of scaphoid nonunions. Therapeutic IV. Copyright © 2014 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.

APP metabolism regulates tau proteostasis in human cerebral cortex neurons.

PubMed

Moore, Steven; Evans, Lewis D B; Andersson, Therese; Portelius, Erik; Smith, James; Dias, Tatyana B; Saurat, Nathalie; McGlade, Amelia; Kirwan, Peter; Blennow, Kaj; Hardy, John; Zetterberg, Henrik; Livesey, Frederick J

2015-05-05

Accumulation of Aβ peptide fragments of the APP protein and neurofibrillary tangles of the microtubule-associated protein tau are the cellular hallmarks of Alzheimer's disease (AD). To investigate the relationship between APP metabolism and tau protein levels and phosphorylation, we studied human-stem-cell-derived forebrain neurons with genetic forms of AD, all of which increase the release of pathogenic Aβ peptides. We identified marked increases in intracellular tau in genetic forms of AD that either mutated APP or increased its dosage, suggesting that APP metabolism is coupled to changes in tau proteostasis. Manipulating APP metabolism by β-secretase and γ-secretase inhibition, as well as γ-secretase modulation, results in specific increases and decreases in tau protein levels. These data demonstrate that APP metabolism regulates tau proteostasis and suggest that the relationship between APP processing and tau is not mediated solely through extracellular Aβ signaling to neurons. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Proteostasis and ageing: insights from long-lived mutant mice.

PubMed

Sands, William A; Page, Melissa M; Selman, Colin

2017-10-15

The global increase in life expectancy is creating significant medical, social and economic challenges to current and future generations. Consequently, there is a need to identify the fundamental mechanisms underlying the ageing process. This knowledge should help develop realistic interventions capable of combatting age-related disease, and thus improving late-life health and vitality. While several mechanisms have been proposed as conserved lifespan determinants, the loss of proteostasis - where proteostasis is defined here as the maintenance of the proteome - appears highly relevant to both ageing and disease. Several studies have shown that multiple proteostatic mechanisms, including the endoplasmic reticulum (ER)-induced unfolded protein response (UPR), the ubiquitin-proteasome system (UPS) and autophagy, appear indispensable for longevity in many long-lived invertebrate mutants. Similarly, interspecific comparisons suggest that proteostasis may be an important lifespan determinant in vertebrates. Over the last 20 years a number of long-lived mouse mutants have been described, many of which carry single-gene mutations within the growth-hormone, insulin/IGF-1 or mTOR signalling pathways. However, we still do not know how these mutations act mechanistically to increase lifespan and healthspan, and accordingly whether mechanistic commonality occurs between different mutants. Recent evidence supports the premise that the successful maintenance of the proteome during ageing may be linked to the increased lifespan and healthspan of long-lived mouse mutants. © 2017 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.

Manipulating proteostasis to repair the F508del-CFTR defect in cystic fibrosis.

PubMed

Esposito, Speranza; Tosco, Antonella; Villella, Valeria R; Raia, Valeria; Kroemer, Guido; Maiuri, Luigi

2016-12-01

Cystic fibrosis (CF) is a lethal monogenic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that entails the (diagnostic) increase in sweat electrolyte concentrations, progressive lung disease with chronic inflammation and recurrent bacterial infections, pancreatic insufficiency, and male infertility. Therapies aimed at restoring the CFTR defect have emerged. Thus, a small molecule which facilitates chloride channel opening, the potentiator Ivacaftor, has been approved for the treatment of CF patients bearing a particular class of rare CFTR mutations. However, small molecules that directly target the most common misfolded CFTR mutant, F508del, and improve its intracellular trafficking in vitro, have been less effective than expected when tested in CF patients, even in combination with Ivacaftor. Thus, new strategies are required to circumvent the F508del-CFTR defect. Airway and intestinal epithelial cells from CF patients bearing the F508del-CFTR mutation exhibit an impressive derangement of cellular proteostasis, with oxidative stress, overactivation of the tissue transglutaminase (TG2), and disabled autophagy. Proteostasis regulators such as cysteamine can rescue and stabilize a functional F508del-CFTR protein through suppressing TG2 activation and restoring autophagy in vivo in F508del-CFTR homozygous mice, in vitro in CF patient-derived cell lines, ex vivo in freshly collected primary patient's nasal cells, as well as in a pilot clinical trial involving homozygous F508del-CFTR patients. Here, we discuss how the therapeutic normalization of defective proteostasis can be harnessed for the treatment of CF patients with the F508del-CFTR mutation.

HSF1 stress response pathway regulates autophagy receptor SQSTM1/p62-associated proteostasis.

PubMed

Watanabe, Yoshihisa; Tsujimura, Atsushi; Taguchi, Katsutoshi; Tanaka, Masaki

2017-01-02

Proteostasis is important for protecting cells from harmful proteins and is mainly controlled by the HSF1 (heat shock transcription factor 1) stress response pathway. This pathway facilitates protein refolding by molecular chaperones; however, it is unclear whether it functions in autophagy or inclusion formation. The autophagy receptor SQSTM1/p62 is involved in selective autophagic clearance and inclusion formation by harmful proteins, and its phosphorylation at S349, S403, and S407 is required for binding to substrates. Here, we demonstrate that casein kinase 1 phosphorylates the SQSTM1 S349 residue when harmful proteins accumulate. Investigation of upstream factors showed that both SQSTM1 S349 and SQSTM1 S403 residues were phosphorylated in an HSF1 dependent manner. Inhibition of SQSTM1 phosphorylation suppressed inclusion formation by ubiquitinated proteins and prevented colocalization of SQSTM1 with aggregation-prone proteins. Moreover, HSF1 inhibition impaired aggregate-induced autophagosome formation and elimination of protein aggregates. Our findings indicate that HSF1 triggers SQSTM1-mediated proteostasis.

HSF1 stress response pathway regulates autophagy receptor SQSTM1/p62-associated proteostasis

PubMed Central

Watanabe, Yoshihisa; Tsujimura, Atsushi; Taguchi, Katsutoshi; Tanaka, Masaki

2017-01-01

ABSTRACT Proteostasis is important for protecting cells from harmful proteins and is mainly controlled by the HSF1 (heat shock transcription factor 1) stress response pathway. This pathway facilitates protein refolding by molecular chaperones; however, it is unclear whether it functions in autophagy or inclusion formation. The autophagy receptor SQSTM1/p62 is involved in selective autophagic clearance and inclusion formation by harmful proteins, and its phosphorylation at S349, S403, and S407 is required for binding to substrates. Here, we demonstrate that casein kinase 1 phosphorylates the SQSTM1 S349 residue when harmful proteins accumulate. Investigation of upstream factors showed that both SQSTM1 S349 and SQSTM1 S403 residues were phosphorylated in an HSF1 dependent manner. Inhibition of SQSTM1 phosphorylation suppressed inclusion formation by ubiquitinated proteins and prevented colocalization of SQSTM1 with aggregation-prone proteins. Moreover, HSF1 inhibition impaired aggregate-induced autophagosome formation and elimination of protein aggregates. Our findings indicate that HSF1 triggers SQSTM1-mediated proteostasis. PMID:27846364

UCHL3 Regulates Topoisomerase-Induced Chromosomal Break Repair by Controlling TDP1 Proteostasis.

PubMed

Liao, Chunyan; Beveridge, Ryan; Hudson, Jessica J R; Parker, Jacob D; Chiang, Shih-Chieh; Ray, Swagat; Ashour, Mohamed E; Sudbery, Ian; Dickman, Mark J; El-Khamisy, Sherif F

2018-06-12

Genomic damage can feature DNA-protein crosslinks whereby their acute accumulation is utilized to treat cancer and progressive accumulation causes neurodegeneration. This is typified by tyrosyl DNA phosphodiesterase 1 (TDP1), which repairs topoisomerase-mediated chromosomal breaks. Although TDP1 levels vary in multiple clinical settings, the mechanism underpinning this variation is unknown. We reveal that TDP1 is controlled by ubiquitylation and identify UCHL3 as the deubiquitylase that controls TDP1 proteostasis. Depletion of UCHL3 increases TDP1 ubiquitylation and turnover rate and sensitizes cells to TOP1 poisons. Overexpression of UCHL3, but not a catalytically inactive mutant, suppresses TDP1 ubiquitylation and turnover rate. TDP1 overexpression in the topoisomerase therapy-resistant rhabdomyosarcoma is driven by UCHL3 overexpression. In contrast, UCHL3 is downregulated in spinocerebellar ataxia with axonal neuropathy (SCAN1), causing elevated levels of TDP1 ubiquitylation and faster turnover rate. These data establish UCHL3 as a regulator of TDP1 proteostasis and, consequently, a fine-tuner of protein-linked DNA break repair. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Lipid disequilibrium disrupts ER proteostasis by impairing ERAD substrate glycan trimming and dislocation

PubMed Central

To, Milton; Peterson, Clark W. H.; Roberts, Melissa A.; Counihan, Jessica L.; Wu, Tiffany T.; Forster, Mercedes S.; Nomura, Daniel K.; Olzmann, James A.

2017-01-01

The endoplasmic reticulum (ER) mediates the folding, maturation, and deployment of the secretory proteome. Proteins that fail to achieve their native conformation are retained in the ER and targeted for clearance by ER-associated degradation (ERAD), a sophisticated process that mediates the ubiquitin-dependent delivery of substrates to the 26S proteasome for proteolysis. Recent findings indicate that inhibition of long-chain acyl-CoA synthetases with triacsin C, a fatty acid analogue, impairs lipid droplet (LD) biogenesis and ERAD, suggesting a role for LDs in ERAD. However, whether LDs are involved in the ERAD process remains an outstanding question. Using chemical and genetic approaches to disrupt diacylglycerol acyltransferase (DGAT)–dependent LD biogenesis, we provide evidence that LDs are dispensable for ERAD in mammalian cells. Instead, our results suggest that triacsin C causes global alterations in the cellular lipid landscape that disrupt ER proteostasis by interfering with the glycan trimming and dislocation steps of ERAD. Prolonged triacsin C treatment activates both the IRE1 and PERK branches of the unfolded protein response and ultimately leads to IRE1-dependent cell death. These findings identify an intimate relationship between fatty acid metabolism and ER proteostasis that influences cell viability. PMID:27881664

TG2 regulates the heat-shock response by the post-translational modification of HSF1.

PubMed

Rossin, Federica; Villella, Valeria Rachela; D'Eletto, Manuela; Farrace, Maria Grazia; Esposito, Speranza; Ferrari, Eleonora; Monzani, Romina; Occhigrossi, Luca; Pagliarini, Vittoria; Sette, Claudio; Cozza, Giorgio; Barlev, Nikolai A; Falasca, Laura; Fimia, Gian Maria; Kroemer, Guido; Raia, Valeria; Maiuri, Luigi; Piacentini, Mauro

2018-05-11

Heat-shock factor 1 (HSF1) is the master transcription factor that regulates the response to proteotoxic stress by controlling the transcription of many stress-responsive genes including the heat-shock proteins. Here, we show a novel molecular mechanism controlling the activation of HSF1. We demonstrate that transglutaminase type 2 (TG2), dependent on its protein disulphide isomerase activity, triggers the trimerization and activation of HSF1 regulating adaptation to stress and proteostasis impairment. In particular, we find that TG2 loss of function correlates with a defect in the nuclear translocation of HSF1 and in its DNA-binding ability to the HSP70 promoter. We show that the inhibition of TG2 restores the unbalance in HSF1-HSP70 pathway in cystic fibrosis (CF), a human disorder characterized by deregulation of proteostasis. The absence of TG2 leads to an increase of about 40% in CFTR function in a new experimental CF mouse model lacking TG2. Altogether, these results indicate that TG2 plays a key role in the regulation of cellular proteostasis under stressful cellular conditions through the modulation of the heat-shock response. © 2018 The Authors.

Proteasome function is not impaired in healthy aging of the lung.

PubMed

Caniard, Anne; Ballweg, Korbinian; Lukas, Christina; Yildirim, Ali Ö; Eickelberg, Oliver; Meiners, Silke

2015-10-01

Aging is the progressive loss of cellular function which inevitably leads to death. Failure of proteostasis including the decrease in proteasome function is one hallmark of aging. In the lung, proteasome activity was shown to be impaired in age-related diseases such as chronic obstructive pulmonary disease. However, little is known on proteasome function during healthy aging. Here, we comprehensively analyzed healthy lung aging and proteasome function in wildtype, proteasome reporter and immunoproteasome knockout mice. Wildtype mice spontaneously developed senile lung emphysema while expression and activity of proteasome complexes and turnover of ubiquitinated substrates was not grossly altered in lungs of aged mice. Immunoproteasome subunits were specifically upregulated in the aged lung and the caspase-like proteasome activity concomitantly decreased. Aged knockout mice for the LMP2 or LMP7 immunoproteasome subunits showed no alteration in proteasome activities but exhibited typical lung aging phenotypes suggesting that immunoproteasome function is dispensable for physiological lung aging in mice. Our results indicate that healthy aging of the lung does not involve impairment of proteasome function. Apparently, the reserve capacity of the proteostasis systems in the lung is sufficient to avoid severe proteostasis imbalance during healthy aging.

Proteostasis and Diseases of the Motor Unit.

PubMed

Rinaldi, Carlo; Mäger, Imre; Wood, Matthew J

2016-01-01

The accumulation in neurons of aberrant protein species, the pathological hallmark of many neurodegenerative diseases, results from a global impairment of key cellular processes governing protein synthesis/degradation and repair mechanisms, also known as the proteostasis network (PN). The growing number of connections between dysfunction of this intricate network of pathways and diseases of the motor unit, where both motor neurons and muscle are primarily affected, has provided momentum to investigate the muscle- and motor neuron-specific response to physiological and pathological stressors and to explore the therapeutic opportunities that manipulation of this process may offer. Furthermore, these diseases offer an unparalleled opportunity to deepen our understanding of the molecular mechanisms behind the intertissue communication and transfer of signals of proteostasis. The most compelling aspect of these investigations is their immediate potential for therapeutic impact: targeting muscle to stem degeneration of the motor unit would represent a dramatic paradigm therapeutic shift for treating these devastating diseases. Here we will review the current state of the art of the research on the alterations of the PN in diseases of the motor unit and its potential to result in effective treatments for these devastating neuromuscular disorders.

Mechanisms of protein balance in skeletal muscle.

PubMed

Anthony, T G

2016-07-01

Increased global demand for adequate protein nutrition against a backdrop of climate change and concern for animal agriculture sustainability necessitates new and more efficient approaches to livestock growth and production. Anabolic growth is achieved when rates of new synthesis exceed turnover, producing a positive net protein balance. Conversely, deterioration or atrophy of lean mass is a consequence of a net negative protein balance. During early life and periods of growth, muscle mass is driven by increases in protein synthesis at the level of mRNA translation. Throughout life, muscle mass is further influenced by degradative processes such as autophagy and the ubiquitin proteasome pathway. Multiple signal transduction networks guide and coordinate these processes alongside quality control mechanisms to maintain protein homeostasis (proteostasis). Genetics, hormones, and environmental stimuli each influence proteostasis control, altering capacity and/or efficiency of muscle growth. An overview of recent findings and current methods to assess muscle protein balance and proteostasis is presented. Current efforts to identify novel control points have the potential through selective breeding design or development of hormetic strategies to better promote growth and health span during environmental stress. Copyright © 2016 Elsevier Inc. All rights reserved.

Intraoperative Comparison of Measured Resection and Gap Balancing Using a Force Sensor: A Prospective, Randomized Controlled Trial.

PubMed

Cidambi, Krishna R; Robertson, Nicholas; Borges, Camille; Nassif, Nader A; Barnett, Steven L

2018-07-01

For establishing femoral component position, gap-balancing (GB) and measured resection (MR) techniques were compared using a force sensor. Ninety-one patients were randomized to undergo primary total knee arthroplasty using either MR (n = 43) or GB (n = 48) technique using a single total knee arthroplasty design. GB was performed with an instrumented tensioner. Force sensor data were obtained before the final implantation. GB resulted in greater range of femoral component rotation vs MR (1.5° ± 2.9° vs 3.1° ± 0.5°, P < .05) and posterior condylar cut thickness medially (10.2 ± 2.0 mm vs 9.0 ± 1.3 mm) and laterally (8.5 ± 1.9 mm vs 6.4 ± 1.0 mm). Force sensor data showed a decreased intercompartmental force difference at full flexion in GB (.8 ± 2.3 vs 2.0 ± 3.3u, 1u ≈ 15 N, P < .05). GB resulted in a greater range of femoral component rotation and thicker posterior condylar cuts resulting in an increased flexion space relative to MR. Intercompartmental force difference trended toward a more uniform distribution between full extension and full flexion in the GB vs MR group. Copyright © 2018 Elsevier Inc. All rights reserved.

Cellular Homeostasis and Aging.

PubMed

Hartl, F Ulrich

2016-06-02

Aging and longevity are controlled by a multiplicity of molecular and cellular signaling events that interface with environmental factors to maintain cellular homeostasis. Modulation of these pathways to extend life span, including insulin-like signaling and the response to dietary restriction, identified the cellular machineries and networks of protein homeostasis (proteostasis) and stress resistance pathways as critical players in the aging process. A decline of proteostasis capacity during aging leads to dysfunction of specific cell types and tissues, rendering the organism susceptible to a range of chronic diseases. This volume of the Annual Review of Biochemistry contains a set of two reviews addressing our current understanding of the molecular mechanisms underlying aging in model organisms and humans.

Engineering and Evolution of Molecular Chaperones and Protein Disaggregases with Enhanced Activity

PubMed Central

Mack, Korrie L.; Shorter, James

2016-01-01

Cells have evolved a sophisticated proteostasis network to ensure that proteins acquire and retain their native structure and function. Critical components of this network include molecular chaperones and protein disaggregases, which function to prevent and reverse deleterious protein misfolding. Nevertheless, proteostasis networks have limits, which when exceeded can have fatal consequences as in various neurodegenerative disorders, including Parkinson's disease and amyotrophic lateral sclerosis. A promising strategy is to engineer proteostasis networks to counter challenges presented by specific diseases or specific proteins. Here, we review efforts to enhance the activity of individual molecular chaperones or protein disaggregases via engineering and directed evolution. Remarkably, enhanced global activity or altered substrate specificity of various molecular chaperones, including GroEL, Hsp70, ClpX, and Spy, can be achieved by minor changes in primary sequence and often a single missense mutation. Likewise, small changes in the primary sequence of Hsp104 yield potentiated protein disaggregases that reverse the aggregation and buffer toxicity of various neurodegenerative disease proteins, including α-synuclein, TDP-43, and FUS. Collectively, these advances have revealed key mechanistic and functional insights into chaperone and disaggregase biology. They also suggest that enhanced chaperones and disaggregases could have important applications in treating human disease as well as in the purification of valuable proteins in the pharmaceutical sector. PMID:27014702

Cytosolic Proteostasis via Importing of Misfolded Proteins into Mitochondria

PubMed Central

Ruan, Linhao; Zhou, Chuankai; Jin, Erli; Kucharavy, Andrei; Zhang, Ying; Wen, Zhihui; Florens, Laurence; Li, Rong

2017-01-01

Loss of proteostasis underlies aging and neurodegeneration characterized by the accumulation of protein aggregates and mitochondrial dysfunction1–5. Although many neurodegenerative-disease proteins can be found in mitochondria4,6, it remains unclear how these disease manifestations may be related. In yeast, protein aggregates formed under stress or during aging are preferentially retained by the mother cell in part through tethering to mitochondria, while the disaggregase Hsp104 helps dissociate aggregates to enable refolding or degradation of misfolded proteins7–10. Here we show that in yeast cytosolic proteins prone to aggregation are imported into mitochondria for degradation. Protein aggregates formed under heat shock (HS) contain both cytosolic and mitochondrial proteins and interact with mitochondrial import complex. Many aggregation-prone proteins enter mitochondrial intermembrane space and matrix after HS, while some do so even without stress. Timely dissolution of cytosolic aggregates requires mitochondrial import machinery and proteases. Blocking mitochondrial import but not the proteasome activity causes a marked delay in the degradation of aggregated proteins. Defects in cytosolic Hsp70s leads to enhanced entry of misfolded proteins into mitochondria and elevated mitochondrial stress. We term this mitochondria-mediated proteostasis mechanism MAGIC (mitochondria as guardian in cytosol) and provide evidence that it may exist in human cells. PMID:28241148

Induction of the Immunoproteasome Subunit Lmp7 Links Proteostasis and Immunity in α-Synuclein Aggregation Disorders.

PubMed

Ugras, Scott; Daniels, Malcolm J; Fazelinia, Hossein; Gould, Neal S; Yocum, Anastasia K; Luk, Kelvin C; Luna, Esteban; Ding, Hua; McKennan, Chris; Seeholzer, Steven; Martinez, Dan; Evans, Perry; Brown, Daniel; Duda, John E; Ischiropoulos, Harry

2018-05-01

Accumulation of aggregated α-synuclein into Lewy bodies is thought to contribute to the onset and progression of dopaminergic neuron degeneration in Parkinson's disease (PD) and related disorders. Although protein aggregation is associated with perturbation of proteostasis, how α-synuclein aggregation affects the brain proteome and signaling remains uncertain. In a mouse model of α-synuclein aggregation, 6% of 6215 proteins and 1.6% of 8183 phosphopeptides changed in abundance, indicating conservation of proteostasis and phosphorylation signaling. The proteomic analysis confirmed changes in abundance of proteins that regulate dopamine synthesis and transport, synaptic activity and integrity, and unearthed changes in mRNA binding, processing and protein translation. Phosphorylation signaling changes centered on axonal and synaptic cytoskeletal organization and structural integrity. Proteostatic responses included a significant increase in the levels of Lmp7, a component of the immunoproteasome. Increased Lmp7 levels and activity were also quantified in postmortem human brains with PD and dementia with Lewy bodies. Functionally, the immunoproteasome degrades α-synuclein aggregates and generates potentially antigenic peptides. Expression and activity of the immunoproteasome may represent testable targets to induce adaptive responses that maintain proteome integrity and modulate immune responses in protein aggregation disorders. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Preventing α-synuclein aggregation: the role of the small heat-shock molecular chaperone proteins.

PubMed

Cox, Dezerae; Carver, John A; Ecroyd, Heath

2014-09-01

Protein homeostasis, or proteostasis, is the process of maintaining the conformational and functional integrity of the proteome. The failure of proteostasis can result in the accumulation of non-native proteins leading to their aggregation and deposition in cells and in tissues. The amyloid fibrillar aggregation of the protein α-synuclein into Lewy bodies and Lewy neuritis is associated with neurodegenerative diseases classified as α-synucleinopathies, which include Parkinson's disease and dementia with Lewy bodies. The small heat-shock proteins (sHsps) are molecular chaperones that are one of the cell's first lines of defence against protein aggregation. They act to stabilise partially folded protein intermediates, in an ATP-independent manner, to maintain cellular proteostasis under stress conditions. Thus, the sHsps appear ideally suited to protect against α-synuclein aggregation, yet these fail to do so in the context of the α-synucleinopathies. This review discusses how sHsps interact with α-synuclein to prevent its aggregation and, in doing so, highlights the multi-faceted nature of the mechanisms used by sHsps to prevent the fibrillar aggregation of proteins. It also examines what factors may contribute to α-synuclein escaping the sHsp chaperones in the context of the α-synucleinopathies. Crown Copyright © 2014. Published by Elsevier B.V. All rights reserved.

Targeting the Intracellular Environment in Cystic Fibrosis: Restoring Autophagy as a Novel Strategy to Circumvent the CFTR Defect

PubMed Central

Villella, Valeria Rachela; Esposito, Speranza; Bruscia, Emanuela M.; Maiuri, Maria Chiara; Raia, Valeria; Kroemer, Guido; Maiuri, Luigi

2013-01-01

Cystic fibrosis (CF) patients harboring the most common deletion mutation of the CF transmembrane conductance regulator (CFTR), F508del, are poor responders to potentiators of CFTR channel activity which can be used to treat a small subset of CF patients who genetically carry plasma membrane (PM)-resident CFTR mutants. The misfolded F508del-CFTR protein is unstable in the PM even if rescued by pharmacological agents that prevent its intracellular retention and degradation. CF is a conformational disease in which defective CFTR induces an impressive derangement of general proteostasis resulting from disabled autophagy. In this review, we discuss how rescuing Beclin 1 (BECN1), a major player of autophagosome formation, either by means of direct gene transfer or indirectly by administration of proteostasis regulators, could stabilize F508del-CFTR at the PM. We focus on the relationship between the improvement of peripheral proteostasis and CFTR PM stability in F508del-CFTR homozygous bronchial epithelia or mouse lungs. Moreover, this article reviews recent pre-clinical evidence indicating that targeting the intracellular environment surrounding the misfolded mutant CFTR instead of protein itself could constitute an attractive therapeutic option to sensitize patients carrying the F508del-CFTR mutation to the beneficial action of CFTR potentiators on lung inflammation. PMID:23346057

Nutrient-driven O-GlcNAc in proteostasis and neurodegeneration.

PubMed

Akan, Ilhan; Olivier-Van Stichelen, Stephanie; Bond, Michelle R; Hanover, John A

2018-01-01

Proteostasis is essential in the mammalian brain where post-mitotic cells must function for decades to maintain synaptic contacts and memory. The brain is dependent on glucose and other metabolites for proper function and is spared from metabolic deficits even during starvation. In this review, we outline how the nutrient-sensitive nucleocytoplasmic post-translational modification O-linked N-acetylglucosamine (O-GlcNAc) regulates protein homeostasis. The O-GlcNAc modification is highly abundant in the mammalian brain and has been linked to proteopathies, including neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's. C. elegans, Drosophila, and mouse models harboring O-GlcNAc transferase- and O-GlcNAcase-knockout alleles have helped define the role O-GlcNAc plays in development as well as age-associated neurodegenerative disease. These enzymes add and remove the single monosaccharide from protein serine and threonine residues, respectively. Blocking O-GlcNAc cycling is detrimental to mammalian brain development and interferes with neurogenesis, neural migration, and proteostasis. Findings in C. elegans and Drosophila model systems indicate that the dynamic turnover of O-GlcNAc is critical for maintaining levels of key transcriptional regulators responsible for neurodevelopment cell fate decisions. In addition, pathways of autophagy and proteasomal degradation depend on a transcriptional network that is also reliant on O-GlcNAc cycling. Like the quality control system in the endoplasmic reticulum which uses a 'mannose timer' to monitor protein folding, we propose that cytoplasmic proteostasis relies on an 'O-GlcNAc timer' to help regulate the lifetime and fate of nuclear and cytoplasmic proteins. O-GlcNAc-dependent developmental alterations impact metabolism and growth of the developing mouse embryo and persist into adulthood. Brain-selective knockout mouse models will be an important tool for understanding the role of O-GlcNAc in the physiology of the brain and its susceptibility to neurodegenerative injury. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.

A Novel mouse model of enhanced proteostasis: Full-length human heat shock factor 1 transgenic mice

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

Pierce, Anson, E-mail: piercea2@uthscsa.edu; Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, 78229; The Department of Veteran's Affairs, South Texas Veterans Health Care System, San Antonio, Texas, 78284

2010-11-05

Research highlights: {yields} Development of mouse overexpressing native human HSF1 in all tissues including CNS. {yields} HSF1 overexpression enhances heat shock response at whole-animal and cellular level. {yields} HSF1 overexpression protects from polyglutamine toxicity and favors aggresomes. {yields} HSF1 overexpression enhances proteostasis at the whole-animal and cellular level. -- Abstract: The heat shock response (HSR) is controlled by the master transcriptional regulator heat shock factor 1 (HSF1). HSF1 maintains proteostasis and resistance to stress through production of heat shock proteins (HSPs). No transgenic model exists that overexpresses HSF1 in tissues of the central nervous system (CNS). We generated a transgenicmore » mouse overexpressing full-length non-mutant HSF1 and observed a 2-4-fold increase in HSF1 mRNA and protein expression in all tissues studied of HSF1 transgenic (HSF1{sup +/0}) mice compared to wild type (WT) littermates, including several regions of the CNS. Basal expression of HSP70 and 90 showed only mild tissue-specific changes; however, in response to forced exercise, the skeletal muscle HSR was more elevated in HSF1{sup +/0} mice compared to WT littermates and in fibroblasts following heat shock, as indicated by levels of inducible HSP70 mRNA and protein. HSF1{sup +/0} cells elicited a significantly more robust HSR in response to expression of the 82 repeat polyglutamine-YFP fusion construct (Q82YFP) and maintained proteasome-dependent processing of Q82YFP compared to WT fibroblasts. Overexpression of HSF1 was associated with fewer, but larger Q82YFP aggregates resembling aggresomes in HSF1{sup +/0} cells, and increased viability. Therefore, our data demonstrate that tissues and cells from mice overexpressing full-length non-mutant HSF1 exhibit enhanced proteostasis.« less

Proximal Pole Scaphoid Nonunion Reconstruction With 1,2 Intercompartmental Supraretinacular Artery Vascularized Graft and Compression Screw Fixation.

PubMed

Morris, Mark S; Zhu, Andy F; Ozer, Kagan; Lawton, Jeffrey N

2018-02-06

To review the incidence of union of patients with proximal pole scaphoid fracture nonunions treated using a 1,2 intercompartmental supraretinacular artery (1,2 ICSRA) vascularized graft and a small compression screw. This is a retrospective case series of 12 patients. Calculations of the size of the proximal pole fragment relative to the total scaphoid were performed using posteroanterior view scaphoid radiographs with the wrist in ulnar deviation and flat on the cassette. Analyses were repeated 3 times per subject, and the average ratio of proximal pole fragment relative to the entire scaphoid was calculated. We reviewed medical records, radiographs, and computed tomography (CT) scans of these 12 patients. The CT scans that were performed after an average of 12 weeks were ultimately used to confirm union of the scaphoid fractures. One patient was unable to have a CT so was excluded from the final calculation. All 11 (100%) scaphoid fractures that were assessed by CT were found to be healed at the 12-week assessment point. The mean proximal pole fragment size was 18% (range, 7%-27%) of the entire scaphoid. The 1,2 ICSRA vascularized graft and compression screw was an effective treatment for patients with proximal pole scaphoid fractures. Therapeutic IV. Copyright © 2018 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.

Soft tissue balancing in total knee arthroplasty using sensor-guided assessment: is there a learning curve?

PubMed

Gharaibeh, Monther A; Chen, Darren B; MacDessi, Samuel J

2018-05-01

Sensor-guided assessment for soft tissue balance in total knee arthroplasty (TKA) has been reported to improve patient satisfaction and self-reported outcome scores. As more surgeons adopt this technology in TKA, we performed this study to identify if there is a learning curve with its use. Analysis of a total of 90 consecutive cases was performed in this study. Initial and final intercompartmental pressure differences were recorded before and after knee ligament balancing. The first 45 patients (group 1) were compared to the last 45 patients (group 2) in terms of operative time and the final state of knee balance. A balanced knee was defined as pressure difference between medial and lateral compartments of ≤15 pounds. Group 1 had 10 unbalanced knees in the final pressure difference assessment, while all cases in group 2 were balanced (P < 0.001). There was no statistically significant difference in mean operative time between the two groups. A scatter plot of intercompartmental pressure difference identified that after 30 cases, the capacity to achieve knee ligament balance improved. This study suggests that there is a learning curve with the use of sensor-guided assessment in TKA in achieving knee balance; however, the differences noted between initial and final groups were small and may not be of clinical significance. © 2018 Royal Australasian College of Surgeons.

Contribution of chaperones to STAT pathway signaling

PubMed Central

Bocchini, Claire E; Kasembeli, Moses M; Roh, Soung-Hun; Tweardy, David J

2014-01-01

Aberrant STAT signaling is associated with the development and progression of many cancers and immune related diseases. Recent findings demonstrate that proteostasis modulators under clinical investigation for cancer therapy have a significant impact on STAT signaling, which may be critical for mediating their anti-cancer effects. Chaperones are critical for protein folding, stability and function and, thus, play an essential role in the maintenance of proteostasis. In this review we discuss the role of chaperones in STAT and tyrosine kinase (TK) protein folding, modulation of STAT and TK activity, and degradation of TKs. We highlight the important role of chaperones in STAT signaling, and how this knowledge has provided a framework for the development of new therapeutic avenues of targeting STAT signaling related pathologies. PMID:26413421

A Novel Interaction Between Aging and ER Overload in a Protein Conformational Dementia

PubMed Central

Schipanski, Angela; Lange, Sascha; Segref, Alexandra; Gutschmidt, Aljona; Lomas, David A.; Miranda, Elena; Schweizer, Michaela; Hoppe, Thorsten; Glatzel, Markus

2013-01-01

Intraneuronal deposition of aggregated proteins in tauopathies, Parkinson disease, or familial encephalopathy with neuroserpin inclusion bodies (FENIB) leads to impaired protein homeostasis (proteostasis). FENIB represents a conformational dementia, caused by intraneuronal polymerization of mutant variants of the serine protease inhibitor neuroserpin. In contrast to the aggregation process, the kinetic relationship between neuronal proteostasis and aggregation are poorly understood. To address aggregate formation dynamics, we studied FENIB in Caenorhabditis elegans and mice. Point mutations causing FENIB also result in aggregation of the neuroserpin homolog SRP-2 most likely within the ER lumen in worms, recapitulating morphological and biochemical features of the human disease. Intriguingly, we identified conserved protein quality control pathways to modulate protein aggregation both in worms and mice. Specifically, downregulation of the unfolded protein response (UPR) pathways in the worm favors mutant SRP-2 accumulation, while mice overexpressing a polymerizing mutant of neuroserpin undergo transient induction of the UPR in young but not in aged mice. Thus, we find that perturbations of proteostasis through impairment of the heat shock response or altered UPR signaling enhance neuroserpin accumulation in vivo. Moreover, accumulation of neuroserpin polymers in mice is associated with an age-related induction of the UPR suggesting a novel interaction between aging and ER overload. These data suggest that targets aimed at increasing UPR capacity in neurons are valuable tools for therapeutic intervention. PMID:23335331

Heat Shock Proteins and Autophagy Pathways in Neuroprotection: From Molecular Bases to Pharmacological Interventions

PubMed Central

Penke, Botond; Bogár, Ferenc; Sántha, Miklós; Tóth, Melinda E.; Vígh, László

2018-01-01

Neurodegenerative diseases (NDDs) such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease (HD), amyotrophic lateral sclerosis, and prion diseases are all characterized by the accumulation of protein aggregates (amyloids) into inclusions and/or plaques. The ubiquitous presence of amyloids in NDDs suggests the involvement of disturbed protein homeostasis (proteostasis) in the underlying pathomechanisms. This review summarizes specific mechanisms that maintain proteostasis, including molecular chaperons, the ubiquitin-proteasome system (UPS), endoplasmic reticulum associated degradation (ERAD), and different autophagic pathways (chaperon mediated-, micro-, and macro-autophagy). The role of heat shock proteins (Hsps) in cellular quality control and degradation of pathogenic proteins is reviewed. Finally, putative therapeutic strategies for efficient removal of cytotoxic proteins from neurons and design of new therapeutic targets against the progression of NDDs are discussed. PMID:29361800

Hormetic heat shock and HSF-1 overexpression improve C. elegans survival and proteostasis by inducing autophagy.

PubMed

Kumsta, Caroline; Hansen, Malene

2017-06-03

The cellular recycling process of macroautophagy/autophagy is an essential homeostatic system induced by various stresses, but it remains unclear how autophagy contributes to organismal stress resistance. In a recent study, we report that a mild and physiologically beneficial ("hormetic") heat shock as well as overexpression of the heat-shock responsive transcription factor HSF-1 systemically increases autophagy in C. elegans. Accordingly, we found HSF-1- and heat stress-inducible autophagy to be required for C. elegans thermoresistance and longevity. Moreover, a hormetic heat shock or HSF-1 overexpression alleviated PolyQ protein aggregation in an autophagy-dependent manner. Collectively, we demonstrate a critical role for autophagy in C. elegans stress resistance and hormesis, and reveal a requirement for autophagy in HSF-1 regulated functions in the heat-shock response, proteostasis, and aging.

Protein aggregation in bacteria: the thin boundary between functionality and toxicity.

PubMed

Bednarska, Natalia G; Schymkowitz, Joost; Rousseau, Frederic; Van Eldere, Johan

2013-09-01

Misfolding and aggregation of proteins have a negative impact on all living organisms. In recent years, aggregation has been studied in detail due to its involvement in neurodegenerative diseases, including Alzheimer's, Parkinson's and Huntington's diseases, and type II diabetes--all associated with accumulation of amyloid fibrils. This research highlighted the central importance of protein homeostasis, or proteostasis for short, defined as the cellular state in which the proteome is both stable and functional. It implicates an equilibrium between synthesis, folding, trafficking, aggregation, disaggregation and degradation. In accordance with the eukaryotic systems, it has been documented that protein aggregation also reduces fitness of bacterial cells, but although our understanding of the cellular protein quality control systems is perhaps most detailed in bacteria, the use of bacterial proteostasis as a drug target remains little explored. Here we describe protein aggregation as a normal physiological process and its role in bacterial virulence and we shed light on how bacteria defend themselves against the toxic threat of aggregates. We review the impact of aggregates on bacterial viability and look at the ways that bacteria use to maintain a balance between aggregation and functionality. The proteostasis in bacteria can be interrupted via overexpression of proteins, certain antibiotics such as aminoglycosides, as well as antimicrobial peptides--all leading to loss of cell viability. Therefore intracellular protein aggregation and disruption of proteostatic balance in bacteria open up another strategy that should be explored towards the discovery of new antimicrobials.

The homeodomain-interacting protein kinase HPK-1 preserves protein homeostasis and longevity through master regulatory control of the HSF-1 chaperone network and TORC1-restricted autophagy in Caenorhabditis elegans

PubMed Central

Morton, Elizabeth A.; Cornwell, Adam B.; Crick, Beresford; Lamitina, Todd; Douglas, Peter M.

2017-01-01

An extensive proteostatic network comprised of molecular chaperones and protein clearance mechanisms functions collectively to preserve the integrity and resiliency of the proteome. The efficacy of this network deteriorates during aging, coinciding with many clinical manifestations, including protein aggregation diseases of the nervous system. A decline in proteostasis can be delayed through the activation of cytoprotective transcriptional responses, which are sensitive to environmental stress and internal metabolic and physiological cues. The homeodomain-interacting protein kinase (hipk) family members are conserved transcriptional co-factors that have been implicated in both genotoxic and metabolic stress responses from yeast to mammals. We demonstrate that constitutive expression of the sole Caenorhabditis elegans Hipk homolog, hpk-1, is sufficient to delay aging, preserve proteostasis, and promote stress resistance, while loss of hpk-1 is deleterious to these phenotypes. We show that HPK-1 preserves proteostasis and extends longevity through distinct but complementary genetic pathways defined by the heat shock transcription factor (HSF-1), and the target of rapamycin complex 1 (TORC1). We demonstrate that HPK-1 antagonizes sumoylation of HSF-1, a post-translational modification associated with reduced transcriptional activity in mammals. We show that inhibition of sumoylation by RNAi enhances HSF-1-dependent transcriptional induction of chaperones in response to heat shock. We find that hpk-1 is required for HSF-1 to induce molecular chaperones after thermal stress and enhances hormetic extension of longevity. We also show that HPK-1 is required in conjunction with HSF-1 for maintenance of proteostasis in the absence of thermal stress, protecting against the formation of polyglutamine (Q35::YFP) protein aggregates and associated locomotory toxicity. These functions of HPK-1/HSF-1 undergo rapid down-regulation once animals reach reproductive maturity. We show that HPK-1 fortifies proteostasis and extends longevity by an additional independent mechanism: induction of autophagy. HPK-1 is necessary for induction of autophagosome formation and autophagy gene expression in response to dietary restriction (DR) or inactivation of TORC1. The autophagy-stimulating transcription factors pha-4/FoxA and mxl-2/Mlx, but not hlh-30/TFEB or the nuclear hormone receptor nhr-62, are necessary for extended longevity resulting from HPK-1 overexpression. HPK-1 expression is itself induced by transcriptional mechanisms after nutritional stress, and post-transcriptional mechanisms in response to thermal stress. Collectively our results position HPK-1 at a central regulatory node upstream of the greater proteostatic network, acting at the transcriptional level by promoting protein folding via chaperone expression, and protein turnover via expression of autophagy genes. HPK-1 therefore provides a promising intervention point for pharmacological agents targeting the protein homeostasis system as a means of preserving robust longevity. PMID:29036198

The intersection between growth factors, autophagy and ER stress: A new target to treat neurodegenerative diseases?

PubMed

Garcia-Huerta, Paula; Troncoso-Escudero, Paulina; Jerez, Carolina; Hetz, Claudio; Vidal, Rene L

2016-10-15

One of the salient features of most neurodegenerative diseases is the aggregation of specific proteins in the brain. This proteostasis imbalance is proposed as a key event triggering the neurodegenerative cascade. The unfolded protein response (UPR) and autophagy pathways are emerging as critical processes implicated in handling disease-related misfolded proteins. However, in some conditions, perturbations in the buffering capacity of the proteostasis network may be part of the etiology of the disease. Thus, pharmacological or gene therapy strategies to enhance autophagy or UPR responses are becoming an attractive target for disease intervention. Here, we discuss current evidence depicting the complex involvement of autophagy and ER stress in brain diseases. Novel pathways to modulate protein misfolding are discussed including the relation between aging and growth factor signaling. This article is part of a Special Issue entitled SI:Autophagy. Copyright © 2016 Elsevier B.V. All rights reserved.

CHIP as a membrane-shuttling proteostasis sensor

PubMed Central

Kopp, Yannick; Martínez-Limón, Adrián; Hofbauer, Harald F; Ernst, Robert; Calloni, Giulia

2017-01-01

Cells respond to protein misfolding and aggregation in the cytosol by adjusting gene transcription and a number of post-transcriptional processes. In parallel to functional reactions, cellular structure changes as well; however, the mechanisms underlying the early adaptation of cellular compartments to cytosolic protein misfolding are less clear. Here we show that the mammalian ubiquitin ligase C-terminal Hsp70-interacting protein (CHIP), if freed from chaperones during acute stress, can dock on cellular membranes thus performing a proteostasis sensor function. We reconstituted this process in vitro and found that mainly phosphatidic acid and phosphatidylinositol-4-phosphate enhance association of chaperone-free CHIP with liposomes. HSP70 and membranes compete for mutually exclusive binding to the tetratricopeptide repeat domain of CHIP. At new cellular locations, access to compartment-specific substrates would enable CHIP to participate in the reorganization of the respective organelles, as exemplified by the fragmentation of the Golgi apparatus (effector function). PMID:29091030

Hypertonic stress induces rapid and widespread protein damage in C. elegans

PubMed Central

Burkewitz, Kris; Choe, Keith

2011-01-01

Proteostasis is defined as the homeostatic mechanisms that maintain the function of all cytoplasmic proteins. We recently demonstrated that the capacity of the proteostasis network is a critical factor that defines the limits of cellular and organismal survival in hypertonic environments. The current studies were performed to determine the extent of protein damage induced by cellular water loss. Using worm strains expressing fluorescently tagged foreign and endogenous proteins and proteins with temperature-sensitive point mutations, we demonstrate that hypertonic stress causes aggregation and misfolding of diverse proteins in multiple cell types. Protein damage is rapid. Aggregation of a polyglutamine yellow fluorescent protein reporter is observable with <1 h of hypertonic stress, and aggregate volume doubles approximately every 10 min. Aggregate formation is irreversible and occurs after as little as 10 min of exposure to hypertonic conditions. To determine whether endogenous proteins are aggregated by hypertonic stress, we quantified the relative amount of total cellular protein present in detergent-insoluble extracts. Exposure for 4 h to 400 mM or 500 mM NaCl induced a 55–120% increase in endogenous protein aggregation. Inhibition of insulin signaling or acclimation to mild hypertonic stress increased survival under extreme hypertonic conditions and prevented aggregation of endogenous proteins. Our results demonstrate that hypertonic stress causes widespread and dramatic protein damage and that cells have a significant capacity to remodel the network of proteins that function to maintain proteostasis. These findings have important implications for understanding how cells cope with hypertonic stress and other protein-damaging stressors. PMID:21613604

The heat-shock, or HSF1-mediated proteotoxic stress, response in cancer: from proteomic stability to oncogenesis.

PubMed

Dai, Chengkai

2018-01-19

The heat-shock, or HSF1-mediated proteotoxic stress, response (HSR/HPSR) is characterized by induction of heat-shock proteins (HSPs). As molecular chaperones, HSPs facilitate the folding, assembly, transportation and degradation of other proteins. In mammals, heat shock factor 1 (HSF1) is the master regulator of this ancient transcriptional programme. Upon proteotoxic insults, the HSR/HPSR is essential to proteome homeostasis, or proteostasis, thereby resisting stress and antagonizing protein misfolding diseases and ageing. Contrasting with these benefits, an unexpected pro-oncogenic role of the HSR/HPSR is unfolding. Whereas HSF1 remains latent in primary cells without stress, it becomes constitutively activated within malignant cells, rendering them addicted to HSF1 for their growth and survival. Highlighting the HSR/HPSR as an integral component of the oncogenic network, several key pathways governing HSF1 activation by environmental stressors are causally implicated in malignancy. Importantly, HSF1 impacts the cancer proteome systemically. By suppressing tumour-suppressive amyloidogenesis, HSF1 preserves cancer proteostasis to support the malignant state, both providing insight into how HSF1 enables tumorigenesis and suggesting disruption of cancer proteostasis as a therapeutic strategy. This review provides an overview of the role of HSF1 in oncogenesis, mechanisms underlying its constitutive activation within cancer cells and its pro-oncogenic action, as well as potential HSF1-targeting strategies.This article is part of the theme issue 'Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective'. © 2017 The Author(s).

Effect of liposome-encapsulated hemoglobin resuscitation on proteostasis in small intestinal epithelium after hemorrhagic shock

PubMed Central

Rao, Geeta; Yadav, Vivek R.; Awasthi, Shanjana; Roberts, Pamela R.

2016-01-01

Gut barrier dysfunction is the major trigger for multiorgan failure associated with hemorrhagic shock (HS). Although the molecular mediators responsible for this dysfunction are unclear, oxidative stress-induced disruption of proteostasis contributes to the gut pathology in HS. The objective of this study was to investigate whether resuscitation with nanoparticulate liposome-encapsulated hemoglobin (LEH) is able to restore the gut proteostatic mechanisms. Sprague-Dawley rats were recruited in four groups: control, HS, HS+LEH, and HS+saline. HS was induced by withdrawing 45% blood, and isovolemic LEH or saline was administered after 15 min of shock. The rats were euthanized at 6 h to collect plasma and ileum for measurement of the markers of oxidative stress, unfolded protein response (UPR), proteasome function, and autophagy. HS significantly increased the protein and lipid oxidation, trypsin-like proteasome activity, and plasma levels of IFNγ. These effects were prevented by LEH resuscitation. However, saline was not able to reduce protein oxidation and plasma IFNγ in hemorrhaged rats. Saline resuscitation also suppressed the markers of UPR and autophagy below the basal levels; the HS or LEH groups showed no effect on the UPR and autophagy. Histological analysis showed that LEH resuscitation significantly increased the villus height and thickness of the submucosal and muscularis layers compared with the HS and saline groups. Overall, the results showed that LEH resuscitation was effective in normalizing the indicators of proteostasis stress in ileal tissue. On the other hand, saline-resuscitated animals showed a decoupling of oxidative stress and cellular protective mechanisms. PMID:27288424

Inhibition of stress-inducible HSP70 impairs mitochondrial proteostasis and function.

PubMed

Leu, Julia I-Ju; Barnoud, Thibaut; Zhang, Gao; Tian, Tian; Wei, Zhi; Herlyn, Meenhard; Murphy, Maureen E; George, Donna L

2017-07-11

Protein quality control is an important component of survival for all cells. The use of proteasome inhibitors for cancer therapy derives from the fact that tumor cells generally exhibit greater levels of proteotoxic stress than do normal cells, and thus cancer cells tend to be more sensitive to proteasome inhibition. However, this approach has been limited in some cases by toxicity to normal cells. Recently, the concept of inhibiting proteostasis in organelles for cancer therapy has been advanced, in part because it is predicted to have reduced toxicity for normal cells. Here we demonstrate that a fraction of the major stress-induced chaperone HSP70 (also called HSPA1A or HSP72, but hereafter HSP70) is abundantly present in mitochondria of tumor cells, but is expressed at quite low or undetectable levels in mitochondria of most normal tissues and non-tumor cell lines. We show that treatment of tumor cells with HSP70 inhibitors causes a marked change in mitochondrial protein quality control, loss of mitochondrial membrane potential, reduced oxygen consumption rate, and loss of ATP production. We identify several nuclear-encoded mitochondrial proteins, including polyadenylate binding protein-1 (PABPC1), which exhibit decreased abundance in mitochondria following treatment with HSP70 inhibitors. We also show that targeting HSP70 function leads to reduced levels of several mitochondrial-encoded RNA species that encode components of the electron transport chain. Our data indicate that small molecule inhibitors of HSP70 represent a new class of organelle proteostasis inhibitors that impair mitochondrial function in cancer cells, and therefore constitute novel therapeutics.

Aggregation of Human S100A8 and S100A9 Amyloidogenic Proteins Perturbs Proteostasis in a Yeast Model

PubMed Central

Eremenko, Ekaterina; Ben-Zvi, Anat; Morozova-Roche, Ludmilla A.; Raveh, Dina

2013-01-01

Amyloid aggregates of the calcium-binding EF-hand proteins, S100A8 and S100A9, have been found in the corpora amylacea of patients with prostate cancer and may play a role in carcinogenesis. Here we present a novel model system using the yeast Saccharomyces cerevisiae to study human S100A8 and S100A9 aggregation and toxicity. We found that S100A8, S100A9 and S100A8/9 cotransfomants form SDS-resistant non-toxic aggregates in yeast cells. Using fluorescently tagged proteins, we showed that S100A8 and S100A9 accumulate in foci. After prolonged induction, S100A8 foci localized to the cell vacuole, whereas the S100A9 foci remained in the cytoplasm when present alone, but entered the vacuole in cotransformants. Biochemical analysis of the proteins indicated that S100A8 and S100A9 alone or coexpressed together form amyloid-like aggregates in yeast. Expression of S100A8 and S100A9 in wild type yeast did not affect cell viability, but these proteins were toxic when expressed on a background of unrelated metastable temperature-sensitive mutant proteins, Cdc53-1p, Cdc34-2p, Srp1-31p and Sec27-1p. This finding suggests that the expression and aggregation of S100A8 and S100A9 may limit the capacity of the cellular proteostasis machinery. To test this hypothesis, we screened a set of chaperone deletion mutants and found that reducing the levels of the heat-shock proteins Hsp104p and Hsp70p was sufficient to induce S100A8 and S100A9 toxicity. This result indicates that the chaperone activity of the Hsp104/Hsp70 bi-chaperone system in wild type cells is sufficient to reduce S100A8 and S100A9 amyloid toxicity and preserve cellular proteostasis. Expression of human S100A8 and S100A9 in yeast thus provides a novel model system for the study of the interaction of amyloid deposits with the proteostasis machinery. PMID:23483999

Changes in translation rate modulate stress-induced damage of diverse proteins

PubMed Central

Kim, Heejung

2013-01-01

Proteostasis is the maintenance of the proper function of cellular proteins. Hypertonic stress disrupts proteostasis and causes rapid and widespread protein aggregation and misfolding in the nematode Caenorhabditis elegans. Optimal survival in hypertonic environments requires degradation of damaged proteins. Inhibition of protein synthesis occurs in response to diverse environmental stressors and may function in part to minimize stress-induced protein damage. We recently tested this idea directly and demonstrated that translation inhibition by acute exposure to cycloheximide suppresses hypertonicity-induced aggregation of polyglutamine::YFP (Q35::YFP) in body wall muscle cells. In this article, we further characterized the relationship between protein synthesis and hypertonic stress-induced protein damage. We demonstrate that inhibition of translation reduces hypertonic stress-induced formation and growth of Q35::YFP, Q44::YFP, and α-synuclein aggregates; misfolding of paramyosin and ras GTPase; and aggregation of multiple endogenous proteins expressed in diverse cell types. Activation of general control nonderepressible-2 (GCN-2) kinase signaling during hypertonic stress inhibits protein synthesis via phosphorylation of eukaryotic initiation factor-2α (eIF-2α). Inhibition of GCN-2 activation prevents the reduction in translation rate and greatly exacerbates the formation and growth of Q35::YFP aggregates and the aggregation of endogenous proteins. The current studies together with our previous work provide the first direct demonstration that hypertonic stress-induced reduction in protein synthesis minimizes protein aggregation and misfolding. Reduction in translation rate also serves as a signal that activates osmoprotective gene expression. The cellular proteostasis network thus plays a critical role in minimizing hypertonic stress-induced protein damage, in degrading stress-damaged proteins, and in cellular osmosensing and signaling. PMID:24153430

Ammonia lowering reverses sarcopenia of cirrhosis by restoring skeletal muscle proteostasis

PubMed Central

Kumar, Avinash; Davuluri, Gangarao; deSilva, Rafaella Nasciemento; Engelen, Marielle PKJ; TenHave, Gabrie; Prayson, Richard; Deutz, Nicolaas EP; Dasarathy, Srinivasan

2017-01-01

Sarcopenia or skeletal muscle loss is a frequent, potentially reversible complication in cirrhosis that adversely affects clinical outcomes. Hyperammonemia is a consistent abnormality in cirrhosis that results in impaired skeletal muscle protein synthesis and breakdown (proteostasis). Despite availability of effective ammonia lowering therapies, whether lowering ammonia restores proteostasis and reverses muscle mass is unknown. Myotube diameter, protein synthesis and molecular responses in C2C12 murine myotubes to withdrawal of ammonium acetate following 24 h exposure to 10mM ammonium acetate were complemented by in vivo studies in the hyperammonemic portacaval anastomosis rat (PCA) and sham operated, pair-fed (SO) Sprague- Dawley rats treated with ammonia lowering therapy by L-ornithine L-aspartate and rifaximin orally for 4 weeks. We observed reduced myotube diameter, impaired protein synthesis and increased autophagy flux in response to hyperammonemia that were partially reversed following 24h and 48h withdrawal of ammonium acetate. Consistently, 4 weeks of ammonia lowering therapy resulted in significant lowering of blood and skeletal muscle ammonia, increase in lean body mass, improved grip strength and higher skeletal muscle mass, diameter and an increase in type II fibers in the treated compared to untreated PCA rats. Increased skeletal muscle myostatin expression, reduced mTORC1 function, and the hyperammonemic stress response including autophagy markers were also reversed in the PCA rats treated with ammonia lowering therapy. Despite significant improvement, molecular and functional readouts were not completely reversed by ammonia lowering measures. Conclusions Ammonia lowering therapy results in improvement in skeletal muscle phenotype, function and molecular perturbations of hyperammonemia. These preclinical studies complement previous studies on ammonia induced skeletal muscle loss and lay the foundation for prolonged ammonia lowering therapy to reverse sarcopenia of cirrhosis. PMID:28195332

Reduced Abundance and Subverted Functions of Proteins in Prion-Like Diseases: Gained Functions Fascinate but Lost Functions Affect Aetiology.

PubMed

Allison, W Ted; DuVal, Michèle G; Nguyen-Phuoc, Kim; Leighton, Patricia L A

2017-10-24

Prions have served as pathfinders that reveal many aspects of proteostasis in neurons. The recent realization that several prominent neurodegenerative diseases spread via a prion-like mechanism illuminates new possibilities for diagnostics and therapeutics. Thus, key proteins in Alzheimer Disease and Amyotrophic lateral sclerosis (ALS), including amyloid-β precursor protein, Tau and superoxide dismutase 1 (SOD1), spread to adjacent cells in their misfolded aggregated forms and exhibit template-directed misfolding to induce further misfolding, disruptions to proteostasis and toxicity. Here we invert this comparison to ask what these prion-like diseases can teach us about the broad prion disease class, especially regarding the loss of these key proteins' function(s) as they misfold and aggregate. We also consider whether functional amyloids might reveal a role for subverted protein function in neurodegenerative disease. Our synthesis identifies SOD1 as an exemplar of protein functions being lost during prion-like protein misfolding, because SOD1 is inherently unstable and loses function in its misfolded disease-associated form. This has under-appreciated parallels amongst the canonical prion diseases, wherein the normally folded prion protein, PrP C , is reduced in abundance in fatal familial insomnia patients and during the preclinical phase in animal models, apparently via proteostatic mechanisms. Thus while template-directed misfolding and infectious properties represent gain-of-function that fascinates proteostasis researchers and defines (is required for) the prion(-like) diseases, loss and subversion of the functions attributed to hallmark proteins in neurodegenerative disease needs to be integrated into design towards effective therapeutics. We propose experiments to uniquely test these ideas.

Azithromycin attenuates myofibroblast differentiation and lung fibrosis development through proteasomal degradation of NOX4.

PubMed

Tsubouchi, Kazuya; Araya, Jun; Minagawa, Shunsuke; Hara, Hiromichi; Ichikawa, Akihiro; Saito, Nayuta; Kadota, Tsukasa; Sato, Nahoko; Yoshida, Masahiro; Kurita, Yusuke; Kobayashi, Kenji; Ito, Saburo; Fujita, Yu; Utsumi, Hirofumi; Yanagisawa, Haruhiko; Hashimoto, Mitsuo; Wakui, Hiroshi; Yoshii, Yutaka; Ishikawa, Takeo; Numata, Takanori; Kaneko, Yumi; Asano, Hisatoshi; Yamashita, Makoto; Odaka, Makoto; Morikawa, Toshiaki; Nakayama, Katsutoshi; Nakanishi, Yoichi; Kuwano, Kazuyoshi

2017-08-03

Accumulation of profibrotic myofibroblasts is involved in the process of fibrosis development during idiopathic pulmonary fibrosis (IPF) pathogenesis. TGFB (transforming growth factor β) is one of the major profibrotic cytokines for myofibroblast differentiation and NOX4 (NADPH oxidase 4) has an essential role in TGFB-mediated cell signaling. Azithromycin (AZM), a second-generation antibacterial macrolide, has a pleiotropic effect on cellular processes including proteostasis. Hence, we hypothesized that AZM may regulate NOX4 levels by modulating proteostasis machineries, resulting in inhibition of TGFB-associated lung fibrosis development. Human lung fibroblasts (LF) were used to evaluate TGFB-induced myofibroblast differentiation. With respect to NOX4 regulation via proteostasis, assays for macroautophagy/autophagy, the unfolded protein response (UPR), and proteasome activity were performed. The potential anti-fibrotic property of AZM was examined by using bleomycin (BLM)-induced lung fibrosis mouse models. TGFB-induced NOX4 and myofibroblast differentiation were clearly inhibited by AZM treatment in LF. AZM-mediated NOX4 reduction was restored by treatment with MG132, a proteasome inhibitor. AZM inhibited autophagy and enhanced the UPR. Autophagy inhibition by AZM was linked to ubiquitination of NOX4 via increased protein levels of STUB1 (STIP1 homology and U-box containing protein 1), an E3 ubiquitin ligase. An increased UPR by AZM was associated with enhanced proteasome activity. AZM suppressed lung fibrosis development induced by BLM with concomitantly reduced NOX4 protein levels and enhanced proteasome activation. These results suggest that AZM suppresses NOX4 by promoting proteasomal degradation, resulting in inhibition of TGFB-induced myofibroblast differentiation and lung fibrosis development. AZM may be a candidate for the treatment of the fibrotic lung disease IPF.

Prefoldin, a jellyfish-like molecular chaperone: functional cooperation with a group II chaperonin and beyond.

PubMed

Sahlan, Muhamad; Zako, Tamotsu; Yohda, Masafumi

2018-04-01

Prefoldin is a hexameric molecular chaperone found in the cytosol of archaea and eukaryotes. Its hexameric complex is built from two related classes of subunits and has the appearance of a jellyfish: its body consists of a double beta-barrel assembly with six long tentacle-like coiled coils protruding from it. Using the tentacles, prefoldin captures an unfolded protein substrate and transfers it to a group II chaperonin. The prefoldin-group II chaperonin system is thought to be important for the folding of newly synthesized proteins and for their maintenance, or proteostasis, in the cytosol. Based on structural information of archaeal prefoldins, the mechanisms of substrate recognition and prefoldin-chaperonin cooperation have been investigated. In contrast, the role and mechanism of eukaryotic PFDs remain unknown. Recent studies have shown that prefoldin plays an important role in proteostasis and is involved in various diseases. In this paper, we review a series of studies on the molecular mechanisms of archaeal prefoldins and introduce recent findings about eukaryotic prefoldin.

Peroxisomal Proteostasis Involves a Lon Family Protein That Functions as Protease and Chaperone*

PubMed Central

Bartoszewska, Magdalena; Williams, Chris; Kikhney, Alexey; Opaliński, Łukasz; van Roermund, Carlo W. T.; de Boer, Rinse; Veenhuis, Marten; van der Klei, Ida J.

2012-01-01

Proteins are subject to continuous quality control for optimal proteostasis. The knowledge of peroxisome quality control systems is still in its infancy. Here we show that peroxisomes contain a member of the Lon family of proteases (Pln). We show that Pln is a heptameric protein and acts as an ATP-fueled protease and chaperone. Hence, Pln is the first chaperone identified in fungal peroxisomes. In cells of a PLN deletion strain peroxisomes contain protein aggregates, a major component of which is catalase-peroxidase. We show that this enzyme is sensitive to oxidative damage. The oxidatively damaged, but not the native protein, is a substrate of the Pln protease. Cells of the pln strain contain enhanced levels of catalase-peroxidase protein but reduced catalase-peroxidase enzyme activities. Together with the observation that Pln has chaperone activity in vitro, our data suggest that catalase-peroxidase aggregates accumulate in peroxisomes of pln cells due to the combined absence of Pln protease and chaperone activities. PMID:22733816

A mammalian nervous system-specific plasma membrane proteasome complex that modulates neuronal function

PubMed Central

Ramachandran, Kapil V.; Margolis, Seth S.

2017-01-01

In the nervous system, rapidly occurring processes such as neuronal transmission and calcium signaling are affected by short-term inhibition of proteasome function. It remains unclear how proteasomes can acutely regulate such processes, as this is inconsistent with their canonical role in proteostasis. Here, we made the discovery of a mammalian nervous system-specific membrane proteasome complex that directly and rapidly modulates neuronal function by degrading intracellular proteins into extracellular peptides that can stimulate neuronal signaling. This proteasome complex is tightly associated with neuronal plasma membranes, exposed to the extracellular space, and catalytically active. Selective inhibition of this membrane proteasome complex by a cell-impermeable proteasome inhibitor blocked extracellular peptide production and attenuated neuronal activity-induced calcium signaling. Moreover, membrane proteasome-derived peptides are sufficient to induce neuronal calcium signaling. Our discoveries challenge the prevailing notion that proteasomes primarily function to maintain proteostasis, and highlight a form of neuronal communication through a membrane proteasome complex. PMID:28287632

Protein Quality Control and the Amyotrophic Lateral Sclerosis/Frontotemporal Dementia Continuum

PubMed Central

Shahheydari, Hamideh; Ragagnin, Audrey; Walker, Adam K.; Toth, Reka P.; Vidal, Marta; Jagaraj, Cyril J.; Perri, Emma R.; Konopka, Anna; Sultana, Jessica M.; Atkin, Julie D.

2017-01-01

Protein homeostasis, or proteostasis, has an important regulatory role in cellular function. Protein quality control mechanisms, including protein folding and protein degradation processes, have a crucial function in post-mitotic neurons. Cellular protein quality control relies on multiple strategies, including molecular chaperones, autophagy, the ubiquitin proteasome system, endoplasmic reticulum (ER)-associated degradation (ERAD) and the formation of stress granules (SGs), to regulate proteostasis. Neurodegenerative diseases are characterized by the presence of misfolded protein aggregates, implying that protein quality control mechanisms are dysfunctional in these conditions. Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases that are now recognized to overlap clinically and pathologically, forming a continuous disease spectrum. In this review article, we detail the evidence for dysregulation of protein quality control mechanisms across the whole ALS-FTD continuum, by discussing the major proteins implicated in ALS and/or FTD. We also discuss possible ways in which protein quality mechanisms could be targeted therapeutically in these disorders and highlight promising protein quality control-based therapeutics for clinical trials. PMID:28539871

Cross Talk of Proteostasis and Mitostasis in Cellular Homeodynamics, Ageing, and Disease

PubMed Central

Gumeni, Sentiljana; Trougakos, Ioannis P.

2016-01-01

Mitochondria are highly dynamic organelles that provide essential metabolic functions and represent the major bioenergetic hub of eukaryotic cell. Therefore, maintenance of mitochondria activity is necessary for the proper cellular function and survival. To this end, several mechanisms that act at different levels and time points have been developed to ensure mitochondria quality control. An interconnected highly integrated system of mitochondrial and cytosolic chaperones and proteases along with the fission/fusion machinery represents the surveillance scaffold of mitostasis. Moreover, nonreversible mitochondrial damage targets the organelle to a specific autophagic removal, namely, mitophagy. Beyond the organelle dynamics, the constant interaction with the ubiquitin-proteasome-system (UPS) has become an emerging aspect of healthy mitochondria. Dysfunction of mitochondria and UPS increases with age and correlates with many age-related diseases including cancer and neurodegeneration. In this review, we discuss the functional cross talk of proteostasis and mitostasis in cellular homeodynamics and the impairment of mitochondrial quality control during ageing, cancer, and neurodegeneration. PMID:26977249

Multifaceted plant responses to circumvent Phe hyperaccumulation by downregulation of flux through the shikimate pathway and by vacuolar Phe sequestration.

PubMed

Lynch, Joseph H; Orlova, Irina; Zhao, Chengsong; Guo, Longyun; Jaini, Rohit; Maeda, Hiroshi; Akhtar, Tariq; Cruz-Lebron, Junellie; Rhodes, David; Morgan, John; Pilot, Guillaume; Pichersky, Eran; Dudareva, Natalia

2017-12-01

Detrimental effects of hyperaccumulation of the aromatic amino acid phenylalanine (Phe) in animals, known as phenylketonuria, are mitigated by excretion of Phe derivatives; however, how plants endure Phe accumulating conditions in the absence of an excretion system is currently unknown. To achieve Phe hyperaccumulation in a plant system, we simultaneously decreased in petunia flowers expression of all three Phe ammonia lyase (PAL) isoforms that catalyze the non-oxidative deamination of Phe to trans-cinnamic acid, the committed step for the major pathway of Phe metabolism. A total decrease in PAL activity by 81-94% led to an 18-fold expansion of the internal Phe pool. Phe accumulation had multifaceted intercompartmental effects on aromatic amino acid metabolism. It resulted in a decrease in the overall flux through the shikimate pathway, and a redirection of carbon flux toward the shikimate-derived aromatic amino acids tyrosine and tryptophan. Accumulation of Phe did not lead to an increase in flux toward phenylacetaldehyde, for which Phe is a direct precursor. Metabolic flux analysis revealed this to be due to the presence of a distinct metabolically inactive pool of Phe, likely localized in the vacuole. We have identified a vacuolar cationic amino acid transporter (PhCAT2) that contributes to sequestering excess of Phe in the vacuole. In vitro assays confirmed PhCAT2 can transport Phe, and decreased PhCAT2 expression in PAL-RNAi transgenic plants resulted in 1.6-fold increase in phenylacetaldehyde emission. These results demonstrate mechanisms by which plants maintain intercompartmental aromatic amino acid homeostasis, and provide critical insight for future phenylpropanoid metabolic engineering strategies. © 2017 The Authors The Plant Journal © 2017 John Wiley & Sons Ltd.

Oxidative Stress, Amyloid-β Peptide, and Altered Key Molecular Pathways in the Pathogenesis and Progression of Alzheimer’s Disease

PubMed Central

Butterfield, D. Allan; Boyd-Kimball, Debra

2018-01-01

Oxidative stress is implicated in the pathogenesis and progression of Alzheimer’s disease (AD) and its earlier stage, amnestic mild cognitive impairment (aMCI). One source of oxidative stress in AD and aMCI brains is that associated with amyloid-β peptide, Aβ1-42 oligomers. Our laboratory first showed in AD elevated oxidative stress occurred in brain regions rich in Aβ1-42, but not in Aβ1-42-poor regions, and was among the first to demonstrate Aβ peptides led to lipid peroxidation (indexed by HNE) in AD and aMCI brains. Oxidatively modified proteins have decreased function and contribute to damaged key biochemical and metabolic pathways in which these proteins normally play a role. Identification of oxidatively modified brain proteins by the methods of redox proteomics was pioneered in the Butterfield laboratory. Four recurring altered pathways secondary to oxidative damage in brain from persons with AD, aMCI, or Down syndrome with AD are interrelated and contribute to neuronal death. This “Quadrilateral of Neuronal Death” includes altered: glucose metabolism, mTOR activation, proteostasis network, and protein phosphorylation. Some of these pathways are altered even in brains of persons with preclinical AD. We opine that targeting these pathways pharmacologically and with lifestyle changes potentially may provide strategies to slow or perhaps one day, prevent, progression or development of this devastating dementing disorder. This invited review outlines both in vitro and in vivo studies from the Butterfield laboratory related to Aβ1-42 and AD and discusses the importance and implications of some of the major achievements of the Butterfield laboratory in AD research. PMID:29562527

Interstitial pressure measurements in the anterior and posterior compartments in athletes with shin splints.

PubMed

D'Ambrosia, R D; Zelis, R F; Chuinard, R G; Wilmore, J

1977-01-01

We found no basis for increased intercompartmental pressure in either the anterior or posterior compartments as the cause of shin splints. The pain in all 14 of the patients studied was localized to the posterior medial border of the tibia at the origin of the posterior tibial muscle, and evidence of periostitis in this area was seen in two of our patients, suggesting the possible tearing away of the posterior tibial muscle from its origin. Shin splints is a lay term which has assumed medical diagnostic significance and should be removed from common usage by more accurately localizing the focus of pain.

Leucine supplementation stimulates protein synthesis and reduces degradation signal activation in muscle of newborn pigs during acute endotoxemia

USDA-ARS?s Scientific Manuscript database

Sepsis disrupts skeletal muscle proteostasis and mitigates the anabolic response to leucine (Leu) in muscle of mature animals. We have shown that Leu stimulates muscle protein synthesis (PS) in healthy neonatal piglets. To determine if supplemental Leu can stimulate PS and reduce protein degradation...

TRNA mutations that affect decoding fidelity deregulate development and the proteostasis network in zebrafish

PubMed Central

Reverendo, Marisa; Soares, Ana R; Pereira, Patrícia M; Carreto, Laura; Ferreira, Violeta; Gatti, Evelina; Pierre, Philippe; Moura, Gabriela R; Santos, Manuel A

2014-01-01

Mutations in genes that encode tRNAs, aminoacyl-tRNA syntheases, tRNA modifying enzymes and other tRNA interacting partners are associated with neuropathies, cancer, type-II diabetes and hearing loss, but how these mutations cause disease is unclear. We have hypothesized that levels of tRNA decoding error (mistranslation) that do not fully impair embryonic development can accelerate cell degeneration through proteome instability and saturation of the proteostasis network. To test this hypothesis we have induced mistranslation in zebrafish embryos using mutant tRNAs that misincorporate Serine (Ser) at various non-cognate codon sites. Embryo viability was affected and malformations were observed, but a significant proportion of embryos survived by activating the unfolded protein response (UPR), the ubiquitin proteasome pathway (UPP) and downregulating protein biosynthesis. Accumulation of reactive oxygen species (ROS), mitochondrial and nuclear DNA damage and disruption of the mitochondrial network, were also observed, suggesting that mistranslation had a strong negative impact on protein synthesis rate, ER and mitochondrial homeostasis. We postulate that mistranslation promotes gradual cellular degeneration and disease through protein aggregation, mitochondrial dysfunction and genome instability. PMID:25483040

Aberrant Proteostasis of BMAL1 Underlies Circadian Abnormalities in a Paradigmatic mTOR-opathy.

PubMed

Lipton, Jonathan O; Boyle, Lara M; Yuan, Elizabeth D; Hochstrasser, Kevin J; Chifamba, Fortunate F; Nathan, Ashwin; Tsai, Peter T; Davis, Fred; Sahin, Mustafa

2017-07-25

Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder characterized by mutations in either the TSC1 or TSC2 genes, whose products form a critical inhibitor of the mechanistic target of rapamycin (mTOR). Loss of TSC1/2 gene function renders an mTOR-overactivated state. Clinically, TSC manifests with epilepsy, intellectual disability, autism, and sleep dysfunction. Here, we report that mouse models of TSC have abnormal circadian rhythms. We show that mTOR regulates the proteostasis of the core clock protein BMAL1, affecting its translation, degradation, and subcellular localization. This results in elevated levels of BMAL1 and a dysfunctional clock that displays abnormal timekeeping under constant conditions and exaggerated responses to phase resetting. Genetically lowering the dose of BMAL1 rescues circadian behavioral phenotypes in TSC mouse models. These findings indicate that BMAL1 deregulation is a feature of the mTOR-activated state and suggest a molecular mechanism for mitigating circadian phenotypes in a neurodevelopmental disorder. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Interactome Screening Identifies the ER Luminal Chaperone Hsp47 as a Regulator of the Unfolded Protein Response Transducer IRE1α.

PubMed

Sepulveda, Denisse; Rojas-Rivera, Diego; Rodríguez, Diego A; Groenendyk, Jody; Köhler, Andres; Lebeaupin, Cynthia; Ito, Shinya; Urra, Hery; Carreras-Sureda, Amado; Hazari, Younis; Vasseur-Cognet, Mireille; Ali, Maruf M U; Chevet, Eric; Campos, Gisela; Godoy, Patricio; Vaisar, Tomas; Bailly-Maitre, Béatrice; Nagata, Kazuhiro; Michalak, Marek; Sierralta, Jimena; Hetz, Claudio

2018-01-18

Maintenance of endoplasmic reticulum (ER) proteostasis is controlled by a dynamic signaling network known as the unfolded protein response (UPR). IRE1α is a major UPR transducer, determining cell fate under ER stress. We used an interactome screening to unveil several regulators of the UPR, highlighting the ER chaperone Hsp47 as the major hit. Cellular and biochemical analysis indicated that Hsp47 instigates IRE1α signaling through a physical interaction. Hsp47 directly binds to the ER luminal domain of IRE1α with high affinity, displacing the negative regulator BiP from the complex to facilitate IRE1α oligomerization. The regulation of IRE1α signaling by Hsp47 is evolutionarily conserved as validated using fly and mouse models of ER stress. Hsp47 deficiency sensitized cells and animals to experimental ER stress, revealing the significance of Hsp47 to global proteostasis maintenance. We conclude that Hsp47 adjusts IRE1α signaling by fine-tuning the threshold to engage an adaptive UPR. Copyright © 2018 Elsevier Inc. All rights reserved.

Control of the structural landscape and neuronal proteotoxicity of mutant Huntingtin by domains flanking the polyQ tract

PubMed Central

Shen, Koning; Calamini, Barbara; Fauerbach, Jonathan A; Ma, Boxue; Shahmoradian, Sarah H; Serrano Lachapel, Ivana L; Chiu, Wah; Lo, Donald C; Frydman, Judith

2016-01-01

Many neurodegenerative diseases are linked to amyloid aggregation. In Huntington’s disease (HD), neurotoxicity correlates with an increased aggregation propensity of a polyglutamine (polyQ) expansion in exon 1 of mutant huntingtin protein (mHtt). Here we establish how the domains flanking the polyQ tract shape the mHtt conformational landscape in vitro and in neurons. In vitro, the flanking domains have opposing effects on the conformation and stabilities of oligomers and amyloid fibrils. The N-terminal N17 promotes amyloid fibril formation, while the C-terminal Proline Rich Domain destabilizes fibrils and enhances oligomer formation. However, in neurons both domains act synergistically to engage protective chaperone and degradation pathways promoting mHtt proteostasis. Surprisingly, when proteotoxicity was assessed in rat corticostriatal brain slices, either flanking region alone sufficed to generate a neurotoxic conformation, while the polyQ tract alone exhibited minimal toxicity. Linking mHtt structural properties to its neuronal proteostasis should inform new strategies for neuroprotection in polyQ-expansion diseases. DOI: http://dx.doi.org/10.7554/eLife.18065.001 PMID:27751235

Hepatic fibrosis and carcinogenesis in α1-antitrypsin deficiency: a prototype for chronic tissue damage in gain-of-function disorders.

PubMed

Perlmutter, David H; Silverman, Gary A

2011-03-01

In α1-antitrypsin (AT) deficiency, a point mutation renders a hepatic secretory glycoprotein prone to misfolding and polymerization. The mutant protein accumulates in the endoplasmic reticulum of liver cells and causes hepatic fibrosis and hepatocellular carcinoma by a gain-of-function mechanism. Genetic and/or environmental modifiers determine whether an affected homozygote is susceptible to hepatic fibrosis/carcinoma. Two types of proteostasis mechanisms for such modifiers have been postulated: variation in the function of intracellular degradative mechanisms and/or variation in the signal transduction pathways that are activated to protect the cell from protein mislocalization and/or aggregation. In recent studies we found that carbamazepine, a drug that has been used safely as an anticonvulsant and mood stabilizer, reduces the hepatic load of mutant AT and hepatic fibrosis in a mouse model by enhancing autophagic disposal of this mutant protein. These results provide evidence that pharmacological manipulation of endogenous proteostasis mechanisms is an appealing strategy for chemoprophylaxis in disorders involving gain-of-function mechanisms.

Phosphorylation and activation of ubiquitin-specific protease-14 by Akt regulates the ubiquitin-proteasome system

PubMed Central

Xu, Daichao; Shan, Bing; Lee, Byung-Hoon; Zhu, Kezhou; Zhang, Tao; Sun, Huawang; Liu, Min; Shi, Linyu; Liang, Wei; Qian, Lihui; Xiao, Juan; Wang, Lili; Pan, Lifeng; Finley, Daniel; Yuan, Junying

2015-01-01

Regulation of ubiquitin-proteasome system (UPS), which controls the turnover of short-lived proteins in eukaryotic cells, is critical in maintaining cellular proteostasis. Here we show that USP14, a major deubiquitinating enzyme that regulates the UPS, is a substrate of Akt, a serine/threonine-specific protein kinase critical in mediating intracellular signaling transducer for growth factors. We report that Akt-mediated phosphorylation of USP14 at Ser432, which normally blocks its catalytic site in the inactive conformation, activates its deubiquitinating activity in vitro and in cells. We also demonstrate that phosphorylation of USP14 is critical for Akt to regulate proteasome activity and consequently global protein degradation. Since Akt can be activated by a wide range of growth factors and is under negative control by phosphoinosotide phosphatase PTEN, we suggest that regulation of UPS by Akt-mediated phosphorylation of USP14 may provide a common mechanism for growth factors to control global proteostasis and for promoting tumorigenesis in PTEN-negative cancer cells. DOI: http://dx.doi.org/10.7554/eLife.10510.001 PMID:26523394

Paradoxical resistance of multiple myeloma to proteasome inhibitors by decreased levels of 19S proteasomal subunits

PubMed Central

Acosta-Alvear, Diego; Cho, Min Y; Wild, Thomas; Buchholz, Tonia J; Lerner, Alana G; Simakova, Olga; Hahn, Jamie; Korde, Neha; Landgren, Ola; Maric, Irina; Choudhary, Chunaram; Walter, Peter; Weissman, Jonathan S; Kampmann, Martin

2015-01-01

Hallmarks of cancer, including rapid growth and aneuploidy, can result in non-oncogene addiction to the proteostasis network that can be exploited clinically. The defining example is the exquisite sensitivity of multiple myeloma (MM) to 20S proteasome inhibitors, such as carfilzomib. However, MM patients invariably acquire resistance to these drugs. Using a next-generation shRNA platform, we found that proteostasis factors, including chaperones and stress-response regulators, controlled the response to carfilzomib. Paradoxically, 19S proteasome regulator knockdown induced resistance to carfilzomib in MM and non-MM cells. 19S subunit knockdown did not affect the activity of the 20S subunits targeted by carfilzomib nor their inhibition by the drug, suggesting an alternative mechanism, such as the selective accumulation of protective factors. In MM patients, lower 19S levels predicted a diminished response to carfilzomib-based therapies. Together, our findings suggest that an understanding of network rewiring can inform development of new combination therapies to overcome drug resistance. DOI: http://dx.doi.org/10.7554/eLife.08153.001 PMID:26327694

Alteration of the proteostasis network of plant cells promotes the post-endoplasmic reticulum trafficking of recombinant mutant (L444P) human β-glucocerebrosidase

PubMed Central

Babajani, Gholamreza; Kermode, Allison R

2014-01-01

Gaucher disease is a prevalent lysosomal storage disease characterized by a deficiency in the activity of lysosomal acid β-glucosidase (glucocerebrosidase, GCase, EC 3.2.1.45). One of the most prevalent disease-causing mutations in humans is a L444P missense mutation in the GCase protein, which results in its disrupted folding in the endoplasmic reticulum (ER) and impaired post-ER trafficking. To determine whether the post-ER trafficking of this severely malfolded protein can be restored, we expressed the mutant L444P GCase as a recombinant protein in transgenic tobacco (Nicotiana tabacum L. cv Bright Yellow 2 [BY2]) cells, in which the GCase variant was equipped with a plant signal peptide to allow for secretion upon rescued trafficking out of the ER. The recombinant L444P mutant GCase was retained in the plant endoplasmic reticulum (ER). Kifunensine and Eeyarestatin I, both inhibitors of ER-associated degradation (ERAD), and the proteostasis regulators, celastrol and MG-132, increased the steady-state levels of the mutant protein inside the plant cells and further promoted the post-ER trafficking of L444P GCase, as indicated by endoglycosidase-H sensitivity- and secretion- analyses. Transcript profiling of genes encoding ER-molecular chaperones, ER stress responsive proteins, and cytoplasmic heat shock response proteins, revealed insignificant or only very modest changes in response to the ERAD inhibitors and proteostasis regulators. An exception was the marked response to celastrol which reduced the steady-state levels of cytoplasmic HSP90 transcripts and protein. As HSP90 participates in the targeting of misfolded proteins to the proteasome pathway, its down-modulation in response to celastrol may partly account for the mechanism of improved homeostasis of L444P GCase mediated by this triterpene. PMID:24713615

High discordance in blood and genital tract HIV-1 drug resistance in Indian women failing first-line therapy.

PubMed

Saravanan, Shanmugam; Gomathi, Selvamurthi; Delong, Allison; Kausalya, Bagavathi; Sivamalar, Sathasivam; Poongulali, Selvamuthu; Brooks, Katherine; Kumarasamy, Nagalingeswaran; Balakrishnan, Pachamuthu; Solomon, Sunil S; Cu-Uvin, Susan; Kantor, Rami

2018-05-24

Examine HIV-1 plasma viral load (PVL) and genital tract (GT) viral load (GVL) and drug resistance in India. At the YRG Centre for AIDS Research and Education, Chennai, we tested: PVL in women on first-line ART for ≥6 months; GVL when PVL >2000 copies/mL; and plasma, genital and proviral reverse transcriptase drug resistance when GVL >2000 copies/mL. Wilcoxon rank-sum and Fisher's exact tests were used to identify failure and resistance associations. Pearson correlations were calculated to evaluate PVL-GVL associations. Inter-compartmental resistance discordance was evaluated using generalized estimating equations. Of 200 women, 37% had detectable (>400 copies/mL) PVL and 31% had PVL >1000 copies/mL. Of women with detectable PVL, 74% had PVL >2000 copies/mL, of which 74% had detectable GVL. Higher PVL was associated with higher GVL. Paired plasma and genital sequences were available for 21 women; mean age of 34 years, median ART duration of 33 months, median CD4 count of 217 cells/mm3, median PVL of 5.4 log10 copies/mL and median GVL of 4.6 log10 copies/mL. Drug resistance was detected in 81%-91% of samples and 67%-76% of samples had dual-class resistance. Complete three-compartment concordance was seen in only 10% of women. GT-proviral discordance was significantly larger than plasma-proviral discordance. GT or proviral mutations discordant from plasma led to clinically relevant resistance in 24% and 30%, respectively. We identified high resistance and high inter-compartmental resistance discordance in Indian women, which might lead to unrecognized resistance transmission and re-emergence compromising treatment outcomes, particularly relevant to countries like India, where sexual HIV transmission is predominant.

Alpha-synuclein levels in blood plasma decline with healthy aging.

PubMed

Koehler, Niklas K U; Stransky, Elke; Meyer, Mirjam; Gaertner, Susanne; Shing, Mona; Schnaidt, Martina; Celej, Maria S; Jovin, Thomas M; Leyhe, Thomas; Laske, Christoph; Batra, Anil; Buchkremer, Gerhard; Fallgatter, Andreas J; Wernet, Dorothee; Richartz-Salzburger, Elke

2015-01-01

There is unequivocal evidence that alpha-synuclein plays a pivotal pathophysiological role in neurodegenerative diseases, and in particular in synucleinopathies. These disorders present with a variable extent of cognitive impairment and alpha-synuclein is being explored as a biomarker in CSF, blood serum and plasma. Considering key events of aging that include proteostasis, alpha-synuclein may not only be useful as a marker for differential diagnosis but also for aging per se. To explore this hypothesis, we developed a highly specific ELISA to measure alpha-synuclein. In healthy males plasma alpha-synuclein levels correlated strongly with age, revealing much lower concentrations in older (avg. 58.1 years) compared to younger (avg. 27.6 years) individuals. This difference between the age groups was enhanced after acidification of the plasmas (p<0.0001), possibly reflecting a decrease of alpha-synuclein-antibody complexes or chaperone activity in older individuals. Our results support the concept that alpha-synuclein homeostasis may be impaired early on, possibly due to disturbance of the proteostasis network, a key component of healthy aging. Thus, alpha-synuclein may be a novel biomarker of aging, a factor that should be considered when analyzing its presence in biological specimens.

Molecular Chaperone Dysfunction in Neurodegenerative Diseases and Effects of Curcumin

PubMed Central

Frautschy, Sally

2014-01-01

The intra- and extracellular accumulation of misfolded and aggregated amyloid proteins is a common feature in several neurodegenerative diseases, which is thought to play a major role in disease severity and progression. The principal machineries maintaining proteostasis are the ubiquitin proteasomal and lysosomal autophagy systems, where heat shock proteins play a crucial role. Many protein aggregates are degraded by the lysosomes, depending on aggregate size, peptide sequence, and degree of misfolding, while others are selectively tagged for removal by heat shock proteins and degraded by either the proteasome or phagosomes. These systems are compromised in different neurodegenerative diseases. Therefore, developing novel targets and classes of therapeutic drugs, which can reduce aggregates and maintain proteostasis in the brains of neurodegenerative models, is vital. Natural products that can modulate heat shock proteins/proteosomal pathway are considered promising for treating neurodegenerative diseases. Here we discuss the current knowledge on the role of HSPs in protein misfolding diseases and knowledge gained from animal models of Alzheimer's disease, tauopathies, and Huntington's diseases. Further, we discuss the emerging treatment regimens for these diseases using natural products, like curcumin, which can augment expression or function of heat shock proteins in the cell. PMID:25386560

Ageing induced vascular smooth muscle cell senescence in atherosclerosis.

PubMed

Uryga, Anna K; Bennett, Martin R

2016-04-15

Atherosclerosis is a disease of ageing in that its incidence and prevalence increase with age. However, atherosclerosis is also associated with biological ageing, manifest by a number of typical hallmarks of ageing in the atherosclerotic plaque. Thus, accelerated biological ageing may be superimposed on the effects of chronological ageing in atherosclerosis. Tissue ageing is seen in all cells that comprise the plaque, but particularly in vascular smooth muscle cells (VSMCs). Hallmarks of ageing include evidence of cell senescence, DNA damage (including telomere attrition), mitochondrial dysfunction, a pro-inflammatory secretory phenotype, defects in proteostasis, epigenetic changes, deregulated nutrient sensing, and exhaustion of progenitor cells. In this model, initial damage to DNA (genomic, telomeric, mitochondrial and epigenetic changes) results in a number of cellular responses (cellular senescence, deregulated nutrient sensing and defects in proteostasis). Ultimately, ongoing damage and attempts at repair by continued proliferation overwhelm reparative capacity, causing loss of specialised cell functions, cell death and inflammation. This review summarises the evidence for accelerated biological ageing in atherosclerosis, the functional consequences of cell ageing on cells comprising the plaque, and the causal role that VSMC senescence plays in atherogenesis. © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.

Loss of proteostasis induced by amyloid beta peptide in brain endothelial cells.

PubMed

Fonseca, Ana Catarina; Oliveira, Catarina R; Pereira, Cláudia F; Cardoso, Sandra M

2014-06-01

Abnormal accumulation of amyloid-β (Aβ) peptide in the brain is a pathological hallmark of Alzheimer's disease (AD). In addition to neurotoxic effects, Aβ also damages brain endothelial cells (ECs) and may thus contribute to the degeneration of cerebral vasculature, which has been proposed as an early pathogenic event in the course of AD and is able to trigger and/or potentiate the neurodegenerative process and cognitive decline. However, the mechanisms underlying Aβ-induced endothelial dysfunction are not completely understood. Here we hypothesized that Aβ impairs protein quality control mechanisms both in the secretory pathway and in the cytosol in brain ECs, leading cells to death. In rat brain RBE4 cells, we demonstrated that Aβ1-40 induces the failure of the ER stress-adaptive unfolded protein response (UPR), deregulates the ubiquitin-proteasome system (UPS) decreasing overall proteasome activity with accumulation of ubiquitinated proteins and impairs the autophagic protein degradation pathway due to failure in the autophagic flux, which culminates in cell demise. In conclusion, Aβ deregulates proteostasis in brain ECs and, as a consequence, these cells die by apoptosis. Copyright © 2014 Elsevier B.V. All rights reserved.

The roles of protein expression in synaptic plasticity and memory consolidation

PubMed Central

Rosenberg, Tali; Gal-Ben-Ari, Shunit; Dieterich, Daniela C.; Kreutz, Michael R.; Ziv, Noam E.; Gundelfinger, Eckart D.; Rosenblum, Kobi

2014-01-01

The amount and availability of proteins are regulated by their synthesis, degradation, and transport. These processes can specifically, locally, and temporally regulate a protein or a population of proteins, thus affecting numerous biological processes in health and disease states. Accordingly, malfunction in the processes of protein turnover and localization underlies different neuronal diseases. However, as early as a century ago, it was recognized that there is a specific need for normal macromolecular synthesis in a specific fragment of the learning process, memory consolidation, which takes place minutes to hours following acquisition. Memory consolidation is the process by which fragile short-term memory is converted into stable long-term memory. It is accepted today that synaptic plasticity is a cellular mechanism of learning and memory processes. Interestingly, similar molecular mechanisms subserve both memory and synaptic plasticity consolidation. In this review, we survey the current view on the connection between memory consolidation processes and proteostasis, i.e., maintaining the protein contents at the neuron and the synapse. In addition, we describe the technical obstacles and possible new methods to determine neuronal proteostasis of synaptic function and better explain the process of memory and synaptic plasticity consolidation. PMID:25429258

A non-BRICHOS SFTPC mutant (SP-CI73T) linked to interstitial lung disease promotes a late block in macroautophagy disrupting cellular proteostasis and mitophagy

PubMed Central

Hawkins, Arie; Guttentag, Susan H.; Deterding, Robin; Funkhouser, William K.; Goralski, Jennifer L.; Chatterjee, Shampa; Beers, Michael F.

2014-01-01

Mutation of threonine for isoleucine at codon 73 (I73T) in the human surfactant protein C (hSP-C) gene (SFTPC) accounts for a significant portion of SFTPC mutations associated with interstitial lung disease (ILD). Cell lines stably expressing tagged primary translation product of SP-C isoforms were generated to test the hypothesis that deposition of hSP-CI73T within the endosomal system promotes disruption of a key cellular quality control pathway, macroautophagy. By fluorescence microscopy, wild-type hSP-C (hSP-CWT) colocalized with exogenously expressed human ATP binding cassette class A3 (hABCA3), an indicator of normal trafficking to lysosomal-related organelles. In contrast, hSP-CI73T was dissociated from hABCA3 but colocalized to the plasma membrane as well as the endosomal network. Cells expressing hSP-CI73T exhibited increases in size and number of cytosolic green fluorescent protein/microtubule-associated protein 1 light-chain 3 (LC3) vesicles, some of which colabeled with red fluorescent protein from the gene dsRed/hSP-CI73T. By transmission electron microscopy, hSP-CI73T cells contained abnormally large autophagic vacuoles containing organellar and proteinaceous debris, which phenocopied ultrastructural changes in alveolar type 2 cells in a lung biopsy from a SFTPC I73T patient. Biochemically, hSP-CI73T cells exhibited increased expression of Atg8/LC3, SQSTM1/p62, and Rab7, consistent with a distal block in autophagic vacuole maturation, confirmed by flux studies using bafilomycin A1 and rapamycin. Functionally, hSP-CI73T cells showed an impaired degradative capacity for an aggregation-prone huntingtin-1 reporter substrate. The disruption of autophagy-dependent proteostasis was accompanied by increases in mitochondria biomass and parkin expression coupled with a decrease in mitochondrial membrane potential. We conclude that hSP-CI73T induces an acquired block in macroautophagy-dependent proteostasis and mitophagy, which could contribute to the increased vulnerability of the lung epithelia to second-hit injury as seen in ILD. PMID:25344067

Heat shock factor 2 is required for maintaining proteostasis against febrile-range thermal stress and polyglutamine aggregation

PubMed Central

Shinkawa, Toyohide; Tan, Ke; Fujimoto, Mitsuaki; Hayashida, Naoki; Yamamoto, Kaoru; Takaki, Eiichi; Takii, Ryosuke; Prakasam, Ramachandran; Inouye, Sachiye; Mezger, Valerie; Nakai, Akira

2011-01-01

Heat shock response is characterized by the induction of heat shock proteins (HSPs), which facilitate protein folding, and non-HSP proteins with diverse functions, including protein degradation, and is regulated by heat shock factors (HSFs). HSF1 is a master regulator of HSP expression during heat shock in mammals, as is HSF3 in avians. HSF2 plays roles in development of the brain and reproductive organs. However, the fundamental roles of HSF2 in vertebrate cells have not been identified. Here we find that vertebrate HSF2 is activated during heat shock in the physiological range. HSF2 deficiency reduces threshold for chicken HSF3 or mouse HSF1 activation, resulting in increased HSP expression during mild heat shock. HSF2-null cells are more sensitive to sustained mild heat shock than wild-type cells, associated with the accumulation of ubiquitylated misfolded proteins. Furthermore, loss of HSF2 function increases the accumulation of aggregated polyglutamine protein and shortens the lifespan of R6/2 Huntington's disease mice, partly through αB-crystallin expression. These results identify HSF2 as a major regulator of proteostasis capacity against febrile-range thermal stress and suggest that HSF2 could be a promising therapeutic target for protein-misfolding diseases. PMID:21813737

Nature Versus Nurture: Does Proteostasis Imbalance Underlie the Genetic, Environmental, and Age-Related Risk Factors for Alzheimer's Disease?

PubMed

Kikis, Elise A

2017-08-22

Aging is a risk factor for a number of "age-related diseases", including Alzheimer's disease (AD). AD affects more than a third of all people over the age of 85, and is the leading cause of dementia worldwide. Symptoms include forgetfulness, memory loss, and cognitive decline, ultimately resulting in the need for full-time care. While there is no cure for AD, pharmacological approaches to alleviate symptoms and target underlying causes of the disease have been developed, albeit with limited success. This review presents the age-related, genetic, and environmental risk factors for AD and proposes a hypothesis for the mechanistic link between genetics and the environment. In short, much is known about the genetics of early-onset familial AD (EO-FAD) and the central role played by the Aβ peptide and protein misfolding, but late-onset AD (LOAD) is not thought to have direct genetic causes. Nonetheless, genetic risk factors such as isoforms of the protein ApoE have been identified. Additional findings suggest that air pollution caused by the combustion of fossil fuels may be an important environmental risk factor for AD. A hypothesis suggesting that poor air quality might act by disrupting protein folding homeostasis (proteostasis) is presented.

Alpha-fetoprotein is a biomarker of unfolded protein response and altered proteostasis in hepatocellular carcinoma cells exposed to sorafenib.

PubMed

Houessinon, Aline; Gicquel, Albane; Bochereau, Flora; Louandre, Christophe; Nyga, Rémy; Godin, Corinne; Degonville, James; Fournier, Emma; Saidak, Zuzana; Drullion, Claire; Barbare, Jean-Claude; Chauffert, Bruno; François, Catherine; Pluquet, Olivier; Galmiche, Antoine

2016-01-28

Sorafenib is the treatment of reference for advanced hepatocellular carcinoma (HCC). A decrease in the serum levels of Alpha-fetoprotein (AFP) is reported to be the biological parameter that is best associated with disease control by sorafenib. In order to provide a biological rationale for the variations of AFP, we analyzed the various steps of AFP production in human HCC cell lines exposed to sorafenib. Sorafenib dramatically reduced the levels of AFP produced by HCC cells independently of its effect on cell viability. The mRNA levels of AFP decreased upon sorafenib treatment, while the AFP protein remained localized in the Golgi apparatus. Sorafenib activated the Regulated Inositol-Requiring Enzyme-1α (IRE-1α) and the PKR-like ER Kinase (PERK)-dependent arms of the Unfolded Protein Response (UPR). The inhibition of IRE-1α partially restored the mRNA levels of AFP upon treatment with sorafenib. The inhibition of both pathways partially prevented the drop in the production of AFP induced by sorafenib. The findings provide new insights on the regulation of AFP, and identify it as a biomarker suitable for the exploration of HCC cell proteostasis in the context of therapeutic targeting. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Augmenting autophagy for prognosis based intervention of COPD-pathophysiology.

PubMed

Bodas, Manish; Vij, Neeraj

2017-05-04

Chronic obstructive pulmonary disease (COPD) is foremost among the non-reversible fatal ailments where exposure to tobacco/biomass-smoke and aging are the major risk factors for the initiation and progression of the obstructive lung disease. The role of smoke-induced inflammatory-oxidative stress, apoptosis and cellular senescence in driving the alveolar damage that mediates the emphysema progression and severe lung function decline is apparent, although the central mechanism that regulates these processes was unknown. To fill in this gap in knowledge, the central role of proteostasis and autophagy in regulating chronic lung disease causing mechanisms has been recently described. Recent studies demonstrate that cigarette/nicotine exposure induces proteostasis/autophagy-impairment that leads to perinuclear accumulation of polyubiquitinated proteins as aggresome-bodies, indicative of emphysema severity. In support of this concept, autophagy inducing FDA-approved anti-oxidant drugs control tobacco-smoke induced inflammatory-oxidative stress, apoptosis, cellular senescence and COPD-emphysema progression in variety of preclinical models. Hence, we propose that precise and early detection of aggresome-pathology can allow the timely assessment of disease severity in COPD-emphysema subjects for prognosis-based intervention. While intervention with autophagy-inducing drugs is anticipated to reduce alveolar damage and lung function decline, resulting in a decrease in the current mortality rates in COPD-emphysema subjects.

Hsp70 Protein Complexes as Drug Targets

PubMed Central

Assimon, Victoria A.; Gillies, Anne T.; Rauch, Jennifer N.; Gestwicki, Jason E.

2013-01-01

Heat shock protein 70 (Hsp70) plays critical roles in proteostasis and is an emerging target for multiple diseases. However, competitive inhibition of the enzymatic activity of Hsp70 has proven challenging and, in some cases, may not be the most productive way to redirect Hsp70 function. Another approach is to inhibit Hsp70’s interactions with important co-chaperones, such as J proteins, nucleotide exchange factors (NEFs) and tetratricopeptide repeat (TPR) domain-containing proteins. These co-chaperones normally bind Hsp70 and guide its many diverse cellular activities. Complexes between Hsp70 and co-chaperones have been shown to have specific functions, such as pro-folding, pro-degradation and pro-trafficking. Thus, a promising strategy may be to block protein-protein interactions between Hsp70 and its co-chaperones or to target allosteric sites that disrupt these contacts. Such an approach might shift the balance of Hsp70 complexes and re-shape the proteome and it has the potential to restore healthy proteostasis. In this review, we discuss specific challenges and opportunities related to those goals. By pursuing Hsp70 complexes as drug targets, we might not only develop new leads for therapeutic development, but also discover new chemical probes for use in understanding Hsp70 biology. PMID:22920901

Control of mitochondrial biogenesis and function by the ubiquitin-proteasome system.

PubMed

Bragoszewski, Piotr; Turek, Michal; Chacinska, Agnieszka

2017-04-01

Mitochondria are pivotal organelles in eukaryotic cells. The complex proteome of mitochondria comprises proteins that are encoded by nuclear and mitochondrial genomes. The biogenesis of mitochondrial proteins requires their transport in an unfolded state with a high risk of misfolding. The mislocalization of mitochondrial proteins is deleterious to the cell. The electron transport chain in mitochondria is a source of reactive oxygen species that damage proteins. Mitochondrial dysfunction is linked to many pathological conditions and, together with the loss of cellular protein homeostasis (proteostasis), are hallmarks of ageing and ageing-related degeneration diseases. The pathogenesis of neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease, has been associated with mitochondrial and proteostasis failure. Thus, mitochondrial proteins require sophisticated surveillance mechanisms. Although mitochondria form a proteasome-exclusive compartment, multiple lines of evidence indicate a crucial role for the cytosolic ubiquitin-proteasome system (UPS) in the quality control of mitochondrial proteins. The proteasome affects mitochondrial proteins at stages of their biogenesis and maturity. The effects of the UPS go beyond the removal of damaged proteins and include the adjustment of mitochondrial proteome composition, the regulation of organelle dynamics and the protection of cellular homeostasis against mitochondrial failure. In turn, mitochondrial activity and mitochondrial dysfunction adjust the activity of the UPS, with implications at the cellular level. © 2017 The Authors.

Control of mitochondrial biogenesis and function by the ubiquitin–proteasome system

PubMed Central

Bragoszewski, Piotr; Turek, Michal

2017-01-01

Mitochondria are pivotal organelles in eukaryotic cells. The complex proteome of mitochondria comprises proteins that are encoded by nuclear and mitochondrial genomes. The biogenesis of mitochondrial proteins requires their transport in an unfolded state with a high risk of misfolding. The mislocalization of mitochondrial proteins is deleterious to the cell. The electron transport chain in mitochondria is a source of reactive oxygen species that damage proteins. Mitochondrial dysfunction is linked to many pathological conditions and, together with the loss of cellular protein homeostasis (proteostasis), are hallmarks of ageing and ageing-related degeneration diseases. The pathogenesis of neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease, has been associated with mitochondrial and proteostasis failure. Thus, mitochondrial proteins require sophisticated surveillance mechanisms. Although mitochondria form a proteasome-exclusive compartment, multiple lines of evidence indicate a crucial role for the cytosolic ubiquitin–proteasome system (UPS) in the quality control of mitochondrial proteins. The proteasome affects mitochondrial proteins at stages of their biogenesis and maturity. The effects of the UPS go beyond the removal of damaged proteins and include the adjustment of mitochondrial proteome composition, the regulation of organelle dynamics and the protection of cellular homeostasis against mitochondrial failure. In turn, mitochondrial activity and mitochondrial dysfunction adjust the activity of the UPS, with implications at the cellular level. PMID:28446709

Poly-Ub-Substrate-Degradative Activity of 26S Proteasome Is Not Impaired in the Aging Rat Brain

PubMed Central

Giannini, Carolin; Kloß, Alexander; Gohlke, Sabrina; Mishto, Michele; Nicholson, Thomas P.; Sheppard, Paul W.; Kloetzel, Peter-Michael; Dahlmann, Burkhardt

2013-01-01

Proteostasis is critical for the maintenance of life. In neuronal cells an imbalance between protein synthesis and degradation is thought to be involved in the pathogenesis of neurodegenerative diseases during aging. Partly, this seems to be due to a decrease in the activity of the ubiquitin-proteasome system, wherein the 20S/26S proteasome complexes catalyse the proteolytic step. We have characterised 20S and 26S proteasomes from cerebrum, cerebellum and hippocampus of 3 weeks old (young) and 24 month old (aged) rats. Our data reveal that the absolute amount of the proteasome is not dfferent between both age groups. Within the majority of standard proteasomes in brain the minute amounts of immuno-subunits are slightly increased in aged rat brain. While this goes along with a decrease in the activities of 20S and 26S proteasomes to hydrolyse synthetic fluorogenic tripeptide substrates from young to aged rats, the capacity of 26S proteasomes for degradation of poly-Ub-model substrates and its activation by poly-Ub-substrates is not impaired or even slightly increased in brain of aged rats. We conclude that these alterations in proteasome properties are important for maintaining proteostasis in the brain during an uncomplicated aging process. PMID:23667697

Canavan disease. Analysis of the nature of the metabolic lesions responsible for development of the observed clinical symptoms.

PubMed

Baslow, M H; Resnik, T R

1997-10-01

Canavan disease (CD), a rare recessive autosomal genetic disorder, is characterized by early onset and a progressive spongy degeneration of the brain involving loss of the axon's myelin sheath. After a relatively normal birth, homozygous individuals generally develop clinical symptoms within months, and usually die within several years of the onset of the disease. A biochemical defect associated with this disease results in reduced activity of the enzyme N-acetyl-L-aspartate amidohydrolase (aspartoacylase) and affected individuals have less ability to hydrolyze N-acetyl-L-asparate (NAA) in brain and other tissues. As a result of aspartoacylase deficiency, NAA builds up in extracellular fluids (ECF) and is excreted in urine. From an analysis of the NAA biochemical cycle in various tissues of many vertebrate species, evidence is presented that there may be two distinct NAA circulation patterns related to aspartoacylase activity. These include near-field circulations in the brain and the eye, and a far-field systemic circulation involving the liver and kidney, the purpose of which in each case is apparently to regenerate aspartate (Asp) in order for it to be recycled into NAA as part of the still unknown function of the NAA cycle. Based on the authors' analysis, they have also identified several metabolic outcomes of the genetic biochemical aspartoacylase lesion. First, there is a daily induced Asp deficit in the central nervous system (CNS) that is at least six times the static level of available free Asp. Second, there is up to a 50-fold drop in the intercompartmental NAA gradient, and third, the ability of the brain to perform its normal intercompartmental cycling of NAA to Asp is terminated, and as a result, the only remaining long-term source of Asp for NAA synthesis is via nutritional supplementation of Asp or its metabolic precursors. Finally, the authors identify a potential maternal-fetal interaction that may be responsible for observed normal fetal development in utero, and that provides a rationale for, and suggests how, CD might respond to far-field nutritional, transplantation, or genetic engineering techniques to alter the course of the disease.

The Role of Co-chaperones in Synaptic Proteostasis and Neurodegenerative Disease

PubMed Central

Gorenberg, Erica L.; Chandra, Sreeganga S.

2017-01-01

Synapses must be preserved throughout an organism's lifespan to allow for normal brain function and behavior. Synapse maintenance is challenging given the long distances between the termini and the cell body, reliance on axonal transport for delivery of newly synthesized presynaptic proteins, and high rates of synaptic vesicle exo- and endocytosis. Hence, synapses rely on efficient proteostasis mechanisms to preserve their structure and function. To this end, the synaptic compartment has specific chaperones to support its functions. Without proper synaptic chaperone activity, local proteostasis imbalances lead to neurotransmission deficits, dismantling of synapses, and neurodegeneration. In this review, we address the roles of four synaptic chaperones in the maintenance of the nerve terminal, as well as their genetic links to neurodegenerative disease. Three of these are Hsp40 co-chaperones (DNAJs): Cysteine String Protein alpha (CSPα; DNAJC5), auxilin (DNAJC6), and Receptor-Mediated Endocytosis 8 (RME-8; DNAJC13). These co-chaperones contain a conserved J domain through which they form a complex with heat shock cognate 70 (Hsc70), enhancing the chaperone's ATPase activity. CSPα is a synaptic vesicle protein known to chaperone the t-SNARE SNAP-25 and the endocytic GTPase dynamin-1, thereby regulating synaptic vesicle exocytosis and endocytosis. Auxilin binds assembled clathrin cages, and through its interactions with Hsc70 leads to the uncoating of clathrin-coated vesicles, a process necessary for the regeneration of synaptic vesicles. RME-8 is a co-chaperone on endosomes and may have a role in clathrin-coated vesicle endocytosis on this organelle. These three co-chaperones maintain client function by preserving folding and assembly to prevent client aggregation, but they do not break down aggregates that have already formed. The fourth synaptic chaperone we will discuss is Heat shock protein 110 (Hsp110), which interacts with Hsc70, DNAJAs, and DNAJBs to constitute a disaggregase. Hsp110-related disaggregase activity is present at the synapse and is known to protect against aggregation of proteins such as α-synuclein. Congruent with their importance in the nervous system, mutations of these co-chaperones lead to familial neurodegenerative disease. CSPα mutations cause adult neuronal ceroid lipofuscinosis, while auxilin mutations result in early-onset Parkinson's disease, demonstrating their significance in preservation of the nervous system. PMID:28579939

Bone graft in the treatment of nonunion of the scaphoid with necrosis of the proximal pole: a literature review.

PubMed

Severo, Antônio Lourenço; Lemos, Marcelo Barreto; Lech, Osvandré Luiz Canfield; Barreto Filho, Danilo; Strack, Daniel Paulo; Candido, Larissa Knapp

2017-01-01

Scaphoid fractures are the most common fractures of the carpal bones, corresponding to 60%. Of these, 10% progress to nonunion; moreover, 3% can present necrosis of the proximal pole. There are various methods of treatment using vascularized and non-vascularized bone grafts. To evaluate and compare the rate of scaphoid consolidation with necrosis of the proximal pole using different surgical techniques. The authors conducted a review of the literature using the following databases: PubMed and BIREME/LILACS, where 13 case series were selected (ten with use of vascularized bone grafts and three of non-vascularized bone grafts), according to inclusion and exclusion criteria. In most cases VBGs were used, especially those based on the 1,2 intercompartmental supraretinacular artery, due to greater reproducibility in performing the surgical technique.

BAG2 Interferes with CHIP-Mediated Ubiquitination of HSP72.

PubMed

Schönbühler, Bianca; Schmitt, Verena; Huesmann, Heike; Kern, Andreas; Gamerdinger, Martin; Behl, Christian

2016-12-30

The maintenance of cellular proteostasis is dependent on molecular chaperones and protein degradation pathways. Chaperones facilitate protein folding, maturation, and degradation, and the particular fate of a misfolded protein is determined by the interaction of chaperones with co-chaperones. The co-factor CHIP (C-terminus of HSP70-inteacting protein, STUB1) ubiquitinates chaperone substrates and directs proteins to the cellular degradation systems. The activity of CHIP is regulated by two co-chaperones, BAG2 and HSPBP1, which are potent inhibitors of the E3 ubiquitin ligase activity. Here, we examined the functional correlation of HSP72, CHIP, and BAG2, employing human primary fibroblasts. We showed that HSP72 is a substrate of CHIP and that BAG2 efficiently prevented the ubiquitination of HSP72 in young cells as well as aged cells. Aging is associated with a decline in proteostasis and we observed increased protein levels of CHIP as well as BAG2 in senescent cells. Interestingly, the ubiquitination of HSP72 was strongly reduced during aging, which revealed that BAG2 functionally counteracted the increased levels of CHIP. Interestingly, HSPBP1 protein levels were down-regulated during aging. The data presented here demonstrates that the co-chaperone BAG2 influences HSP72 protein levels and is an important modulator of the ubiquitination activity of CHIP in young as well as aged cells.

Regulatory module involving FGF13, miR-504, and p53 regulates ribosomal biogenesis and supports cancer cell survival

PubMed Central

Bublik, Débora R.; Bursać, Slađana; Sheffer, Michal; Oršolić, Ines; Shalit, Tali; Tarcic, Ohad; Kotler, Eran; Mouhadeb, Odelia; Hoffman, Yonit; Fuchs, Gilad; Levin, Yishai; Volarević, Siniša; Oren, Moshe

2017-01-01

The microRNA miR-504 targets TP53 mRNA encoding the p53 tumor suppressor. miR-504 resides within the fibroblast growth factor 13 (FGF13) gene, which is overexpressed in various cancers. We report that the FGF13 locus, comprising FGF13 and miR-504, is transcriptionally repressed by p53, defining an additional negative feedback loop in the p53 network. Furthermore, we show that FGF13 1A is a nucleolar protein that represses ribosomal RNA transcription and attenuates protein synthesis. Importantly, in cancer cells expressing high levels of FGF13, the depletion of FGF13 elicits increased proteostasis stress, associated with the accumulation of reactive oxygen species and apoptosis. Notably, stepwise neoplastic transformation is accompanied by a gradual increase in FGF13 expression and increased dependence on FGF13 for survival (“nononcogene addiction”). Moreover, FGF13 overexpression enables cells to cope more effectively with the stress elicited by oncogenic Ras protein. We propose that, in cells in which activated oncogenes drive excessive protein synthesis, FGF13 may favor survival by maintaining translation rates at a level compatible with the protein quality-control capacity of the cell. Thus, FGF13 may serve as an enabler, allowing cancer cells to evade proteostasis stress triggered by oncogene activation. PMID:27994142

AAA+ Machines of Protein Destruction in Mycobacteria.

PubMed

Alhuwaider, Adnan Ali H; Dougan, David A

2017-01-01

The bacterial cytosol is a complex mixture of macromolecules (proteins, DNA, and RNA), which collectively are responsible for an enormous array of cellular tasks. Proteins are central to most, if not all, of these tasks and as such their maintenance (commonly referred to as protein homeostasis or proteostasis) is vital for cell survival during normal and stressful conditions. The two key aspects of protein homeostasis are, (i) the correct folding and assembly of proteins (coupled with their delivery to the correct cellular location) and (ii) the timely removal of unwanted or damaged proteins from the cell, which are performed by molecular chaperones and proteases, respectively. A major class of proteins that contribute to both of these tasks are the AAA+ (ATPases associated with a variety of cellular activities) protein superfamily. Although much is known about the structure of these machines and how they function in the model Gram-negative bacterium Escherichia coli , we are only just beginning to discover the molecular details of these machines and how they function in mycobacteria. Here we review the different AAA+ machines, that contribute to proteostasis in mycobacteria. Primarily we will focus on the recent advances in the structure and function of AAA+ proteases, the substrates they recognize and the cellular pathways they control. Finally, we will discuss the recent developments related to these machines as novel drug targets.

The metazoan protein disaggregase and amyloid depolymerase system: Hsp110, Hsp70, Hsp40, and small heat shock proteins.

PubMed

Torrente, Mariana P; Shorter, James

2013-01-01

A baffling aspect of metazoan proteostasis is the lack of an Hsp104 ortholog that rapidly disaggregates and reactivates misfolded polypeptides trapped in stress induced disordered aggregates, preamyloid oligomers, or amyloid fibrils. By contrast, in bacteria, protozoa, chromista, fungi, and plants, Hsp104 orthologs are highly conserved and confer huge selective advantages in stress tolerance. Moreover, in fungi, the amyloid remodeling activity of Hsp104 has enabled deployment of prions for various beneficial modalities. Thus, a longstanding conundrum has remained unanswered: how do metazoan cells renature aggregated proteins or resolve amyloid fibrils without Hsp104? Here, we highlight recent advances that unveil the metazoan protein-disaggregase machinery, comprising Hsp110, Hsp70, and Hsp40, which synergize to dissolve disordered aggregates, but are unable to rapidly solubilize stable amyloid fibrils. However, Hsp110, Hsp70, and Hsp40 exploit the slow monomer exchange dynamics of amyloid, and can slowly depolymerize amyloid fibrils from their ends in a manner that is stimulated by small heat shock proteins. Upregulation of this system could have key therapeutic applications in various protein-misfolding disorders. Intriguingly, yeast Hsp104 can interface with metazoan Hsp110, Hsp70, and Hsp40 to rapidly eliminate disease associated amyloid. Thus, metazoan proteostasis is receptive to augmentation with exogenous disaggregases, which opens a number of therapeutic opportunities.

A Short-Term Population Model of the Suicide Risk: The Case of Spain.

PubMed

De la Poza, Elena; Jódar, Lucas

2018-06-14

A relevant proportion of deaths by suicide have been attributed to other causes that produce the number of suicides remains hidden. The existence of a hidden number of cases is explained by the nature of the problem. Problems like this involve violence, and produce fear and social shame in victims' families. The existence of violence, fear and social shame experienced by victims favours a considerable number of suicides, identified as accidents or natural deaths. This paper proposes a short time discrete compartmental mathematical model to measure the suicidal risk for the case of Spain. The compartment model classifies and quantifies the amount of the Spanish population within the age intervals (16, 78) by their degree of suicide risk and their changes over time. Intercompartmental transits are due to the combination of quantitative and qualitative factors. Results are computed and simulations are performed to analyze the sensitivity of the model under uncertain coefficients.

Control mechanisms of circadian rhythms in body composition: Implications for manned spaceflight

NASA Technical Reports Server (NTRS)

Ede, M. C. M.

1975-01-01

The mechanisms that underlie the circadian variations in electrolyte content in body fluid compartments were investigated, and the mechanisms that control the oscillations were studied in order to investigate what effects internal desynchronization in such a system would have during manned space flight. The studies were performed using volunteer human subjects and squirrel monkeys. The intercompartmental distribution of potassium was examined when dietary intake, activity, and posture are held constant throughout each 24-hour day. A net flux of potassium was observed out of the body cell mass during the day and a reverse flux from the extracellular fluid into the body cell mass during the night, counterbalanced by changes in urinary potassium excretion. Experiments with monkeys provided evidence for the synchronization of renal potassium excretion by the rhythm of cortisol secretion with the light-dark cycle. Three models of the circadian timing system were formalized.

Gaucher disease and other storage disorders.

PubMed

Grabowski, Gregory A

2012-01-01

In 1882, Philippe Gaucher described a 32-year-old woman with massive splenomegaly and unusually large cells in the spleen, which he called a "primary epithelioma of the spleen." The systemic nature and inheritance of the disease and its variants involving the viscera and CNS were described over the next century. The delineation of the causal enzymatic defects, genetics, molecular pathology, and genomics have provided pathogenic insights into the phenotypic spectrum and the bases for development of specific therapies for what is now known as Gaucher disease. As a prototype, the clinically and economically successful intracellular enzyme therapy provided the impetus for the expansion of similar research and therapeutic developments for other lysosomal storage diseases (LSDs) and orphan diseases, including Fabry, Pompe, and Niemann-Pick diseases, as well as several mucopolysaccharidoses. Continuing studies of such LSDs, which occur as a group in more than 7000 live births, have revealed the complex molecular interdigitation with the autophagy and apoptotic pathways and proteostasis and the impact of disruptions of the lysosomal/autophagy and proteostasis systems on more common diseases has been recognized. Examples include age-related neurodegenerative diseases (eg, Parkinson disease and Gaucher disease), idiopathic hypertrophic myocardiopathies, stroke and renal failure (eg, Fabry disease), and Nonalcoholic Fatty Liver Disease/Nonalcoholic SteatoHepatitis (NAFLD/NASH) and atherosclerosis (eg, lysosomal acid lipase deficiencies). Although perceived as rare, the availability of treatment and the impact of the LSDs on more common diseases require their integration into routine clinical practice.

Protein Folding and the Challenges of Maintaining Endoplasmic Reticulum Proteostasis in Idiopathic Pulmonary Fibrosis.

PubMed

Romero, Freddy; Summer, Ross

2017-11-01

Alveolar epithelial type II (AEII) cells are "professional" secretory cells that synthesize and secrete massive quantities of proteins to produce pulmonary surfactant and maintain airway immune defenses. To facilitate this high level of protein synthesis, AEII cells are equipped with an elaborate endoplasmic reticulum (ER) structure and possess an abundance of the machinery needed to fold, assemble, and secrete proteins. However, conditions that suddenly increase the quantity of new proteins entering the ER or that impede the capacity of the ER to fold proteins can cause misfolded or unfolded proteins to accumulate in the ER lumen, also called ER stress. To minimize this stress, AEII cells adapt by (1) reducing the quantity of proteins entering the ER, (2) increasing the amount of protein-folding machinery, and (3) removing misfolded proteins when they accumulate. Although these adaptive responses, aptly named the unfolded protein response, are usually effective in reducing ER stress, chronic aggregation of misfolded proteins is recognized as a hallmark feature of AEII cells in patients with idiopathic pulmonary fibrosis (IPF). Although mutations in surfactant proteins are linked to the development of ER stress in some rare IPF cases, the mechanisms causing protein misfolding in most cases are unknown. In this article, we review the mechanisms regulating ER proteostasis and highlight specific aspects of protein folding and the unfolded protein response that are most vulnerable to failure. Then, we postulate mechanisms other than genetic mutations that might contribute to protein aggregation in the alveolar epithelium of IPF lung.

The Role of the Multifunctional BAG3 Protein in Cellular Protein Quality Control and in Disease.

PubMed

Stürner, Elisabeth; Behl, Christian

2017-01-01

In neurons, but also in all other cells the complex proteostasis network is monitored and tightly regulated by the cellular protein quality control (PQC) system. Beyond folding of newly synthesized polypeptides and their refolding upon misfolding the PQC also manages the disposal of aberrant proteins either by the ubiquitin-proteasome machinery or by the autophagic-lysosomal system. Aggregated proteins are primarily degraded by a process termed selective macroautophagy (or aggrephagy). One such recently discovered selective macroautophagy pathway is mediated by the multifunctional HSP70 co-chaperone BAG3 ( BCL-2-associated athanogene 3 ). Under acute stress and during cellular aging, BAG3 in concert with the molecular chaperones HSP70 and HSPB8 as well as the ubiquitin receptor p62/SQSTM1 specifically targets aggregation-prone proteins to autophagic degradation. Thereby, BAG3-mediated selective macroautophagy represents a pivotal adaptive safeguarding and emergency system of the PQC which is activated under pathophysiological conditions to ensure cellular proteostasis. Interestingly, BAG3-mediated selective macroautophagy is also involved in the clearance of aggregated proteins associated with age-related neurodegenerative disorders, like Alzheimer's disease (tau-protein), Huntington's disease (mutated huntingtin/polyQ proteins), and amyotrophic lateral sclerosis (mutated SOD1). In addition, based on its initial description BAG3 is an anti-apoptotic protein that plays a decisive role in other widespread diseases, including cancer and myopathies. Therefore, in the search for novel therapeutic intervention avenues in neurodegeneration, myopathies and cancer BAG3 is a promising candidate.

The Impact of the Computerization of a High School's Pedagogical Administration on Homeroom Teacher-Parents Interrelations: A Case Study

ERIC Educational Resources Information Center

Telem, M.

2005-01-01

The introduction of a school management information system (SMIS) in an urban vocational high school, located in a middle-class socio-economic neighborhood, notably affected the learning, behavior and attendance (LBA) interrelations between homeroom teachers (HRTs) and parents. HRT-parents interrelations in general, but those involving parents…

Rapid flow cytometric measurement of protein inclusions and nuclear trafficking

PubMed Central

Whiten, D. R.; San Gil, R.; McAlary, L.; Yerbury, J. J.; Ecroyd, H.; Wilson, M. R.

2016-01-01

Proteinaceous cytoplasmic inclusions are an indicator of dysfunction in normal cellular proteostasis and a hallmark of many neurodegenerative diseases. We describe a simple and rapid new flow cytometry-based method to enumerate, characterise and, if desired, physically recover protein inclusions from cells. This technique can analyse and resolve a broad variety of inclusions differing in both size and protein composition, making it applicable to essentially any model of intracellular protein aggregation. The method also allows rapid quantification of the nuclear trafficking of fluorescently labelled molecules. PMID:27516358

Spousal Interrelations in Happiness in the Seattle Longitudinal Study: Considerable Similarities in Levels and Change over Time

ERIC Educational Resources Information Center

Hoppmann, Christiane A.; Gerstorf, Denis; Willis, Sherry L.; Schaie, K. Warner

2011-01-01

Development does not take place in isolation and is often interrelated with close others such as marital partners. To examine interrelations in spousal happiness across midlife and old age, we used 35-year longitudinal data from both members of 178 married couples in the Seattle Longitudinal Study. Latent growth curve models revealed sizeable…

Proteostasis and REDOX state in the heart

PubMed Central

Christians, Elisabeth S.

2012-01-01

Force-generating contractile cells of the myocardium must achieve and maintain their primary function as an efficient mechanical pump over the life span of the organism. Because only half of the cardiomyocytes can be replaced during the entire human life span, the maintenance strategy elicited by cardiac cells relies on uninterrupted renewal of their components, including proteins whose specialized functions constitute this complex and sophisticated contractile apparatus. Thus cardiac proteins are continuously synthesized and degraded to ensure proteome homeostasis, also termed “proteostasis.” Once synthesized, proteins undergo additional folding, posttranslational modifications, and trafficking and/or become involved in protein-protein or protein-DNA interactions to exert their functions. This includes key transient interactions of cardiac proteins with molecular chaperones, which assist with quality control at multiple levels to prevent misfolding or to facilitate degradation. Importantly, cardiac proteome maintenance depends on the cellular environment and, in particular, the reduction-oxidation (REDOX) state, which is significantly different among cardiac organelles (e.g., mitochondria and endoplasmic reticulum). Taking into account the high metabolic activity for oxygen consumption and ATP production by mitochondria, it is a challenge for cardiac cells to maintain the REDOX state while preventing either excessive oxidative or reductive stress. A perturbed REDOX environment can affect protein handling and conformation (e.g., disulfide bonds), disrupt key structure-function relationships, and trigger a pathogenic cascade of protein aggregation, decreased cell survival, and increased organ dysfunction. This review covers current knowledge regarding the general domain of REDOX state and protein folding, specifically in cardiomyocytes under normal-healthy conditions and during disease states associated with morbidity and mortality in humans. PMID:22003057

Chaperoning the Cancer: The Proteostatic Functions of the Heat Shock Proteins in Cancer.

PubMed

Vahid, Sepideh; Thaper, Daksh; Zoubeidi, Amina

2017-01-01

Protein homeostasis (proteostasis) is vital for the survival of cells in physiological and pathological conditions. Particularly, cancer cells are in constant state of cellular stress due to rapid proliferation and decreased quality control in proteosynthesis and therefore, are exceedingly dependent on the homeostasis pathways. Among the complex biological mechanisms regulating proteostasis are the highly conserved molecular chaperones, heat shock proteins (HSPs). HSPs assist cell survival by catalysing the proper folding of proteins, modulation of the apoptotic machinery and finally regulating the protein degradation machinery, providing either the stability or the degradation of selected proteins under stress conditions. Inevitably, HSPs are upregulated in malignancies and participate in different hallmarks of cancer, with indispensable roles in the onset and progression of the disease. Moreover, high levels of HSPs contribute to poor prognosis and treatment resistance in various cancers. Therefore these molecular chaperones present as attractive targets for anti-cancer therapy. This review describes how HSPs regulate different hallmarks of cancer and provides an overview on the most relevant patents which have recently appeared in the literature. The patents were extracted from Google Patents (2012-2016) while the clinical trial results were mined from www.clinicaltrial.gov. Review of literature shows that the proteostatic functions of HSPs can modify different hallmarks of cancer. Moreover, targeting HSPs (notably HSP27, HSP70 and HSP90) exhibited positive results in clinical trials so far. However, more studies should be designed to optimize the efficacy of mono or combination therapy in various malignancies. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

The UPR reduces glucose metabolism via IRE1 signaling.

PubMed

van der Harg, Judith M; van Heest, Jessica C; Bangel, Fabian N; Patiwael, Sanne; van Weering, Jan R T; Scheper, Wiep

2017-04-01

Neurons are highly dependent on glucose. A disturbance in glucose homeostasis therefore poses a severe risk that is counteracted by activation of stress responses to limit damage and restore the energy balance. A major stress response that is activated under conditions of glucose deprivation is the unfolded protein response (UPR) that is aimed to restore proteostasis in the endoplasmic reticulum. The key signaling of the UPR involves the transient activation of a transcriptional program and an overall reduction of protein synthesis. Since the UPR is strategically positioned to sense and integrate metabolic stress signals, it is likely that - apart from its adaptive response to restore proteostasis - it also directly affects metabolic pathways. Here we investigate the direct role of the UPR in glucose homeostasis. O-GlcNAc is a post-translational modification that is highly responsive to glucose fluctuations. We find that UPR activation results in decreased O-GlcNAc modification, in line with reduced glucose metabolism. Our data indicate that UPR activation has no direct impact on the upstream processes in glucose metabolism; glucose transporter expression, glucose uptake and hexokinase activity. In contrast, prolonged UPR activation decreases glycolysis and mitochondrial metabolism. Decreased mitochondrial respiration is not accompanied by apoptosis or a structural change in mitochondria indicating that the reduction in metabolic rate upon UPR activation is a physiological non-apoptotic response. Metabolic decrease is prevented if the IRE1 pathway of the UPR is inhibited. This indicates that activation of IRE1 signaling induces a reduction in glucose metabolism, as part of an adaptive response. Copyright © 2017 Elsevier B.V. All rights reserved.

The Role of the Multifunctional BAG3 Protein in Cellular Protein Quality Control and in Disease

PubMed Central

Stürner, Elisabeth; Behl, Christian

2017-01-01

In neurons, but also in all other cells the complex proteostasis network is monitored and tightly regulated by the cellular protein quality control (PQC) system. Beyond folding of newly synthesized polypeptides and their refolding upon misfolding the PQC also manages the disposal of aberrant proteins either by the ubiquitin-proteasome machinery or by the autophagic-lysosomal system. Aggregated proteins are primarily degraded by a process termed selective macroautophagy (or aggrephagy). One such recently discovered selective macroautophagy pathway is mediated by the multifunctional HSP70 co-chaperone BAG3 (BCL-2-associated athanogene 3). Under acute stress and during cellular aging, BAG3 in concert with the molecular chaperones HSP70 and HSPB8 as well as the ubiquitin receptor p62/SQSTM1 specifically targets aggregation-prone proteins to autophagic degradation. Thereby, BAG3-mediated selective macroautophagy represents a pivotal adaptive safeguarding and emergency system of the PQC which is activated under pathophysiological conditions to ensure cellular proteostasis. Interestingly, BAG3-mediated selective macroautophagy is also involved in the clearance of aggregated proteins associated with age-related neurodegenerative disorders, like Alzheimer’s disease (tau-protein), Huntington’s disease (mutated huntingtin/polyQ proteins), and amyotrophic lateral sclerosis (mutated SOD1). In addition, based on its initial description BAG3 is an anti-apoptotic protein that plays a decisive role in other widespread diseases, including cancer and myopathies. Therefore, in the search for novel therapeutic intervention avenues in neurodegeneration, myopathies and cancer BAG3 is a promising candidate. PMID:28680391

Proteostasis and REDOX state in the heart.

PubMed

Christians, Elisabeth S; Benjamin, Ivor J

2012-01-01

Force-generating contractile cells of the myocardium must achieve and maintain their primary function as an efficient mechanical pump over the life span of the organism. Because only half of the cardiomyocytes can be replaced during the entire human life span, the maintenance strategy elicited by cardiac cells relies on uninterrupted renewal of their components, including proteins whose specialized functions constitute this complex and sophisticated contractile apparatus. Thus cardiac proteins are continuously synthesized and degraded to ensure proteome homeostasis, also termed "proteostasis." Once synthesized, proteins undergo additional folding, posttranslational modifications, and trafficking and/or become involved in protein-protein or protein-DNA interactions to exert their functions. This includes key transient interactions of cardiac proteins with molecular chaperones, which assist with quality control at multiple levels to prevent misfolding or to facilitate degradation. Importantly, cardiac proteome maintenance depends on the cellular environment and, in particular, the reduction-oxidation (REDOX) state, which is significantly different among cardiac organelles (e.g., mitochondria and endoplasmic reticulum). Taking into account the high metabolic activity for oxygen consumption and ATP production by mitochondria, it is a challenge for cardiac cells to maintain the REDOX state while preventing either excessive oxidative or reductive stress. A perturbed REDOX environment can affect protein handling and conformation (e.g., disulfide bonds), disrupt key structure-function relationships, and trigger a pathogenic cascade of protein aggregation, decreased cell survival, and increased organ dysfunction. This review covers current knowledge regarding the general domain of REDOX state and protein folding, specifically in cardiomyocytes under normal-healthy conditions and during disease states associated with morbidity and mortality in humans.

Long noncoding RNAs(lncRNAs) and the molecular hallmarks of aging.

PubMed

Grammatikakis, Ioannis; Panda, Amaresh C; Abdelmohsen, Kotb; Gorospe, Myriam

2014-12-01

During aging, progressive deleterious changes increase the risk of disease and death. Prominent molecular hallmarks of aging are genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, cellular senescence, stem cell exhaustion, and altered intercellular communication. Long noncoding RNAs (lncRNAs) play important roles in a wide range of biological processes, including age-related diseases like cancer, cardiovascular pathologies, and neurodegenerative disorders. Evidence is emerging that lncRNAs influence the molecular processes that underlie age-associated phenotypes. Here, we review our current understanding of lncRNAs that control the development of aging traits.

MicroRNAs meet calcium: joint venture in ER proteostasis.

PubMed

Finger, Fabian; Hoppe, Thorsten

2014-11-04

The endoplasmic reticulum (ER) is a cellular compartment that has a key function in protein translation and folding. Maintaining its integrity is of fundamental importance for organism's physiology and viability. The dynamic regulation of intraluminal ER Ca(2+) concentration directly influences the activity of ER-resident chaperones and stress response pathways that balance protein load and folding capacity. We review the emerging evidence that microRNAs play important roles in adjusting these processes to frequently changing intracellular and environmental conditions to modify ER Ca(2+) handling and storage and maintain ER homeostasis. Copyright © 2014, American Association for the Advancement of Science.

The search for anti-aging interventions: From elixirs to fasting regimens

PubMed Central

de Cabo, Rafael; Carmona-Gutierrez, Didac; Bernier, Michel; Hall, Michael N.; Madeo, Frank

2014-01-01

The phenomenon of aging is an intrinsic feature of life. Accordingly, the possibility to manipulate it has fascinated humans likely since time immemorial. Recent evidence is shaping a picture where low caloric regimes and exercise may improve healthy senescence, and several pharmacological strategies have been suggested to counteract aging. Surprisingly, the most effective interventions proposed to date converge on only a few cellular processes, in particular nutrient signaling, mitochondrial efficiency, proteostasis, and autophagy. Here, we critically examine drugs and behaviors to which life- or healthspan-extending properties have been ascribed and discuss the underlying molecular mechanisms. PMID:24949965

Long noncoding RNAs (lncRNAs) and the molecular hallmarks of aging

PubMed Central

Abdelmohsen, Kotb; Gorospe, Myriam

2014-01-01

During aging, progressive deleterious changes increase the risk of disease and death. Prominent molecular hallmarks of aging are genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, cellular senescence, stem cell exhaustion, and altered intercellular communication. Long noncoding RNAs (lncRNAs) play important roles in a wide range of biological processes, including age-related diseases like cancer, cardiovascular pathologies, and neurodegenerative disorders. Evidence is emerging that lncRNAs influence the molecular processes that underlie age-associated phenotypes. Here, we review our current understanding of lncRNAs that control the development of aging traits. PMID:25543668

Lead discovery and chemical biology approaches targeting the ubiquitin proteasome system.

PubMed

Akinjiyan, Favour A; Carbonneau, Seth; Ross, Nathan T

2017-10-15

Protein degradation is critical for proteostasis, and the addition of polyubiquitin chains to a substrate is necessary for its recognition by the 26S proteasome. Therapeutic intervention in the ubiquitin proteasome system has implications ranging from cancer to neurodegeneration. Novel screening methods and chemical biology tools for targeting E1-activating, E2-conjugating and deubiquitinating enzymes will be discussed in this review. Approaches for targeting E3 ligase-substrate interactions as well as the proteasome will also be covered, with a focus on recently described approaches. Copyright © 2017. Published by Elsevier Ltd.

Interrelation of creep and relaxation: a modeling approach for ligaments.

PubMed

Lakes, R S; Vanderby, R

1999-12-01

Experimental data (Thornton et al., 1997) show that relaxation proceeds more rapidly (a greater slope on a log-log scale) than creep in ligament, a fact not explained by linear viscoelasticity. An interrelation between creep and relaxation is therefore developed for ligaments based on a single-integral nonlinear superposition model. This interrelation differs from the convolution relation obtained by Laplace transforms for linear materials. We demonstrate via continuum concepts of nonlinear viscoelasticity that such a difference in rate between creep and relaxation phenomenologically occurs when the nonlinearity is of a strain-stiffening type, i.e., the stress-strain curve is concave up as observed in ligament. We also show that it is inconsistent to assume a Fung-type constitutive law (Fung, 1972) for both creep and relaxation. Using the published data of Thornton et al. (1997), the nonlinear interrelation developed herein predicts creep behavior from relaxation data well (R > or = 0.998). Although data are limited and the causal mechanisms associated with viscoelastic tissue behavior are complex, continuum concepts demonstrated here appear capable of interrelating creep and relaxation with fidelity.

Measuring change in relating and interrelating during the early stages of psychotherapy: Comparison with a nonpatients' sample.

PubMed

Kalaitzaki, Argyroula E; Birtchnell, John; Hammond, Sean

2016-01-01

The study examined whether the relative short time period of two months of individual psychotherapy improved patients' psychiatric symptoms, their negative relating (i.e., destructive and undesirable interpersonal attitudes and behavior to others) and their negative interrelating (i.e., destructive and undesirable relationship with their partners). A sample of 60 outpatients, reportedly suffering mainly from a mood or anxiety disorder, were compared with a sample of 48 nonpatients and their partners, over a comparable time span. It was shown that the patients' psychopathology scores dropped significantly. Significant changes in some relating and interrelating scores also occurred, even though the therapy had not specifically addressed these issues. Unexpectedly, the partners demonstrated some degree of deterioration both in their relating and their interrelating scores.

Sympathy and Personal Distress: Development, Gender Differences, and Interrelations of Indexes.

ERIC Educational Resources Information Center

Eisenberg, Nancy; And Others

1989-01-01

Investigates developmental change and gender differences in sympathy and personal distress reactions in children. Examines interrelations among indexes used to assess sympathy and personal distress. (PCB)

Endoplasmic Reticulum Stress Is Associated With Autophagy and Cardiomyocyte Remodeling in Experimental and Human Atrial Fibrillation.

PubMed

Wiersma, Marit; Meijering, Roelien A M; Qi, Xiao-Yan; Zhang, Deli; Liu, Tao; Hoogstra-Berends, Femke; Sibon, Ody C M; Henning, Robert H; Nattel, Stanley; Brundel, Bianca J J M

2017-10-24

Derailment of proteostasis, the homeostasis of production, function, and breakdown of proteins, contributes importantly to the self-perpetuating nature of atrial fibrillation (AF), the most common heart rhythm disorder in humans. Autophagy plays an important role in proteostasis by degrading aberrant proteins and organelles. Herein, we investigated the role of autophagy and its activation pathway in experimental and clinical AF. Tachypacing of HL-1 atrial cardiomyocytes causes a gradual and significant activation of autophagy, as evidenced by enhanced LC3B-II expression, autophagic flux and autophagosome formation, and degradation of p62, resulting in reduction of Ca 2+ amplitude. Autophagy is activated downstream of endoplasmic reticulum (ER) stress: blocking ER stress by the chemical chaperone 4-phenyl butyrate, overexpression of the ER chaperone-protein heat shock protein A5, or overexpression of a phosphorylation-blocked mutant of eukaryotic initiation factor 2α (eIF2α) prevents autophagy activation and Ca 2+ -transient loss in tachypaced HL-1 cardiomyocytes. Moreover, pharmacological inhibition of ER stress in tachypaced Drosophila confirms its role in derailing cardiomyocyte function. In vivo treatment with sodium salt of phenyl butyrate protected atrial-tachypaced dog cardiomyocytes from electrical remodeling (action potential duration shortening, L-type Ca 2+ -current reduction), cellular Ca 2+ -handling/contractile dysfunction, and ER stress and autophagy; it also attenuated AF progression. Finally, atrial tissue from patients with persistent AF reveals activation of autophagy and induction of ER stress, which correlates with markers of cardiomyocyte damage. These results identify ER stress-associated autophagy as an important pathway in AF progression and demonstrate the potential therapeutic action of the ER-stress inhibitor 4-phenyl butyrate. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Metabolic Turnover of Synaptic Proteins: Kinetics, Interdependencies and Implications for Synaptic Maintenance

PubMed Central

Cohen, Laurie D.; Zuchman, Rina; Sorokina, Oksana; Müller, Anke; Dieterich, Daniela C.; Armstrong, J. Douglas; Ziv, Tamar; Ziv, Noam E.

2013-01-01

Chemical synapses contain multitudes of proteins, which in common with all proteins, have finite lifetimes and therefore need to be continuously replaced. Given the huge numbers of synaptic connections typical neurons form, the demand to maintain the protein contents of these connections might be expected to place considerable metabolic demands on each neuron. Moreover, synaptic proteostasis might differ according to distance from global protein synthesis sites, the availability of distributed protein synthesis facilities, trafficking rates and synaptic protein dynamics. To date, the turnover kinetics of synaptic proteins have not been studied or analyzed systematically, and thus metabolic demands or the aforementioned relationships remain largely unknown. In the current study we used dynamic Stable Isotope Labeling with Amino acids in Cell culture (SILAC), mass spectrometry (MS), Fluorescent Non–Canonical Amino acid Tagging (FUNCAT), quantitative immunohistochemistry and bioinformatics to systematically measure the metabolic half-lives of hundreds of synaptic proteins, examine how these depend on their pre/postsynaptic affiliation or their association with particular molecular complexes, and assess the metabolic load of synaptic proteostasis. We found that nearly all synaptic proteins identified here exhibited half-lifetimes in the range of 2–5 days. Unexpectedly, metabolic turnover rates were not significantly different for presynaptic and postsynaptic proteins, or for proteins for which mRNAs are consistently found in dendrites. Some functionally or structurally related proteins exhibited very similar turnover rates, indicating that their biogenesis and degradation might be coupled, a possibility further supported by bioinformatics-based analyses. The relatively low turnover rates measured here (∼0.7% of synaptic protein content per hour) are in good agreement with imaging-based studies of synaptic protein trafficking, yet indicate that the metabolic load synaptic protein turnover places on individual neurons is very substantial. PMID:23658807

Global Data Spatially Interrelate System for Scientific Big Data Spatial-Seamless Sharing

NASA Astrophysics Data System (ADS)

Yu, J.; Wu, L.; Yang, Y.; Lei, X.; He, W.

2014-04-01

A good data sharing system with spatial-seamless services will prevent the scientists from tedious, boring, and time consuming work of spatial transformation, and hence encourage the usage of the scientific data, and increase the scientific innovation. Having been adopted as the framework of Earth datasets by Group on Earth Observation (GEO), Earth System Spatial Grid (ESSG) is potential to be the spatial reference of the Earth datasets. Based on the implementation of ESSG, SDOG-ESSG, a data sharing system named global data spatially interrelate system (GASE) was design to make the data sharing spatial-seamless. The architecture of GASE was introduced. The implementation of the two key components, V-Pools, and interrelating engine, and the prototype is presented. Any dataset is firstly resampled into SDOG-ESSG, and is divided into small blocks, and then are mapped into hierarchical system of the distributed file system in V-Pools, which together makes the data serving at a uniform spatial reference and at a high efficiency. Besides, the datasets from different data centres are interrelated by the interrelating engine at the uniform spatial reference of SDOGESSG, which enables the system to sharing the open datasets in the internet spatial-seamless.

Magnetic Evolution Linked to the Interrelated Activity Complexes Involving Transequatorial Coronal Holes

NASA Astrophysics Data System (ADS)

Gutiérrez, Heidy; Taliashvili, Lela; Lazarian, Alexandre

2018-06-01

We studied a magnetic evolution linked to a cadence of interrelated activities developed in a large solar region during Carrington rotations, CRs 2119 - 2121, based on multi-wavelength and multi-spacecraft observations. Three coronal holes (CHs), two transequatorial and one isolated, eight filaments and some active regions were distributed closely in the region. Every of these filaments partial and/or complete eruption was linked to a Coronal Mass Ejection (CME) or coronal jet. We found different types of interrelated activities: eruptions of three pairs of interrelated filaments close to a CH and eruptions of two filaments close to the active region and CH. Some indicators of the magnetic reconnection were observed frequently during the pre- as well as post-filament eruptions. Additionally, post-filament eruption and/or post-CME processes show their implication in the evolution of nearby CHs and newly formed transient CHs or dimming regions, including a new CH formation. We discussed the small- and large-scale magnetic reconfigurations associated with these interrelated activity complexes, the ones involving long-lived transequatorial CHs, and their possible implication in the evolution of the global solar magnetic field, especially with the starting processes of quadruple configuration and polarity reversal of the solar cycle 24.

Spousal interrelations in happiness in the Seattle Longitudinal Study: considerable similarities in levels and change over time.

PubMed

Hoppmann, Christiane A; Gerstorf, Denis; Willis, Sherry L; Schaie, K Warner

2011-01-01

Development does not take place in isolation and is often interrelated with close others such as marital partners. To examine interrelations in spousal happiness across midlife and old age, we used 35-year longitudinal data from both members of 178 married couples in the Seattle Longitudinal Study. Latent growth curve models revealed sizeable spousal similarities not only in levels of happiness but also in how happiness changed over time. These spousal interrelations were considerably larger in size than those found among random pairs of women and men from the same sample. Results are in line with life-span theories emphasizing an interactive minds perspective by showing that adult happiness waxes and wanes in close association with the respective spouse. Our findings also complement previous individual-level work on age-related changes in well-being by pointing to the importance of using the couple as the unit of analysis.

The search for antiaging interventions: from elixirs to fasting regimens.

PubMed

de Cabo, Rafael; Carmona-Gutierrez, Didac; Bernier, Michel; Hall, Michael N; Madeo, Frank

2014-06-19

The phenomenon of aging is an intrinsic feature of life. Accordingly, the possibility to manipulate it has fascinated humans likely since time immemorial. Recent evidence is shaping a picture where low caloric regimes and exercise may improve healthy senescence, and several pharmacological strategies have been suggested to counteract aging. Surprisingly, the most effective interventions proposed to date converge on only a few cellular processes, in particular nutrient signaling, mitochondrial efficiency, proteostasis, and autophagy. Here, we critically examine drugs and behaviors to which life- or healthspan-extending properties have been ascribed and discuss the underlying molecular mechanisms. Copyright © 2014 Elsevier Inc. All rights reserved.

An Air Quality Data Analysis System for Interrelating Effects, Standards and Needed Source Reductions

ERIC Educational Resources Information Center

Larsen, Ralph I.

1973-01-01

Makes recommendations for a single air quality data system (using average time) for interrelating air pollution effects, air quality standards, air quality monitoring, diffusion calculations, source-reduction calculations, and emission standards. (JR)

Enhancing Elementary Pre-Service Teachers' Plant Processes Conceptions

ERIC Educational Resources Information Center

Thompson, Stephen L.; Lotter, Christine; Fann, Xumei; Taylor, Laurie

2016-01-01

Researchers examined how an inquiry-based instructional treatment emphasizing interrelated plant processes influenced 210 elementary pre-service teachers' (PTs) conceptions of three plant processes, photosynthesis, cellular respiration, and transpiration, and the interrelated nature of these processes. The instructional treatment required PTs to…

Intersection Syndrome: The Subtle Squeak of an Overused Wrist.

PubMed

Skinner, Thomas M

2017-01-01

Patient histories that include wrist pain can be pivotal in the distinction between intersection syndrome (IS) and the more common de Quervain's tenosynovitis (DQT). Presented here is a 26-year-old pregnant woman with a history of rowing who developed left radial/dorsal wrist pain and a rubbing/squeaking sensation. Nine months of conservative DQT therapy and a landmark-guided corticosteroid injection failed to relieve her symptoms. An in-clinic ultrasound showed tenosynovitis at the intersection of the first and second compartments, confirming a diagnosis of IS. She found immediate relief with ultrasound-guided saline hydrodissection, the injection of saline into the intercompartmental space to reduce adhesions. Both DQT and IS are overuse injuries caused by repetitive wrist extension, as occurs in rowing, and either condition can worsen after pregnancy. Distinguishing the subtleties between DQT and IS can be challenging. Close attention to the patient's description of the pain can guide treatment, potentially expediting recovery. In addition, saline hydrodissection can be both a diagnostic tool and a potentially therapeutic alternative to steroid injections for such tendinopathies. © Copyright 2017 by the American Board of Family Medicine.

Fluid shifts and endocrine responses during chair rest and water immersion in man

NASA Technical Reports Server (NTRS)

Greenleaf, J. E.; Shvartz, E.; Kravik, S.; Keil, L. C.

1980-01-01

The effects of external water pressure on intercompartmental fluid volume shifts and endocrine responses in man are investigated. Extracellular fluid volumes and plasma and urine electrolyte and endocrine responses of four male subjects were measured during eight hours of head-out water immersion and 16 hours of recovery bed rest and compared to responses obtained during eight hours of chair rest and 16 hours of bed rest without external hydrostatic pressure obtained in the same subjects five months later. Immersion is found to result in a substantial diuresis with respect to chair rest, accounted for by decreases in extracellular volume. A negative water balance during immersion and a positive water balance during chair rest were observed to be accompanied by a shift of extracellular volume to the intracellular compartment, as well as the suppression of plasma arginine vasopressin and renin activities in both regimes. The vasopressin and renin activity decreases are attributed to the increased central blood volume, and half of the plasma loss in immersed subjects is attributed to the effects of external water pressure.

Mathematics Used in Occupations: An Interrelated Guide.

ERIC Educational Resources Information Center

Minneapolis Public Schools, Minn. Dept. of Vocational Technical Education.

Intended for use by counselors and mathematics teachers, this guide brings together mathematical and occupational skills to form an interrelated curriculum. Eight occupational clusters are included as follow: (1) business and office, (2) communications, (3) construction, (4) hospitality, (5) manufacturing, (6) marketing and distribution, (7)…

Interrelated striated elements in vestibular hair cells of the rat

NASA Technical Reports Server (NTRS)

Ross, M. D.; Bourne, C.

1983-01-01

A series of interrelated striated organelles in types I and II vestibular hair cells of the rat which appear to be less developed in cochlear hair cells have been revealed by unusual fixation procedures, suggesting that contractile elements may play a role in sensory transduction in the inner ear, especially in the vestibular system. Included in the series of interrelated striated elements are the cuticular plate and its basal attachments to the hair cell margins, the connections of the strut array of the kinociliary basal body to the cuticular plate, and striated organelles associated with the plasma membrane and extending below the apical junctional complexes.

The Interrelations between Competences for Sustainable Development and Research Competences

ERIC Educational Resources Information Center

Lambrechts, Wim; Van Petegem, Peter

2016-01-01

Purpose: The purpose of this paper is to explore how competences for sustainable development and research interrelate within a context of competence-based higher education. Specific focus is oriented towards strengthening research competences for sustainability. Design/methodology/approach: Following a hermeneutic-interpretive methodology, this…

Therapeutic approaches against common structural features of toxic oligomers shared by multiple amyloidogenic proteins.

PubMed

Guerrero-Muñoz, Marcos J; Castillo-Carranza, Diana L; Kayed, Rakez

2014-04-15

Impaired proteostasis is one of the main features of all amyloid diseases, which are associated with the formation of insoluble aggregates from amyloidogenic proteins. The aggregation process can be caused by overproduction or poor clearance of these proteins. However, numerous reports suggest that amyloid oligomers are the most toxic species, rather than insoluble fibrillar material, in Alzheimer's, Parkinson's, and Prion diseases, among others. Although the exact protein that aggregates varies between amyloid disorders, they all share common structural features that can be used as therapeutic targets. In this review, we focus on therapeutic approaches against shared features of toxic oligomeric structures and future directions. Copyright © 2014 Elsevier Inc. All rights reserved.

ER stress signaling and neurodegeneration: At the intersection between Alzheimer's disease and Prion-related disorders.

PubMed

Torres, Mauricio; Matamala, José Manuel; Duran-Aniotz, Claudia; Cornejo, Victor Hugo; Foley, Andrew; Hetz, Claudio

2015-09-02

Alzheimer's and Prion diseases are two neurodegenerative conditions sharing different pathophysiological characteristics. Disease symptoms are associated with the abnormal accumulation of protein aggregates, which are generated by the misfolding and oligomerization of specific proteins. Recent functional studies uncovered a key role of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in the occurrence of synaptic dysfunction and neurodegeneration in Prion-related disorders and Alzheimer's disease. Here we review common pathological features of both diseases, emphasizing the link between amyloid formation, its pathogenesis and alterations in ER proteostasis. The potential benefits of targeting the UPR as a therapeutic strategy is also discussed. Copyright © 2014 Elsevier B.V. All rights reserved.

P97/CDC-48: proteostasis control in tumor cell biology.

PubMed

Fessart, Delphine; Marza, Esther; Taouji, Saïd; Delom, Frédéric; Chevet, Eric

2013-08-28

P97/CDC-48 is a prominent member of a highly evolutionary conserved Walker cassette - containing AAA+ATPases. It has been involved in numerous cellular processes ranging from the control of protein homeostasis to membrane trafficking through the intervention of specific accessory proteins. Expression of p97/CDC-48 in cancers has been correlated with tumor aggressiveness and prognosis, however the precise underlying molecular mechanisms remain to be characterized. Moreover p97/CDC-48 inhibitors were developed and are currently under intense investigation as anticancer drugs. Herein, we discuss the role of p97/CDC-48 in cancer development and its therapeutic potential in tumor cell biology. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Interrelations between Self-Efficacy and Learning Approaches: A Developmental Approach

ERIC Educational Resources Information Center

Phan, Huy Phuong

2011-01-01

Two major theoretical frameworks in educational psychology, namely student approaches to learning (SAL) and self-efficacy have been used extensively to explain and predict students' learning and academic achievement. There is a substantial body of research studies, for example, that documents the positive interrelations between individuals'…

Dexmedetomidine Pharmacology in Neonates and Infants After Open Heart Surgery.

PubMed

Su, Felice; Gastonguay, Marc R; Nicolson, Susan C; DiLiberto, MaryAnn; Ocampo-Pelland, Alanna; Zuppa, Athena F

2016-05-01

Dexmedetomidine is a highly selective α2-agonist with hypnotic, analgesic, and anxiolytic properties. Despite off-label administration, dexmedetomidine has found a niche in critically ill neonates and infants with congenital heart disease because of its minimal effects on respiratory function at sedative doses, facilitating early extubation and fast-track postoperative care. There are little pharmacokinetic data regarding newborns who have immature drug metabolizing capacity and who are at risk for reduced dexmedetomidine clearance and drug toxicity. The aim of this study was to determine the pharmacokinetics of dexmedetomidine in neonates and infants after open heart surgery. This study included 23 evaluable neonates (age, 1 day-1 month) and 36 evaluable infants (age, 1 month-24 months) after open heart surgery. Full-term neonates and infants requiring mechanical ventilation after open heart surgery received dexmedetomidine in a dose-escalation study. Dexmedetomidine was administered as a loading dose over 10 minutes followed by a continuous IV infusion up to 24 hours. Cohorts of 12 infants were enrolled sequentially to receive 0.35, 0.7, or 1 μg/kg dexmedetomidine followed by 0.25, 0.5, or 0.75 μg/kg/h dexmedetomidine, respectively. Cohorts of 9 neonates received 0.25, 0.35, or 0.5 μg/kg dexmedetomidine followed by 0.2, 0.3, or 0.4 μg/kg/h dexmedetomidine, respectively. Plasma dexmedetomidine concentrations were determined using a validated high-performance liquid chromatography-tandem mass spectrometry assay. A population nonlinear mixed effects modeling approach was used to characterize dexmedetomidine pharmacokinetics. Pharmacokinetic parameters of dexmedetomidine were estimated using a 2-compartment disposition model with weight allometrically scaled as a covariate on drug clearance, intercompartmental clearance, central and peripheral volume of distributions and age, total bypass time, and intracardiac shunting on clearance. Dexmedetomidine demonstrated a plasma drug clearance of 657 × (weight/70) mL/min, intercompartmental clearance of 6780 × (weight/70) mL/min, central volume of distribution of 88 × (weight/70) L and peripheral volume of distribution of 112 × (weight/70) L for a typical subject with age >1 month with a cardiopulmonary bypass time of 60 minutes and without right-to-left intracardiac shunt. Dexmedetomidine pharmacokinetics may be influenced by age during the neonatal period, weight, total bypass time, and presence of intracardiac shunt. Dexmedetomidine clearance is significantly diminished in full-term newborns and increases rapidly in the first few weeks of life. The dependence of clearance on age during the first few weeks of life reflects the relative immaturity of metabolic processes during the newborn period. Continuous infusions of up to 0.3 μg/kg/h in neonates and 0.75 μg/kg/h in infants were well tolerated after open heart surgery.

Examining the Interrelations among Knowledge, Interests, and Learning Strategies

ERIC Educational Resources Information Center

Shen, Bo; Chen, Ang

2006-01-01

Guided by the Model of Domain Learning (MDL), the study was designed to explore the extent of interrelations among prior knowledge, learning strategies, interests, physical engagement, and learning outcomes in a sixth-grade (N = 91) volleyball unit. Pearson product-moment correlations and a path analysis were conducted for the research purpose.…

Interrelations between Policymakers' Intentions and School Agents' Interpretation of Accountability Policy in Israel

ERIC Educational Resources Information Center

Amdur, Lisa; Mero-Jaffe, Irit

2017-01-01

The study examined the interrelations between policymakers' intentions for test-based accountability policy and school agents' perceptions and actions with regard to this policy. Mixed methods were used and encompassed 24 policymakers, 80 school principals, 168 teachers and case studies of four schools. New institutional theory, including the…

Interrelations of Down Syndrome and Alzheimer Disease. ARC Facts.

ERIC Educational Resources Information Center

Schweber, Miriam

This fact sheet summarizes the interrelations of Down syndrome and Alzheimer disease in a question and answer format. The following questions are addressed: What is Alzheimer disease? Why is a relationship suggested between Down syndrome and Alzheimer disease? Is there a genetic link between Alzheimer disease and Down syndrome? Why is a…

Focusing on the Complexity of Emotion Issues in Academic Learning: A Dynamical Component Systems Approach

ERIC Educational Resources Information Center

Eynde, Peter Op 't; Turner, Jeannine E.

2006-01-01

Understanding the interrelations among students' cognitive, emotional, motivational, and volitional processes is an emergening focus in educational psychology. A dynamical, component systems theory of emotions is presented as a promising framework to further unravel these complex interrelations. This framework considers emotions to be a process…

Remodeling of the malaria parasite and host human red cell by vesicle amplification that induces artemisinin resistance

PubMed Central

Coppens, Isabelle; Mbengue, Alassane; Suresh, Niraja; Ghorbal, Mehdi; Slouka, Zdenek; Safeukui, Innocent; Tang, Hsin-Yao; Speicher, David W.; Stahelin, Robert V.; Mohandas, Narla

2018-01-01

Artemisinin resistance threatens worldwide malaria control and elimination. Elevation of phosphatidylinositol-3-phosphate (PI3P) can induce resistance in blood stages of Plasmodium falciparum. The parasite unfolded protein response (UPR) has also been implicated as a proteostatic mechanism that may diminish artemisinin-induced toxic proteopathy. How PI3P acts and its connection to the UPR remain unknown, although both are conferred by mutation in P falciparum Kelch13 (K13), the marker of artemisinin resistance. Here we used cryoimmunoelectron microscopy to show that K13 concentrates at PI3P tubules/vesicles of the parasite’s endoplasmic reticulum (ER) in infected red cells. K13 colocalizes and copurifies with the major virulence adhesin PfEMP1. The PfEMP1-K13 proteome is comprehensively enriched in multiple proteostasis systems of protein export, quality control, and folding in the ER and cytoplasm and UPR. Synthetic elevation of PI3P that induces resistance in absence of K13 mutation also yields signatures of proteostasis and clinical resistance. These findings imply a key role for PI3P-vesicle amplification as a mechanism of resistance of infected red cells. As validation, the major resistance mutation K13C580Y quantitatively increased PI3P tubules/vesicles, exporting them throughout the parasite and the red cell. Chemical inhibitors and fluorescence microscopy showed that alterations in PfEMP1 export to the red cell and cytoadherence of infected cells to a host endothelial receptor are features of multiple K13 mutants. Together these data suggest that amplified PI3P vesicles disseminate widespread proteostatic capacity that may neutralize artemisinins toxic proteopathy and implicate a role for the host red cell in artemisinin resistance. The mechanistic insights generated will have an impact on malaria drug development. PMID:29363540

Sulforaphane synergistically enhances the cytotoxicity of arsenic trioxide in multiple myeloma cells via stress-mediated pathways

PubMed Central

DOUDICAN, NICOLE A.; WEN, SHIH YA; MAZUMDER, AMITABHA; ORLOW, SETH J.

2012-01-01

Persistent paraprotein production in plasma cells necessitates a highly developed rough endoplasmic reticulum (ER) that is unusually susceptible to perturbations in protein synthesis. This biology is believed to account for the exquisite sensitivity of multiple myeloma (MM) to the proteasomal inhibitor bortezomib (BTZ). Despite remarkable response rates to BTZ in MM, BTZ carries the potential for serious side-effects and development of resistance. We, therefore, sought to identify therapeutic combinations that effectively disrupt proteostasis in order to provide new potential treatments for MM. We found that sulforaphane, a dietary isothiocyanate found in cruciferous vegetables, inhibits TNFα-induced Iκβ proteasomal degradation in a manner similar to BTZ. Like BTZ, sulforaphane synergistically enhances the cytotoxicity of arsenic trioxide (ATO), an agent with clinical activity in MM. ATO and sulforaphane co-treatment augmented apoptotic induction as demonstrated by cleavage of caspase-3, -4 and PARP. The enhanced apoptotic response was dependent upon production of reactive oxygen species (ROS) as demonstrated by glutathione depletion and partial inhibition of the apoptotic cascade after pretreatment with the radical scavenger N-acetyl-cysteine (NAC). Combination treatment resulted in enhanced ER stress signaling and activation of the unfolded protein response (UPR), indicative of perturbation of proteostasis. Specifically, combination treatment caused elevated expression of the molecular chaperone HSP90 (heat shock protein 90) along with increased PERK (protein kinase RNA-like endoplasmic reticulum kinase) and eIF2α phosphorylation and XBP1 (X-box binding protein 1) splicing, key indicators of UPR activation. Moreover, increased splicing of XBP1 was apparent upon combination treatment compared to treatment with either agent alone. Sulforaphane in combination with ATO effectively disrupts protein homeostasis through ROS generation and induction of ER stress to culminate in inhibition of protein secretion and apoptotic induction in MM. Our results suggest that sulforaphane deserves further investigation in combination with ATO in the treatment of MM. PMID:22922937

Nuclear inclusion bodies of mutant and wild-type p53 in cancer: a hallmark of p53 inactivation and proteostasis remodelling by p53 aggregation.

PubMed

De Smet, Frederik; Saiz Rubio, Mirian; Hompes, Daphne; Naus, Evelyne; De Baets, Greet; Langenberg, Tobias; Hipp, Mark S; Houben, Bert; Claes, Filip; Charbonneau, Sarah; Delgado Blanco, Javier; Plaisance, Stephane; Ramkissoon, Shakti; Ramkissoon, Lori; Simons, Colinda; van den Brandt, Piet; Weijenberg, Matty; Van England, Manon; Lambrechts, Sandrina; Amant, Frederic; D'Hoore, André; Ligon, Keith L; Sagaert, Xavier; Schymkowitz, Joost; Rousseau, Frederic

2017-05-01

Although p53 protein aggregates have been observed in cancer cell lines and tumour tissue, their impact in cancer remains largely unknown. Here, we extensively screened for p53 aggregation phenotypes in tumour biopsies, and identified nuclear inclusion bodies (nIBs) of transcriptionally inactive mutant or wild-type p53 as the most frequent aggregation-like phenotype across six different cancer types. p53-positive nIBs co-stained with nuclear aggregation markers, and shared molecular hallmarks of nIBs commonly found in neurodegenerative disorders. In cell culture, tumour-associated stress was a strong inducer of p53 aggregation and nIB formation. This was most prominent for mutant p53, but could also be observed in wild-type p53 cell lines, for which nIB formation correlated with the loss of p53's transcriptional activity. Importantly, protein aggregation also fuelled the dysregulation of the proteostasis network in the tumour cell by inducing a hyperactivated, oncogenic heat-shock response, to which tumours are commonly addicted, and by overloading the proteasomal degradation system, an observation that was most pronounced for structurally destabilized mutant p53. Patients showing tumours with p53-positive nIBs suffered from a poor clinical outcome, similar to those with loss of p53 expression, and tumour biopsies showed a differential proteostatic expression profile associated with p53-positive nIBs. p53-positive nIBs therefore highlight a malignant state of the tumour that results from the interplay between (1) the functional inactivation of p53 through mutation and/or aggregation, and (2) microenvironmental stress, a combination that catalyses proteostatic dysregulation. This study highlights several unexpected clinical, biological and therapeutically unexplored parallels between cancer and neurodegeneration. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

The small heat shock proteins αB-crystallin (HSPB5) and Hsp27 (HSPB1) inhibit the intracellular aggregation of α-synuclein.

PubMed

Cox, Dezerae; Ecroyd, Heath

2017-07-01

Protein homeostasis, or proteostasis, is the process of maintaining the conformational and functional integrity of the proteome. Proteostasis is preserved in the face of stress by a complex network of cellular machinery, including the small heat shock molecular chaperone proteins (sHsps), which act to inhibit the aggregation and deposition of misfolded protein intermediates. Despite this, the pathogenesis of several neurodegenerative diseases has been inextricably linked with the amyloid fibrillar aggregation and deposition of α-synuclein (α-syn). The sHsps are potent inhibitors of α-syn aggregation in vitro. However, the limited availability of a robust, cell-based model of α-syn aggregation has, thus far, restricted evaluation of sHsp efficacy in the cellular context. As such, this work sought to establish a robust model of intracellular α-syn aggregation using Neuro-2a cells. Aggregation of α-syn was found to be sensitive to inhibition of autophagy and the proteasome, resulting in a significant increase in the proportion of cells containing α-syn inclusions. This model was then used to evaluate the capacity of the sHsps, αB-c and Hsp27, to prevent α-syn aggregation in cells. To do so, we used bicistronic expression plasmids to express the sHsps. Unlike traditional fluorescent fusion constructs, these bicistronic expression plasmids enable only individual transfected cells expressing the sHsps (via expression of the fluorescent reporter) to be analysed, but without the need to tag the sHsp, which can affect its oligomeric structure and chaperone activity. Overexpression of both αB-c and Hsp27 significantly reduced the intracellular aggregation of α-syn. Thus, these findings suggest that overexpressing or boosting the activity of sHsps may be a way of preventing amyloid fibrillar aggregation of α-syn in the context of neurodegenerative disease.

A Novel Pulse-Chase SILAC Strategy Measures Changes in Protein Decay and Synthesis Rates Induced by Perturbation of Proteostasis with an Hsp90 Inhibitor

PubMed Central

Fierro-Monti, Ivo; Racle, Julien; Hernandez, Celine; Waridel, Patrice; Hatzimanikatis, Vassily; Quadroni, Manfredo

2013-01-01

Standard proteomics methods allow the relative quantitation of levels of thousands of proteins in two or more samples. While such methods are invaluable for defining the variations in protein concentrations which follow the perturbation of a biological system, they do not offer information on the mechanisms underlying such changes. Expanding on previous work [1], we developed a pulse-chase (pc) variant of SILAC (stable isotope labeling by amino acids in cell culture). pcSILAC can quantitate in one experiment and for two conditions the relative levels of proteins newly synthesized in a given time as well as the relative levels of remaining preexisting proteins. We validated the method studying the drug-mediated inhibition of the Hsp90 molecular chaperone, which is known to lead to increased synthesis of stress response proteins as well as the increased decay of Hsp90 “clients”. We showed that pcSILAC can give information on changes in global cellular proteostasis induced by treatment with the inhibitor, which are normally not captured by standard relative quantitation techniques. Furthermore, we have developed a mathematical model and computational framework that uses pcSILAC data to determine degradation constants kd and synthesis rates Vs for proteins in both control and drug-treated cells. The results show that Hsp90 inhibition induced a generalized slowdown of protein synthesis and an increase in protein decay. Treatment with the inhibitor also resulted in widespread protein-specific changes in relative synthesis rates, together with variations in protein decay rates. The latter were more restricted to individual proteins or protein families than the variations in synthesis. Our results establish pcSILAC as a viable workflow for the mechanistic dissection of changes in the proteome which follow perturbations. Data are available via ProteomeXchange with identifier PXD000538. PMID:24312217

Interrelations between Executive Function and Symptoms of Hyperactivity/Impulsivity and Inattention in Preschoolers: A Two Year Longitudinal Study

ERIC Educational Resources Information Center

Brocki, Karin C.; Eninger, Lilianne; Thorell, Lisa B.; Bohlin, Gunilla

2010-01-01

The present study, including children at risk for developing Attention Deficit Hyperactivity Disorder (ADHD), examined the idea that complex executive functions (EFs) build upon more simple ones. This notion was applied in the study of longitudinal interrelations between core EF components--simple and complex inhibition, selective attention, and…

"It's the Method, Stupid." Interrelations between Methodological and Theoretical Advances: The Example of Comparing Higher Education Systems Internationally

ERIC Educational Resources Information Center

Hoelscher, Michael

2017-01-01

This article argues that strong interrelations between methodological and theoretical advances exist. Progress in, especially comparative, methods may have important impacts on theory evaluation. By using the example of the "Varieties of Capitalism" approach and an international comparison of higher education systems, it can be shown…

The Hegemonic Triumvirate--Ideologies, Discourses, and Habitus in Sport and Physical Education: Implications and Suggestions

ERIC Educational Resources Information Center

Fernandez-Balboa, Juan-Miguel; Muros, Beatriz

2006-01-01

In this paper, we introduce the concept of "the hegemonic triumvirate" (HT)--a powerful system of "reality" construction resulting from the interrelation of dominant ideologies, habitus, and discourses. Then, after analyzing HT's components and some of their interrelations within the contexts of sport and physical education (PE), we examine some…

Characterization of ZrO2-Y2O3 thermal spray powder systems

NASA Technical Reports Server (NTRS)

Mantkowski, Thomas E.; Rigney, David V.; Froning, Marc J.; Jayaraman, N.

1985-01-01

The overall objective is to establish the interrelation between the raw material in the coating process and the performance of the coating deposit. It is anticipated that these interrelations will help establish more precise specifications for the procurement of the raw materials. Some of the preliminary results of the program are presented.

Development in Multiple Areas of Life in Adolescence: Interrelations between Academic Achievement, Perceived Peer Acceptance, and Self-Esteem

ERIC Educational Resources Information Center

Tetzner, Julia; Becker, Michael; Maaz, Kai

2017-01-01

This study examined interrelations between three indicators of main challenges during adolescence: academic achievement, self-perceived peer acceptance, and self-esteem. An additional aim was to investigate whether the findings hold for girls and boys and across school types (academically oriented track vs. non-academically oriented track). We…

Re-Imagining Democratic Citizenship Education: Towards a Culture of Compassionate Responsibility

ERIC Educational Resources Information Center

Davids, Nuraan; Waghid, Yusef

2012-01-01

Benhabib (2002:134) maintains that, in order for individuals to become democratic citizens they need to be exposed to at least three inter-related elements: collective identity, privileges of membership, and social rights and benefits. Through exposure to these three inter-related items it is hoped that, by means of the teaching and learning of…

Autophagy and oxidative stress in non-communicable diseases: A matter of the inflammatory state?

PubMed

Peña-Oyarzun, Daniel; Bravo-Sagua, Roberto; Diaz-Vega, Alexis; Aleman, Larissa; Chiong, Mario; Garcia, Lorena; Bambs, Claudia; Troncoso, Rodrigo; Cifuentes, Mariana; Morselli, Eugenia; Ferreccio, Catterina; Quest, Andrew F G; Criollo, Alfredo; Lavandero, Sergio

2018-05-30

Non-communicable diseases (NCDs), also known as chronic diseases, are long-lasting conditions that affect millions of people around the world. Different factors contribute to their genesis and progression; however they share common features, which are critical for the development of novel therapeutic strategies. A persistently altered inflammatory response is typically observed in many NCDs together with redox imbalance. Additionally, dysregulated proteostasis, mainly derived as a consequence of compromised autophagy, is a common feature of several chronic diseases. In this review, we discuss the crosstalk among inflammation, autophagy and oxidative stress, and how they participate in the progression of chronic diseases such as cancer, cardiovascular diseases, obesity and type II diabetes mellitus. Copyright © 2018 Elsevier Inc. All rights reserved.

Multiple genes contribute to anhydrobiosis (tolerance to extreme desiccation) in the nematode Panagrolaimus superbus

PubMed Central

Evangelista, Cláudia Carolina Silva; Guidelli, Giovanna Vieira; Borges, Gustavo; Araujo, Thais Fenz; de Souza, Tiago Alves Jorge; Neves, Ubiraci Pereira da Costa; Tunnacliffe, Alan; Pereira, Tiago Campos

2017-01-01

Abstract The molecular basis of anhydrobiosis, the state of suspended animation entered by some species during extreme desiccation, is still poorly understood despite a number of transcriptome and proteome studies. We therefore conducted functional screening by RNA interference (RNAi) for genes involved in anhydrobiosis in the holo-anhydrobiotic nematode Panagrolaimus superbus. A new method of survival analysis, based on staining, and proof-of-principle RNAi experiments confirmed a role for genes involved in oxidative stress tolerance, while a novel medium-scale RNAi workflow identified a further 40 anhydrobiosis-associated genes, including several involved in proteostasis, DNA repair and signal transduction pathways. This suggests that multiple genes contribute to anhydrobiosis in P. superbus. PMID:29111563

Mitochondria in the spotlight of aging and idiopathic pulmonary fibrosis

PubMed Central

Mora, Ana L.; Rojas, Mauricio

2017-01-01

Idiopathic pulmonary fibrosis (IPF) is a chronic age-related lung disease with high mortality that is characterized by abnormal scarring of the lung parenchyma. There has been a recent attempt to define the age-associated changes predisposing individuals to develop IPF. Age-related perturbations that are increasingly found in epithelial cells and fibroblasts from IPF lungs compared with age-matched cells from normal lungs include defective autophagy, telomere attrition, altered proteostasis, and cell senescence. These divergent processes seem to converge in mitochondrial dysfunction and metabolic distress, which potentiate maladaptation to stress and susceptibility to age-related diseases such as IPF. Therapeutic approaches that target aging processes may be beneficial for halting the progression of disease and improving quality of life in IPF patients. PMID:28145905

Studying Interrelation of Professional Motivation and Professional Concepts of Specialists with Different Professional Orientation as a Basis for Career Building

ERIC Educational Resources Information Center

Rogova, Evgenia E.; Pankratova, Irina A.; Zholudeva, Svetlana V.; Sheveleva, Anna M.; Naumenko, Marina V.; Skrynnik, Natalya E.

2016-01-01

The article focuses on some peculiarities of interrelation of professional motivation and professional concepts of specialists with different professional orientation. The results of empirical research are revealed on the sampling of 164 specialists in the field of management who have been divided into five subgroups according to the types of…

Calculation and Word Problem-Solving Skills in Primary Grades--Impact of Cognitive Abilities and Longitudinal Interrelations with Task-persistent Behaviour

ERIC Educational Resources Information Center

Jõgi, Anna-Liisa; Kikas, Eve

2016-01-01

Background: Primary school math skills form a basis for academic success down the road. Different math skills have different antecedents and there is a reason to believe that more complex math tasks require better self-regulation. Aims: The study aimed to investigate longitudinal interrelations of calculation and problem-solving skills, and…

Identifying associations between pig pathologies using a multi-dimensional machine learning methodology.

PubMed

Sanchez-Vazquez, Manuel J; Nielen, Mirjam; Edwards, Sandra A; Gunn, George J; Lewis, Fraser I

2012-08-31

Abattoir detected pathologies are of crucial importance to both pig production and food safety. Usually, more than one pathology coexist in a pig herd although it often remains unknown how these different pathologies interrelate to each other. Identification of the associations between different pathologies may facilitate an improved understanding of their underlying biological linkage, and support the veterinarians in encouraging control strategies aimed at reducing the prevalence of not just one, but two or more conditions simultaneously. Multi-dimensional machine learning methodology was used to identify associations between ten typical pathologies in 6485 batches of slaughtered finishing pigs, assisting the comprehension of their biological association. Pathologies potentially associated with septicaemia (e.g. pericarditis, peritonitis) appear interrelated, suggesting on-going bacterial challenges by pathogens such as Haemophilus parasuis and Streptococcus suis. Furthermore, hepatic scarring appears interrelated with both milk spot livers (Ascaris suum) and bacteria-related pathologies, suggesting a potential multi-pathogen nature for this pathology. The application of novel multi-dimensional machine learning methodology provided new insights into how typical pig pathologies are potentially interrelated at batch level. The methodology presented is a powerful exploratory tool to generate hypotheses, applicable to a wide range of studies in veterinary research.

Implicit theories about interrelations of anger components in 25 countries.

PubMed

Alonso-Arbiol, Itziar; van de Vijver, Fons J R; Fernandez, Itziar; Paez, Dario; Campos, Miryam; Carrera, Pilar

2011-02-01

We were interested in the cross-cultural comparison of implicit theories of the interrelations of eight anger components (antecedents, body sensations, cognitive reactions, verbal expressions, nonverbal expressions, interpersonal responses, and primary and secondary self-control). Self-report scales of each of these components were administered to a total of 5,006 college students in 25 countries. Equivalence of the scales was supported in that scales showed acceptable congruence coefficients in almost all comparisons. A multigroup confirmatory factor model with three latent variables (labeled internal processes, behavioral outcomes, and self-control mechanisms) could well account for the interrelations of the eight observed variables; measurement and structural weights were invariant. Behavioral outcomes and self-control mechanisms were only associated through their common dependence on internal processes. Verbal expressions and cognitive reactions showed the largest cross-cultural differences in means, whereas self-control mechanisms scales showed the smallest differences. Yet, cultural differences between the countries were small. It is concluded that anger, as measured by these scales, shows more pronounced cross-cultural similarities than differences in terms of both interrelations and mean score levels. PsycINFO Database Record (c) 2011 APA, all rights reserved.

[Pedicled vascularized bone grafts from the dorsum of the distal radius for treatment of scaphoid nonunions].

PubMed

Sauerbier, Michael; Bishop, Allen T; Ofer, Nina

2009-11-01

Bony healing and reconstruction of the scaphoid with use of a reverse-flow pedicle vascularized bone graft from the dorsal aspect of the distal radius. Revitalization of the proximal fragment in case of avascular necrosis. Scaphoid nonunion, especially of the proximal pole. Nonunion after failed attempts of autogenous nonvascularized bone grafting. Avascular necrosis of the scaphoid (Preiser's disease). Avascular osteonecrosis of other carpal bones (i.e., Kienböck's disease stage II and IIIa). However, these will not be addressed in this paper. Advance carpal collapse (SNAC [scaphoid nonunion advanced collapse] wrist stage II and III). Avascular necrosis with broken proximal pole of the scaphoid. Malformation, disease or previous injury of the vascular system. Reconstruction of the scaphoid by interposition of a vascularized bone graft from the dorsum of the distal radius, where several vascularized bone grafts can be harvested, and fixation by a scaphoid screw. Management Immobilization for 6 weeks in a forearm cast including the first phalanx of the thumb. 48 scaphoid nonunions were treated with 1,2-ICSRA-based (intercompartmental supraretinacular artery) vascularized bone grafts: 34 scaphoid nonunions went on to union at an average of 15.6 weeks after surgery.

The Florence Bird Lecture: "From Strength to Strength: The Interrelated Rights of Women and Children over the Life Cycle"

ERIC Educational Resources Information Center

Pearson, Landon

2012-01-01

This article presents the author's Florence Bird lecture, which was delivered at Carleton University in Ottawa, Canada on International Women's Day, March 8, 2012. In the lecture, the author focuses on the interrelated rights of women and children over the life cycle. The author explores this linkage and offers a caveat. The author shares a…

Interrelating Selected Aspects of Home Economics and Physical Education for a Health Program in the Middle School at the Sixth Grade Level.

ERIC Educational Resources Information Center

Lamb, Virginia Malzahn

This study was conducted to develop, implement, and evaluate a 9-week unit interrelating the health aspects of home economics and physical education at the sixth grade level. The curriculum, which emphasizes physical, social, and mental health, was designed by: (1) diagnosing needs of the students, (2) formulating specific objectives, (3)…

Particular Features of Interrelation of Motivation, Values and Sense of Life's Meaning as Subjective Factors of Individualizing Trajectory in the System of Continuous Education

ERIC Educational Resources Information Center

Zavodchikov, Dmitry P.; Sharov, Anton A.; Tolstykh, Anastasia ?.; Kholopova, Ekaterina S.; Krivtsov, Artem I.

2016-01-01

The relevance of the problem under study is based on the fact that, as regards methodological and theoretical aspects, the problem of value and motivational sphere is poorly elaborated regarding the interrelation between professional education and professional activity and on the empirical level there is no clear understanding of how the sense of…

Compressing interpreted satellite imagery for geographic information systems applications over extensive regions

USGS Publications Warehouse

Miller, Stephan W.

1981-01-01

A second set of related problems deals with how this format and other representations of spatial entities, such as vector formats for point and line features, can be interrelated for manipulation, retrieval, and analysis by a spatial database management subsystem. Methods have been developed for interrelating areal data sets in the raster format with point and line data in a vector format and these are described.

A Latent Growth Curve Analysis of the Structure of Aggression, Drug Use, and Delinquent Behaviors and their Interrelations over Time in Urban and Rural Adolescents

ERIC Educational Resources Information Center

Farrell, Albert D.; Sullivan, Terri N.; Esposito, Layla E.; Meyer, Aleta L.; Valois, Robert F.

2005-01-01

Latent growth curve analysis was used to examine the structure and interrelations among aggression, drug use, and delinquent behavior during early adolescence. Five waves of data were collected from 667 students at three urban middle schools serving a predominantly African American population, and from a more ethnically diverse sample of 950…

Absence without leave or leave without absence: Examining the interrelations among mind wandering, metacognition and cognitive control.

PubMed

Drescher, Leonhard Hakon; Van den Bussche, Eva; Desender, Kobe

2018-01-01

Despite the abundance of recent publications about mind wandering (i.e., off-task thought), its interconnection with metacognition and cognitive control has not yet been examined. In the current study, we hypothesized that these three constructs would show clear interrelations. Metacognitive capacity was predicted to correlate positively with cognitive control ability, which in turn was predicted to be positively related to resistance to mind wandering during sustained attention. Moreover, it was expected that participants with good metacognitive capacity would be better at the subjective recognition of behaviorally present mind wandering. Three tasks were used: The Sustained Attention to Response Task (SART) to measure mind wandering, a perceptual decision task with confidence ratings to measure metacognitive efficiency, and a conflict task to measure cognitive control. Structural Equation Modelling was used to test the interrelations among the three constructs. As expected, metacognitive efficiency was positively related to cognitive control ability. Surprisingly, there was a negative relation between metacognitive efficiency and the degree to which subjective mind wandering reports tracked the behavioral index of mind wandering. No relation was found between cognitive control and behavioral mind wandering. The results of the current work are the first to shed light on the interrelations among these three constructs.

Absence without leave or leave without absence: Examining the interrelations among mind wandering, metacognition and cognitive control

PubMed Central

Van den Bussche, Eva; Desender, Kobe

2018-01-01

Despite the abundance of recent publications about mind wandering (i.e., off-task thought), its interconnection with metacognition and cognitive control has not yet been examined. In the current study, we hypothesized that these three constructs would show clear interrelations. Metacognitive capacity was predicted to correlate positively with cognitive control ability, which in turn was predicted to be positively related to resistance to mind wandering during sustained attention. Moreover, it was expected that participants with good metacognitive capacity would be better at the subjective recognition of behaviorally present mind wandering. Three tasks were used: The Sustained Attention to Response Task (SART) to measure mind wandering, a perceptual decision task with confidence ratings to measure metacognitive efficiency, and a conflict task to measure cognitive control. Structural Equation Modelling was used to test the interrelations among the three constructs. As expected, metacognitive efficiency was positively related to cognitive control ability. Surprisingly, there was a negative relation between metacognitive efficiency and the degree to which subjective mind wandering reports tracked the behavioral index of mind wandering. No relation was found between cognitive control and behavioral mind wandering. The results of the current work are the first to shed light on the interrelations among these three constructs. PMID:29425205

Targeting Insulin-Degrading Enzyme to Treat Type 2 Diabetes Mellitus.

PubMed

Tang, Wei-Jen

2016-01-01

Insulin-degrading enzyme (IDE) selectively degrades peptides, such as insulin, amylin, and amyloid β (Aβ) that form toxic aggregates, to maintain proteostasis. IDE defects are linked to the development of type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD). Structural and biochemical analyses revealed the molecular basis for IDE-mediated destruction of amyloidogenic peptides and this information has been exploited to develop promising inhibitors of IDE to improve glucose homeostasis. However, the inhibition of IDE can also lead to glucose intolerance. In this review, I focus on recent advances regarding our understanding of the structure and function of IDE and the discovery of IDE inhibitors, as well as challenges in developing IDE-based therapy for human diseases, particularly T2DM. Copyright © 2015 Elsevier Ltd. All rights reserved.

Ubiquilin-1 and protein quality control in Alzheimer disease.

PubMed

El Ayadi, Amina; Stieren, Emily S; Barral, José M; Boehning, Darren

2013-01-01

Single nucleotide polymorphisms in the ubiquilin-1 gene may confer risk for late-onset Alzheimer disease (AD). We have shown previously that ubiquilin-1 functions as a molecular chaperone for the amyloid precursor protein (APP) and that protein levels of ubiquilin-1 are decreased in the brains of AD patients. We have recently found that ubiquilin-1 regulates APP trafficking and subsequent secretase processing by stimulating non-degradative ubiquitination of a single lysine residue in the cytosolic domain of APP. Thus, ubiquilin-1 plays a central role in regulating APP biosynthesis, trafficking and ultimately toxicity. As ubiquilin-1 and other ubiquilin family members have now been implicated in the pathogenesis of numerous neurodegenerative diseases, these findings provide mechanistic insights into the central role of ubiquilin proteins in maintaining neuronal proteostasis.

Graphical Modeling of Shipboard Electric Power Distribution Systems

DTIC Science & Technology

1993-12-01

examined. A means of modeling a load for a synchronous generator is then shown which accurately interrelates the loading of the generator and the...frequency and voltage output of the machine. This load is then connected to the synchronous generator and two different scenarios are examined including a...examined. A means of modeling a load for a synchronous generator is then shown which accurately interrelates the loading of the generator and tht

Modeling the Dynamic Interrelations between Mobility, Utility, and Land Asking Price

NASA Astrophysics Data System (ADS)

Hidayat, E.; Rudiarto, I.; Siegert, F.; Vries, W. D.

2018-02-01

Limited and insufficient information about the dynamic interrelation among mobility, utility, and land price is the main reason to conduct this research. Several studies, with several approaches, and several variables have been conducted so far in order to model the land price. However, most of these models appear to generate primarily static land prices. Thus, a research is required to compare, design, and validate different models which calculate and/or compare the inter-relational changes of mobility, utility, and land price. The applied method is a combination of analysis of literature review, expert interview, and statistical analysis. The result is newly improved mathematical model which have been validated and is suitable for the case study location. This improved model consists of 12 appropriate variables. This model can be implemented in the Salatiga city as the case study location in order to arrange better land use planning to mitigate the uncontrolled urban growth.

Self-Efficacy and Planning as Predictors of Physical Activity in the Context of Workplace Health Promotion.

PubMed

Keller, Jan; Gellert, Paul; Knoll, Nina; Schneider, Michael; Ernsting, Anna

2016-11-01

Fostering self-efficacy and planning in individuals can support the uptake and maintenance of regular physical activity. This study examined self-efficacy and planning as mechanisms of an online-delivered workplace health promotion intervention to enhance employees' physical activity. A special focus lay on reciprocal interrelations among self-efficacy and planning over time, as previous work predominantly accounted for only one predictive direction at a time. Data from N = 1,063 employees of a pharmaceutical company who reported an intention to increase their physical activity levels were assessed at three measurement points up to 12 weeks following the intervention. Cross-lagged panel analyses were performed to examine effects of self-efficacy and planning on physical activity as well as reciprocal interrelations between self-efficacy and planning. Findings indicated an increase in self-efficacy, planning, and physical activity following the intervention. Planning was consistently linked to subsequent physical activity, whereas self-efficacy was not associated. Also, reciprocal interrelations among self-efficacy and planning were found across both measurement lags. Planning was confirmed as a predictor of physical activity, whereas self-efficacy was not. However, cross-lagged interrelations indicated reciprocal reactivation among self-efficacy and planning over time, suggesting beneficial effects of including strategies that foster both volitional constructs in interventions. © 2016 The International Association of Applied Psychology.

Dual Use Study of Systems and Software Technologies: Defence and IST Analysis Report

DTIC Science & Technology

2002-11-01

civil et de la ddfense des technologies de l’information (TI). L’analyse proposde r6duit les risques possibles de partialitd politique et industrielle et...devraient faire l’objet d’attention et de financement en R & D. La m~thode de classement des technologies de l’information se fonde sur une analyse...systems. Figure 1 illustrates a simplified overview of the interrelations between the defence and civilian use systems. These interrelations are

Ultrasonic nondestructive evaluation, microstructure, and mechanical property interrelations

NASA Technical Reports Server (NTRS)

Vary, A.

1984-01-01

Ultrasonic techniques for mechanical property characterizations are reviewed and conceptual models are advanced for explaining and interpreting the empirically based results. At present, the technology is generally empirically based and is emerging from the research laboratory. Advancement of the technology will require establishment of theoretical foundations for the experimentally observed interrelations among ultrasonic measurements, mechanical properties, and microstructure. Conceptual models are applied to ultrasonic assessment of fracture toughness to illustrate an approach for predicting correlations found among ultrasonic measurements, microstructure, and mechanical properties.

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

Costa, David A.; Cournoyer, Michael E.; Merhege, James F.

Criticality is the state of a nuclear chain reacting medium when the chain reaction is just self-sustaining (or critical). Criticality is dependent on nine interrelated parameters. Moreover, we design criticality safety controls in order to constrain these parameters to minimize fissions and maximize neutron leakage and absorption in other materials, which makes criticality more difficult or impossible to achieve. We present the consequences of criticality accidents are discussed, the nine interrelated parameters that combine to affect criticality are described, and criticality safety controls used to minimize the likelihood of a criticality accident are presented.

Heterogeneity of spontaneous DNA replication errors in single isogenic Escherichia coli cells

PubMed Central

2018-01-01

Despite extensive knowledge of the molecular mechanisms that control mutagenesis, it is not known how spontaneous mutations are produced in cells with fully operative mutation-prevention systems. By using a mutation assay that allows visualization of DNA replication errors and stress response transcriptional reporters, we examined populations of isogenic Escherichia coli cells growing under optimal conditions without exogenous stress. We found that spontaneous DNA replication errors in proliferating cells arose more frequently in subpopulations experiencing endogenous stresses, such as problems with proteostasis, genome maintenance, and reactive oxidative species production. The presence of these subpopulations of phenotypic mutators is not expected to affect the average mutation frequency or to reduce the mean population fitness in a stable environment. However, these subpopulations can contribute to overall population adaptability in fluctuating environments by serving as a reservoir of increased genetic variability.

CCPG1, a cargo receptor required for reticulophagy and endoplasmic reticulum proteostasis.

PubMed

Smith, Matthew D; Wilkinson, Simon

2018-06-19

The importance of selective macroautophagy/autophagy in cellular health is increasingly evident. The selective degradation of portions of the endoplasmic reticulum (ER), or reticulophagy, is an emerging example but requires further mechanistic detail and broad evidence of physiological relevance. In a recent study, we identified CCPG1, an ER-resident transmembrane protein that can bind to Atg8-family proteins and, independently and discretely, to RB1CC1/FIP200. Both of these interactions are required to facilitate CCPG1's function as a reticulophagy cargo receptor. CCPG1 transcripts are inducible by ER stress, providing a direct link between ER stress and reticulophagy. In vivo, CCPG1 prevents the hyper-accumulation of insoluble protein within the ER lumen of pancreatic acinar cells and alleviates ER stress. Accordingly, CCPG1 loss sensitizes the exocrine pancreas to tissue injury.

Substrate- and isoform-specific proteome stability in normal and stressed cardiac mitochondria.

PubMed

Lau, Edward; Wang, Ding; Zhang, Jun; Yu, Hongxiu; Lam, Maggie P Y; Liang, Xiangbo; Zong, Nobel; Kim, Tae-Young; Ping, Peipei

2012-04-27

Mitochondrial protein homeostasis is an essential component of the functions and oxidative stress responses of the heart. To determine the specificity and efficiency of proteome turnover of the cardiac mitochondria by endogenous and exogenous proteolytic mechanisms. Proteolytic degradation of the murine cardiac mitochondria was assessed by 2-dimensional differential gel electrophoresis and liquid chromatography-tandem mass spectrometry. Mitochondrial proteases demonstrated a substrate preference for basic protein variants, which indicates a possible recognition mechanism based on protein modifications. Endogenous mitochondrial proteases and the cytosolic 20S proteasome exhibited different substrate specificities. The cardiac mitochondrial proteome contains low amounts of proteases and is remarkably stable in isolation. Oxidative damage lowers the proteolytic capacity of cardiac mitochondria and reduces substrate availability for mitochondrial proteases. The 20S proteasome preferentially degrades specific substrates in the mitochondria and may contribute to cardiac mitochondrial proteostasis.

Age-Related Pseudocapillarization of the Liver Sinusoidal Endothelium Impairs the Hepatic Clearance of Acetaminophen in Rats

PubMed Central

Huizer-Pajkos, Aniko; Cogger, Victoria C.; McLachlan, Andrew J.; Le Couteur, David G.; Jones, Brett; de Cabo, Rafael; Hilmer, Sarah N.

2011-01-01

We investigated the effect of age-related pseudocapillarization of the liver sinusoidal endothelium on the hepatic disposition of acetaminophen. The multiple indicator dilution technique assessed the hepatic disposition of tracer 14C-acetaminophen and reference markers in isolated perfused livers of young (n = 11) and old (n = 12) rats. Electron microscopy confirmed defenestration of the sinusoidal endothelium in old rats compared with young rats. Acetaminophen recovery following a single pass through the liver was significantly increased in old rats (0.64 ± 0.04, old; 0.59 ± 0.05, young; p < .05). In old age, there was significant reduction of the intercompartmental rate constant k1 (0.34 ± 0.10s-1, old; 0.61 ± 0.38s-1, young; p < .05) and the permeability-surface area product for the transfer of acetaminophen across the sinusoidal endothelium (0.034 ± 0.006 mL/s/g, old; 0.048 ± 0.014 mL/s/g, young; p < .005). There was no difference in k3, the measure of sequestration of acetaminophen that reflects enzyme activity. Age-related pseudocapillarization of the liver sinusoid resulted in increased acetaminophen recovery and decreased transfer of acetaminophen into the liver. PMID:21300741

Regulation Mechanism of the Lateral Diffusion of Band 3 in Erythrocyte Membranes by the Membrane Skeleton

PubMed Central

Tomishige, Michio; Sako, Yasushi; Kusumi, Akihiro

1998-01-01

Mechanisms that regulate the movement of a membrane spanning protein band 3 in erythrocyte ghosts were investigated at the level of a single or small groups of molecules using single particle tracking with an enhanced time resolution (0.22 ms). Two-thirds of band 3 undergo macroscopic diffusion: a band 3 molecule is temporarily corralled in a mesh of 110 nm in diameter, and hops to an adjacent mesh an average of every 350 ms. The rest (one-third) of band 3 exhibited oscillatory motion similar to that of spectrin, suggesting that these band 3 molecules are bound to spectrin. When the membrane skeletal network was dragged and deformed/translated using optical tweezers, band 3 molecules that were undergoing hop diffusion were displaced toward the same direction as the skeleton. Mild trypsin treatment of ghosts, which cleaves off the cytoplasmic portion of band 3 without affecting spectrin, actin, and protein 4.1, increased the intercompartmental hop rate of band 3 by a factor of 6, whereas it did not change the corral size and the microscopic diffusion rate within a corral. These results indicate that the cytoplasmic portion of band 3 collides with the membrane skeleton, which causes temporal confinement of band 3 inside a mesh of the membrane skeleton. PMID:9722611

CrosstalkNet: A Visualization Tool for Differential Co-expression Networks and Communities.

PubMed

Manem, Venkata; Adam, George Alexandru; Gruosso, Tina; Gigoux, Mathieu; Bertos, Nicholas; Park, Morag; Haibe-Kains, Benjamin

2018-04-15

Variations in physiological conditions can rewire molecular interactions between biological compartments, which can yield novel insights into gain or loss of interactions specific to perturbations of interest. Networks are a promising tool to elucidate intercellular interactions, yet exploration of these large-scale networks remains a challenge due to their high dimensionality. To retrieve and mine interactions, we developed CrosstalkNet, a user friendly, web-based network visualization tool that provides a statistical framework to infer condition-specific interactions coupled with a community detection algorithm for bipartite graphs to identify significantly dense subnetworks. As a case study, we used CrosstalkNet to mine a set of 54 and 22 gene-expression profiles from breast tumor and normal samples, respectively, with epithelial and stromal compartments extracted via laser microdissection. We show how CrosstalkNet can be used to explore large-scale co-expression networks and to obtain insights into the biological processes that govern cross-talk between different tumor compartments. Significance: This web application enables researchers to mine complex networks and to decipher novel biological processes in tumor epithelial-stroma cross-talk as well as in other studies of intercompartmental interactions. Cancer Res; 78(8); 2140-3. ©2018 AACR . ©2018 American Association for Cancer Research.

Interrelations between siblings and parents in families living with children with cancer.

PubMed

Kobayashi, Kyoko; Hayakawa, Akira; Hohashi, Naohiro

2015-02-01

Having a child diagnosed with cancer is a stressful event for the family. This exploratory multimethod study utilized both quantitative and qualitative multiinformant methodologies to investigate the relationships between parental family functioning and siblings' health-related quality of life (HRQOL) and to describe interrelations between the experiences of parents and siblings of children with childhood cancer. A total of 14 Japanese families participated in the quantitative study, and 4 families of the 14 participated in the qualitative study. In-depth, semistructured interviews revealed three family-unit stages during the time course of the ill child's treatment that included particular parent-sibling interrelations. We also found strong correlation between parental family functioning and siblings' HRQOL in the quantitative study. The results suggest the importance of family nursing interventions directed to individual family members and the family unit that focus on strengthening the parent-sibling relationship and supporting families who are experiencing childhood cancer. © The Author(s) 2014.

Numerical model of the evolution of asteroid orbits at the 2:5 resonance

NASA Astrophysics Data System (ADS)

Ipatov, S. I.

1992-12-01

The interrelations of the variations in the orbital elements of asteroids at the 2:5 resonance and in its vicinity are investigated.. These investigations are based on the numerical integration of the complete equations of motion of the three-body problem (sun-Jupiter-asteroid) for 500 model asteroids. The time interval under consideration for most versions of the calculations equaled 10(4) orbital periods of Jupiter. The limits of the variations in the orbital elements and the regions of initial data corresponding to different types of interrelations of the variations in the eccentricity and longitude of perihelion are examined. It is shown that thr 2:5 gap may play a larger role than other gaps in the replenishment of the Apollo and Amor groups. The time over which the argument of perihelion changed by 360 degrees was usually equal to two periods of variation in the orbital inclination. When this interrelation was not found, the time over which the longitude of the ascending node changed by 360 degrees was equal, as a rule, to one period of variation in this inclination. For some asteroids moving along orbits of small eccentricity and inclination, interrelations were found between the periods of variation in four orbital elements: eccentricity, inclination, argument of perihelion, and longitude of the ascending node. For initial inclinations i° = 40° of asteroid orbits, the maximum values of inclinations of some model asteroids reached 160 degrees. Such asteroids could reach the sun or nearly parabolic orbits.

A Study on the Interrelations between the Security-Related Antecedents of Customers' Online Trust

NASA Astrophysics Data System (ADS)

Peikari, Hamid Reza

Despite the wide attention of previous studies to explore the influence of different security-related factors on customers' online trust, the interrelations between such factors and their direct and indirect influences on customers' trust have been neglected. This study investigates the direct and indirect interrelations between the factors authentication, encryption, technical protection and externally provided assurances including third party security and privacy seals with customers' trust in the business-to-customer (B2C) environment. The data was collected from 238 respondents and after the test of reliability and validity of the scale, the hypotheses were tested using structural equation modeling. The results showed that customers' perception of encryption and authentication mechanisms implemented by a Website have a positive significant influence on their perceived technical protection while technical protection was found to significantly influence customers' trust to the Website. However, the analysis did not find any relation between the third party assurance and customers' trust, indicating that despite the high expenses companies involve to obtain such assurances from reputed third parties, such mechanisms and assurances do not have any direct or indirect significant influence on customers' trust; which raises questions on the value of such mechanisms .finally, after discussing the findings and implication of this study for both academic and business worlds, suggestions for future studies were made to have a better understanding of the dimensions of the interrelations between the security-related factors.

Enhancing Elementary Pre-service Teachers' Plant Processes Conceptions

NASA Astrophysics Data System (ADS)

Thompson, Stephen L.; Lotter, Christine; Fann, Xumei; Taylor, Laurie

2016-06-01

Researchers examined how an inquiry-based instructional treatment emphasizing interrelated plant processes influenced 210 elementary pre-service teachers' (PTs) conceptions of three plant processes, photosynthesis, cellular respiration, and transpiration, and the interrelated nature of these processes. The instructional treatment required PTs to predict the fate of a healthy plant in a sealed terrarium (Plant-in-a-Jar), justify their predictions, observe the plant over a 5-week period, and complete guided inquiry activities centered on one of the targeted plant processes each week. Data sources included PTs' pre- and post-predictions with accompanying justifications, course artifacts such as weekly terrarium observations and science journal entries, and group models of the interrelated plant processes occurring within the sealed terraria. A subset of 33 volunteer PTs also completed interviews the week the Plant-in-a-Jar scenario was introduced and approximately 4 months after the instructional intervention ended. Pre- and post-predictions from all PTs as well as interview responses from the subgroup of PTs, were coded into categories based on key plant processes emphasized in the Next Generation Science Standards. Study findings revealed that PTs developed more accurate conceptions of plant processes and their interrelated nature as a result of the instructional intervention. Primary patterns of change in PTs' plant process conceptions included development of more accurate conceptions of how water is used by plants, more accurate conceptions of photosynthesis features, and more accurate conceptions of photosynthesis and cellular respiration as transformative processes.

A primer on criticality safety

DOE PAGES

Costa, David A.; Cournoyer, Michael E.; Merhege, James F.; ...

2017-05-01

Criticality is the state of a nuclear chain reacting medium when the chain reaction is just self-sustaining (or critical). Criticality is dependent on nine interrelated parameters. Moreover, we design criticality safety controls in order to constrain these parameters to minimize fissions and maximize neutron leakage and absorption in other materials, which makes criticality more difficult or impossible to achieve. We present the consequences of criticality accidents are discussed, the nine interrelated parameters that combine to affect criticality are described, and criticality safety controls used to minimize the likelihood of a criticality accident are presented.

[Arabian food pyramid: unified framework for nutritional health messages].

PubMed

Shokr, Adel M

2008-01-01

There are several ways to present nutritional health messages, particularly pyramidic indices, but they have many deficiencies such as lack of agreement on a unified or clear methodology for food grouping and ignoring nutritional group inter-relation and integration. This causes confusion for health educators and target individuals. This paper presents an Arabian food pyramid that aims to unify the bases of nutritional health messages, bringing together the function, contents, source and nutritional group servings and indicating the inter-relation and integration of nutritional groups. This provides comprehensive, integrated, simple and flexible health messages.

[Simulation of administrative influence on a public health under conditions of changing the terminal values during the process of society transformation].

PubMed

Fed'ko, O A

2010-01-01

The article is devoted to the study of interrelation between terminal values and subjective health in the context of community development and modeling of possible directions of administrative influence on a public health taking into account such interrelation. The structural model of influence of terminal values on a subjective health is presented and the assessment of possible changes of health on the population level under condition of the introduction of the proper administrative interventions is given.

Alzheimer's Disease: The Role of Microglia in Brain Homeostasis and Proteopathy

PubMed Central

Clayton, Kevin A.; Van Enoo, Alicia A.; Ikezu, Tsuneya

2017-01-01

Brain aging is central to late-onset Alzheimer's disease (LOAD), although the mechanisms by which it occurs at protein or cellular levels are not fully understood. Alzheimer's disease is the most common proteopathy and is characterized by two unique pathologies: senile plaques and neurofibrillary tangles, the former accumulating earlier than the latter. Aging alters the proteostasis of amyloid-β peptides and microtubule-associated protein tau, which are regulated in both autonomous and non-autonomous manners. Microglia, the resident phagocytes of the central nervous system, play a major role in the non-autonomous clearance of protein aggregates. Their function is significantly altered by aging and neurodegeneration. This is genetically supported by the association of microglia-specific genes, TREM2 and CD33, and late onset Alzheimer's disease. Here, we propose that the functional characterization of microglia, and their contribution to proteopathy, will lead to a new therapeutic direction in Alzheimer's disease research. PMID:29311768

Effects of Sex, Strain, and Energy Intake on Hallmarks of Aging in Mice.

PubMed

Mitchell, Sarah J; Madrigal-Matute, Julio; Scheibye-Knudsen, Morten; Fang, Evandro; Aon, Miguel; González-Reyes, José A; Cortassa, Sonia; Kaushik, Susmita; Gonzalez-Freire, Marta; Patel, Bindi; Wahl, Devin; Ali, Ahmed; Calvo-Rubio, Miguel; Burón, María I; Guiterrez, Vincent; Ward, Theresa M; Palacios, Hector H; Cai, Huan; Frederick, David W; Hine, Christopher; Broeskamp, Filomena; Habering, Lukas; Dawson, John; Beasley, T Mark; Wan, Junxiang; Ikeno, Yuji; Hubbard, Gene; Becker, Kevin G; Zhang, Yongqing; Bohr, Vilhelm A; Longo, Dan L; Navas, Placido; Ferrucci, Luigi; Sinclair, David A; Cohen, Pinchas; Egan, Josephine M; Mitchell, James R; Baur, Joseph A; Allison, David B; Anson, R Michael; Villalba, José M; Madeo, Frank; Cuervo, Ana Maria; Pearson, Kevin J; Ingram, Donald K; Bernier, Michel; de Cabo, Rafael

2016-06-14

Calorie restriction (CR) is the most robust non-genetic intervention to delay aging. However, there are a number of emerging experimental variables that alter CR responses. We investigated the role of sex, strain, and level of CR on health and survival in mice. CR did not always correlate with lifespan extension, although it consistently improved health across strains and sexes. Transcriptional and metabolomics changes driven by CR in liver indicated anaplerotic filling of the Krebs cycle together with fatty acid fueling of mitochondria. CR prevented age-associated decline in the liver proteostasis network while increasing mitochondrial number, preserving mitochondrial ultrastructure and function with age. Abrogation of mitochondrial function negated life-prolonging effects of CR in yeast and worms. Our data illustrate the complexity of CR in the context of aging, with a clear separation of outcomes related to health and survival, highlighting complexities of translation of CR into human interventions. Published by Elsevier Inc.

Reversible Age-Related Phenotypes Induced during Larval Quiescence in C. elegans

PubMed Central

Roux, Antoine E.; Langhans, Kelley; Huynh, Walter; Kenyon, Cynthia

2017-01-01

Summary Cells can enter quiescent states in which cell cycling and growth are suspended. We find that during a long developmental arrest (quiescence) induced by starvation, newly-hatched C. elegans acquire features associated with impaired proteostasis and aging: mitochondrial fission, ROS production, protein aggregation, decreased proteotoxic-stress resistance, and at the organismal level, decline of mobility and high mortality. All signs of aging but one, the presence of protein aggregates, were reversed upon return to development induced by feeding. The endoplasmic reticulum receptor IRE-1 is completely required for recovery, and the downstream transcription factor XBP-1, as well as a protein kinase, KGB-1, are partially required. Interestingly, kgb-1(−) mutants that do recover fail to reverse aging-like mitochondrial phenotypes and have a short adult lifespan. Our study describes the first pathway that reverses phenotypes of aging at the exit of prolonged quiescence. PMID:27304510

Approaches for Defining the Hsp90-dependent Proteome

PubMed Central

Hartson, Steven D.; Matts, Robert L.

2011-01-01

Hsp90 is the target of ongoing drug discovery studies seeking new compounds to treat cancer, neurodegenerative diseases, and protein folding disorders. To better understand Hsp90’s roles in cellular pathologies and in normal cells, numerous studies have utilized proteomics assays and related high-throughput tools to characterize its physical and functional protein partnerships. This review surveys these studies, and summarizes the strengths and limitations of the individual attacks. We also include downloadable spreadsheets compiling all of the Hsp90-interacting proteins identified in more than 23 studies. These tools include cross-references among gene aliases, human homologues of yeast Hsp90-interacting proteins, hyperlinks to database entries, summaries of canonical pathways that are enriched in the Hsp90 interactome, and additional bioinformatic annotations. In addition to summarizing Hsp90 proteomics studies performed to date and the insights they have provided, we identify gaps in our current understanding of Hsp90-mediated proteostasis. PMID:21906632

Protein Misfolding Diseases.

PubMed

Hartl, F Ulrich

2017-06-20

The majority of protein molecules must fold into defined three-dimensional structures to acquire functional activity. However, protein chains can adopt a multitude of conformational states, and their biologically active conformation is often only marginally stable. Metastable proteins tend to populate misfolded species that are prone to forming toxic aggregates, including soluble oligomers and fibrillar amyloid deposits, which are linked with neurodegeneration in Alzheimer and Parkinson disease, and many other pathologies. To prevent or regulate protein aggregation, all cells contain an extensive protein homeostasis (or proteostasis) network comprising molecular chaperones and other factors. These defense systems tend to decline during aging, facilitating the manifestation of aggregate deposition diseases. This volume of the Annual Review of Biochemistry contains a set of three articles addressing our current understanding of the structures of pathological protein aggregates and their associated disease mechanisms. These articles also discuss recent insights into the strategies cells have evolved to neutralize toxic aggregates by sequestering them in specific cellular locations.

dFOXO Activates Large and Small Heat Shock Protein Genes in Response to Oxidative Stress to Maintain Proteostasis in Drosophila.

PubMed

Donovan, Marissa R; Marr, Michael T

2016-09-02

Maintaining protein homeostasis is critical for survival at the cellular and organismal level (Morimoto, R. I. (2011) Cold Spring Harb. Symp. Quant. Biol. 76, 91-99). Cells express a family of molecular chaperones, the heat shock proteins, during times of oxidative stress to protect against proteotoxicity. We have identified a second stress responsive transcription factor, dFOXO, that works alongside the heat shock transcription factor to activate transcription of both the small heat shock protein and the large heat shock protein genes. This expression likely protects cells from protein misfolding associated with oxidative stress. Here we identify the regions of the Hsp70 promoter essential for FOXO-dependent transcription using in vitro methods and find a physiological role for FOXO-dependent expression of heat shock proteins in vivo. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Transthyretin Amyloidosis: Chaperone Concentration Changes and Increased Proteolysis in the Pathway to Disease

PubMed Central

Ribeiro, Raquel; Gilberto, Samuel; Gomes, Ricardo A.; Ferreira, António; Mateus, Élia; Barroso, Eduardo; Coelho, Ana V.; Freire, Ana Ponces; Cordeiro, Carlos

2015-01-01

Transthyretin amyloidosis is a conformational pathology characterized by the extracellular formation of amyloid deposits and the progressive impairment of the peripheral nervous system. Point mutations in this tetrameric plasma protein decrease its stability and are linked to disease onset and progression. Since non-mutated transthyretin also forms amyloid in systemic senile amyloidosis and some mutation bearers are asymptomatic throughout their lives, non-genetic factors must also be involved in transthyretin amyloidosis. We discovered, using a differential proteomics approach, that extracellular chaperones such as fibrinogen, clusterin, haptoglobin, alpha-1-anti-trypsin and 2-macroglobulin are overrepresented in transthyretin amyloidosis. Our data shows that a complex network of extracellular chaperones are over represented in human plasma and we speculate that they act synergistically to cope with amyloid prone proteins. Proteostasis may thus be as important as point mutations in transthyretin amyloidosis. PMID:26147092

The Hallmarks of Aging

PubMed Central

López-Otín, Carlos; Blasco, Maria A.; Partridge, Linda; Serrano, Manuel; Kroemer, Guido

2013-01-01

Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. This deterioration is the primary risk factor for major human pathologies including cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases. Aging research has experienced an unprecedented advance over recent years, particularly with the discovery that the rate of aging is controlled, at least to some extent, by genetic pathways and biochemical processes conserved in evolution. This review enumerates nine tentative hallmarks that represent common denominators of aging in different organisms, with special emphasis on mammalian aging. These hallmarks are: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. A major challenge is to dissect the interconnectedness between the candidate hallmarks and their relative contribution to aging, with the final goal of identifying pharmaceutical targets to improve human health during aging with minimal side-effects. PMID:23746838

Metabolic Dysregulation in Amyotrophic Lateral Sclerosis: Challenges and Opportunities

PubMed Central

Joardar, Archi; Manzo, Ernesto

2017-01-01

Purpose of Review Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease for which there is no cure and treatments are at best palliative. Several genes have been linked to ALS, which highlight defects in multiple cellular processes including RNA processing, proteostasis and metabolism. Clinical observations have identified glucose intolerance and dyslipidemia as key features of ALS however the causes of these metabolic alterations remain elusive. Recent Findings Recent studies reveal that motor neurons and muscle cells may undergo cell type specific metabolic changes that lead to utilization of alternate fuels. For example, ALS patients’ muscles exhibit reduced glycolysis and increased reliance on fatty acids. In contrast, ALS motor neurons contain damaged mitochondria and exhibit impaired lipid beta oxidation, potentially leading to increased glycolysis as a compensatory mechanism. Summary These findings highlight the complexities of metabolic alterations in ALS and provide new opportunities for designing therapeutic strategies based on restoring cellular energetics. PMID:29057168

Metabolic Dysregulation in Amyotrophic Lateral Sclerosis: Challenges and Opportunities.

PubMed

Joardar, Archi; Manzo, Ernesto; Zarnescu, Daniela C

2017-06-01

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease for which there is no cure and treatments are at best palliative. Several genes have been linked to ALS, which highlight defects in multiple cellular processes including RNA processing, proteostasis and metabolism. Clinical observations have identified glucose intolerance and dyslipidemia as key features of ALS however the causes of these metabolic alterations remain elusive. Recent studies reveal that motor neurons and muscle cells may undergo cell type specific metabolic changes that lead to utilization of alternate fuels. For example, ALS patients' muscles exhibit reduced glycolysis and increased reliance on fatty acids. In contrast, ALS motor neurons contain damaged mitochondria and exhibit impaired lipid beta oxidation, potentially leading to increased glycolysis as a compensatory mechanism. These findings highlight the complexities of metabolic alterations in ALS and provide new opportunities for designing therapeutic strategies based on restoring cellular energetics.

ERα promotes murine hematopoietic regeneration through the Ire1α-mediated unfolded protein response

PubMed Central

Chapple, Richard H; Hu, Tianyuan; Tseng, Yu-Jung; Liu, Lu; Kitano, Ayumi; Luu, Victor; Hoegenauer, Kevin A; Iwawaki, Takao; Li, Qing

2018-01-01

Activation of the unfolded protein response (UPR) sustains protein homeostasis (proteostasis) and plays a fundamental role in tissue maintenance and longevity of organisms. Long-range control of UPR activation has been demonstrated in invertebrates, but such mechanisms in mammals remain elusive. Here, we show that the female sex hormone estrogen regulates the UPR in hematopoietic stem cells (HSCs). Estrogen treatment increases the capacity of HSCs to regenerate the hematopoietic system upon transplantation and accelerates regeneration after irradiation. We found that estrogen signals through estrogen receptor α (ERα) expressed in hematopoietic cells to activate the protective Ire1α-Xbp1 branch of the UPR. Further, ERα-mediated activation of the Ire1α-Xbp1 pathway confers HSCs with resistance against proteotoxic stress and promotes regeneration. Our findings reveal a systemic mechanism through which HSC function is augmented for hematopoietic regeneration. PMID:29451493

Role of Carbonyl Modifications on Aging-Associated Protein Aggregation

PubMed Central

Tanase, Maya; Urbanska, Aleksandra M.; Zolla, Valerio; Clement, Cristina C.; Huang, Liling; Morozova, Kateryna; Follo, Carlo; Goldberg, Michael; Roda, Barbara; Reschiglian, Pierluigi; Santambrogio, Laura

2016-01-01

Protein aggregation is a common biological phenomenon, observed in different physiological and pathological conditions. Decreased protein solubility and a tendency to aggregate is also observed during physiological aging but the causes are currently unknown. Herein we performed a biophysical separation of aging-related high molecular weight aggregates, isolated from the bone marrow and splenic cells of aging mice and followed by biochemical and mass spectrometric analysis. The analysis indicated that compared to younger mice an increase in protein post-translational carbonylation was observed. The causative role of these modifications in inducing protein misfolding and aggregation was determined by inducing carbonyl stress in young mice, which recapitulated the increased protein aggregation observed in old mice. Altogether our analysis indicates that oxidative stress-related post-translational modifications accumulate in the aging proteome and are responsible for increased protein aggregation and altered cell proteostasis. PMID:26776680

Inference of financial networks using the normalised mutual information rate.

PubMed

Goh, Yong Kheng; Hasim, Haslifah M; Antonopoulos, Chris G

2018-01-01

In this paper, we study data from financial markets, using the normalised Mutual Information Rate. We show how to use it to infer the underlying network structure of interrelations in the foreign currency exchange rates and stock indices of 15 currency areas. We first present the mathematical method and discuss its computational aspects, and apply it to artificial data from chaotic dynamics and to correlated normal-variates data. We then apply the method to infer the structure of the financial system from the time-series of currency exchange rates and stock indices. In particular, we study and reveal the interrelations among the various foreign currency exchange rates and stock indices in two separate networks, of which we also study their structural properties. Our results show that both inferred networks are small-world networks, sharing similar properties and having differences in terms of assortativity. Importantly, our work shows that global economies tend to connect with other economies world-wide, rather than creating small groups of local economies. Finally, the consistent interrelations depicted among the 15 currency areas are further supported by a discussion from the viewpoint of economics.

Interrelations among the soil-water retention, hydraulic conductivity, and suction-stress characteristic curves

USGS Publications Warehouse

Lu, Ning; Kaya, Murat; Godt, Jonathan W.

2014-01-01

The three fundamental constitutive relations that describe fluid flow, strength, and deformation behavior of variably saturated soils are the soil-water retention curve (SWRC), hydraulic conductivity function (HCF), and suction-stress characteristic curve (SSCC). Until recently, the interrelations among the SWRC, HCF, and SSCC have not been well established. This work sought experimental confirmation of interrelations among these three constitutive functions. Results taken from the literature for six soils and those obtained for 11 different soils were used. Using newly established analytical relations among the SWRC, HCF, and SSCC and these test results, the authors showed that these three constitutive relations can be defined by a common set of hydromechanical parameters. The coefficient of determination for air-entry pressures determined independently using hydraulic and mechanical methods is >0.99, >0.98 for the pore size parameter, and 0.94 for the residual degree of saturation. One practical implication is that one of any of the four experiments (axis-translation, hydraulic, shear-strength, or deformation) is sufficient to quantify all three constitutive relations.

Only one small sin: How self-construal affects self-control.

PubMed

Steinmetz, Janina; Mussweiler, Thomas

2017-12-01

Past research has shown that self-construal can influence self-control by reducing interdependent people's impulsivity in the presence of peers. We broaden these findings by examining the hypothesis that an interdependent (vs. independent) self-construal fosters self-control even in the absence of peers and for non-impulsive decisions. We further explore whether this effect could be mediated by the more interrelated (vs. isolated) processing style of interdependent (vs. independent) people. Such an interrelated (vs. isolated) processing style of temptations makes the impact of a single temptation more salient and can thereby increase self-control. Study 1 demonstrated that more interdependent participants show more self-control behaviour by refraining from chocolate consumption to secure a monetary benefit. Studies 2a and 2b highlighted a link between self-construal and trait self-control via the processing of temptations. Study 3 suggested that an interrelated (vs. isolated) perspective on temptations could mediate the effect of (primed) self-construal on self-control. Taken together, self-construal shapes self-control across various decision contexts. © 2017 The British Psychological Society.

Inference of financial networks using the normalised mutual information rate

PubMed Central

2018-01-01

In this paper, we study data from financial markets, using the normalised Mutual Information Rate. We show how to use it to infer the underlying network structure of interrelations in the foreign currency exchange rates and stock indices of 15 currency areas. We first present the mathematical method and discuss its computational aspects, and apply it to artificial data from chaotic dynamics and to correlated normal-variates data. We then apply the method to infer the structure of the financial system from the time-series of currency exchange rates and stock indices. In particular, we study and reveal the interrelations among the various foreign currency exchange rates and stock indices in two separate networks, of which we also study their structural properties. Our results show that both inferred networks are small-world networks, sharing similar properties and having differences in terms of assortativity. Importantly, our work shows that global economies tend to connect with other economies world-wide, rather than creating small groups of local economies. Finally, the consistent interrelations depicted among the 15 currency areas are further supported by a discussion from the viewpoint of economics. PMID:29420644

Interrelations between cerebrospinal fluid and plasma inorganic ions and glucose in patients with chronic renal failure.

PubMed Central

Pye, I F; Aber, G M

1982-01-01

The concentrations of inorganic ions and glucose in the plasma and CSF of 11 patients with "steady-state" chronic renal failure have been measured and their CSF: plasma interrelations studied. The results have been compared with the corresponding data from 34 control subjects. In the patients with renal failure, there was a positive correlation between raised CSF and plasma potassium concentrations. In contrast to the impaired potassium homeostasis, normal CSF magnesium and calcium concentrations were observed despite wide variations in the plasma concentrations of these ions. PMID:7085915

Metabolic Plasticity and Inter-Compartmental Interactions in Rice Metabolism: An Analysis from Reaction Deletion Study.

PubMed

Shaw, Rahul; Kundu, Sudip

2015-01-01

More than 20% of the total caloric intake of human population comes from rice. The expression of rice genes and hence, the concentration of enzymatic proteins might vary due to several biotic and abiotic stresses. It in turn, can influence the overall metabolism and survivability of rice plant. Thus, understanding the rice cellular metabolism, its plasticity and potential readjustments under different perturbations can help rice biotechnologists to design efficient rice cultivars. Here, using the flux balance analysis (FBA) method, with the help of in-silico reaction deletion strategy, we study the metabolic plasticity of genome-scale metabolic model of rice leaf. A set of 131 reactions, essential for the production of primary biomass precursors is identified; deletion of any of them can inhibit the overall biomass production. Usability Index (IU) for the rest of the reactions are estimated and based on this parameter, they are classified into three categories-maximally-favourable, quasi-favourable and unfavourable for the primary biomass production. The lower value of 1 - IU of a reaction suggests that the cell cannot easily bypass it for biomass production. While some of the alternative paths are energetically equally efficient, others demand for higher photon. The variations in (i) ATP/NADPH ratio, (ii) exchange of metabolites through chloroplastic transporters and (iii) total biomass production are also presented here. Mutual metabolic dependencies of different cellular compartments are also demonstrated.

Simultaneous Characterization of Intravenous and Oral Pharmacokinetics of Lychnopholide in Rats by Transit Compartment Model.

PubMed

Lachi-Silva, Larissa; Sy, Sherwin K B; Voelkner, Alexander; de Sousa, João Paulo Barreto; Lopes, João Luis C; Silva, Denise B; Lopes, Norberto P; Kimura, Elza; Derendorf, Hartmut; Diniz, Andrea

2015-08-01

The pharmacokinetic properties of a new molecular entity are important aspects in evaluating the viability of the compound as a pharmacological agent. The sesquiterpene lactone lychnopholide exhibits important biological activities. The objective of this study was to characterize the pharmacokinetics of lychnopholide after intravenous administration of 1.65 mg/kg (n = 5) and oral administration of 3.3 mg/kg (n = 3) lychnopholide in rats (0.2 ± 0.02 kg in weight) through nonlinear mixed effects modeling and non-compartmental pharmacokinetic analysis. A highly sensitive analytical method was used to quantify the plasma lychnopholide concentrations in rats. Plasma protein binding of this compound was over 99 % as determined by a filtration method. A two-compartment body model plus three transit compartments to characterize the absorption process best described the disposition of lychnopholide after both routes of administration. The oral bioavailability was approximately 68 %. The clearance was 0.131 l/min and intercompartmental clearance was 0.171 l/min; steady-state volume of distribution was 4.83 l. The mean transit time for the absorption process was 9.15 minutes. No flip-flop phenomenon was observed after oral administration. The pharmacokinetic properties are favorable for further development of lychnopholide as a potential oral pharmacological agent. Georg Thieme Verlag KG Stuttgart · New York.

Cell-autonomous mechanisms of chronological aging in the yeast Saccharomyces cerevisiae.

PubMed

Arlia-Ciommo, Anthony; Leonov, Anna; Piano, Amanda; Svistkova, Veronika; Titorenko, Vladimir I

2014-05-27

A body of evidence supports the view that the signaling pathways governing cellular aging - as well as mechanisms of their modulation by longevity-extending genetic, dietary and pharmacological interventions - are conserved across species. The scope of this review is to critically analyze recent advances in our understanding of cell-autonomous mechanisms of chronological aging in the budding yeast Saccharomyces cerevisiae . Based on our analysis, we propose a concept of a biomolecular network underlying the chronology of cellular aging in yeast. The concept posits that such network progresses through a series of lifespan checkpoints. At each of these checkpoints, the intracellular concentrations of some key intermediates and products of certain metabolic pathways - as well as the rates of coordinated flow of such metabolites within an intricate network of intercompartmental communications - are monitored by some checkpoint-specific "master regulator" proteins. The concept envisions that a synergistic action of these master regulator proteins at certain early-life and late-life checkpoints modulates the rates and efficiencies of progression of such processes as cell metabolism, growth, proliferation, stress resistance, macromolecular homeostasis, survival and death. The concept predicts that, by modulating these vital cellular processes throughout lifespan (i.e., prior to an arrest of cell growth and division, and following such arrest), the checkpoint-specific master regulator proteins orchestrate the development and maintenance of a pro- or anti-aging cellular pattern and, thus, define longevity of chronologically aging yeast.

Tibiofemoral forces for the native and post-arthroplasty knee: relationship to maximal laxity through a functional arc of motion.

PubMed

Manning, William A; Ghosh, Kanishka; Blain, Alasdair; Longstaff, Lee; Deehan, David John

2017-06-01

Accurate soft tissue balance must be achieved to improve functional outcome after total knee arthroplasty (TKA). Sensor-integrated tibial trials have been introduced that allow real-time measurement of tibiofemoral kinematics during TKA. This study examined the interplay between tibiofemoral force and laxity, under defined intraoperative conditions, so as to quantify the kinematic behaviour of the CR femoral single-radius knee. TKA was undertaken in eight loaded cadaveric specimens. Computer navigation in combination with sensor data defined laxity and tibiofemoral contact force, respectively, during manual laxity testing. Fixed-effect linear modelling allowed quantification of the effect for flexion angle, direction of movement and TKA implantation upon the knee. An inverse relationship between laxity and contact force was demonstrated. With flexion, laxity increased as contact force decreased under manual stress. Change in laxity was significant beyond 30° for coronal plane laxity and beyond 60° for rotatory laxity (p < 0.01). Rotational stress in mid-flexion demonstrated the greatest mismatch in inter-compartmental forces. Contact point position over the tibial sensor demonstrated paradoxical roll-forward with knee flexion. Traditional balancing techniques may not reliably equate to uniform laxity or contact forces across the tibiofemoral joint through a range of flexion and argue for the role of per-operative sensor use to aid final balancing of the knee.

Assessing the Impacts of Climate Change on the Water-Energy Nexus

NASA Astrophysics Data System (ADS)

Mo, W.; Jacobs, J. M.

2014-12-01

Water-energy nexus refers to the fact that a lot of energy is used for treating and delivering water, and a large amount of water is needed for energy production. This interrelation reinforces water and energy consumptions and challenges the sustainable management of both resources in light of growing population, developing economy, and dwindling resources. Climate change often exacerbates the negative effects of the water-energy nexus by intervening water and energy allocation, availability, and quality, forcing communities to seek more energy dependent alternative water sources and/or more water dependent alternative energy sources. The climate-water-energy interrelations play an important role in water and energy management, yet our understandings on the interactions between climate and the water-energy nexus are still very limited. Therefore, this study aims at qualitatively and quantitatively assessing the impacts of climate change from the water-energy nexus perspective by investigating previous literatures, case studies, climate change patterns, and recent extreme climate events. Management difficulties resulted from climate related source shifts as well as policy and regulation changes will be illustrated and discussed. Research needs and gaps on the climate-water-energy interrelations will be addressed.

Multi-Pixel Simultaneous Classification of PolSAR Image Using Convolutional Neural Networks

PubMed Central

Xu, Xin; Gui, Rong; Pu, Fangling

2018-01-01

Convolutional neural networks (CNN) have achieved great success in the optical image processing field. Because of the excellent performance of CNN, more and more methods based on CNN are applied to polarimetric synthetic aperture radar (PolSAR) image classification. Most CNN-based PolSAR image classification methods can only classify one pixel each time. Because all the pixels of a PolSAR image are classified independently, the inherent interrelation of different land covers is ignored. We use a fixed-feature-size CNN (FFS-CNN) to classify all pixels in a patch simultaneously. The proposed method has several advantages. First, FFS-CNN can classify all the pixels in a small patch simultaneously. When classifying a whole PolSAR image, it is faster than common CNNs. Second, FFS-CNN is trained to learn the interrelation of different land covers in a patch, so it can use the interrelation of land covers to improve the classification results. The experiments of FFS-CNN are evaluated on a Chinese Gaofen-3 PolSAR image and other two real PolSAR images. Experiment results show that FFS-CNN is comparable with the state-of-the-art PolSAR image classification methods. PMID:29510499

Multi-Pixel Simultaneous Classification of PolSAR Image Using Convolutional Neural Networks.

PubMed

Wang, Lei; Xu, Xin; Dong, Hao; Gui, Rong; Pu, Fangling

2018-03-03

Convolutional neural networks (CNN) have achieved great success in the optical image processing field. Because of the excellent performance of CNN, more and more methods based on CNN are applied to polarimetric synthetic aperture radar (PolSAR) image classification. Most CNN-based PolSAR image classification methods can only classify one pixel each time. Because all the pixels of a PolSAR image are classified independently, the inherent interrelation of different land covers is ignored. We use a fixed-feature-size CNN (FFS-CNN) to classify all pixels in a patch simultaneously. The proposed method has several advantages. First, FFS-CNN can classify all the pixels in a small patch simultaneously. When classifying a whole PolSAR image, it is faster than common CNNs. Second, FFS-CNN is trained to learn the interrelation of different land covers in a patch, so it can use the interrelation of land covers to improve the classification results. The experiments of FFS-CNN are evaluated on a Chinese Gaofen-3 PolSAR image and other two real PolSAR images. Experiment results show that FFS-CNN is comparable with the state-of-the-art PolSAR image classification methods.

Continuous-spin mixed-symmetry fields in AdS(5)

NASA Astrophysics Data System (ADS)

Metsaev, R. R.

2018-05-01

Free mixed-symmetry continuous-spin fields propagating in AdS(5) space and flat R(4,1) space are studied. In the framework of a light-cone gauge formulation of relativistic dynamics, we build simple actions for such fields. The realization of relativistic symmetries on the space of light-cone gauge mixed-symmetry continuous-spin fields is also found. Interrelations between constant parameters entering the light-cone gauge actions and eigenvalues of the Casimir operators of space-time symmetry algebras are obtained. Using these interrelations and requiring that the field dynamics in AdS(5) be irreducible and classically unitary, we derive restrictions on the constant parameters and eigenvalues of the second-order Casimir operator of the algebra.

The Interrelation of Prayer and Worship Service Attendance in Moderating the Negative Impact of Life Event Stressors on Mental Well-Being.

PubMed

Rainville, G

2017-09-13

The interrelation of worship service attendance and private prayer in moderating the negative impact of life event stressors on mental well-being is examined using hierarchical multiple regressions on a national sample of 2601 Americans. A theoretical model is proposed in which stressful life events are made less distressing under conditions in which exposure to pro-social content at worship services is internalized through frequent private prayer. Interactive models controlling for a block of potential confounds are run to confirm that the stress-moderating effects of worship service attendance are noted only when attendance is complemented by relatively frequent engagement in private prayer.

The inter-relations of mother and father attachment, self-esteem and aggression during late adolescence.

PubMed

Gomez, Rapson; McLaren, Suzanne

2007-01-01

This study examined three models depicting the relations between mother and father attachment, self-esteem and aggression. A total of 385 participants (173 males and 212 females), aged from 18 to 20 years, completed self-rating questionnaires covering mother and father attachment, self-esteem and aggression. Results showed that self-esteem had additive and mediation effects on both the father attachment-aggression and mother attachment-aggression relationships, and also moderated the mother attachment-aggression relation. These findings are discussed in terms of different models for the inter-relations of mother and father attachment, self-esteem and aggression in late adolescence. Copyright 2006 Wiley-Liss, Inc.

Cell-Nonautonomous Mechanisms Underlying Cellular and Organismal Aging.

PubMed

Medkour, Younes; Svistkova, Veronika; Titorenko, Vladimir I

2016-01-01

Cell-autonomous mechanisms underlying cellular and organismal aging in evolutionarily distant eukaryotes have been established; these mechanisms regulate longevity-defining processes within a single eukaryotic cell. Recent findings have provided valuable insight into cell-nonautonomous mechanisms modulating cellular and organismal aging in eukaryotes across phyla; these mechanisms involve a transmission of various longevity factors between different cells, tissues, and organisms. Herein, we review such cell-nonautonomous mechanisms of aging in eukaryotes. We discuss the following: (1) how low molecular weight transmissible longevity factors modulate aging and define longevity of cells in yeast populations cultured in liquid media or on solid surfaces, (2) how communications between proteostasis stress networks operating in neurons and nonneuronal somatic tissues define longevity of the nematode Caenorhabditis elegans by modulating the rates of aging in different tissues, and (3) how different bacterial species colonizing the gut lumen of C. elegans define nematode longevity by modulating the rate of organismal aging. Copyright © 2016. Published by Elsevier Inc.

A quantitative chaperone interaction network reveals the architecture of cellular protein homeostasis pathways

PubMed Central

Taipale, Mikko; Tucker, George; Peng, Jian; Krykbaeva, Irina; Lin, Zhen-Yuan; Larsen, Brett; Choi, Hyungwon; Berger, Bonnie; Gingras, Anne-Claude; Lindquist, Susan

2014-01-01

Chaperones are abundant cellular proteins that promote the folding and function of their substrate proteins (clients). In vivo, chaperones also associate with a large and diverse set of co-factors (co-chaperones) that regulate their specificity and function. However, how these co-chaperones regulate protein folding and whether they have chaperone-independent biological functions is largely unknown. We have combined mass spectrometry and quantitative high-throughput LUMIER assays to systematically characterize the chaperone/co-chaperone/client interaction network in human cells. We uncover hundreds of novel chaperone clients, delineate their participation in specific co-chaperone complexes, and establish a surprisingly distinct network of protein/protein interactions for co-chaperones. As a salient example of the power of such analysis, we establish that NUDC family co-chaperones specifically associate with structurally related but evolutionarily distinct β-propeller folds. We provide a framework for deciphering the proteostasis network, its regulation in development and disease, and expand the use of chaperones as sensors for drug/target engagement. PMID:25036637

VCP-dependent muscle degeneration is linked to defects in a dynamic tubular lysosomal network in vivo

PubMed Central

Johnson, Alyssa E; Shu, Huidy; Hauswirth, Anna G; Tong, Amy; Davis, Graeme W

2015-01-01

Lysosomes are classically viewed as vesicular structures to which cargos are delivered for degradation. Here, we identify a network of dynamic, tubular lysosomes that extends throughout Drosophila muscle, in vivo. Live imaging reveals that autophagosomes merge with tubular lysosomes and that lysosomal membranes undergo extension, retraction, fusion and fission. The dynamics and integrity of this tubular lysosomal network requires VCP, an AAA-ATPase that, when mutated, causes degenerative diseases of muscle, bone and neurons. We show that human VCP rescues the defects caused by loss of Drosophila VCP and overexpression of disease relevant VCP transgenes dismantles tubular lysosomes, linking tubular lysosome dysfunction to human VCP-related diseases. Finally, disruption of tubular lysosomes correlates with impaired autophagosome-lysosome fusion, increased cytoplasmic poly-ubiquitin aggregates, lipofuscin material, damaged mitochondria and impaired muscle function. We propose that VCP sustains sarcoplasmic proteostasis, in part, by controlling the integrity of a dynamic tubular lysosomal network. DOI: http://dx.doi.org/10.7554/eLife.07366.001 PMID:26167652

The Energy Maintenance Theory of Aging: Maintaining Energy Metabolism to Allow Longevity.

PubMed

Chaudhari, Snehal N; Kipreos, Edward T

2018-06-14

Fused, elongated mitochondria are more efficient in generating ATP than fragmented mitochondria. In diverse C. elegans longevity pathways, increased levels of fused mitochondria are associated with lifespan extension. Blocking mitochondrial fusion in these animals abolishes their extended longevity. The long-lived C. elegans vhl-1 mutant is an exception that does not have increased fused mitochondria, and is not dependent on fusion for longevity. Loss of mammalian VHL upregulates alternate energy generating pathways. This suggests that mitochondrial fusion facilitates longevity in C. elegans by increasing energy metabolism. In diverse animals, ATP levels broadly decreases with age. Substantial evidence supports the theory that increasing or maintaining energy metabolism promotes the survival of older animals. Increased ATP levels in older animals allow energy-intensive repair and homeostatic mechanisms such as proteostasis that act to prevent cellular aging. These observations support the emerging paradigm that maintaining energy metabolism promotes the survival of older animals. © 2018 WILEY Periodicals, Inc.

Antibiotic use and abuse: A threat to mitochondria and chloroplasts with impact on research, health, and environment

PubMed Central

Wang, Xu; Ryu, Dongryeol

2015-01-01

Recently, several studies have demonstrated that tetracyclines, the antibiotics most intensively used in livestock and that are also widely applied in biomedical research, interrupt mitochondrial proteostasis and physiology in animals ranging from round worms, fruit flies, and mice to human cell lines. Importantly, plant chloroplasts, like their mitochondria, are also under certain conditions vulnerable to these and other antibiotics that are leached into our environment. Together these endosymbiotic organelles are not only essential for cellular and organismal homeostasis stricto sensu, but also have an important role to play in the sustainability of our ecosystem as they maintain the delicate balance between autotrophs and heterotrophs, which fix and utilize energy, respectively. Therefore, stricter policies on antibiotic usage are absolutely required as their use in research confounds experimental outcomes, and their uncontrolled applications in medicine and agriculture pose a significant threat to a balanced ecosystem and the well‐being of these endosymbionts that are essential to sustain health. Also watch the Video Abstract. PMID:26347282

Loss of PINK1 attenuates HIF-1α induction by preventing 4E-BP1-dependent switch in protein translation under hypoxia.

PubMed

Lin, William; Wadlington, Natasha L; Chen, Linan; Zhuang, Xiaoxi; Brorson, James R; Kang, Un Jung

2014-02-19

Parkinson's disease (PD) has multiple proposed etiologies with implication of abnormalities in cellular homeostasis ranging from proteostasis to mitochondrial dynamics to energy metabolism. PINK1 mutations are associated with familial PD and here we discover a novel PINK1 mechanism in cellular stress response. Using hypoxia as a physiological trigger of oxidative stress and disruption in energy metabolism, we demonstrate that PINK1(-/-) mouse cells exhibited significantly reduced induction of HIF-1α protein, HIF-1α transcriptional activity, and hypoxia-responsive gene upregulation. Loss of PINK1 impairs both hypoxia-induced 4E-BP1 dephosphorylation and increase in the ratio of internal ribosomal entry site (IRES)-dependent to cap-dependent translation. These data suggest that PINK1 mediates adaptive responses by activating IRES-dependent translation, and the impairments in translation and the HIF-1α pathway may contribute to PINK1-associated PD pathogenesis that manifests under cellular stress.

Chemical Screens Against A Reconstituted Multi-Protein Complex: Myricetin Blocks DnaJ Regulation of DnaK through an Allosteric Mechanism

PubMed Central

Chang, Lyra; Miyata, Yoshinari; Ung, Peter M. U.; Bertelsen, Eric B.; McQuade, Thomas J.; Carlson, Heather A.; Zuiderweg, Erik R. P.; Gestwicki, Jason E.

2011-01-01

SUMMARY DnaK is a molecular chaperone responsible for multiple aspects of proteostasis. The intrinsically slow ATPase activity of DnaK is stimulated by its co-chaperone, DnaJ, and these proteins often work in concert. To identify inhibitors, we screened plant-derived extracts against a re-constituted mixture of DnaK and DnaJ. This approach resulted in the identification of flavonoids, including myricetin, which inhibited activity by up to 75%. Interestingly, myricetin prevented DnaJ-mediated stimulation of ATPase activity, with minimal impact on either DnaK’s intrinsic turnover rate or its stimulation by another co-chaperone, GrpE. Using NMR, we found that myricetin binds DnaK at an unanticipated site between the IB and IIB subdomains and that it allosterically blocked binding of DnaJ. Together, these results highlight a “gray box” screening approach, which approximates a limited amount of the complexity expected in physiological, multi-protein systems. PMID:21338918

The Mechanism and Function of Group II Chaperonins

DOE PAGES

Lopez, Tom; Dalton, Kevin; Frydman, Judith

2015-04-30

We report protein folding in the cell requires the assistance of enzymes collectively called chaperones. Among these, the chaperonins are 1-MDa ring-shaped oligomeric complexes that bind unfolded polypeptides and promote their folding within an isolated chamber in an ATP-dependent manner. Group II chaperonins, found in archaea and eukaryotes, contain a built-in lid that opens and closes over the central chamber. In eukaryotes, the chaperonin TRiC/CCT is hetero-oligomeric, consisting of two stacked rings of eight paralogous subunits each. TRiC facilitates folding of approximately 10% of the eukaryotic proteome, including many cytoskeletal components and cell cycle regulators. Folding of many cellular substratesmore » of TRiC cannot be assisted by any other chaperone. A complete structural and mechanistic understanding of this highly conserved and essential chaperonin remains elusive. However, recent work is beginning to shed light on key aspects of chaperonin function and how their unique properties underlie their contribution to maintaining cellular proteostasis.« less

Autophagy meets fused in sarcoma-positive stress granules.

PubMed

Matus, Soledad; Bosco, Daryl A; Hetz, Claudio

2014-12-01

Mutations in fused in sarcoma and/or translocated in liposarcoma (FUS, TLS or FUS) are linked to familial cases of amyotrophic lateral sclerosis (ALS). Mutant FUS selectively accumulates into discrete cytosolic structures known as stress granules under various stress conditions. In addition, mutant FUS expression can alter the dynamics and morphology of stress granules. Although the link between mutant FUS and stress granules is well established, the mechanisms modulating stress granule formation and disassembly in the context of ALS are poorly understood. In this issue of Neurobiology of Aging, Ryu et al. uncover the impact of autophagy on the potential toxicity of mutant FUS-positive stress granules. The authors provide evidence indicating that enhanced autophagy activity reduces the number of stress granules, which in the case of cells containing mutant FUS-positive stress granules, is neuroprotective. Overall, this study identifies an intersection between the proteostasis network and alterations in RNA metabolism in ALS through the dynamic assembly and disassembly of stress granules. Copyright © 2014 Elsevier Inc. All rights reserved.

Sensitive detection of proteasomal activation using the Deg-On mammalian synthetic gene circuit.

PubMed

Zhao, Wenting; Bonem, Matthew; McWhite, Claire; Silberg, Jonathan J; Segatori, Laura

2014-04-08

The ubiquitin proteasome system (UPS) has emerged as a drug target for diverse diseases characterized by altered proteostasis, but pharmacological agents that enhance UPS activity have been challenging to establish. Here we report the Deg-On system, a genetic inverter that translates proteasomal degradation of the transcriptional regulator TetR into a fluorescent signal, thereby linking UPS activity to an easily detectable output, which can be tuned using tetracycline. We demonstrate that this circuit responds to modulation of UPS activity in cell culture arising from the inhibitor MG-132 and activator PA28γ. Guided by predictive modelling, we enhanced the circuit's signal sensitivity and dynamic range by introducing a feedback loop that enables self-amplification of TetR. By linking UPS activity to a simple and tunable fluorescence output, these genetic inverters will enable a variety of applications, including screening for UPS activating molecules and selecting for mammalian cells with different levels of proteasome activity.

Dissecting Endoplasmic Reticulum Unfolded Protein Response (UPRER) in Managing Clandestine Modus Operandi of Alzheimer’s Disease

PubMed Central

Rahman, Safikur; Archana, Ayyagari; Jan, Arif Tasleem; Minakshi, Rinki

2018-01-01

Alzheimer’s disease (AD), a neurodegenerative disorder, is most common cause of dementia witnessed among aged people. The pathophysiology of AD develops as a consequence of neurofibrillary tangle formation which consists of hyperphosphorylated microtubule associated tau protein and senile plaques of amyloid-β (Aβ) peptide in specific brain regions that result in synaptic loss and neuronal death. The feeble buffering capacity of endoplasmic reticulum (ER) proteostasis in AD is evident through alteration in unfolded protein response (UPR), where UPR markers express invariably in AD patient’s brain samples. Aging weakens UPRER causing neuropathology and memory loss in AD. This review highlights molecular signatures of UPRER and its key molecular alliance that are affected in aging leading to the development of intriguing neuropathologies in AD. We present a summary of recent studies reporting usage of small molecules as inhibitors or activators of UPRER sensors/effectors in AD that showcase avenues for therapeutic interventions. PMID:29467648

Hsp83 loss suppresses proteasomal activity resulting in an upregulation of caspase-dependent compensatory autophagy.

PubMed

Choutka, Courtney; DeVorkin, Lindsay; Go, Nancy Erro; Hou, Ying-Chen Claire; Moradian, Annie; Morin, Gregg B; Gorski, Sharon M

2017-09-02

The 2 main degradative pathways that contribute to proteostasis are the ubiquitin-proteasome system and autophagy but how they are molecularly coordinated is not well understood. Here, we demonstrate an essential role for an effector caspase in the activation of compensatory autophagy when proteasomal activity is compromised. Functional loss of Hsp83, the Drosophila ortholog of human HSP90 (heat shock protein 90), resulted in reduced proteasomal activity and elevated levels of the effector caspase Dcp-1. Surprisingly, genetic analyses showed that the caspase was not required for cell death in this context, but instead was essential for the ensuing compensatory autophagy, female fertility, and organism viability. The zymogen pro-Dcp-1 was found to interact with Hsp83 and undergo proteasomal regulation in an Hsp83-dependent manner. Our work not only reveals unappreciated roles for Hsp83 in proteasomal activity and regulation of Dcp-1, but identifies an effector caspase as a key regulatory factor for sustaining adaptation to cell stress in vivo.

Defining Hsp70 Subnetworks in Dengue Virus Replication Reveals Key Vulnerability in Flavivirus Infection

PubMed Central

Taguwa, Shuhei; Maringer, Kevin; Li, Xiaokai; Bernal-Rubio, Dabeiba; Rauch, Jennifer N.; Gestwicki, Jason E.; Andino, Raul; Fernandez-Sesma, Ana; Frydman, Judith

2015-01-01

Summary Viral protein homeostasis depends entirely on the machinery of the infected cell. Accordingly, viruses can illuminate the interplay between cellular proteostasis components and their distinct substrates. Here we define how the Hsp70 chaperone network mediates the dengue virus life cycle. Cytosolic Hsp70 isoforms are required at distinct steps of the viral cycle, including entry, RNA replication and virion biogenesis. Hsp70 function at each step is specified by nine distinct DNAJ cofactors. Of these, DnaJB11 relocalizes to virus-induced replication complexes to promote RNA synthesis, while DnaJB6 associates with capsid protein and facilitates virion biogenesis. Importantly, an allosteric Hsp70 inhibitor, JG40, potently blocks infection of different dengue serotypes in human primary blood cells without eliciting viral resistance or exerting toxicity to the host cells. JG40 also blocks replication of other medically-important flaviviruses including yellow fever, West Nile and Japanese encephalitis viruses. Thus, targeting host Hsp70 subnetworks provides a path for broad-spectrum antivirals. PMID:26582131

An organelle-specific protein landscape identifies novel diseases and molecular mechanisms

PubMed Central

Boldt, Karsten; van Reeuwijk, Jeroen; Lu, Qianhao; Koutroumpas, Konstantinos; Nguyen, Thanh-Minh T.; Texier, Yves; van Beersum, Sylvia E. C.; Horn, Nicola; Willer, Jason R.; Mans, Dorus A.; Dougherty, Gerard; Lamers, Ideke J. C.; Coene, Karlien L. M.; Arts, Heleen H.; Betts, Matthew J.; Beyer, Tina; Bolat, Emine; Gloeckner, Christian Johannes; Haidari, Khatera; Hetterschijt, Lisette; Iaconis, Daniela; Jenkins, Dagan; Klose, Franziska; Knapp, Barbara; Latour, Brooke; Letteboer, Stef J. F.; Marcelis, Carlo L.; Mitic, Dragana; Morleo, Manuela; Oud, Machteld M.; Riemersma, Moniek; Rix, Susan; Terhal, Paulien A.; Toedt, Grischa; van Dam, Teunis J. P.; de Vrieze, Erik; Wissinger, Yasmin; Wu, Ka Man; Apic, Gordana; Beales, Philip L.; Blacque, Oliver E.; Gibson, Toby J.; Huynen, Martijn A.; Katsanis, Nicholas; Kremer, Hannie; Omran, Heymut; van Wijk, Erwin; Wolfrum, Uwe; Kepes, François; Davis, Erica E.; Franco, Brunella; Giles, Rachel H.; Ueffing, Marius; Russell, Robert B.; Roepman, Ronald; Al-Turki, Saeed; Anderson, Carl; Antony, Dinu; Barroso, Inês; Bentham, Jamie; Bhattacharya, Shoumo; Carss, Keren; Chatterjee, Krishna; Cirak, Sebahattin; Cosgrove, Catherine; Danecek, Petr; Durbin, Richard; Fitzpatrick, David; Floyd, Jamie; Reghan Foley, A.; Franklin, Chris; Futema, Marta; Humphries, Steve E.; Hurles, Matt; Joyce, Chris; McCarthy, Shane; Mitchison, Hannah M.; Muddyman, Dawn; Muntoni, Francesco; O'Rahilly, Stephen; Onoufriadis, Alexandros; Payne, Felicity; Plagnol, Vincent; Raymond, Lucy; Savage, David B.; Scambler, Peter; Schmidts, Miriam; Schoenmakers, Nadia; Semple, Robert; Serra, Eva; Stalker, Jim; van Kogelenberg, Margriet; Vijayarangakannan, Parthiban; Walter, Klaudia; Whittall, Ros; Williamson, Kathy

2016-01-01

Cellular organelles provide opportunities to relate biological mechanisms to disease. Here we use affinity proteomics, genetics and cell biology to interrogate cilia: poorly understood organelles, where defects cause genetic diseases. Two hundred and seventeen tagged human ciliary proteins create a final landscape of 1,319 proteins, 4,905 interactions and 52 complexes. Reverse tagging, repetition of purifications and statistical analyses, produce a high-resolution network that reveals organelle-specific interactions and complexes not apparent in larger studies, and links vesicle transport, the cytoskeleton, signalling and ubiquitination to ciliary signalling and proteostasis. We observe sub-complexes in exocyst and intraflagellar transport complexes, which we validate biochemically, and by probing structurally predicted, disruptive, genetic variants from ciliary disease patients. The landscape suggests other genetic diseases could be ciliary including 3M syndrome. We show that 3M genes are involved in ciliogenesis, and that patient fibroblasts lack cilia. Overall, this organelle-specific targeting strategy shows considerable promise for Systems Medicine. PMID:27173435

The Disordered C-Terminus of Yeast Hsf1 Contains a Cryptic Low-Complexity Amyloidogenic Region.

PubMed

Pujols, Jordi; Santos, Jaime; Pallarès, Irantzu; Ventura, Salvador

2018-05-06

Response mechanisms to external stress rely on networks of proteins able to activate specific signaling pathways to ensure the maintenance of cell proteostasis. Many of the proteins mediating this kind of response contain intrinsically disordered regions, which lack a defined structure, but still are able to interact with a wide range of clients that modulate the protein function. Some of these interactions are mediated by specific short sequences embedded in the longer disordered regions. Because the physicochemical properties that promote functional and abnormal interactions are similar, it has been shown that, in globular proteins, aggregation-prone and binding regions tend to overlap. It could be that the same principle applies for disordered protein regions. In this context, we show here that a predicted low-complexity interacting region in the disordered C-terminus of the stress response master regulator heat shock factor 1 (Hsf1) protein corresponds to a cryptic amyloid region able to self-assemble into fibrillary structures resembling those found in neurodegenerative disorders.

Anti-aging treatments slow propagation of synucleinopathy by restoring lysosomal function.

PubMed

Kim, Dong-Kyu; Lim, Hee-Sun; Kawasaki, Ichiro; Shim, Yhong-Hee; Vaikath, Nishant N; El-Agnaf, Omar M A; Lee, He-Jin; Lee, Seung-Jae

2016-10-02

Aging is the major risk factor for neurodegenerative diseases that are also associated with impaired proteostasis, resulting in abnormal accumulation of protein aggregates. However, the role of aging in development and progression of disease remains elusive. Here, we used Caenorhabditis elegans models to show that aging-promoting genetic variations accelerated the rate of cell-to-cell transmission of SNCA/α-synuclein aggregates, hallmarks of Parkinson disease, and the progression of disease phenotypes, such as nerve degeneration, behavioral deficits, and reduced life span. Genetic and pharmacological anti-aging manipulations slowed the spread of aggregates and the associated phenotypes. Lysosomal degradation was significantly impaired in aging models, while anti-aging treatments reduced the impairment. Transgenic expression of hlh-30p::hlh-30, the master controller of lysosomal biogenesis, alleviated intercellular transmission of aggregates in the aging model. Our results demonstrate that the rate of aging closely correlates with the rate of aggregate propagation and that general anti-aging treatments can slow aggregate propagation and associated disease progression by restoring lysosomal function.

A Mitochondrial ATP synthase Subunit Interacts with TOR Signaling to Modulate Protein Homeostasis and Lifespan in Drosophila

PubMed Central

Sun, Xiaoping; Wheeler, Charles T.; Yolitz, Jason; Laslo, Mara; Alberico, Thomas; Sun, Yaning; Song, Qisheng; Zou, Sige

2014-01-01

SUMMARY Diet composition is a critical determinant of lifespan and nutrient imbalance is detrimental health. However, how nutrients interact with genetic factors to modulate lifespan remains elusive. We investigated how diet composition influences mitochondrial ATP synthase subunit d (ATPsyn-d) in modulating lifespan in Drosophila. ATPsyn-d knockdown extended lifespan in females fed low carbohydrate-to-protein (C:P) diets, but not the high C:P ratio diet. This extension was associated with increased resistance to oxidative stress, transcriptional changes in metabolism, proteostasis and immune genes, reduced protein damage and aggregation, and reduced phosphorylation of S6K and ERK in TOR and MAPK signaling, respectively. ATPsyn-d knockdown did not extend lifespan in females with reduced TOR signaling induced genetically by Tsc2 overexpression or pharmacologically by rapamycin. Our data reveal a link among diet, mitochondria, MAPK and TOR signaling in aging and stresses the importance of considering genetic background and diet composition in implementing interventions for promoting healthy aging. PMID:25220459

Heat Shock Proteins in Vascular Diabetic Complications: Review and Future Perspective

PubMed Central

Bellini, Stefania; Barutta, Federica; Imperatore, Luigi; Bruno, Graziella; Gruden, Gabriella

2017-01-01

Heat shock proteins (HSPs) are a large family of proteins highly conserved throughout evolution because of their unique cytoprotective properties. Besides assisting protein refolding and regulating proteostasis under stressful conditions, HSPs also play an important role in protecting cells from oxidative stress, inflammation, and apoptosis. Therefore, HSPs are crucial in counteracting the deleterious effects of hyperglycemia in target organs of diabetes vascular complications. Changes in HSP expression have been demonstrated in diabetic complications and functionally related to hyperglycemia-induced cell injury. Moreover, associations between diabetic complications and altered circulating levels of both HSPs and anti-HSPs have been shown in clinical studies. HSPs thus represent an exciting therapeutic opportunity and might also be valuable as clinical biomarkers. However, this field of research is still in its infancy and further studies in both experimental diabetes and humans are required to gain a full understanding of HSP relevance. In this review, we summarize current knowledge and discuss future perspective. PMID:29240668

Emerging therapies for idiopathic pulmonary fibrosis, a progressive age-related disease

PubMed Central

Mora, Ana L.; Rojas, Mauricio; Pardo, Annie; Selman, Moises

2018-01-01

Idiopathic pulmonary fibrosis (IPF) is a fatal age-associated disease that is characterized by progressive and irreversible scarring of the lung. The pathogenesis of IPF is not completely understood and current therapies are limited to those that reduce the rate of functional decline in patients with mild-to-moderate disease. In this context, new therapeutic approaches that substantially improve the survival time and quality of life of these patients are urgently needed. Our incomplete understanding of the pathogenic mechanisms of IPF and the lack of appropriate experimental models that reproduce the key characteristics of the human disease are major challenges. As ageing is a major risk factor for IPF, age-related cell perturbations such as telomere attrition, senescence, epigenetic drift, stem cell exhaustion, loss of proteostasis and mitochondrial dysfunction are becoming targets of interest for IPF therapy. In this Review, we discuss current and emerging therapies for IPF, particularly those targeting age-related mechanisms, and discuss future therapeutic approaches. PMID:29081515

Antibiotic use and abuse: a threat to mitochondria and chloroplasts with impact on research, health, and environment.

PubMed

Wang, Xu; Ryu, Dongryeol; Houtkooper, Riekelt H; Auwerx, Johan

2015-10-01

Recently, several studies have demonstrated that tetracyclines, the antibiotics most intensively used in livestock and that are also widely applied in biomedical research, interrupt mitochondrial proteostasis and physiology in animals ranging from round worms, fruit flies, and mice to human cell lines. Importantly, plant chloroplasts, like their mitochondria, are also under certain conditions vulnerable to these and other antibiotics that are leached into our environment. Together these endosymbiotic organelles are not only essential for cellular and organismal homeostasis stricto sensu, but also have an important role to play in the sustainability of our ecosystem as they maintain the delicate balance between autotrophs and heterotrophs, which fix and utilize energy, respectively. Therefore, stricter policies on antibiotic usage are absolutely required as their use in research confounds experimental outcomes, and their uncontrolled applications in medicine and agriculture pose a significant threat to a balanced ecosystem and the well-being of these endosymbionts that are essential to sustain health. © 2015 The Authors. Bioessays published by WILEY Periodicals, Inc.

Editing activity for eliminating mischarged tRNAs is essential in mammalian mitochondria

PubMed Central

Hilander, Taru; Zhou, Xiao-Long; Konovalova, Svetlana; Zhang, Fu-Ping; Euro, Liliya; Chilov, Dmitri; Poutanen, Matti; Chihade, Joseph

2018-01-01

Abstract Accuracy of protein synthesis is enabled by the selection of amino acids for tRNA charging by aminoacyl-tRNA synthetases (ARSs), and further enhanced by the proofreading functions of some of these enzymes for eliminating tRNAs mischarged with noncognate amino acids. Mouse models of editing-defective cytoplasmic alanyl-tRNA synthetase (AlaRS) have previously demonstrated the importance of proofreading for cytoplasmic protein synthesis, with embryonic lethal and progressive neurodegeneration phenotypes. Mammalian mitochondria import their own set of nuclear-encoded ARSs for translating critical polypeptides of the oxidative phosphorylation system, but the importance of editing by the mitochondrial ARSs for mitochondrial proteostasis has not been known. We demonstrate here that the human mitochondrial AlaRS is capable of editing mischarged tRNAs in vitro, and that loss of the proofreading activity causes embryonic lethality in mice. These results indicate that tRNA proofreading is essential in mammalian mitochondria, and cannot be overcome by other quality control mechanisms. PMID:29228266

Multifunctional Mitochondrial AAA Proteases

PubMed Central

Glynn, Steven E.

2017-01-01

Mitochondria perform numerous functions necessary for the survival of eukaryotic cells. These activities are coordinated by a diverse complement of proteins encoded in both the nuclear and mitochondrial genomes that must be properly organized and maintained. Misregulation of mitochondrial proteostasis impairs organellar function and can result in the development of severe human diseases. ATP-driven AAA+ proteins play crucial roles in preserving mitochondrial activity by removing and remodeling protein molecules in accordance with the needs of the cell. Two mitochondrial AAA proteases, i-AAA and m-AAA, are anchored to either face of the mitochondrial inner membrane, where they engage and process an array of substrates to impact protein biogenesis, quality control, and the regulation of key metabolic pathways. The functionality of these proteases is extended through multiple substrate-dependent modes of action, including complete degradation, partial processing, or dislocation from the membrane without proteolysis. This review discusses recent advances made toward elucidating the mechanisms of substrate recognition, handling, and degradation that allow these versatile proteases to control diverse activities in this multifunctional organelle. PMID:28589125

Unfolded Protein Response of the Endoplasmic Reticulum in Tumor Progression and Immunogenicity

PubMed Central

Yoo, Yoon Seon; Han, Hye Gyeong

2017-01-01

The endoplasmic reticulum (ER) is a pivotal regulator of folding, quality control, trafficking, and targeting of secreted and transmembrane proteins, and accordingly, eukaryotic cells have evolved specialized machinery to ensure that the ER enables these proteins to acquire adequate folding and maturation in the presence of intrinsic and extrinsic insults. This adaptive capacity of the ER to intrinsic and extrinsic perturbations is important for maintaining protein homeostasis, which is termed proteostasis. Failure in adaptation to these perturbations leads to accumulation of misfolded or unassembled proteins in the ER, which is termed ER stress, resulting in the activation of unfolded protein response (UPR) of the ER and the execution of ER-associated degradation (ERAD) to restore homeostasis. Furthermore, both of the two axes play key roles in the control of tumor progression, inflammation, immunity, and aging. Therefore, understanding UPR of the ER and subsequent ERAD will provide new insights into the pathogenesis of many human diseases and contribute to therapeutic intervention in these diseases. PMID:29430279

Targeting the hallmarks of cancer with therapy-induced endoplasmic reticulum (ER) stress

PubMed Central

Garg, Abhishek D; Maes, Hannelore; van Vliet, Alexander R; Agostinis, Patrizia

2015-01-01

The endoplasmic reticulum (ER) is at the center of a number of vital cellular processes such as cell growth, death, and differentiation, crosstalk with immune or stromal cells, and maintenance of proteostasis or homeostasis, and ER functions have implications for various pathologies including cancer. Recently, a number of major hallmarks of cancer have been delineated that are expected to facilitate the development of anticancer therapies. However, therapeutic induction of ER stress as a strategy to broadly target multiple hallmarks of cancer has been seldom discussed despite the fact that several primary or secondary ER stress-inducing therapies have been found to exhibit positive clinical activity in cancer patients. In the present review we provide a brief historical overview of the major discoveries and milestones in the field of ER stress biology with important implications for anticancer therapy. Furthermore, we comprehensively discuss possible strategies enabling the targeting of multiple hallmarks of cancer with therapy-induced ER stress. PMID:27308392

Impulse control disorder, lysosomal malfunction and ATP13A2 insufficiency in Parkinsonism.

PubMed

Liu, Jun-Ping; Li, Jianfeng; Lu, Yanhua; Wang, Lihui; Chen, Gang

2017-02-01

Lysosomal transport of cargos in neurons is essential for neuronal proteostasis, transmission and functional motors and behaviours. Lysosomal malfunction including storage disorders is involved in the pathogenesis of Parkinson's disease (PD). Given the unclear molecular mechanisms of diverse defects in PD phenotypes, especially behavioural deficits, this mini review explores the cellular contexts of PD impulse control disorders and the molecular aspects of lysosomal cross-membrane transports. Focuses are paid to trace metal involvements in α-synuclein assembly in Lewy bodies, the functions and molecular interactions of ATP13A2 as ATPase transporters in lysosomal membranes for cross-membrane trafficking and lysosomal homeostasis, and our current understandings of the neural circuits in ICD. Erroneously polarized distributions of cargos such as metals and lipids on each side of lysosomal membranes triggered by gene mutations and deregulated expression of ATP13A2 may thus instigate sensing protein structural changes such as aggregations, organelle degeneration, and specific neuronal ageing and death in Parkinsonism. © 2016 John Wiley & Sons Australia, Ltd.

Multifunctional Mitochondrial AAA Proteases.

PubMed

Glynn, Steven E

2017-01-01

Mitochondria perform numerous functions necessary for the survival of eukaryotic cells. These activities are coordinated by a diverse complement of proteins encoded in both the nuclear and mitochondrial genomes that must be properly organized and maintained. Misregulation of mitochondrial proteostasis impairs organellar function and can result in the development of severe human diseases. ATP-driven AAA+ proteins play crucial roles in preserving mitochondrial activity by removing and remodeling protein molecules in accordance with the needs of the cell. Two mitochondrial AAA proteases, i-AAA and m-AAA, are anchored to either face of the mitochondrial inner membrane, where they engage and process an array of substrates to impact protein biogenesis, quality control, and the regulation of key metabolic pathways. The functionality of these proteases is extended through multiple substrate-dependent modes of action, including complete degradation, partial processing, or dislocation from the membrane without proteolysis. This review discusses recent advances made toward elucidating the mechanisms of substrate recognition, handling, and degradation that allow these versatile proteases to control diverse activities in this multifunctional organelle.

Mitochondrial AAA proteases--towards a molecular understanding of membrane-bound proteolytic machines.

PubMed

Gerdes, Florian; Tatsuta, Takashi; Langer, Thomas

2012-01-01

Mitochondrial AAA proteases play an important role in the maintenance of mitochondrial proteostasis. They regulate and promote biogenesis of mitochondrial proteins by acting as processing enzymes and ensuring the selective turnover of misfolded proteins. Impairment of AAA proteases causes pleiotropic defects in various organisms including neurodegeneration in humans. AAA proteases comprise ring-like hexameric complexes in the mitochondrial inner membrane and are functionally conserved from yeast to man, but variations are evident in the subunit composition of orthologous enzymes. Recent structural and biochemical studies revealed how AAA proteases degrade their substrates in an ATP dependent manner. Intersubunit coordination of the ATP hydrolysis leads to an ordered ATP hydrolysis within the AAA ring, which ensures efficient substrate dislocation from the membrane and translocation to the proteolytic chamber. In this review, we summarize recent findings on the molecular mechanisms underlying the versatile functions of mitochondrial AAA proteases and their relevance to those of the other AAA+ machines. Copyright © 2011 Elsevier B.V. All rights reserved.

Systematic analysis of protein turnover in primary cells.

PubMed

Mathieson, Toby; Franken, Holger; Kosinski, Jan; Kurzawa, Nils; Zinn, Nico; Sweetman, Gavain; Poeckel, Daniel; Ratnu, Vikram S; Schramm, Maike; Becher, Isabelle; Steidel, Michael; Noh, Kyung-Min; Bergamini, Giovanna; Beck, Martin; Bantscheff, Marcus; Savitski, Mikhail M

2018-02-15

A better understanding of proteostasis in health and disease requires robust methods to determine protein half-lives. Here we improve the precision and accuracy of peptide ion intensity-based quantification, enabling more accurate protein turnover determination in non-dividing cells by dynamic SILAC-based proteomics. This approach allows exact determination of protein half-lives ranging from 10 to >1000 h. We identified 4000-6000 proteins in several non-dividing cell types, corresponding to 9699 unique protein identifications over the entire data set. We observed similar protein half-lives in B-cells, natural killer cells and monocytes, whereas hepatocytes and mouse embryonic neurons show substantial differences. Our data set extends and statistically validates the previous observation that subunits of protein complexes tend to have coherent turnover. Moreover, analysis of different proteasome and nuclear pore complex assemblies suggests that their turnover rate is architecture dependent. These results illustrate that our approach allows investigating protein turnover and its implications in various cell types.

Constraints and consequences of the emergence of amino acid repeats in eukaryotic proteins.

PubMed

Chavali, Sreenivas; Chavali, Pavithra L; Chalancon, Guilhem; de Groot, Natalia Sanchez; Gemayel, Rita; Latysheva, Natasha S; Ing-Simmons, Elizabeth; Verstrepen, Kevin J; Balaji, Santhanam; Babu, M Madan

2017-09-01

Proteins with amino acid homorepeats have the potential to be detrimental to cells and are often associated with human diseases. Why, then, are homorepeats prevalent in eukaryotic proteomes? In yeast, homorepeats are enriched in proteins that are essential and pleiotropic and that buffer environmental insults. The presence of homorepeats increases the functional versatility of proteins by mediating protein interactions and facilitating spatial organization in a repeat-dependent manner. During evolution, homorepeats are preferentially retained in proteins with stringent proteostasis, which might minimize repeat-associated detrimental effects such as unregulated phase separation and protein aggregation. Their presence facilitates rapid protein divergence through accumulation of amino acid substitutions, which often affect linear motifs and post-translational-modification sites. These substitutions may result in rewiring protein interaction and signaling networks. Thus, homorepeats are distinct modules that are often retained in stringently regulated proteins. Their presence facilitates rapid exploration of the genotype-phenotype landscape of a population, thereby contributing to adaptation and fitness.

Chemical methods for encoding and decoding of posttranslational modifications

PubMed Central

Chuh, Kelly N.; Batt, Anna R.; Pratt, Matthew R.

2016-01-01

A large array of posttranslational modifications can dramatically change the properties of proteins and influence different aspects of their biological function such as enzymatic activity, binding interactions, and proteostasis. Despite the significant knowledge that has been gained about the function of posttranslational modifications using traditional biological techniques, the analysis of the site-specific effects of a particular modification, the identification of the full compliment of modified proteins in the proteome, and the detection of new types of modifications remains challenging. Over the years, chemical methods have contributed significantly in both of these areas of research. This review highlights several posttranslational modifications where chemistry-based approaches have made significant contributions to our ability to both prepare homogeneously modified proteins and identify and characterize particular modifications in complex biological settings. As the number and chemical diversity of documented posttranslational modifications continues to rise, we believe that chemical strategies will be essential to advance the field in years to come. PMID:26933738

Systematic harmonic power laws inter-relating multiple fundamental constants

NASA Astrophysics Data System (ADS)

Chakeres, Donald; Buckhanan, Wayne; Andrianarijaona, Vola

2017-01-01

Power laws and harmonic systems are ubiquitous in physics. We hypothesize that 2, π, the electron, Bohr radius, Rydberg constant, neutron, fine structure constant, Higgs boson, top quark, kaons, pions, muon, Tau, W, and Z when scaled in a common single unit are all inter-related by systematic harmonic powers laws. This implies that if the power law is known it is possible to derive a fundamental constant's scale in the absence of any direct experimental data of that constant. This is true for the case of the hydrogen constants. We created a power law search engine computer program that randomly generated possible positive or negative powers searching when the product of logical groups of constants equals 1, confirming they are physically valid. For 2, π, and the hydrogen constants the search engine found Planck's constant, Coulomb's energy law, and the kinetic energy law. The product of ratios defined by two constants each was the standard general format. The search engine found systematic resonant power laws based on partial harmonic fraction powers of the neutron for all of the constants with products near 1, within their known experimental precision, when utilized with appropriate hydrogen constants. We conclude that multiple fundamental constants are inter-related within a harmonic power law system.

Experiences of university students living with mental health problems: Interrelations between the self, the social, and the school.

PubMed

Kirsh, Bonnie; Friedland, Judith; Cho, Sunny; Gopalasuntharanathan, Nisha; Orfus, Shauna; Salkovitch, Marni; Snider, Katrina; Webber, Colleen

2015-01-01

A university education is becoming ever-more important in preparing for employment in the knowledge-driven economy. Yet, many university students are not able to complete their degrees because they experience mental health problems during the course of their higher education. Despite the growing numbers of students seeking help, there is limited knowledge about the issues that these students face. The purpose of this study was to understand the range of individual, interpersonal, and environmental factors that affect the lives of university students living with mental health problems. The study was based at a large public university in Canada. Semi-structured interviews were conducted with 19 students with self-identified mental health problems. Their narratives were analyzed using grounded theory methods and a model was developed which drew upon social-ecological theory. Findings depict student experiences as a function of the self (individual factors), the social (interpersonal factors) and the school (environmental factors) and their interrelations. Interventions must be designed to address all three of these areas and their interrelations. The model can be used to guide universities in designing interventions; however, a fourth level that incorporates a university policy that values and supports student mental health, should be included.

Patterned-string tasks: relation between fine motor skills and visual-spatial abilities in parrots.

PubMed

Krasheninnikova, Anastasia

2013-01-01

String-pulling and patterned-string tasks are often used to analyse perceptual and cognitive abilities in animals. In addition, the paradigm can be used to test the interrelation between visual-spatial and motor performance. Two Australian parrot species, the galah (Eolophus roseicapilla) and the cockatiel (Nymphicus hollandicus), forage on the ground, but only the galah uses its feet to manipulate food. I used a set of string pulling and patterned-string tasks to test whether usage of the feet during foraging is a prerequisite for solving the vertical string pulling problem. Indeed, the two species used techniques that clearly differed in the extent of beak-foot coordination but did not differ in terms of their success in solving the string pulling task. However, when the visual-spatial skills of the subjects were tested, the galahs outperformed the cockatiels. This supports the hypothesis that the fine motor skills needed for advanced beak-foot coordination may be interrelated with certain visual-spatial abilities needed for solving patterned-string tasks. This pattern was also found within each of the two species on the individual level: higher motor abilities positively correlated with performance in patterned-string tasks. This is the first evidence of an interrelation between visual-spatial and motor abilities in non-mammalian animals.

Risk behaviours of an interrelated syphilis-infected sexual network of men who have sex with men.

PubMed

Diesterheft, Richie; Brady, John P; Shattell, Mona

2016-12-01

We examined the risk behaviours in an interrelated sexual network of 33 syphilis-infected men who have sex with men on the use of condoms, substances and websites to meet sexual partners. Our study used a descriptive exploratory design to investigate co-occurring high-risk behaviours in this interrelated sexual network to inform future health interventions and research directions. Although the risk behaviours for human immunodeficiency virus transmission in men who have sex with men have been studied, few have studied the high-risk population of men who already have syphilis, and even fewer have studied the risk behaviours in sexual networks of syphilis-infected men who have sex with men who were identified using contact tracing. The data were collected from semi-structured, individual interviews at a not-for-profit lesbian, gay, bisexual and transgender health centre in a large city in the Midwestern USA. Inconsistent condom use was substantial during both insertive (92%) and receptive (88%) anal intercourse. Most participants (97%) reported using one or more substances prior to or during anal intercourse, and Internet websites were the most common place to meet sexual partners (88%). High-risk behaviours were significant within this syphilis-infected sexual network of men who have sex with men. The majority of our 33 participants were non-Hispanic Whites (n = 27, 82%), possessed a baccalaureate degree or higher (n = 23, 70%), and actively sought out unprotected anal intercourse [21 participants (64%) used BareBackRT.com, a website to seek out unprotected anal intercourse]. Nurses should be more informed about the risk factors of a high-risk sexual network of syphilis-infected men who have sex with men. Interrelated sexual networks have high levels of similarity among participants' high-risk behaviours; contact tracing may be used to identify individual participants for relevant risk-reduction interventions. © 2016 John Wiley & Sons Ltd.

Population pharmacokinetics of empagliflozin, a sodium glucose cotransporter 2 inhibitor, in patients with type 2 diabetes.

PubMed

Riggs, Matthew M; Staab, Alexander; Seman, Leo; MacGregor, Thomas R; Bergsma, Timothy T; Gastonguay, Marc R; Macha, Sreeraj

2013-10-01

Data from five randomized, placebo-controlled, multiple oral dose studies of empagliflozin in patients with type 2 diabetes mellitus (T2DM; N = 974; 1-100 mg q.d.; ≤12 weeks) were used to develop a population pharmacokinetic (PK) model for empagliflozin. The model consisted of two-compartmental disposition, lagged first-order absorption and first-order elimination, and incorporated appropriate covariates. Population estimates (interindividual variance, CV%) of oral apparent clearance, central and peripheral volumes of distribution, and inter-compartmental clearance were 9.87 L/h (26.9%), 3.02 L, 60.4 L (30.8%), and 5.16 L/h, respectively. An imposed allometric weight effect was the most influential PK covariate effect, with a maximum effect on exposure of ±30%, using 2.5th and 97.5th percentiles of observed weights, relative to the median observed weight. Sex and race did not lend additional description to PK variability beyond allometric weight effects, other than ∼25% greater oral absorption rate constant for Asian patients. Age, total protein, and smoking/alcohol history did not affect PK parameters. Predictive check plots were consistent with observed data, implying an adequate description of empagliflozin PKs following multiple dosing in patients with T2DM. The lack of marked covariate effects, including weight, suggests that no exposure-based dose adjustments were required within the study population and dose range. © The Author(s) 2013 John Wiley & Sons, Ltd.

In vivo dynamic turnover of cerebral 13C isotopomers from [U- 13C]glucose

NASA Astrophysics Data System (ADS)

Xu, Su; Shen, Jun

2006-10-01

An INEPT-based 13C MRS method and a cost-effective and widely available 11.7 Tesla 89-mm bore vertical magnet were used to detect dynamic 13C isotopomer turnover from intravenously infused [U- 13C]glucose in a 211 μL voxel located in the adult rat brain. The INEPT-based 1H → 13C polarization transfer method is mostly adiabatic and therefore minimizes signal loss due to B 1 inhomogeneity of the surface coils used. High quality and reproducible data were acquired as a result of combined use of outer volume suppression, ISIS, and the single-shot three-dimensional localization scheme built in the INEPT pulse sequence. Isotopomer patterns of both glutamate C4 at 34.00 ppm and glutamine C4 at 31.38 ppm are dominated first by a doublet originated from labeling at C4 and C5 but not at C3 (with 1JC4C5 = 51 Hz) and then by a quartet originated from labeling at C3, C4, and C5 (with 1JC3C4 = 35 Hz). A lag in the transition of glutamine C4 pattern from doublet-dominance to quartet dominance as compared to glutamate C4 was observed, which provides an independent verification of the precursor-product relationship between neuronal glutamate and glial glutamine and a significant intercompartmental cerebral glutamate-glutamine cycle between neurons and glial cells.

Knee joint passive stiffness and moment in sagittal and frontal planes markedly increase with compression.

PubMed

Marouane, H; Shirazi-Adl, A; Adouni, M

2015-01-01

Knee joints are subject to large compression forces in daily activities. Due to artefact moments and instability under large compression loads, biomechanical studies impose additional constraints to circumvent the compression position-dependency in response. To quantify the effect of compression on passive knee moment resistance and stiffness, two validated finite element models of the tibiofemoral (TF) joint, one refined with depth-dependent fibril-reinforced cartilage and the other less refined with homogeneous isotropic cartilage, are used. The unconstrained TF joint response in sagittal and frontal planes is investigated at different flexion angles (0°, 15°, 30° and 45°) up to 1800 N compression preloads. The compression is applied at a novel joint mechanical balance point (MBP) identified as a point at which the compression does not cause any coupled rotations in sagittal and frontal planes. The MBP of the unconstrained joint is located at the lateral plateau in small compressions and shifts medially towards the inter-compartmental area at larger compression forces. The compression force substantially increases the joint moment-bearing capacities and instantaneous angular rigidities in both frontal and sagittal planes. The varus-valgus laxities diminish with compression preloads despite concomitant substantial reductions in collateral ligament forces. While the angular rigidity would enhance the joint stability, the augmented passive moment resistance under compression preloads plays a role in supporting external moments and should as such be considered in the knee joint musculoskeletal models.

Cellular and molecular modifier pathways in tauopathies: the big picture from screening invertebrate models.

PubMed

Hannan, Shabab B; Dräger, Nina M; Rasse, Tobias M; Voigt, Aaron; Jahn, Thomas R

2016-04-01

Abnormal tau accumulations were observed and documented in post-mortem brains of patients affected by Alzheimer's disease (AD) long before the identification of mutations in the Microtubule-associated protein tau (MAPT) gene, encoding the tau protein, in a different neurodegenerative disease called Frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17). The discovery of mutations in the MAPT gene associated with FTDP-17 highlighted that dysfunctions in tau alone are sufficient to cause neurodegeneration. Invertebrate models have been diligently utilized in investigating tauopathies, contributing to the understanding of cellular and molecular pathways involved in disease etiology. An important discovery came with the demonstration that over-expression of human tau in Drosophila leads to premature mortality and neuronal dysfunction including neurodegeneration, recapitulating some key neuropathological features of the human disease. The simplicity of handling invertebrate models combined with the availability of a diverse range of experimental resources make these models, in particular Drosophila a powerful invertebrate screening tool. Consequently, several large-scale screens have been performed using Drosophila, to identify modifiers of tau toxicity. The screens have revealed not only common cellular and molecular pathways, but in some instances the same modifier has been independently identified in two or more screens suggesting a possible role for these modifiers in regulating tau toxicity. The purpose of this review is to discuss the genetic modifier screens on tauopathies performed in Drosophila and C. elegans models, and to highlight the common cellular and molecular pathways that have emerged from these studies. Here, we summarize results of tau toxicity screens providing mechanistic insights into pathological alterations in tauopathies. Key pathways or modifiers that have been identified are associated with a broad range of processes including, but not limited to, phosphorylation, cytoskeleton organization, axonal transport, regulation of cellular proteostasis, transcription, RNA metabolism, cell cycle regulation, and apoptosis. We discuss the utility and application of invertebrate models in elucidating the cellular and molecular functions of novel and uncharacterized disease modifiers identified in large-scale screens as well as for investigating the function of genes identified as risk factors in genome-wide association studies from human patients in the post-genomic era. In this review, we combined and summarized several large-scale modifier screens performed in invertebrate models to identify modifiers of tau toxicity. A summary of the screens show that diverse cellular processes are implicated in the modification of tau toxicity. Kinases and phosphatases are the most predominant class of modifiers followed by components required for cellular proteostasis and axonal transport and cytoskeleton elements. © 2016 International Society for Neurochemistry.

[Standardisation of nursing care amongst patients in prison].

PubMed

Martínez-Delgado, M M

2014-01-01

To develop the Standardized Nursing Care Process format amongst patients in a prison. Observational, descriptive study, conducted on a sample of thirty patients in Soria Prison between March and June 2011. We collected information via a review of medical records and conducted an interview of nursing assessments using functional patterns. Subsequent nursing diagnoses and interrelated problems were obtained using NANDA taxonomy. The subsequent use of NIC and NOC taxonomy marked the activities and performance criteria for each diagnosis, in the same way as for interrelated problems. The nursing diagnoses found in the patient sample analyzed, and the frequency thereof, reveal peculiarities in terms of the health care needs of the prison population, which makes it possible to standardize nursing care plans for the population under study.

The origins of Penrose diagrams in physics, art, and the psychology of perception, 1958-62.

PubMed

Wright, Aaron Sidney

2013-09-01

Penrose diagrams gave mid-twentieth century physicists studying General Relativity (GR) a new tool for understanding Einstein's theory of gravity. Starting in 1962 they allowed new understandings and conceptualizations of the mathematical objects of theoretical physics. One origin of the diagrams is found in Roger Penrose's engagement with the art of "impossible objects". These new understandings contributed to the "renaissance" GR experienced starting in the late 1950s. By following the diagrams through the GR community, the interrelation of research and pedagogy is explicated. This interrelation rapidly disseminated the tools to new workers in the field, further amplifying the effect of this new theoretical tool on disciplinary growth. Copyright © 2013 Elsevier Ltd. All rights reserved.

Regional cooperation in transportation planning.

DOT National Transportation Integrated Search

2012-02-01

As Floridas urbanized areas grow and merge, : neighboring jurisdictions experience interrelated : problems and opportunities, and regional : cooperation becomes an imperative. In the : transportation sector, Floridas metropolitan : planning org...

Regional cooperation in transportation planning : [summary].

DOT National Transportation Integrated Search

2012-01-01

As Floridas urbanized areas grow and merge, : neighboring jurisdictions experience interrelated : problems and opportunities, and regional : cooperation becomes an imperative. In the : transportation sector, Floridas metropolitan : planning org...

Operationalizing Heedful Interrelating: How Attending, Responding, and Feeling Comprise Coordinating and Predict Performance in Self-Managing Teams.

PubMed

Stephens, John Paul; Lyddy, Christopher J

2016-01-01

Team coordination implies a system of individual behavioral contributions occurring within a network of interpersonal relationships to achieve a collective goal. Current research on coordination has emphasized its relational aspects, but has not adequately accounted for how team members also simultaneously manage individual behavioral contributions and represent the whole system of the team's work. In the current study, we develop theory and test how individuals manage all three aspects of coordinating through the three facets described in the theory of heedful interrelating. We operationalize the facet of contributing as distributing attention between self and others, subordinating as responsively communicating, and representing as feeling the system of the team's work as a cohesive whole. We then test the relationships among these facets and their influence on team performance in an experiment with 50 ad hoc triads of undergraduate student self-managing teams tasked with collectively composing a song in the lab. In analyzing thin-slices of video data of these teams' coordination, we found that teams with members displaying greater dispersion of attentional distribution and more responsive communicating experienced a stronger feeling of the team as a whole. Responsive communication also predicted team performance. Accounting for how the three aspects of coordinating are managed by individual team members provides a more critical understanding of heedful interrelating, and insight into emergent coordination processes.

Operationalizing Heedful Interrelating: How Attending, Responding, and Feeling Comprise Coordinating and Predict Performance in Self-Managing Teams

PubMed Central

Stephens, John Paul; Lyddy, Christopher J.

2016-01-01

Team coordination implies a system of individual behavioral contributions occurring within a network of interpersonal relationships to achieve a collective goal. Current research on coordination has emphasized its relational aspects, but has not adequately accounted for how team members also simultaneously manage individual behavioral contributions and represent the whole system of the team's work. In the current study, we develop theory and test how individuals manage all three aspects of coordinating through the three facets described in the theory of heedful interrelating. We operationalize the facet of contributing as distributing attention between self and others, subordinating as responsively communicating, and representing as feeling the system of the team's work as a cohesive whole. We then test the relationships among these facets and their influence on team performance in an experiment with 50 ad hoc triads of undergraduate student self-managing teams tasked with collectively composing a song in the lab. In analyzing thin-slices of video data of these teams' coordination, we found that teams with members displaying greater dispersion of attentional distribution and more responsive communicating experienced a stronger feeling of the team as a whole. Responsive communication also predicted team performance. Accounting for how the three aspects of coordinating are managed by individual team members provides a more critical understanding of heedful interrelating, and insight into emergent coordination processes. PMID:27047407

Structure and Correlates of Cognitive Aging in a Narrow Age Cohort

PubMed Central

2014-01-01

Aging-related changes occur for multiple domains of cognitive functioning. An accumulating body of research indicates that, rather than representing statistically independent phenomena, aging-related cognitive changes are moderately to strongly correlated across domains. However, previous studies have typically been conducted in age-heterogeneous samples over longitudinal time lags of 6 or more years, and have failed to consider whether results are robust to a comprehensive set of controls. Capitalizing on 3-year longitudinal data from the Lothian Birth Cohort of 1936, we took a longitudinal narrow age cohort approach to examine cross-domain cognitive change interrelations from ages 70 to 73 years. We fit multivariate latent difference score models to factors representing visuospatial ability, processing speed, memory, and crystallized ability. Changes were moderately interrelated, with a general factor of change accounting for 47% of the variance in changes across domains. Change interrelations persisted at close to full strength after controlling for a comprehensive set of demographic, physical, and medical factors including educational attainment, childhood intelligence, physical function, APOE genotype, smoking status, diagnosis of hypertension, diagnosis of cardiovascular disease, and diagnosis of diabetes. Thus, the positive manifold of aging-related cognitive changes is highly robust in that it can be detected in a narrow age cohort followed over a relatively brief longitudinal period, and persists even after controlling for many potential confounders. PMID:24955992

Structure and correlates of cognitive aging in a narrow age cohort.

PubMed

Tucker-Drob, Elliot M; Briley, Daniel A; Starr, John M; Deary, Ian J

2014-06-01

Aging-related changes occur for multiple domains of cognitive functioning. An accumulating body of research indicates that, rather than representing statistically independent phenomena, aging-related cognitive changes are moderately to strongly correlated across domains. However, previous studies have typically been conducted in age-heterogeneous samples over longitudinal time lags of 6 or more years, and have failed to consider whether results are robust to a comprehensive set of controls. Capitalizing on 3-year longitudinal data from the Lothian Birth Cohort of 1936, we took a longitudinal narrow age cohort approach to examine cross-domain cognitive change interrelations from ages 70 to 73 years. We fit multivariate latent difference score models to factors representing visuospatial ability, processing speed, memory, and crystallized ability. Changes were moderately interrelated, with a general factor of change accounting for 47% of the variance in changes across domains. Change interrelations persisted at close to full strength after controlling for a comprehensive set of demographic, physical, and medical factors including educational attainment, childhood intelligence, physical function, APOE genotype, smoking status, diagnosis of hypertension, diagnosis of cardiovascular disease, and diagnosis of diabetes. Thus, the positive manifold of aging-related cognitive changes is highly robust in that it can be detected in a narrow age cohort followed over a relatively brief longitudinal period, and persists even after controlling for many potential confounders. PsycINFO Database Record (c) 2014 APA, all rights reserved.

Self-esteem, negative emotionality, and depression as a common temperamental core: a study of mid-adolescent twin girls.

PubMed

Neiss, Michelle B; Stevenson, Jim; Legrand, Lisa N; Iacono, William G; Sedikides, Constantine

2009-04-01

We tested the structure and magnitude of genetic and environmental influences on the overlap among self-esteem, negative emotionality, and major depression symptoms in adolescent girls (N=706) from the Minnesota Twin Family Study. Genetic and environmental influences on all three operated via a general, heritable factor. Genetic influences explained the majority of overlap among the three constructs, as well as most of the variance in self-esteem and negative emotionality. Genetic influences on depression were more modest and largely due to genetic factors specific to depression. These findings support the theory that self-esteem, depression, and neuroticism represent aspects of a common temperamental core. The interrelations among the three constructs in mid-adolescence is consistent with their interrelations in adulthood.

Interrelation of the effects caused by the rotation of the whispering gallery modes resonator

NASA Astrophysics Data System (ADS)

Dmitriyeva, Anna D.; Filatov, Yuri V.; Shalymov, Egor V.; Venediktov, Vladimir Yu.

2016-11-01

Optical whispering gallery modes resonators are characterized by unique properties: ultrahigh quality factor, small amount of the modes and small size. It allows to use them in compact high-precision measuring devices. In particular these resonators can be used in the composition of gyros. For today all researches, devoted to the application of the whispering gallery modes resonators in gyros, deals only with one of induced by the rotation effects (Sagnac effect or the influence of centrifugal forces on the resonator size). In this work we study the interrelation of the effects caused by the rotation of the whispering gallery modes resonator. Also in work we consider the possibility of joint application of both effects (the influence of centrifugal forces and Sagnac effect) for measuring angular velocity.

Current Issues and Priorities in Childhood Nutrition, Growth, and Infections123

PubMed Central

Salam, Rehana A; Das, Jai K; Bhutta, Zulfiqar A

2015-01-01

Forty-five percent of the 6.6 million under-5 deaths in 2012 were attributable to infectious disease, of which pneumonia and diarrhea were the leading causes. Despite the close interrelation between these infections and nutrition conditions, key nutrition interventions for prevention of childhood diarrhea and pneumonia have not received deserved attention, especially in low- and middle-income countries. Several interventions and strategies can effectively address these issues but are not available to those in need. This article discusses in detail the burden and trends of global under-5 mortality, infections, and nutrition conditions; etiology and associated risk factors; biological plausibility and the interrelation between infections, nutrition, and growth; and existing interventions and strategies to reduce major childhood infections and improve nutrition and growth and implications. PMID:25833888

On the biology of Tropidurus delanonis, Baur (Iguanidae).

PubMed

Werner, D I

1978-08-01

A field study of Tropidurus delanonis was carried out on an uninhabited island (Hood) of the Galapagos Archipelago over 18 months. The purpose of the study is to show the interrelation between social structure, behaviour and ecological aspects of the iguanid lizard Tropidurus delanonis. Five lizard categories are distinguished and the interrelation between colouration type and behaviour is shown. Data are given on population structure, composition and flexibility, reproductive cycle, clutch size, ontogeny and changes in colouration and behaviour. Detailed maps show the distribution of female and male territories and the area occupied by those male male that attempt to acquire a territory. The biomass is calculated for all categories in resect to total area available and to favorable and unfavorable areas within the observation area. The significance of various colouration types was tested experimentally.

Investigation of influence of hypomagnetic conditions closely similar to interplanetary magnetic filed on behavioral and vegetative reactions of higher mammals

NASA Astrophysics Data System (ADS)

Krivova, Natalie; Trukhanov, Kiril; Zamotshina, Tatyana; Zaeva, Olga; Khodanovich, Marina; Misina, Tatyana; Tukhvatulin, Ravil; Suhko, Valery

To study the influence of long being under reduced magnetic field on behavioral and vegetative reactions of higher mammals the white rat males were put into the 700-1000 times reduced geomagnetic field (50-70 nT) for 25 days. Such field was obtained by using automatic compensation of the horizontal and vertical components of the GMF at a frequencies up to 10 Hz by means of solenoids of the experimental magnetic system. Control animals were located in the same room under usual laboratory GMF conditions (52 uT). Two days before the experiment the behavioral reactions were studied in the "open field" by means of a set of tests, characterizing the level of emotionality, moving and orientational-investigative activities of the animals under conditions of unimpeded behavior. 60 white underbred rat males with the initial body mass of 200 g were divided into three clusters. Animals with average indices were selected for the experiment. We have judged behavioral reaction disturbances of the rats under hypomagnetic conditions using videotape recordings carried out in the entire course of the chronic experiment. According to the obtained results during the period of maximum activity (from 230 to 330 a.m.) the number of interrelations between the individuals increased appreciably for experimental rats including interrelations with aggressive character. This was real during all 25 days of observation. We observed a certain dynamics of this index differed from that of the control group. We have also analyzed the final period of observation from the 21th to the 25th days. In this period we studied the 24 hours' dynamics of interrelations which were noted during 5 minutes in every hour around the clock. In the control group the number of interrelation was at a constantly low level. For experimental animals the number of interrelations was higher in the night hours than in the day ones. Moreover it exceeded the similar indexes observed from the 1st to the 20th day. For example from 300 to 305 a.m. on the 23th day we recorded 27 contacts of aggressive character between the individuals. So, in hypomagnetic field conditions the irritability of the animals' central nervous system grows, that expresses itself in the increase of contacts of aggressive and non-aggressive character between the individuals. Also we have carried out the Spirman correlation analysis between studied indices of moving activity and chemiluminescence of blood plasma and urine, electrolytic composition of urine and muscles. For control animals the quantity of correlation connections between electrolyte concentrations in studied substrata was higher than for experimental animals. The physiological sense of these correlation connections is discussed.

Chaos: Choto delat?

NASA Astrophysics Data System (ADS)

Campbell, David

1987-11-01

I provide a brief overview of the current status of the field of deterministic "chaos" stressing its interrelations and applications to other fields and suggesting a number of important open problems for future study.

MIMS for TRIM

EPA Pesticide Factsheets

MIMS supports complex computational studies that use multiple interrelated models / programs, such as the modules within TRIM. MIMS is used by TRIM to run various models in sequence, while sharing input and output files.

Counseling Suicidal Persons.

ERIC Educational Resources Information Center

Sinick, Daniel

1979-01-01

There are many interrelated reasons why people commit suicide. Emotional and situational clues are available to alert counselors, who must remain nonjudgemental. Counselors who accept and respect suicidal clients help improve their self esteem. (JAC)

Intermodal terminals.

DOT National Transportation Integrated Search

2013-05-01

The location and development of an intermodal terminal is an important decision for a : railroad; however, such decisions are increasingly interrelated to private and/or public : initiatives. Not only are these projects significant for the railroad, ...

Interdisciplinary Interactions During R&D and Early Design of Large Engineered Systems

NASA Technical Reports Server (NTRS)

McGowan, Anna-Maria Rivas

2014-01-01

Designing Large-Scale Complex Engineered Systems (LaCES) such as aircraft and submarines requires the input of thousands of engineers and scientists whose work is proximate in neither time nor space. Comprehensive knowledge of the system is dispersed among specialists whose expertise is in typically one system component or discipline. This study examined the interactive work practices among such specialists seeking to improve engineering practice through a rigorous and theoretical understanding of current practice. This research explored current interdisciplinary practices and perspectives during R&D and early LaCES design and identified why these practices and perspectives prevail and persist. The research design consisted of a three-fold, integrative approach that combined an open-ended survey, semi-structured interviews, and ethnography. Significant empirical data from experienced engineers and scientists in a large engineering organization were obtained and integrated with theories from organization science and engineering. Qualitative analysis was used to obtain a holistic, contextualized understanding. The over-arching finding is that issues related to cognition, organization, and social interrelations mostly dominate interactions across disciplines. Engineering issues, such as the integration of hardware or physics-based models, are not as significant. For example, organization culture is an important underlying factor that guided researchers more toward individual sovereignty over cross-disciplinarity. The organization structure and the engineered system architecture also serve as constraints to the engineering work. Many differences in work practices were observed, including frequency and depth of interactions, definition or co-construction of requirements, clarity or creation of the system architecture, work group proximity, and cognitive challenges. Practitioners are often unaware of these differences resulting in confusion and incorrect assumptions regarding work expectations. Cognitively, the enactment and coconstruction of knowledge are the fundamental tasks of the interdisciplinary interactions. Distributed and collective cognition represent most of the efforts. Argument, ignorance, learning, and creativity are interrelated aspects of the interactions that cause discomfort but yield benefits such as problem mitigation, broader understanding, and improved system design and performance. The quality and quantity of social interrelations are central to all work across disciplines with reciprocity, respectful engagement, and heedful interrelations being significant to the effectiveness of the engineering and scientific work.

Accounting principles, reporting rules, and payment practices.

PubMed

Kovener, R R

1979-12-01

Misconceptions concerning the distinction between accounting principles, reporting rules, and payment practices and how they interrelate can lessen the effectiveness of hospital financial managers in these areas/clarification and recommendations are offered.

Future directions for transportation safety research

DOT National Transportation Integrated Search

2005-08-01

Many opportunities now exist that can contribute significantly to preventing accidents, mitigating consequences, and improving responses to incidents in all modes. Two parallel and interrelated areas that offer particularly promising results are tech...

Aging, metabolism and stem cells: Spotlight on muscle stem cells.

PubMed

García-Prat, Laura; Muñoz-Cánoves, Pura

2017-04-15

All tissues and organs undergo a progressive regenerative decline as they age. This decline has been mainly attributed to loss of stem cell number and/or function, and both stem cell-intrinsic changes and alterations in local niches and/or systemic environment over time are known to contribute to the stem cell aging phenotype. Advancing in the molecular understanding of the deterioration of stem cell cells with aging is key for targeting the specific causes of tissue regenerative dysfunction at advanced stages of life. Here, we revise exciting recent findings on why stem cells age and the consequences on tissue regeneration, with a special focus on regeneration of skeletal muscle. We also highlight newly identified common molecular pathways affecting diverse types of aging stem cells, such as altered proteostasis, metabolism, or senescence entry, and discuss the questions raised by these findings. Finally, we comment on emerging stem cell rejuvenation strategies, principally emanating from studies on muscle stem cells, which will surely burst tissue regeneration research for future benefit of the increasing human aging population. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Defining Hsp70 Subnetworks in Dengue Virus Replication Reveals Key Vulnerability in Flavivirus Infection.

PubMed

Taguwa, Shuhei; Maringer, Kevin; Li, Xiaokai; Bernal-Rubio, Dabeiba; Rauch, Jennifer N; Gestwicki, Jason E; Andino, Raul; Fernandez-Sesma, Ana; Frydman, Judith

2015-11-19

Viral protein homeostasis depends entirely on the machinery of the infected cell. Accordingly, viruses can illuminate the interplay between cellular proteostasis components and their distinct substrates. Here, we define how the Hsp70 chaperone network mediates the dengue virus life cycle. Cytosolic Hsp70 isoforms are required at distinct steps of the viral cycle, including entry, RNA replication, and virion biogenesis. Hsp70 function at each step is specified by nine distinct DNAJ cofactors. Of these, DnaJB11 relocalizes to virus-induced replication complexes to promote RNA synthesis, while DnaJB6 associates with capsid protein and facilitates virion biogenesis. Importantly, an allosteric Hsp70 inhibitor, JG40, potently blocks infection of different dengue serotypes in human primary blood cells without eliciting viral resistance or exerting toxicity to the host cells. JG40 also blocks replication of other medically-important flaviviruses including yellow fever, West Nile and Japanese encephalitis viruses. Thus, targeting host Hsp70 subnetworks provides a path for broad-spectrum antivirals. Copyright © 2015 Elsevier Inc. All rights reserved.

Poly-Small Ubiquitin-like Modifier (PolySUMO)-binding Proteins Identified through a String Search*

PubMed Central

Sun, Huaiyu; Hunter, Tony

2012-01-01

Polysumoylation is a crucial cellular response to stresses against genomic integrity or proteostasis. Like the small ubiquitin-like modifier (SUMO)-targeted ubiquitin ligase RNF4, proteins with clustered SUMO-interacting motifs (SIMs) can be important signal transducers downstream of polysumoylation. To identify novel polySUMO-binding proteins, we conducted a computational string search with a custom Python script. We found clustered SIMs in another RING domain protein Arkadia/RNF111. Detailed biochemical analysis of the Arkadia SIMs revealed that dominant SIMs in a SIM cluster often contain a pentameric VIDLT ((V/I/L/F/Y)(V/I)DLT) core sequence that is also found in the SIMs in PIAS family E3s and is likely the best-fitted structure for SUMO recognition. This idea led to the identification of additional novel SIM clusters in FLASH/CASP8AP2, C5orf25, and SOBP/JXC1. We suggest that the clustered SIMs in these proteins form distinct SUMO binding domains to recognize diverse forms of protein sumoylation. PMID:23086935

Two Distinct Types of E3 Ligases Work in Unison to Regulate Substrate Ubiquitylation.

PubMed

Scott, Daniel C; Rhee, David Y; Duda, David M; Kelsall, Ian R; Olszewski, Jennifer L; Paulo, Joao A; de Jong, Annemieke; Ovaa, Huib; Alpi, Arno F; Harper, J Wade; Schulman, Brenda A

2016-08-25

Hundreds of human cullin-RING E3 ligases (CRLs) modify thousands of proteins with ubiquitin (UB) to achieve vast regulation. Current dogma posits that CRLs first catalyze UB transfer from an E2 to their client substrates and subsequent polyubiquitylation from various linkage-specific E2s. We report an alternative E3-E3 tagging cascade: many cellular NEDD8-modified CRLs associate with a mechanistically distinct thioester-forming RBR-type E3, ARIH1, and rely on ARIH1 to directly add the first UB and, in some cases, multiple additional individual monoubiquitin modifications onto CRL client substrates. Our data define ARIH1 as a component of the human CRL system, demonstrate that ARIH1 can efficiently and specifically mediate monoubiquitylation of several CRL substrates, and establish principles for how two distinctive E3s can reciprocally control each other for simultaneous and joint regulation of substrate ubiquitylation. These studies have broad implications for CRL-dependent proteostasis and mechanisms of E3-mediated UB ligation. Copyright © 2016 Elsevier Inc. All rights reserved.

Mitotic Dysfunction Associated with Aging Hallmarks.

PubMed

Macedo, Joana Catarina; Vaz, Sara; Logarinho, Elsa

2017-01-01

Aging is a biological process characterized by the progressive deterioration of physiological functions known to be the main risk factor for chronic diseases and declining health. There has been an emerging connection between aging and aneuploidy, an aberrant number of chromosomes, even though the molecular mechanisms behind age-associated aneuploidy remain largely unknown. In recent years, several genetic pathways and biochemical processes controlling the rate of aging have been identified and proposed as aging hallmarks. Primary hallmarks that cause the accumulation of cellular damage include genomic instability, telomere attrition, epigenetic alterations and loss of proteostasis (López-Otín et al., Cell 153:1194-1217, 2013). Here we review the provocative link between these aging hallmarks and the loss of chromosome segregation fidelity during cell division, which could support the correlation between aging and aneuploidy seen over the past decades. Secondly, we review the systemic impacts of aneuploidy in cell physiology and emphasize how these include some of the primary hallmarks of aging. Based on the evidence, we propose a mutual causality between aging and aneuploidy, and suggest modulation of mitotic fidelity as a potential means to ameliorate healthy lifespan.

Promiscuous binding by Hsp70 results in conformational heterogeneity and fuzzy chaperone-substrate ensembles

PubMed Central

Rosenzweig, Rina; Sekhar, Ashok; Nagesh, Jayashree; Kay, Lewis E

2017-01-01

The Hsp70 chaperone system is integrated into a myriad of biochemical processes that are critical for cellular proteostasis. Although detailed pictures of Hsp70 bound with peptides have emerged, correspondingly detailed structural information on complexes with folding-competent substrates remains lacking. Here we report a methyl-TROSY based solution NMR study showing that the Escherichia coli version of Hsp70, DnaK, binds to as many as four distinct sites on a small 53-residue client protein, hTRF1. A fraction of hTRF1 chains are also bound to two DnaK molecules simultaneously, resulting in a mixture of DnaK-substrate sub-ensembles that are structurally heterogeneous. The interactions of Hsp70 with a client protein at different sites results in a fuzzy chaperone-substrate ensemble and suggests a mechanism for Hsp70 function whereby the structural heterogeneity of released substrate molecules enables them to circumvent kinetic traps in their conformational free energy landscape and fold efficiently to the native state. DOI: http://dx.doi.org/10.7554/eLife.28030.001 PMID:28708484

Oxidative Stress and Autophagy in Cardiovascular Homeostasis

PubMed Central

Morales, Cyndi R.; Pedrozo, Zully; Lavandero, Sergio

2014-01-01

Abstract Significance: Autophagy is an evolutionarily ancient process of intracellular protein and organelle recycling required to maintain cellular homeostasis in the face of a wide variety of stresses. Dysregulation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) leads to oxidative damage. Both autophagy and ROS/RNS serve pathological or adaptive roles within cardiomyocytes, depending on the context. Recent Advances: ROS/RNS and autophagy communicate with each other via both transcriptional and post-translational events. This cross talk, in turn, regulates the structural integrity of cardiomyocytes, promotes proteostasis, and reduces inflammation, events critical to disease pathogenesis. Critical Issues: Dysregulation of either autophagy or redox state has been implicated in many cardiovascular diseases. Cardiomyocytes are rich in mitochondria, which make them particularly sensitive to oxidative damage. Maintenance of mitochondrial homeostasis and elimination of defective mitochondria are each critical to the maintenance of redox homeostasis. Future Directions: The complex interplay between autophagy and oxidative stress underlies a wide range of physiological and pathological events and its elucidation holds promise of potential clinical applicability. Antioxid. Redox Signal. 20, 507–518. PMID:23641894

Advances and New Concepts in Alcohol-Induced Organelle Stress, Unfolded Protein Responses and Organ Damage.

PubMed

Ji, Cheng

2015-06-03

Alcohol is a simple and consumable biomolecule yet its excessive consumption disturbs numerous biological pathways damaging nearly all organs of the human body. One of the essential biological processes affected by the harmful effects of alcohol is proteostasis, which regulates the balance between biogenesis and turnover of proteins within and outside the cell. A significant amount of published evidence indicates that alcohol and its metabolites directly or indirectly interfere with protein homeostasis in the endoplasmic reticulum (ER) causing an accumulation of unfolded or misfolded proteins, which triggers the unfolded protein response (UPR) leading to either restoration of homeostasis or cell death, inflammation and other pathologies under severe and chronic alcohol conditions. The UPR senses the abnormal protein accumulation and activates transcription factors that regulate nuclear transcription of genes related to ER function. Similarly, this kind of protein stress response can occur in other cellular organelles, which is an evolving field of interest. Here, I review recent advances in the alcohol-induced ER stress response as well as discuss new concepts on alcohol-induced mitochondrial, Golgi and lysosomal stress responses and injuries.

Atrogin-1 Deficiency Leads to Myopathy and Heart Failure in Zebrafish.

PubMed

Bühler, Anja; Kustermann, Monika; Bummer, Tiziana; Rottbauer, Wolfgang; Sandri, Marco; Just, Steffen

2016-01-30

Orchestrated protein synthesis and degradation is fundamental for proper cell function. In muscle, impairment of proteostasis often leads to severe cellular defects finally interfering with contractile function. Here, we analyze for the first time the role of Atrogin-1, a muscle-specific E3 ubiquitin ligase known to be involved in the regulation of protein degradation via the ubiquitin proteasome and the autophagy/lysosome systems, in the in vivo model system zebrafish (Danio rerio). We found that targeted inactivation of zebrafish Atrogin-1 leads to progressive impairment of heart and skeletal muscle function and disruption of muscle structure without affecting early cardiogenesis and skeletal muscle development. Autophagy is severely impaired in Atrogin-1-deficient zebrafish embryos resulting in the disturbance of the cytoarchitecture of cardiomyocytes and skeletal muscle cells. These observations are consistent with molecular and ultrastructural findings in an Atrogin-1 knockout mouse and demonstrate that the zebrafish is a suitable vertebrate model to study the molecular mechanisms of Atrogin-1-mediated autophagic muscle pathologies and to screen for novel therapeutically active substances in high-throughput in vivo small compound screens (SCS).

αB-crystallin: Portrait of a malignant chaperone as a cancer therapeutic target

PubMed Central

Malin, Dmitry; Petrovic, Vladimir; Strekalova, Elena; Sharma, Bhawna; Cryns, Vincent L.

2016-01-01

αB-crystallin is a widely expressed member of the small heat shock protein family that protects cells from stress by its dual function as a molecular chaperone to preserve proteostasis and as a cell death antagonist that negatively regulates components of the conserved apoptotic cell death machinery. Deregulated expression of αB-crystallin occurs in a broad array of solid tumors and has been linked to tumor progression and poor clinical outcomes. This review will focus on new insights into the molecular mechanisms by which oncogenes, oxidative stress, matrix detachment and other tumor microenvironmental stressors deregulate αB-crystallin expression. We will also review accumulating evidence pointing to an essential role for αB-crystallin in the multi-step metastatic cascade whereby tumor cells colonize distant organs by circumventing a multitude of barriers to cell migration and survival. Finally, we will evaluate emerging strategies to therapeutically target αB-crystallin and/or interacting proteins to selectively activate apoptosis and/or derail the metastatic cascade in an effort to improve outcomes for patients with metastatic disease. PMID:26820756

αB-crystallin: Portrait of a malignant chaperone as a cancer therapeutic target.

PubMed

Malin, Dmitry; Petrovic, Vladimir; Strekalova, Elena; Sharma, Bhawna; Cryns, Vincent L

2016-04-01

αB-crystallin is a widely expressed member of the small heat shock protein family that protects cells from stress by its dual function as a molecular chaperone to preserve proteostasis and as a cell death antagonist that negatively regulates components of the conserved apoptotic cell death machinery. Deregulated expression of αB-crystallin occurs in a broad array of solid tumors and has been linked to tumor progression and poor clinical outcomes. This review will focus on new insights into the molecular mechanisms by which oncogenes, oxidative stress, matrix detachment and other tumor microenvironmental stressors deregulate αB-crystallin expression. We will also review accumulating evidence pointing to an essential role for αB-crystallin in the multi-step metastatic cascade whereby tumor cells colonize distant organs by circumventing a multitude of barriers to cell migration and survival. Finally, we will evaluate emerging strategies to therapeutically target αB-crystallin and/or interacting proteins to selectively activate apoptosis and/or derail the metastatic cascade in an effort to improve outcomes for patients with metastatic disease. Copyright © 2016 Elsevier Inc. All rights reserved.

Celastrol: Molecular targets of Thunder God Vine.

PubMed

Salminen, Antero; Lehtonen, Marko; Paimela, Tuomas; Kaarniranta, Kai

2010-04-09

Celastrol, a quinone methide triterpene, is a pharmacologically active compound present in Thunder God Vine root extracts used as a remedy of inflammatory and autoimmune diseases, e.g. rheumatoid arthritis. Celastrol is one of the most promising medicinal molecules isolated from the plant extracts of traditional medicines. Molecular studies have identified several molecular targets which are mostly centered on the inhibition of IKK-NF-kappaB signaling. Celastrol (i) inhibits directly the IKKalpha and beta kinases, (ii) inactivates the Cdc37 and p23 proteins which are co-chaperones of HSP90, (iii) inhibits the function of proteasomes, and (iv) activates the HSF1 and subsequently triggers the heat shock response. It seems that the quinone methide structure present in celastrol can react with the thiol groups of cysteine residues, forming covalent protein adducts. In laboratory experiments, celastrol has proved to be a potent inhibitor of inflammatory responses and cancer formation as well as alleviating diseases of proteostasis deficiency. Celastrol needs still to pass several hurdles, e.g. ADMET assays, before it can enter the armoury of western drugs. Copyright 2010 Elsevier Inc. All rights reserved.

Strategies for the etiological therapy of cystic fibrosis.

PubMed

Maiuri, Luigi; Raia, Valeria; Kroemer, Guido

2017-11-01

Etiological therapies aim at repairing the underlying cause of cystic fibrosis (CF), which is the functional defect of the cystic fibrosis transmembrane conductance regulator (CFTR) protein owing to mutations in the CFTR gene. Among these, the F508del CFTR mutation accounts for more than two thirds of CF cases worldwide. Two somehow antinomic schools of thought conceive CFTR repair in a different manner. According to one vision, drugs should directly target the mutated CFTR protein to increase its plasma membrane expression (correctors) or improve its ion transport function (potentiators). An alternative strategy consists in modulating the cellular environment and proteostasis networks in which the mutated CFTR protein is synthesized, traffics to its final destination, the plasma membrane, and is turned over. We will analyze distinctive advantages and drawbacks of these strategies in terms of their scientific and clinical dimensions, and we will propose a global strategy for CF research and development based on a reconciliatory approach. Moreover, we will discuss the utility of preclinical biomarkers that may guide the personalized, patient-specific implementation of CF therapies.

Structural and Biological Interaction of hsc-70 Protein with Phosphatidylserine in Endosomal Microautophagy*

PubMed Central

Morozova, Kateryna; Clement, Cristina C.; Kaushik, Susmita; Stiller, Barbara; Arias, Esperanza; Ahmad, Atta; Rauch, Jennifer N.; Chatterjee, Victor; Melis, Chiara; Scharf, Brian; Gestwicki, Jason E.; Cuervo, Ana-Maria; Zuiderweg, Erik R. P.; Santambrogio, Laura

2016-01-01

hsc-70 (HSPA8) is a cytosolic molecular chaperone, which plays a central role in cellular proteostasis, including quality control during protein refolding and regulation of protein degradation. hsc-70 is pivotal to the process of macroautophagy, chaperone-mediated autophagy, and endosomal microautophagy. The latter requires hsc-70 interaction with negatively charged phosphatidylserine (PS) at the endosomal limiting membrane. Herein, by combining plasmon resonance, NMR spectroscopy, and amino acid mutagenesis, we mapped the C terminus of the hsc-70 LID domain as the structural interface interacting with endosomal PS, and we estimated an hsc-70/PS equilibrium dissociation constant of 4.7 ± 0.1 μm. This interaction is specific and involves a total of 4–5 lysine residues. Plasmon resonance and NMR results were further experimentally validated by hsc-70 endosomal binding experiments and endosomal microautophagy assays. The discovery of this previously unknown contact surface for hsc-70 in this work elucidates the mechanism of hsc-70 PS/membrane interaction for cytosolic cargo internalization into endosomes. PMID:27405763

Structural and Biological Interaction of hsc-70 Protein with Phosphatidylserine in Endosomal Microautophagy.

PubMed

Morozova, Kateryna; Clement, Cristina C; Kaushik, Susmita; Stiller, Barbara; Arias, Esperanza; Ahmad, Atta; Rauch, Jennifer N; Chatterjee, Victor; Melis, Chiara; Scharf, Brian; Gestwicki, Jason E; Cuervo, Ana-Maria; Zuiderweg, Erik R P; Santambrogio, Laura

2016-08-26

hsc-70 (HSPA8) is a cytosolic molecular chaperone, which plays a central role in cellular proteostasis, including quality control during protein refolding and regulation of protein degradation. hsc-70 is pivotal to the process of macroautophagy, chaperone-mediated autophagy, and endosomal microautophagy. The latter requires hsc-70 interaction with negatively charged phosphatidylserine (PS) at the endosomal limiting membrane. Herein, by combining plasmon resonance, NMR spectroscopy, and amino acid mutagenesis, we mapped the C terminus of the hsc-70 LID domain as the structural interface interacting with endosomal PS, and we estimated an hsc-70/PS equilibrium dissociation constant of 4.7 ± 0.1 μm. This interaction is specific and involves a total of 4-5 lysine residues. Plasmon resonance and NMR results were further experimentally validated by hsc-70 endosomal binding experiments and endosomal microautophagy assays. The discovery of this previously unknown contact surface for hsc-70 in this work elucidates the mechanism of hsc-70 PS/membrane interaction for cytosolic cargo internalization into endosomes. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

A mitochondrial ATP synthase subunit interacts with TOR signaling to modulate protein homeostasis and lifespan in Drosophila.

PubMed

Sun, Xiaoping; Wheeler, Charles T; Yolitz, Jason; Laslo, Mara; Alberico, Thomas; Sun, Yaning; Song, Qisheng; Zou, Sige

2014-09-25

Diet composition is a critical determinant of lifespan, and nutrient imbalance is detrimental to health. However, how nutrients interact with genetic factors to modulate lifespan remains elusive. We investigated how diet composition influences mitochondrial ATP synthase subunit d (ATPsyn-d) in modulating lifespan in Drosophila. ATPsyn-d knockdown extended lifespan in females fed low carbohydrate-to-protein (C:P) diets but not the high C:P ratio diet. This extension was associated with increased resistance to oxidative stress; transcriptional changes in metabolism, proteostasis, and immune genes; reduced protein damage and aggregation, and reduced phosphorylation of S6K and ERK in TOR and mitogen-activated protein kinase (MAPK) signaling, respectively. ATPsyn-d knockdown did not extend lifespan in females with reduced TOR signaling induced genetically by Tsc2 overexpression or pharmacologically by rapamycin. Our data reveal a link among diet, mitochondria, and MAPK and TOR signaling in aging and stresses the importance of considering genetic background and diet composition in implementing interventions for promoting healthy aging. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Molecular Basis of Substrate Recognition and Degradation by Human Presequence Protease

PubMed Central

King, John V.; Liang, Wenguang G.; Scherpelz, Kathryn P.; Schilling, Alexander B.; Meredith, Stephen C.; Tang, Wei-Jen

2014-01-01

Summary Human Presequence Protease (hPreP) is an M16 metalloprotease localized in mitochondria. There, hPreP facilitates proteostasis by utilizing a ∼13,300Å3 catalytic chamber to degrade a diverse array of potentially toxic peptides, including mitochondrial presequences and amyloid-β (Aβ), the latter of which contributes to Alzheimer's disease pathogenesis. Here we report crystal structures for hPreP alone and in complex with Aβ, which show that hPreP uses size-exclusion and charge complementation for substrate recognition. These structures also reveal hPreP-specific features that permit a diverse array of peptides, with distinct distributions of charged and hydrophobic residues, to be specifically captured, cleaved, and their amyloidogenic features destroyed. SAXS analysis demonstrates that hPreP in solution exists in dynamic equilibrium between closed and open states, with the former being preferred. Furthermore, Aβ binding induces the closed state and hPreP dimerization. Together, these data reveal the molecular basis for flexible yet specific substrate recognition and degradation by hPreP. PMID:24931469

Targeting the Endoplasmic Reticulum Unfolded Protein Response to Counteract the Oxidative Stress-Induced Endothelial Dysfunction

PubMed Central

Moltedo, Ornella; Faraonio, Raffaella

2018-01-01

In endothelial cells, the tight control of the redox environment is essential for the maintenance of vascular homeostasis. The imbalance between ROS production and antioxidant response can induce endothelial dysfunction, the initial event of many cardiovascular diseases. Recent studies have revealed that the endoplasmic reticulum could be a new player in the promotion of the pro- or antioxidative pathways and that in such a modulation, the unfolded protein response (UPR) pathways play an essential role. The UPR consists of a set of conserved signalling pathways evolved to restore the proteostasis during protein misfolding within the endoplasmic reticulum. Although the first outcome of the UPR pathways is the promotion of an adaptive response, the persistent activation of UPR leads to increased oxidative stress and cell death. This molecular switch has been correlated to the onset or to the exacerbation of the endothelial dysfunction in cardiovascular diseases. In this review, we highlight the multiple chances of the UPR to induce or ameliorate oxidative disturbances and propose the UPR pathways as a new therapeutic target for the clinical management of endothelial dysfunction. PMID:29725497

Mitohormesis: Promoting Health and Lifespan by Increased Levels of Reactive Oxygen Species (ROS)

PubMed Central

Ristow, Michael; Schmeisser, Kathrin

2014-01-01

Increasing evidence indicates that reactive oxygen species (ROS), consisting of superoxide, hydrogen peroxide, and multiple others, do not only cause oxidative stress, but rather may function as signaling molecules that promote health by preventing or delaying a number of chronic diseases, and ultimately extend lifespan. While high levels of ROS are generally accepted to cause cellular damage and to promote aging, low levels of these may rather improve systemic defense mechanisms by inducing an adaptive response. This concept has been named mitochondrial hormesis or mitohormesis. We here evaluate and summarize more than 500 publications from current literature regarding such ROS-mediated low-dose signaling events, including calorie restriction, hypoxia, temperature stress, and physical activity, as well as signaling events downstream of insulin/IGF-1 receptors, AMP-dependent kinase (AMPK), target-of-rapamycin (TOR), and lastly sirtuins to culminate in control of proteostasis, unfolded protein response (UPR), stem cell maintenance and stress resistance. Additionally, consequences of interfering with such ROS signals by pharmacological or natural compounds are being discussed, concluding that particularly antioxidants are useless or even harmful. PMID:24910588

The m-AAA Protease Associated with Neurodegeneration Limits MCU Activity in Mitochondria.

PubMed

König, Tim; Tröder, Simon E; Bakka, Kavya; Korwitz, Anne; Richter-Dennerlein, Ricarda; Lampe, Philipp A; Patron, Maria; Mühlmeister, Mareike; Guerrero-Castillo, Sergio; Brandt, Ulrich; Decker, Thorsten; Lauria, Ines; Paggio, Angela; Rizzuto, Rosario; Rugarli, Elena I; De Stefani, Diego; Langer, Thomas

2016-10-06

Mutations in subunits of mitochondrial m-AAA proteases in the inner membrane cause neurodegeneration in spinocerebellar ataxia (SCA28) and hereditary spastic paraplegia (HSP7). m-AAA proteases preserve mitochondrial proteostasis, mitochondrial morphology, and efficient OXPHOS activity, but the cause for neuronal loss in disease is unknown. We have determined the neuronal interactome of m-AAA proteases in mice and identified a complex with C2ORF47 (termed MAIP1), which counteracts cell death by regulating the assembly of the mitochondrial Ca 2+ uniporter MCU. While MAIP1 assists biogenesis of the MCU subunit EMRE, the m-AAA protease degrades non-assembled EMRE and ensures efficient assembly of gatekeeper subunits with MCU. Loss of the m-AAA protease results in accumulation of constitutively active MCU-EMRE channels lacking gatekeeper subunits in neuronal mitochondria and facilitates mitochondrial Ca 2+ overload, mitochondrial permeability transition pore opening, and neuronal death. Together, our results explain neuronal loss in m-AAA protease deficiency by deregulated mitochondrial Ca 2+ homeostasis. Copyright © 2016 Elsevier Inc. All rights reserved.

The role of fibrinogen glycation in ATTR: evidence for chaperone activity loss in disease.

PubMed

Fonseca, Daniel; Gilberto, Samuel; Ribeiro-Silva, Cristina; Ribeiro, Raquel; Guinote, Inês Batista; Saraiva, Susana; Gomes, Ricardo A; Mateus, Élia; Viana, Ana; Barroso, Eduardo; Freire, Ana Ponces; Freire, Patrick; Cordeiro, Carlos; da Costa, Gonçalo

2016-07-15

Transthyretin amyloidosis (ATTR) belongs to a class of disorders caused by protein misfolding and aggregation. ATTR is a disabling disorder of autosomal dominant trait, where transthyretin (TTR) forms amyloid deposits in different organs, causing dysfunction of the peripheral nervous system. We previously discovered that amyloid fibrils from ATTR patients are glycated by methylglyoxal. Even though no consensus has been reached about the actual role of methylglyoxal-derived advanced glycation end-products in amyloid diseases, evidence collected so far points to a role for protein glycation in conformational abnormalities, being ubiquitously found in amyloid deposits in Alzheimer's disease, dialysis-related amyloidosis and Parkinson's diseases. Human fibrinogen, an extracellular chaperone, was reported to specifically interact with a wide spectrum of stressed proteins and suppress their aggregation, being an interacting protein with TTR. Fibrinogen is differentially glycated in ATTR, leading to its chaperone activity loss. Here we show the existence of a proteostasis imbalance in ATTR linked to fibrinogen glycation by methylglyoxal. © 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

Strategies for the etiological therapy of cystic fibrosis

PubMed Central

Maiuri, Luigi; Raia, Valeria; Kroemer, Guido

2017-01-01

Etiological therapies aim at repairing the underlying cause of cystic fibrosis (CF), which is the functional defect of the cystic fibrosis transmembrane conductance regulator (CFTR) protein owing to mutations in the CFTR gene. Among these, the F508del CFTR mutation accounts for more than two thirds of CF cases worldwide. Two somehow antinomic schools of thought conceive CFTR repair in a different manner. According to one vision, drugs should directly target the mutated CFTR protein to increase its plasma membrane expression (correctors) or improve its ion transport function (potentiators). An alternative strategy consists in modulating the cellular environment and proteostasis networks in which the mutated CFTR protein is synthesized, traffics to its final destination, the plasma membrane, and is turned over. We will analyze distinctive advantages and drawbacks of these strategies in terms of their scientific and clinical dimensions, and we will propose a global strategy for CF research and development based on a reconciliatory approach. Moreover, we will discuss the utility of preclinical biomarkers that may guide the personalized, patient-specific implementation of CF therapies. PMID:28937684

ATM directs DNA damage responses and proteostasis via genetically separable pathways

PubMed Central

Lee, Ji-Hoon; Mand, Michael R.; Kao, Chung-Hsuan; Zhou, Yi; Ryu, Seung W.; Richards, Alicia L.; Coon, Joshua J.; Paull, Tanya T.

2018-01-01

The protein kinase ATM is a master regulator of the DNA damage response but also responds directly to oxidative stress. Loss of ATM causes Ataxia telangiectasia, a neurodegenerative disorder with pleiotropic symptoms that include cerebellar dysfunction, cancer, diabetes, and premature aging. Here, we genetically separated DNA damage activation of ATM from oxidative activation using separation-of-function mutations. We found that deficiency in ATM activation by Mre11-Rad50-Nbs1 and DNA double-strand breaks resulted in loss of cell viability, checkpoint activation, and DNA end resection in response to DNA damage. In contrast, loss of oxidative activation of ATM had minimal effects on DNA damage-related outcomes but blocked ATM-mediated initiation of checkpoint responses after oxidative stress and resulted in deficiencies in mitochondrial function and autophagy. In addition, expression of ATM lacking oxidative activation generates widespread protein aggregation. These results indicate a direct relationship between the mechanism of ATM activation and its effects on cellular metabolism and DNA damage responses in human cells and implicates ATM in the control of protein homeostasis. PMID:29317520

Dynamic control of Hsf1 during heat shock by a chaperone switch and phosphorylation

PubMed Central

Zheng, Xu; Krakowiak, Joanna; Patel, Nikit; Beyzavi, Ali; Ezike, Jideofor; Khalil, Ahmad S; Pincus, David

2016-01-01

Heat shock factor (Hsf1) regulates the expression of molecular chaperones to maintain protein homeostasis. Despite its central role in stress resistance, disease and aging, the mechanisms that control Hsf1 activity remain unresolved. Here we show that in budding yeast, Hsf1 basally associates with the chaperone Hsp70 and this association is transiently disrupted by heat shock, providing the first evidence that a chaperone repressor directly regulates Hsf1 activity. We develop and experimentally validate a mathematical model of Hsf1 activation by heat shock in which unfolded proteins compete with Hsf1 for binding to Hsp70. Surprisingly, we find that Hsf1 phosphorylation, previously thought to be required for activation, in fact only positively tunes Hsf1 and does so without affecting Hsp70 binding. Our work reveals two uncoupled forms of regulation - an ON/OFF chaperone switch and a tunable phosphorylation gain - that allow Hsf1 to flexibly integrate signals from the proteostasis network and cell signaling pathways. DOI: http://dx.doi.org/10.7554/eLife.18638.001 PMID:27831465

On polars of mixed projection bodies

NASA Astrophysics Data System (ADS)

Zhao, Chang-Jian; Leng, Gang-Song

2006-04-01

Recently, Lutwak established general Minkowski inequality, Brunn-Minkowski inequality and Aleksandrov-Fenchel inequality for mixed projection bodies. In this paper, following Lutwak, we established their polar forms. As applications, we prove some interrelated results.

Fraunhofer Diffraction and Polarization.

ERIC Educational Resources Information Center

Fortin, E.

1979-01-01

Describes an experiment for the intermediate undergraduate optics laboratory designed to illustrate simultaneously some aspects of the phenomena of diffraction; interference, coherence, apodization, the Fresnel-Arago law; as well as of the interrelations between these concepts. (HM)

Mass Media Functions, Knowledge and Social Control

ERIC Educational Resources Information Center

Donohue, G. A.; And Others

1973-01-01

Develops a macro-view of mass media as interdependent parts of a total social system including a series of interrelated subsystems with primary function involving the generation, dissemination, and assimilation of information. (RB)

ITS system specification

DOT National Transportation Integrated Search

1997-01-21

The objective of the Polaris Project is to define an Intelligent Transportation Systems (ITS) architecture for the state of Minnesota. An architecture is a framework that defines how multiple ITS Components interrelate and contribute to the overall I...

A Cognition Account of Differences between Children's Comprehension and Production of Language.

ERIC Educational Resources Information Center

Rice, Mabel

1984-01-01

Suggests that there are no sharp distinctions among children's linguistic comprehension, production, and knowledge. Instead, all performance and understanding are embedded in a fluctuating, interrelated thought system. (PD)

ITS component specification

DOT National Transportation Integrated Search

1997-01-20

The objective of the Polaris Project is to define an Intelligent Transportation Systems (ITS) architecture for the state of Minnesota. An architecture is a framework that defines how multiple ITS Components interrelate and contribute to the overall I...

Predator perception and the interrelation between different forms of protective coloration

PubMed Central

Stevens, Martin

2007-01-01

Animals possess a range of defensive markings to reduce the risk of predation, including warning colours, camouflage, eyespots and mimicry. These different strategies are frequently considered independently, and with little regard towards predator vision, even though they may be linked in various ways and can be fully understood only in terms of predator perception. For example, camouflage and warning coloration need not be mutually exclusive, and may frequently exploit similar features of visual perception. This paper outlines how different forms of protective markings can be understood from predator perception and illustrates how this is fundamental in determining the mechanisms underlying, and the interrelation between, different strategies. Suggestions are made for future work, and potential mechanisms discussed in relation to various forms of defensive coloration, including disruptive coloration, eyespots, dazzle markings, motion camouflage, aposematism and mimicry. PMID:17426012

Interrelation of exhaust-gas constituents

NASA Technical Reports Server (NTRS)

Gerrish, Harold C; Voss, Fred

1938-01-01

This report presents the results of an investigation conducted to determine the interrelation of the constituents of the exhaust gases of internal-combustion engines and the effect of engine performance on these relations. Six single-cylinder, liquid-cooled tests engines and one 9-cylinder radial air-cooled engine were tested. Various types of combustion chambers were used and the engines were operated at compression ratios from 5.1 to 7.0 using spark ignition and from 13.5 to 15.6 using compression ignition. The investigation covered a range of engine speeds from 1,500 to 2,100 r.p.m. The fuels used were two grades of aviation gasoline, auto diesel fuel, and laboratory diesel fuel. Power, friction, and fuel-consumption data were obtained from the single-cylinder engines at the same time that the exhaust-gas samples were collected.

Interrelation of soft and hard X-ray emissions during solar flares. I - Observations

NASA Technical Reports Server (NTRS)

Winglee, R. M.; Kiplinger, A. L.; Zarro, D. M.; Dulk, G. A.; Lemen, J. R.

1991-01-01

The interrelation between the acceleration and heating of electrons and ions during impulsive solar flares is determined on the basis of simulataneous observations of hard and soft X-ray emission from the Solar Maximum Mission at high time resolution (6 s). For all the flares, the hard X-rays are found to have a power-law spectrum which breaks down during the rise phase and beginning of the decay phase. After that, the spectrum changes to either a single power law or a power law that breaks up at high energies. The characteristics of the soft X-ray are found to depend on the flare position. It is suggested that small-scale quasi-static electric fields are important for determining the acceleration of the X-ray-producing electrons and the outflowing chromospheric ions.

Control of dispersed-phase temperature in plasma flows by the spectral-brightness pyrometry method

NASA Astrophysics Data System (ADS)

Dolmatov, A. V.; Gulyaev, I. P.; Gulyaev, P. Yu; Iordan, V. I.

2016-02-01

In the present work, we propose a new method for measuring the distribution of temperature in the ensembles of condensed-phase particles in plasma spray flows. Interrelation between the spectral temperature of the particles and the distribution of camera brightness signal is revealed. The established inter-relation enables an in-situ calibration of measuring instruments using the objects under study. The spectral-brightness pyrometry method was approbated on a Plazer plasma-arc wire spraying facility at the Paton Institute of Electrical Welding (Ukrainian Academy of Sciences, Kiev) and on the Thermoplasma 50-1 powder spraying facility at the Institute of Theoretical and Applied Mechanics (Russian Academy of Sciences, Siberian Branch, Novosibirsk). The work was supported by the Russian Foundation for Basic Research (Grants Nos. 14-08-90428 and 15-48-00100).

Intellectual functioning in old and very old age: cross-sectional results from the Berlin Aging Study.

PubMed

Lindenberger, U; Baltes, P B

1997-09-01

This study documents age trends, interrelations, and correlates of intellectual abilities in old and very old age (70-103 years) from the Berlin Aging Study (N = 516). Fourteen tests were used to assess 5 abilities: reasoning, memory, and perceptual speed from the mechanic (broad fluid) domain and knowledge and fluency from the pragmatic (broad crystallized) domain. Intellectual abilities had negative linear age relations, with more pronounced age reductions in mechanic than in pragmatic abilities. Interrelations among intellectual abilities were highly positive and did not follow the mechanic-pragmatic distinction. Sociobiographical indicators were less closely linked to intellectual functioning than sensory-sensorimotor variables, which predicted 59% of the total reliable variance in general intelligence. Results suggest that aging-induced biological factors are a prominent source of individual differences in intelligence in old and very old age.

Energetics of Table Tennis and Table Tennis-Specific Exercise Testing.

PubMed

Zagatto, Alessandro Moura; Leite, Jorge Vieira de Mello; Papoti, Marcelo; Beneke, Ralph

2016-11-01

To test the hypotheses that the metabolic profile of table tennis is dominantly aerobic, anaerobic energy is related to the accumulated duration and intensity of rallies, and activity and metabolic profile are interrelated with the individual fitness profile determined via table tennis-specific tests. Eleven male experienced table tennis players (22 ± 3 y, 77.6 ± 18.9 kg, 177.1 ± 8.1 cm) underwent 2 simulated table tennis matches to analyze aerobic (W OXID ) energy, anaerobic glycolytic (W BLC ) energy, and phosphocreatine breakdown (W PCr ); a table tennis-specific graded exercise test to measure ventilatory threshold and peak oxygen uptake; and an exhaustive supramaximal table tennis effort to determine maximal accumulated deficit of oxygen. W OXID , W BLC , and W PCr corresponded to 96.5% ± 1.7%, 1.0% ± 0.7%, and 2.5% ± 1.4%, respectively. W OXID was interrelated with rally duration (r = .81) and number of shots per rally (r = .77), whereas match intensity was correlated with WPCr (r = .62) and maximal accumulated oxygen deficit (r = .58). The metabolic profile of table tennis is predominantly aerobic and interrelated with the individual fitness profile determined via table tennis-specific tests. Table tennis-specific ventilatory threshold determines the average oxygen uptake and overall W OXID , whereas table tennis-specific maximal accumulated oxygen deficit indicates the ability to use and sustain slightly higher blood lactate concentration and W BLC during the match.

Atmospheric water budget over the South Asian summer monsoon region

NASA Astrophysics Data System (ADS)

Unnikrishnan, C. K.; Rajeevan, M.

2018-04-01

High resolution hybrid atmospheric water budget over the South Asian monsoon region is examined. The regional characteristics, variability, regional controlling factors and the interrelations of the atmospheric water budget components are investigated. The surface evapotranspiration was created using the High Resolution Land Data Assimilation System (HRLDAS) with the satellite-observed rainfall and vegetation fraction. HRLDAS evapotranspiration shows significant similarity with in situ observations and MODIS satellite-observed evapotranspiration. Result highlights the fundamental importance of evapotranspiration over northwest and southeast India on atmospheric water balance. The investigation shows that the surface net radiation controls the annual evapotranspiration over those regions, where the surface evapotranspiration is lower than 550 mm. The rainfall and evapotranspiration show a linear relation over the low-rainfall regions (<500 mm/year). Similar result is observed in in NASA GLDAS data (1980-2014). The atmospheric water budget shows annual, seasonal, and intra-seasonal variations. Evapotranspiration does not show a high intra-seasonal variability as compared to other water budget components. The coupling among the water budget anomalies is investigated. The results show that regional inter-annual evapotranspiration anomalies are not exactly in phase with rainfall anomalies; it is strongly influenced by the surface conditions and other atmospheric forcing (like surface net radiation). The lead and lag correlation of water budget components show that the water budget anomalies are interrelated in the monsoon season even up to 4 months lead. These results show the important regional interrelation of water budget anomalies on south Asian monsoon.

Parental stress, family quality of life, and family-teacher partnerships: Families of children with autism spectrum disorder.

PubMed

Hsiao, Yun-Ju; Higgins, Kyle; Pierce, Tom; Whitby, Peggy J Schaefer; Tandy, Richard D

2017-11-01

Reducing parental stress and improving family quality of Life (FQOL) are continuing concerns for families of children with autism spectrum disorder (ASD). Family-teacher partnerships have been identified as a positive factor to help parents reduce their stress and improve their FQOL. However, the interrelations among parental stress, FQOL, and family-teacher partnerships need to be further examined so as to identify the possible paths to help parents reduce their stress and improve their FQOL. The purpose of this study was to examine the interrelations among these three variables. A total of 236 parents of school children with ASD completed questionnaires, which included three measures: (a) the Beach Center Family Quality of Life Scale, (b) the Parental Stress Scale, and (c) the Beach Center Family-Professional Partnerships Scale. The structural equation modeling was used to analyze the interrelations among these three variables. Perceived parental stress had a direct effect on parental satisfaction concerning FQOL and vice versa. Perceived family-teacher partnerships had a direct effect on FQOL, but did not have a direct effect on parental stress. However, family-teacher partnerships had an indirect effect on parental stress through FQOL. Reducing parental stress could improve FQOL for families of children with ASD and vice versa. Strong family-teacher partnerships could help parents of children with ASD improve their FQOL and indirectly reduce their stress. Copyright © 2017 Elsevier Ltd. All rights reserved.

Targeting Endoplasmic Reticulum and/or Mitochondrial Ca2+ Fluxes as Therapeutic Strategy for HCV Infection.

PubMed

Scrima, Rosella; Piccoli, Claudia; Moradpour, Darius; Capitanio, Nazzareno

2018-01-01

Chronic hepatitis C is characterized by metabolic disorders and by a microenvironment in the liver dominated by oxidative stress, inflammation and regeneration processes that can in the long term lead to liver cirrhosis and hepatocellular carcinoma. Several lines of evidence suggest that mitochondrial dysfunctions play a central role in these processes. However, how these dysfunctions are induced by the virus and whether they play a role in disease progression and neoplastic transformation remains to be determined. Most in vitro studies performed so far have shown that several of the hepatitis C virus (HCV) proteins also localize to mitochondria, but the consequences of these interactions on mitochondrial functions remain contradictory and need to be confirmed in the context of productively replicating virus and physiologically relevant in vitro and in vivo model systems. In the past decade we have been proposing a temporal sequence of events in the HCV-infected cell whereby the primary alteration is localized at the mitochondria-associated ER membranes and causes release of Ca 2+ from the ER, followed by uptake into mitochondria. This ensues successive mitochondrial dysfunction leading to the generation of reactive oxygen and nitrogen species and a progressive metabolic adaptive response consisting in decreased oxidative phosphorylation and enhanced aerobic glycolysis and lipogenesis. Here we resume the major results provided by our group in the context of HCV-mediated alterations of the cellular inter-compartmental calcium flux homeostasis and present new evidence suggesting targeting of ER and/or mitochondrial calcium transporters as a novel therapeutic strategy.

Targeting endoplasmic reticulum and/or mitochondrial Ca2+ fluxes as therapeutic strategy for HCV infection

NASA Astrophysics Data System (ADS)

Scrima, Rosella; Piccoli, Claudia; Moradpour, Darius; Capitanio, Nazzareno

2018-03-01

Chronic hepatitis C is characterized by metabolic disorders and by a microenvironment in the liver dominated by oxidative stress, inflammation and regeneration processes that can in the long term lead to liver cirrhosis and hepatocellular carcinoma. Several lines of evidence suggest that mitochondrial dysfunctions play a central role in these processes. However, how these dysfunctions are induced by the virus and whether they play a role in disease progression and neoplastic transformation remains to be determined. Most in vitro studies performed so far have shown that several of the hepatitis C virus (HCV) proteins also localize to mitochondria, but the consequences of these interactions on mitochondrial functions remain contradictory and need to be confirmed in the context of productively replicating virus and physiologically relevant in vitro and in vivo model systems. In the past decade we have been proposing a temporal sequence of events in the HCV-infected cell whereby the primary alteration is localized at the mitochondria-associated ER membranes and causes release of Ca2+ from the ER, followed by uptake into mitochondria. This ensues successive mitochondrial dysfunction leading to the generation of reactive oxygen and nitrogen species and a progressive metabolic adaptive response consisting in decreased oxidative phosphorylation and enhanced aerobic glycolysis and lipogenesis. Here we resume the major results provided by our group in the context of HCV-mediated alterations of the cellular inter-compartmental calcium flux homeostasis and present new evidence suggesting targeting of ER and/or mitochondrial calcium transporters as a novel therapeutic strategy.

Absolute Bioavailability and Pharmacokinetics of Linezolid in Hospitalized Patients Given Enteral Feedings

PubMed Central

Beringer, Paul; Nguyen, Megan; Hoem, Nils; Louie, Stan; Gill, Mark; Gurevitch, Michael; Wong-Beringer, Annie

2005-01-01

Linezolid is a new antimicrobial agent effective against drug-resistant gram-positive pathogens which are common causes of infections in hospitalized patients. Many such patients rely on the intravenous or enteral route for nutrition and drug administration. Therefore, the bioavailability of linezolid administered enterally in the presence of enteral feedings in hospitalized patients was examined. Eighteen subjects were assessed in a randomized single-dose crossover study; 12 received continuous enteral feedings, while 6 did not (controls). Both groups received linezolid 600 mg intravenously and orally (control) or enterally, with the alternate route of administration separated by a 24-h washout period. Pharmacokinetic parameters derived from noncompartmental and compartmental analysis incorporating linear and nonlinear elimination pathways were compared between groups: F, Ka, Vs, K23, K32, Vmax, Km, and K20 (bioavailability, absorption rate constant, volume of central compartment normalized to body weight, intercompartmental rate constants, maximum velocity, Michaelis-Menten constant, and elimination rate constant, respectively). Pharmacokinetic (PK) data were available from 17 patients. The linezolid oral suspension was rapidly and completely absorbed by either the oral or enteral route of administration. Bioavailability was unaltered in the presence of enteral feedings. PK estimates remain similar regardless of the model applied. At the therapeutic dose used, only slight nonlinearity in elimination was observed. A linezolid oral suspension may be administered via the enteral route to hospitalized patients without compromise in its excellent bioavailability and rapid rate of absorption. Compartmental pharmacokinetic analysis offers a more flexible study application, since bioavailability (F) can be estimated directly with intermixed intravenous/oral doses without a need for a washout period. PMID:16127039

Assessing circadian rhythms in propofol PK and PD during prolonged infusion in ICU patients

PubMed Central

Kusza, Krzysztof; Wawrzyniak, Katarzyna; Grześkowiak, Edmund; Kokot, Zenon J.; Matysiak, Jan; Grabowski, Tomasz; Wolc, Anna; Wiczling, Paweł; Regulski, Miłosz

2010-01-01

This study evaluates possible circadian rhythms during prolonged propofol infusion in patients in the intensive care unit. Eleven patients were sedated with a constant propofol infusion. The blood samples for the propofol assay were collected every hour during the second day, the third day, and after the termination of the propofol infusion. Values of electroencephalographic bispectral index (BIS), arterial blood pressure, heart rate, blood oxygen saturation and body temperature were recorded every hour at the blood collection time points. A two-compartment model was used to describe propofol pharmacokinetics. Typical values of the central and peripheral volume of distribution and inter-compartmental clearance were VC = 27.7 l, VT = 801 l, and CLD = 2.73 l/min. The systolic blood pressure (SBP) was found to influence the propofol metabolic clearance according to Cl (l/min) = 2.65·(1 − 0.00714·(SBP − 135)). There was no significant circadian rhythm detected with respect to propofol pharmacokinetics. The BIS score was assessed as a direct effect model with EC50 equal 1.98 mg/l. There was no significant circadian rhythm detected within the BIS scores. We concluded that the light–dark cycle did not influence propofol pharmacokinetics and pharmacodynamics in intensive care units patients. The lack of night–day differences was also noted for systolic blood pressure, diastolic blood pressure and blood oxygenation. Circadian rhythms were detected for heart rate and body temperature, however they were severely disturbed from the pattern of healthy patients. PMID:20544262

Pharmacokinetics of amikacin in serum and in tissue contiguous with pressure sores in humans with spinal cord injury.

PubMed Central

Segal, J L; Brunnemann, S R; Eltorai, I M

1990-01-01

Pressure sores are a common occurrence in immobilized patients. They increase morbidity and mortality and impede rehabilitation. Antibiotics are routinely used to assist in effecting a cure when infection is present. Nevertheless, for patients with spinal cord injuries (SCI), strategies for effective therapy with antibiotics based on measurement of concentrations in tissue and pharmacokinetic behavior in extravascular spaces do not exist. By analyzing the concentration-time profile and protein binding of amikacin in the interstitial fluid (IF) in contact with pressure sores, we found that the disposition of amikacin in the tissue contiguous with pressure sores appears to be governed by simultaneous first-order and capacity-limited pharmacokinetic behavior. Amikacin disposition in IF proceeded without a simple relationship to amikacin concentrations in serum, and the time course in IF was not accurately simulated by linear models of amikacin pharmacokinetic behavior. Total amikacin clearance estimated from a pharmacokinetic model using simultaneous first-order and nonlinear intercompartmental transfer of amikacin was not significantly different from clearance calculated by us in a prior study of amikacin pharmacokinetic behavior in patients with SCI. In patients with SCI, optimal use of amikacin in the treatment of infected pressure sores is contingent upon accurate characterization of the pharmacokinetic behavior of this aminoglycoside in serum and in the IF in contact with these lesions. Only methods which quantitate amikacin concentration and protein binding in IF and incorporate a model that can simultaneously simulate nonlinear and linear disposition processes should be relied upon to influence therapeutic decision making. PMID:2386372

Coupled near-field and far-field exposure assessment framework for chemicals in consumer products.

PubMed

Fantke, Peter; Ernstoff, Alexi S; Huang, Lei; Csiszar, Susan A; Jolliet, Olivier

2016-09-01

Humans can be exposed to chemicals in consumer products through product use and environmental emissions over the product life cycle. Exposure pathways are often complex, where chemicals can transfer directly from products to humans during use or exchange between various indoor and outdoor compartments until sub-fractions reach humans. To consistently evaluate exposure pathways along product life cycles, a flexible mass balance-based assessment framework is presented structuring multimedia chemical transfers in a matrix of direct inter-compartmental transfer fractions. By matrix inversion, we quantify cumulative multimedia transfer fractions and exposure pathway-specific product intake fractions defined as chemical mass taken in by humans per unit mass of chemical in a product. Combining product intake fractions with chemical mass in the product yields intake estimates for use in life cycle impact assessment and chemical alternatives assessment, or daily intake doses for use in risk-based assessment and high-throughput screening. Two illustrative examples of chemicals used in personal care products and flooring materials demonstrate how this matrix-based framework offers a consistent and efficient way to rapidly compare exposure pathways for adult and child users and for the general population. This framework constitutes a user-friendly approach to develop, compare and interpret multiple human exposure scenarios in a coupled system of near-field ('user' environment), far-field and human intake compartments, and helps understand the contribution of individual pathways to overall human exposure in various product application contexts to inform decisions in different science-policy fields for which exposure quantification is relevant. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Concrete pavement mixture design and analysis (MDA) : factors influencing drying shrinkage.

DOT National Transportation Integrated Search

2014-10-01

This literature review focuses on factors influencing drying shrinkage of concrete. Although the factors are normally interrelated, they : can be categorized into three groups: paste quantity, paste quality, and other factors.

Fleet replacement modeling : final report, July 2009.

DOT National Transportation Integrated Search

2009-07-01

This project focused on two interrelated areas in equipment replacement modeling for fleets. The first area was research-oriented and addressed a fundamental assumption in engineering economic replacement modeling that all assets providing a similar ...

New Futures for Comparative Education

ERIC Educational Resources Information Center

Butts, R. Freeman

1973-01-01

Author considered the future of comparative education in terms of four interrelated worlds of discourse'', the world of new nations, crises in old nations, the world of scholarship, and the professional world of teacher education. (Author/RK)

Social Dynamics Management and Functional Behavioral Assessment

ERIC Educational Resources Information Center

Lee, David L.

2018-01-01

Managing social dynamics is a critical aspect of creating a positive learning environment in classrooms. In this paper three key interrelated ideas, reinforcement, function, and motivating operations, are discussed with relation to managing social behavior.

The Sphinx's Riddle: Life and Career Cycles.

ERIC Educational Resources Information Center

Burack, Elmer H.

1984-01-01

Career cycles should be considered apart from life cycles, even though the two are interrelated. This essay examines five theories about life and career cycles, and offers insights into their limitations and potential uses. (JB)

Dynamic Stochastic Control of Freeway Corridor Systems : Summary and Project Overview

DOT National Transportation Integrated Search

1978-12-01

Systematic methodological approaches to overall traffic management from both short-term (real-time) and long-term (planning) perspectives have been developed. The approach embodies formulation and solution of interrelated mathematical problems from o...

An overview of artificial intelligence and robotics. Volume 1: Artificial intelligence. Part C: Basic AI topics

NASA Technical Reports Server (NTRS)

Gevarter, W. B.

1983-01-01

Readily understandable overviews of search oriented problem solving, knowledge representation, and computational logic are provided. Mechanization, automation and artificial intelligence are discussed as well as how they interrelate.

Crash analysis, statistics & information notebook 2008

DOT National Transportation Integrated Search

2008-01-01

Traditionally crash data is often presented as single fact sheets highlighting a single factor such as Vehicle Type or Road Type. This document will try to show how the risk factors interrelate to produce a crash. Complete detailed analys...

76 FR 27315 - EPA Science Advisory Board Staff Invitation to a Session on Public Involvement in EPA Advisory...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-05-11

... and SAB Three inter-related public access Web sites ( http://www.epa.gov/advisorycouncilcaa , http...) ``Recent Happenings'' and ``Recent Additions'' sections and related ``really simple syndication'' (RSS...

Systems-Dynamic Analysis for Neighborhood Study

EPA Science Inventory

Systems-dynamic analysis (or system dynamics (SD)) helps planners identify interrelated impacts of transportation and land-use policies on neighborhood-scale economic outcomes for households and businesses, among other applications. This form of analysis can show benefits and tr...

Scaling Considerations Related to Interactions of Hydrologics, Pedologic and Geomorphic Processes

EPA Science Inventory

Hydrologic, pedologic, and geomorphic processes are strongly interrelated and affected by scale. These interactions exert important controls on runoff generation, preferential flow, contaminant transport, surface erosion, and mass wasting. Measurement of hydraulic conductivity (K...

Seven Modeling Perspectives on Teaching and Learning: Some Interrelations and Cognitive Effects

ERIC Educational Resources Information Center

Easley, J. A., Jr.

1977-01-01

The categories of models associated with the seven perspectives are designated as combinatorial models, sampling models, cybernetic models, game models, critical thinking models, ordinary language analysis models, and dynamic structural models. (DAG)

Air Quality Management Process Cycle

EPA Pesticide Factsheets

Air quality management are activities a regulatory authority undertakes to protect human health and the environment from the harmful effects of air pollution. The process of managing air quality can be illustrated as a cycle of inter-related elements.

Liberating minds: Consciousness-raising as a bridge between feminism and psychology in 1970s Canada.

PubMed

Ruck, Nora

2015-08-01

This article examines the interrelations between psychology and feminism in the work of feminist psychologists and radical feminists in Toronto in the early 1970s. For Canadian feminist psychology as well as for second-wave activism, Toronto was a particular hotspot. It was the academic home of some of the first Canadian feminist psychologists, and was the site of a lively scene of feminists working in established women's organizations along with younger socialist and radical feminists. This article analyzes the interrelations of academic feminist psychology and feminist activism by focusing on consciousness-raising, a practice that promised to bridge tensions between the personal and the political, psychological and social liberation, everyday knowledge and institutionalized knowledge production, theory and practice, as well as the women's movement and other spheres of women's lives. (c) 2015 APA, all rights reserved).

The Plasma Archipelago: Plasma Physics in the 1960s

NASA Astrophysics Data System (ADS)

Weisel, Gary J.

2017-09-01

With the foundation of the Division of Plasma Physics of the American Physical Society in April 1959, plasma physics was presented as the general study of ionized gases. This paper investigates the degree to which plasma physics, during its first decade, established a community of interrelated specialties, one that brought together work in gaseous electronics, astrophysics, controlled thermonuclear fusion, space science, and aerospace engineering. It finds that, in some regards, the plasma community was indeed greater than the sum of its parts and that its larger identity was sometimes glimpsed in inter-specialty work and studies of fundamental plasma behaviors. Nevertheless, the plasma specialties usually worked separately for two inter-related reasons: prejudices about what constituted "basic physics," both in the general physics community and within the plasma community itself; and a compartmentalized funding structure, in which each funding agency served different missions.

In-Factory Learning - Qualification For The Factory Of The Future

NASA Astrophysics Data System (ADS)

Quint, Fabian; Mura, Katharina; Gorecky, Dominic

2015-07-01

The Industry 4.0 vision anticipates that internet technologies will find their way into future factories replacing traditional components by dynamic and intelligent cyber-physical systems (CPS) that combine the physical objects with their digital representation. Reducing the gap between the real and digital world makes the factory environment more flexible, more adaptive, but also more complex for the human workers. Future workers require interdisciplinary competencies from engineering, information technology, and computer science in order to understand and manage the diverse interrelations between physical objects and their digital counterpart. This paper proposes a mixed-reality based learning environment, which combines physical objects and visualisation of digital content via Augmented Reality. It uses reality-based interaction in order to make the dynamic interrelations between real and digital factory visible and tangible. We argue that our learning system does not work as a stand-alone solution, but should fit into existing academic and advanced training curricula.

a New Golf-Swing Robot Model Utilizing Shaft Elasticity

NASA Astrophysics Data System (ADS)

Suzuki, S.; Inooka, H.

1998-10-01

The performance of golf clubs and balls is generally evaluated by using golf-swing robots that conventionally have two or three joints with completely interrelated motion. This interrelation allows the user of this robot to specify only the initial posture and swing velocity of the robot and therefore the swing motion of this type of robot cannot be subtly adjusted to the specific characteristics of individual golf clubs. Consequently, golf-swing robots cannot accurately emulate advanced golfers, and this causes serious problems for the evaluation of golf club performance. In this study, a new golf-swing robot that can adjust its motion to both a specified value of swing velocity and the specific characteristics of individual golf clubs was analytically investigated. This robot utilizes the dynamic interference force produced by its swing motion and by shaft vibration and can therefore emulate advanced golfers and perform highly reliable evaluations of golf clubs.

[Role of psychosocial stress in complex diseases].

PubMed

Scantamburlo, G; Scheen, A J

2012-01-01

Complex diseases are chronic diseases where the interrelations between genetic predisposition and environmental factors play an essential role in the arisen and the maintenance of the pathology. Upon psychological stress, the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system are activated resulting in release of glucocorticoids and catecholamines. Chronic stress may induce complex diseases where alterations of nervous, endocrine and immune systems are involved. Thus, chronic stress is more likely to induce a range of effects, depending on the capacity of the subject to cope with stress. CRH ("Corticotropin Releasing Hormone") is a key factor in the stress-immunity relationship. In this article, we propose an overview of the interrelations between central nervous, endocrine and immune systems and implications for health and diseases. The objective for the clinician is to propose therapeutic strategies targeting changes in human behaviour to cope with a potentially stressful environment.

Boundaries, borders, and limits. A phenomenological reflection on ethics and euthanasia.

PubMed

Leget, C

2006-05-01

The subject of euthanasia divides both people and nations. It will always continue to do so because the arguments for and against this issue are intrinsically related to each other. This paper offers an analysis of the interrelation of the arguments, departing from a phenomenology of boundaries. From the participant perspective the boundary of euthanasia appears as a limit. From a helicopter perspective it appears as a border. Reflecting on both perspectives they turn out to complement each other: the positive effects of the former correspond to the negative effects of the latter. In order to see how this interrelation of viewpoints works out in the case of euthanasia a paradigmatic case is analysed from the perspective of the patient, the doctor, and the family. This phenomenological analysis does not directly lead to normative conclusions. It helps by both paying attention to, and dealing with, the complexity of the issue with intellectual honesty.

Boundaries, borders, and limits. A phenomenological reflection on ethics and euthanasia

PubMed Central

Leget, C

2006-01-01

The subject of euthanasia divides both people and nations. It will always continue to do so because the arguments for and against this issue are intrinsically related to each other. This paper offers an analysis of the interrelation of the arguments, departing from a phenomenology of boundaries. From the participant perspective the boundary of euthanasia appears as a limit. From a helicopter perspective it appears as a border. Reflecting on both perspectives they turn out to complement each other: the positive effects of the former correspond to the negative effects of the latter. In order to see how this interrelation of viewpoints works out in the case of euthanasia a paradigmatic case is analysed from the perspective of the patient, the doctor, and the family. This phenomenological analysis does not directly lead to normative conclusions. It helps by both paying attention to, and dealing with, the complexity of the issue with intellectual honesty. PMID:16648273

Information Transfer Analysis of Spontaneous Low-frequency Fluctuations in Cerebral Hemodynamics and Cardiovascular Dynamics

NASA Astrophysics Data System (ADS)

Katura, Takusige; Tanaka, Naoki; Obata, Akiko; Sato, Hiroki; Maki, Atsushi

2005-08-01

In this study, from the information-theoretic viewpoint, we analyzed the interrelation between the spontaneous low-frequency fluctuations around 0.1Hz in the hemoglobin concentration in the cerebral cortex, mean arterial blood pressure and the heart rate. For this analysis, as measures of information transfer, we used transfer entropy (TE) proposed for two-factor systems by Schreiber and intrinsic transfer entropy (ITE) introduced for further analysis of three-factor systems by extending the original TE. In our analysis, information transfer analysis based on both TE and ITE suggests the systemic cardiovascular fluctuations alone cannot account for the cerebrovascular fluctuations, that is, the regulation of the regional cerebral energetic metabolism is important as a candidate of its generation mechanism Such an information transfer analysis seems useful to reveal the interrelation between the elements regulated each other in a complex manner.

The Interrelations Between Internalized Homophobia, Depressive Symptoms, and Suicidal Ideation Among Australian Gay Men, Lesbians, and Bisexual Women.

PubMed

McLaren, Suzanne

2016-01-01

Internalized homophobia has been linked to depression among gay men, lesbians, and bisexuals. Relatively little research has investigated the link between internalized homophobia and suicidal thoughts and behaviors. The current research investigated the interrelations among internalized homophobia, depressive symptoms, and suicidal ideation by testing additive, mediation, and moderation models. Self-identified Australian gay men (n = 360), lesbians (n = 444), and bisexual women (n = 114) completed the Internalized Homophobia Scale, the Center for Epidemiological Studies Depression Scale, and the suicide subscale of the General Health Questionnaire. Results supported the additive and partial mediation models for gay men and the mediation and moderation models for lesbians. None of the models were supported for bisexual women. The findings imply that clinicians should focus on reducing internalized homophobia and depressive symptoms among gay men and lesbians, and depressive symptoms among bisexual women, to reduce suicidal ideation.

Associations among selective attention, memory bias, cognitive errors and symptoms of anxiety in youth.

PubMed

Watts, Sarah E; Weems, Carl F

2006-12-01

The purpose of this study was to examine the linkages among selective attention, memory bias, cognitive errors, and anxiety problems by testing a model of the interrelations among these cognitive variables and childhood anxiety disorder symptoms. A community sample of 81 youth (38 females and 43 males) aged 9-17 years and their parents completed measures of the child's anxiety disorder symptoms. Youth completed assessments measuring selective attention, memory bias, and cognitive errors. Results indicated that selective attention, memory bias, and cognitive errors were each correlated with childhood anxiety problems and provide support for a cognitive model of anxiety which posits that these three biases are associated with childhood anxiety problems. Only limited support for significant interrelations among selective attention, memory bias, and cognitive errors was found. Finally, results point towards an effective strategy for moving the assessment of selective attention to younger and community samples of youth.

Examination of the interrelations between the factors of PTSD, major depression, and generalized anxiety disorder in a heterogeneous trauma-exposed sample using DSM 5 criteria.

PubMed

Price, Matthew; van Stolk-Cooke, Katherine

2015-11-01

Exposure to traumatic events places individuals at high risk for multiple psychiatric disorders, including posttraumatic stress disorder (PTSD), major depressive disorder (MDD), and generalized anxiety disorder (GAD). The high rates of comorbidity among these conditions merit evaluation in order to improve diagnosis and treatment approaches. The current study evaluated the association between PTSD, MDD, and GAD factors as presented in the DSM 5. 602 trauma-exposed individuals who experienced an event that met Criterion A for the DSM 5 PTSD diagnosis were recruited through Amazon.com, Inc.'s Mechanical Turk (MTurk) to complete an assessment of the impact of stressful events on their lives. High interrelations were detected among the 4 PTSD factors, 2 MDD factors that corresponded to somatic and affective symptoms, and the single GAD factor. The affective factor of MDD was most strongly related to the emotional numbing factor of PTSD, whereas the somatic factor of MDD was most strongly related to the hyperarousal factor of PTSD. The GAD factor was most strongly related to the hyperarousal factor of PTSD, relative to the other PTSD factors. The strength of the interrelations between factors of the three disorders is largely a function of the overlap in symptoms and calls into question the uniqueness of negative affective symptoms of PTSD, MDD and GAD. Results suggest that improved understanding of the trauma reaction requires a focus on the unique presentation of each individual and assessment of multiple disorders. Copyright © 2015 Elsevier B.V. All rights reserved.

Time-Based Indicators of Emotional Complexity: Interrelations and Correlates

PubMed Central

Grühn, Daniel; Lumley, Mark A.; Diehl, Manfred; Labouvie-Vief, Gisela

2012-01-01

Emotional complexity has been regarded as one correlate of adaptive emotion regulation in adulthood. One novel and potentially valuable approach to operationalizing emotional complexity is to use reports of emotions obtained repeatedly in real time, which can generate a number of potential time-based indicators of emotional complexity. It is not known, however, how these indicators relate to each other, to other measures of affective complexity, such as those derived from a cognitive-developmental view of emotional complexity, or to measures of adaptive functioning, such as well-being. A sample of 109 adults, aged 23 to 90 years, participated in an experience-sampling study and reported their negative and positive affect five times a day for one week. Based on these reports, we calculated nine different time-based indicators potentially reflecting emotional complexity. Analyses showed three major findings: First, the indicators showed a diverse pattern of interrelations suggestive of four distinct components of emotional complexity. Second, age was generally not related to time-based indicators of emotional complexity; however, older adults showed overall low variability in negative affect. Third, time-based indicators of emotional complexity were either unrelated or inversely related to measures of adaptive functioning; that is, these measures tended to predict a less adaptive profile, such as lower subjective and psychological well-being. In sum, time-based indicators of emotional complexity displayed a more complex and less beneficial picture than originally thought. In particular, variability in negative affect seems to indicate suboptimal adjustments. Future research would benefit from collecting empirical data for the interrelations and correlates of time-based indicators of emotional complexity in different contexts. PMID:23163712

The influence of the Bible geographic objects peculiarities on the concept of the spatiotemporal geoinformation system

NASA Astrophysics Data System (ADS)

Linsebarth, A.; Moscicka, A.

2010-01-01

The article describes the infl uence of the Bible geographic object peculiarities on the spatiotemporal geoinformation system of the Bible events. In the proposed concept of this system the special attention was concentrated to the Bible geographic objects and interrelations between the names of these objects and their location in the geospace. In the Bible, both in the Old and New Testament, there are hundreds of geographical names, but the selection of these names from the Bible text is not so easy. The same names are applied for the persons and geographic objects. The next problem which arises is the classification of the geographical object, because in several cases the same name is used for the towns, mountains, hills, valleys etc. Also very serious problem is related to the time-changes of the names. The interrelation between the object name and its location is also complicated. The geographic object of this same name is located in various places which should be properly correlated with the Bible text. Above mentioned peculiarities of Bible geographic objects infl uenced the concept of the proposed system which consists of three databases: reference, geographic object, and subject/thematic. The crucial component of this system is proper architecture of the geographic object database. In the paper very detailed description of this database is presented. The interrelation between the databases allows to the Bible readers to connect the Bible text with the geography of the terrain on which the Bible events occurred and additionally to have access to the other geographical and historical information related to the geographic objects.

[Validation of the Scale of Hope in Terminal Illness for relatives brief version (SHTI-b). Validity and reliability analysis.

PubMed

Villacieros, M; Bermejo, J C; Hassoun, H

2017-12-29

Bermejo and Villacieros' Scale of Hope in Terminal Disease (SHTD) specifically collects meanings of hope facing terminal disease, including considerations relating to psycho-emotional support and that have a transcendental sense. The objective of this paper is to validate the SHTD abbreviated and rephrased to adapt all the items to a single domain. Starting from the published SHTD, an exploratory factor analysis (EFA) was carried out with a sample of 177 valid questionnaires. In a second study, with another sample of 180 valid questionnaires, a confirmatory factor analysis (CFA) and a correlation analysis with other measurements of spiritual wellbeing (Functional Assessment of Chronic Illness Therapy-Sp) and hope (Herth Hope Index) were done. A bidimensional model with satisfactory goodness of fit index values was obtained (GFI = 0.991; CFI = 0.984; SRMR = 0.08; RMSEA = 0.057); the Relations of Transcendence factor obtained a Cronbach's alpha of 0.872 and Personal Relations an alpha of 0.762. The correlations of the SHTI-rb with external measures were: r = 0.527with FACIT; r = 0.266 with HHI; r = 0.667 with the Spirituality subscale of FACIT; and r = 0.348 with the Interrelation factor of HHI. The Relations of Transcendence subscale correlated with both Layout and Expectation and Interrelation of HHI (r = 0.162 and r = 0.329 respectively), while the scale of Personal Relations only correlated with Interrelation of HHI (r = 0.244). The Scale of Hope in Terminal Illness for relatives (brief version) is a valid and reliable specific instrument for terminal patients.

Concurrent 3-D sonifications enable the head-up monitoring of two interrelated aircraft navigation instruments.

PubMed

Towers, John; Burgess-Limerick, Robin; Riek, Stephan

2014-12-01

The aim of this study was to enable the head-up monitoring of two interrelated aircraft navigation instruments by developing a 3-D auditory display that encodes this navigation information within two spatially discrete sonifications. Head-up monitoring of aircraft navigation information utilizing 3-D audio displays, particularly involving concurrently presented sonifications, requires additional research. A flight simulator's head-down waypoint bearing and course deviation instrument readouts were conveyed to participants via a 3-D auditory display. Both readouts were separately represented by a colocated pair of continuous sounds, one fixed and the other varying in pitch, which together encoded the instrument value's deviation from the norm. Each sound pair's position in the listening space indicated the left/right parameter of its instrument's readout. Participants' accuracy in navigating a predetermined flight plan was evaluated while performing a head-up task involving the detection of visual flares in the out-of-cockpit scene. The auditory display significantly improved aircraft heading and course deviation accuracy, head-up time, and flare detections. Head tracking did not improve performance by providing participants with the ability to orient potentially conflicting sounds, suggesting that the use of integrated localizing cues was successful. Conclusion: A supplementary 3-D auditory display enabled effective head-up monitoring of interrelated navigation information normally attended to through a head-down display. Pilots operating aircraft, such as helicopters and unmanned aerial vehicles, may benefit from a supplementary auditory display because they navigate in two dimensions while performing head-up, out-of-aircraft, visual tasks.

Biases in attention, interpretation, memory, and associations in children with varying levels of spider fear: Inter-relations and prediction of behavior.

PubMed

Klein, Anke M; van Niekerk, Rianne; Ten Brink, Giovanni; Rapee, Ronald M; Hudson, Jennifer L; Bögels, Susan M; Becker, Eni S; Rinck, Mike

2017-03-01

Cognitive theories suggest that cognitive biases may be related and together influence the anxiety response. However, little is known about the interrelations of cognitive bias tasks and whether they allow for an improved prediction of fear-related behavior in addition to self-reports. This study simultaneously addressed several types of cognitive biases in children, to investigate attention bias, interpretation bias, memory bias and fear-related associations, their interrelations and the prediction of behavior. Eighty-one children varying in their levels of spider fear completed the Spider Anxiety and Disgust Screening for Children and performed two Emotional Stroop tasks, a Free Recall task, an interpretation task including size and distance indication, an Affective Priming Task, and a Behavioral Assessment Test. We found an attention bias, interpretation bias, and fear-related associations, but no evidence for a memory bias. The biases showed little overlap. Attention bias, interpretation bias, and fear-related associations predicted unique variance in avoidance of spiders. Interpretation bias and fear-related associations remained significant predictors, even when self-reported fear was included as a predictor. Children were not seeking help for their spider fear and were not tested on clinical levels of spider phobia. This is the first study to find evidence that different cognitive biases each predict unique variance in avoidance behavior. Furthermore, it is also the first study in which we found evidence for a relation between fear of spiders and size and distance indication. We showed that this bias is distinct from other cognitive biases. Copyright © 2016 Elsevier Ltd. All rights reserved.

Interrelation of Sport Participation, Physical Activity, Social Capital and Mental Health in Disadvantaged Communities: A SEM-Analysis

PubMed Central

Marlier, Mathieu; Van Dyck, Delfien; Cardon, Greet; De Bourdeaudhuij, Ilse; Babiak, Kathy; Willem, Annick

2015-01-01

Background The Health through Sport conceptual model links sport participation with physical, social and psychological outcomes and stresses the need for more understanding between these outcomes. The present study aims to uncover how sport participation, physical activity, social capital and mental health are interrelated by examining these outcomes in one model. Methods A cross-sectional survey was conducted in nine disadvantaged communities in Antwerp (Belgium). Two hundred adults (aged 18–56) per community were randomly selected and visited at home to fill out a questionnaire on socio-demographics, sport participation, physical activity, social capital and mental health. A sample of 414 adults participated in the study. Results Structural Equation Modeling analysis showed that sport participation (β = .095) and not total physical activity (β = .027) was associated with better mental health. No association was found between sport participation and community social capital (β = .009) or individual social capital (β = .045). Furthermore, only community social capital was linked with physical activity (β = .114), individual social capital was not (β = -.013). In contrast, only individual social capital was directly associated with mental health (β = .152), community social capital was not (β = .070). Conclusion This study emphasizes the importance of sport participation and individual social capital to improve mental health in disadvantaged communities. It further gives a unique insight into the functionalities of how sport participation, physical activity, social capital and mental health are interrelated. Implications for policy are that cross-sector initiatives between the sport, social and health sector need to be supported as their outcomes are directly linked to one another. PMID:26451731

Interrelation of Sport Participation, Physical Activity, Social Capital and Mental Health in Disadvantaged Communities: A SEM-Analysis.

PubMed

Marlier, Mathieu; Van Dyck, Delfien; Cardon, Greet; De Bourdeaudhuij, Ilse; Babiak, Kathy; Willem, Annick

2015-01-01

The Health through Sport conceptual model links sport participation with physical, social and psychological outcomes and stresses the need for more understanding between these outcomes. The present study aims to uncover how sport participation, physical activity, social capital and mental health are interrelated by examining these outcomes in one model. A cross-sectional survey was conducted in nine disadvantaged communities in Antwerp (Belgium). Two hundred adults (aged 18-56) per community were randomly selected and visited at home to fill out a questionnaire on socio-demographics, sport participation, physical activity, social capital and mental health. A sample of 414 adults participated in the study. Structural Equation Modeling analysis showed that sport participation (β = .095) and not total physical activity (β = .027) was associated with better mental health. No association was found between sport participation and community social capital (β = .009) or individual social capital (β = .045). Furthermore, only community social capital was linked with physical activity (β = .114), individual social capital was not (β = -.013). In contrast, only individual social capital was directly associated with mental health (β = .152), community social capital was not (β = .070). This study emphasizes the importance of sport participation and individual social capital to improve mental health in disadvantaged communities. It further gives a unique insight into the functionalities of how sport participation, physical activity, social capital and mental health are interrelated. Implications for policy are that cross-sector initiatives between the sport, social and health sector need to be supported as their outcomes are directly linked to one another.

Improvement of Speaking Ability through Interrelated Skills

ERIC Educational Resources Information Center

Liao, Guoqiang

2009-01-01

How to improve students' ability of speaking English? That is the key point we are concerned about. This paper discusses the possibility and necessity of improving students' ability by combining the four skills of speaking, listening, reading and writing.

ITS system specification. Appendix A, architectural trade-off analysis

DOT National Transportation Integrated Search

1997-01-01

The objective of the Polaris Project is to define an Intelligent Transportation Systems (ITS) architecture for the state of Minnesota. An architecture is a framework that defines how multiple ITS Components interrelate and contribute to the overall I...

Systems approach provides management control of complex programs

NASA Technical Reports Server (NTRS)

Dudek, E. F., Jr.; Mc Carthy, J. F., Jr.

1970-01-01

Integrated program management process provides management visual assistance through three interrelated charts - system model that identifies each function to be performed, matrix that identifies personnel responsibilities for these functions, process chart that breaks down the functions into discrete tasks.

Models for Individualized Instruction.

ERIC Educational Resources Information Center

Georgiades, William, Ed.; Clark, Donald C., Ed.

This book, consisting of five parts, provides a collection of source materials that will assist in implementing individualized instruction; provides examples of interrelated systems for individualizing instruction; and describes the components of individualized instructional systems, including flexible use of time, differentiated staffing, new…

14 CFR 1203.302 - Combination, interrelation or compilation.

Code of Federal Regulations, 2011 CFR

2011-01-01

... INFORMATION SECURITY PROGRAM Classification Principles and Considerations § 1203.302 Combination.... Compilations of unclassified information are considered unclassified unless some additional significant factor is added in the process of compilation. For example: (a) The way unclassified information is compiled...

Electronic depiction of Instrument Approach Procedure (IAP) charts phase 1: development and evaluation

DOT National Transportation Integrated Search

1995-05-01

This report describes the research program being conducted at the Volpe National Transportation Systems Center on the development of electronic aeronautical charts. The design of electronic aeronautical navigation charts raises many interrelated huma...

Understanding Population.

ERIC Educational Resources Information Center

Mothner, Ira

Activities and concerns of Ford Foundation supported population research and training centers are described in this report. The centers are concerned with population growth, consequences of growth for human welfare, forces that determine family planning, interrelations among population variables, economics of contraceptive distribution, and…

OPTIMIZING EXPOSURE MEASUREMENT TECHNIQUES

EPA Science Inventory

The research reported in this task description addresses one of a series of interrelated NERL tasks with the common goal of optimizing the predictive power of low cost, reliable exposure measurements for the planned Interagency National Children's Study (NCS). Specifically, we w...

14 CFR 1203.302 - Combination, interrelation or compilation.

Code of Federal Regulations, 2010 CFR

2010-01-01

... INFORMATION SECURITY PROGRAM Classification Principles and Considerations § 1203.302 Combination.... Compilations of unclassified information are considered unclassified unless some additional significant factor is added in the process of compilation. For example: (a) The way unclassified information is compiled...

Ecology as a Unifying Theme for Home Economics/Human Ecology.

ERIC Educational Resources Information Center

Vaines, Eleanore

1994-01-01

Discusses the complex character of everyday life as the deep ecology of Home Economics/Human Ecology. Explores the meanings of ecology and the ways in which diversity and harmony are interrelated companions of dynamic living systems. (JOW)

ITS system specification. Appendix D, physical architecture component interfaces

DOT National Transportation Integrated Search

1997-01-01

The objective of the Polaris Project is to define an Intelligent Transportation Systems (ITS) architecture for the state of Minnesota. An architecture is a framework that defines how multiple ITS Components interrelate and contribute to the overall I...

The Challenge of Training in Applied Sociology.

ERIC Educational Resources Information Center

Johnson, Doyle Paul; And Others

1987-01-01

Explores the challenge of expanding nonacademic employment opportunities for sociologists and training sociology students for such employment. Suggests several interrelated strategies for these students that address issues of marketing and public relations as well as curriculum revision. (Author/BSR)

Notification: The California Air Resources Board (ARB) Purchase and Use of Selected Equipment

EPA Pesticide Factsheets

October 14, 2014. The EPA OIG plans to begin research on the California Air Resources Board (ARB) purchase and use of selected equipment and interrelated service contracts with EPA funds, and reviewing related allegations.

The Evolution of Web Searching.

ERIC Educational Resources Information Center

Green, David

2000-01-01

Explores the interrelation between Web publishing and information retrieval technologies and lists new approaches to Web indexing and searching. Highlights include Web directories; search engines; portalisation; Internet service providers; browser providers; meta search engines; popularity based analysis; natural language searching; links-based…

Integrative Family Therapy: Theoretical Considerations.

ERIC Educational Resources Information Center

Walsh, William M.

Integrative family therapy is an integration of personality theory and counseling theory actualized in the counseling process. Personality theory contributes five interrelated concepts to a model of family therapy, including communication/perception, individual roles, family subunits, family themes, and individual personality dynamics; these…

Port modernization : a pyramid of interrelated challenges

DOT National Transportation Integrated Search

1999-04-13

This document forms the basis of a course of the same name developed by the Economic Commission for Latin America and the Caribbean of the United Nations. The course seeks to encourage participants to analyze a series of factors affecting the adminis...

LESSONS LEARNED FROM THE NATIONAL HUMAN EXPOSURE ASSESSMENT SURVEY (NHEXAS)

EPA Science Inventory

Three NHEXAS Studies were conducted from 1995-1997 to evaluate total human exposure to multiple chemicals on community and regional scales. EPA established cooperative agreements with three Consortia to conduct three interrelated NHEXAS field studies. The University of Arizona...

The Directed Case Method.

ERIC Educational Resources Information Center

Cliff, William H.; Curtin, Leslie Nesbitt

2000-01-01

Provides an example of a directed case on human anatomy and physiology. Uses brief real life newspaper articles and clinical descriptions of medical reference texts to describe an actual, fictitious, or composite event. Includes interrelated human anatomy and physiology topics in the scenario. (YDS)

Reducing School Violence: School-Based Curricular Programs and School Climate

ERIC Educational Resources Information Center

Greene, Michael B.

2008-01-01

This article examines two different, but interrelated approaches to reduce school violence: school-based curricular programs and efforts to change school climate. The state of the research for each is reviewed and the relationship between them is explored.

Postage Stamps as Pedagogical Instruments in the Italian Curriculum.

ERIC Educational Resources Information Center

Nuessel, Frank; Cicogna, Caterina

1992-01-01

Examination of several interrelated topics on postage stamps, including their multiple functions and significance as semiotic artifacts, precedes suggestions for incorporating them into the Italian language curriculum in such activities as reading, writing, speaking, listening, and cultural understanding. (CB)

Seismic Waveform Analysis of Underground Nuclear Explosions

DTIC Science & Technology

1979-11-15

parameters to be discussed here are Bouguer gravity (Figure 18), and station elevation (Figure 19). Tn this simple comparison of various geophysical...noted the frequent strong correlation between Bouguer gravity and elevation. Indeed, many of the geophysical parameters discussed above are interrelated

The general deterrence of driving while intoxicated. Volume 2, Subsystem analyses

DOT National Transportation Integrated Search

1978-04-01

A system analysis was completed of the general deterrence of driving while intoxicated (DWI). Elements which influence DWI 'decisions were identified and interrelated in a system model; then, potential countermeasures which might be employed in DWI g...

ITS system specification. Appendix B, requirements by service/function/subfunction

DOT National Transportation Integrated Search

1997-01-01

The objective of the Polaris Project is to define an Intelligent Transportation Systems (ITS) architecture for the state of Minnesota. An architecture is a framework that defines how multiple ITS Components interrelate and contribute to the overall I...

Systems Operation Studies for Automated Guideway Transit Systems : Detailed Station Model Functional Specifications

DOT National Transportation Integrated Search

1981-07-01

The Detailed Station Model (DSM) is a discrete event model representing the interrelated queueing processes associated with vehicle and passenger activities in an AGT station. The DSM will provide operational and performance measures of alternative s...

17 CFR 229.303 - (Item 303) Management's discussion and analysis of financial condition and results of operations.

Code of Federal Regulations, 2011 CFR

2011-04-01

... may be combined whenever the two topics are interrelated. Where in the registrant's judgment a... or credit risk support to, or engages in leasing, hedging or research and development services with...

Improving Health-care Delivery for Post-Traumatic Stress Disorder: An Interrelated Approach Leveraging Systems Engineering and Optimization

DTIC Science & Technology

2011-09-01

AND EXPERIMENTAL DESIGN ..........................................................................................................31   1...PRIMARY RESERCH QUESTION ............................................................41   C.   OBJECTIVE ACHIEVEMENT...Based Outpatient Clinic CPT Cognitive Processing Therapy DISE Distributed Information Systems Experimentation EBT Evidence-Based Treatment GMC

The Ethical Dimension of Leadership.

ERIC Educational Resources Information Center

Boatman, Sara; Adams, Todd C.

1992-01-01

Ethics begin personally but ultimately provide empowerment. Practicing ethical leadership requires three major interrelated activities: knowing (awareness of own and others' values); feeling (creating awareness of or sensing values and dilemmas); and acting (behavior). Ethical leadership is tested through ethical dilemmas, and practicing it…

Geographical Theories.

ERIC Educational Resources Information Center

Golledge, Reginald G.

1996-01-01

Discusses the origin of theories in geography and particularly the development of location theories. Considers the influence of economic theory on agricultural land use, industrial location, and geographic location theories. Explores a set of interrelated activities that show how the marketing process illustrates process theory. (MJP)

LANDSCAPE INDICATORS OF SURFACE WATER CONDITIONS

EPA Science Inventory

This task comprises three inter-related projects: 1) impervious surface mapping and evaluation of its impact ; 2) detection of BMPs and estimation of their ability to reduce nutrient input into streams, and; 3) detection of isolated wetlands. Each substask addresses critical is...

Prosocial Development in Middle Childhood: A Longitudinal Study.

ERIC Educational Resources Information Center

Eisenberg, Nancy; And Others

1987-01-01

Examines change in prosocial moral judgment over a seven-year period; determines whether there are gender differences in the development of prosocial moral judgment; and examines the interrelations of moral judgment, affect (sympathy), and behavior in middle childhood. (Author/RWB)

System Operations Studies for Automated Guideway Transit Systems : Detailed Station Model User's Manual

DOT National Transportation Integrated Search

1981-07-01

The Detailed Station Model (DSM) is a discrete event model representing the interrelated queueing processes associated with vehicle and passenger activities in an AGT station. The DSM will provide operational and performance measures of alternative s...

Collards and Caterpillars

ERIC Educational Resources Information Center

Ashbrook, Peggy

2007-01-01

"Community," "assemblage," "network," "complex," "interdependent," "web," and "synergism"--definitions of an ecosystem often include these words to highlight the dynamic interrelated workings of plants and animals with their physical environment. Young children don't understand the complexities of ecosystems, but they can begin to understand that…

SCREENING MODEL FOR VOLATILE POLLUTANTS IN DUEL POROSITY SOILT

EPA Science Inventory

This paper develops mass fraction models for transport and fate of volatile organic chemicals, such as pesticides, in two-region soils. It addressed two main and interrelated parts. First, expressions are derived which describe the rate mass transfer coefficient in a periodical...

How-To-Do-It. A Beetle, a Bur, and the Potato: An Introduction to Ecology.

ERIC Educational Resources Information Center

Jantzen, Paul G.

1983-01-01

Describes how the interrelation of the potato beetle, the buffalo-bur, and the potato is used as an introduction to ecology. Methods of controlling the beetle and ecological principles illustrated in the interrelationship are discussed. (JN)

Hands-On Activities and Challenge Tests in Agricultural and Environmental Education

ERIC Educational Resources Information Center

Poudel, D. D.; Vincent, L. M.; Anzalone, C.; Huner, J.; Wollard, D.; Clement, T.; DeRamus, A.; Blakewood, G.

2005-01-01

Many agricultural and environmental problems are interrelated and overlapping. Several agencies, including nonprofit organizations, have developed programs to educate schoolchildren about agricultural and environmental issues; however, programs that integrate both agricultural and environmental learning, especially among middle and high school…

77 FR 11544 - Proposed Data Collections Submitted for Public Comment and Recommendations

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-27

... Outcome Evaluation of ``Teenage Pregnancy Prevention: Integrating Services, Programs, and Strategies... teens ages 15-19 years. Although the evidence strongly suggests that teenage pregnancy is a multifaceted problem stemming from interrelated internal and external factors, pregnancy prevention programs have...

Work Family Relations: Antecedents and Outcomes

ERIC Educational Resources Information Center

Cinamon, Rachel Gali; Rich, Yisrael

2010-01-01

This study investigated interrelations between conflict and facilitation in work and family domains, with spousal, managerial, and collegial social support serving as antecedents, and professional vigor and burnout as outcomes. Participants were 322 female, married teachers. Regression analyses revealed complex relations between conflict and…

ITS system specification. Appendix C, data flows by function for ITS services

DOT National Transportation Integrated Search

1997-01-01

The objective of the Polaris Project is to define an Intelligent Transportation Systems (ITS) architecture for the state of Minnesota. An architecture is a framework that defines how multiple ITS Components interrelate and contribute to the overall I...

ECOS Process for Curriculum Development.

ERIC Educational Resources Information Center

Putnam and Northern Westchester Counties Board of Cooperative Educational Services, Yorktown Heights, NY.

This booklet details a methodology for infusing almost any subject into a school district's ongoing curriculum. The process involved three interrelated parts: infusion, community, and stewardship. The infusion component makes it possible to upgrade teacher's skills, improve classroom management, strengthen community-school cooperation, and diffuse…

Layering the Introductory History of Europe Course.

ERIC Educational Resources Information Center

Waddy, Helena

1997-01-01

Describes an introductory undergraduate survey course on European history that incorporates three interrelated sections: constitutional government in Europe, the American revolution, and the French Revolution. The instruction emphasizes the interconnectedness among the events and includes repetition of key ideas and information. Discusses the…

Career Education--The Final Impoverishment of Learning?

ERIC Educational Resources Information Center

Nash, Robert J.; Agne, Russell M.

1973-01-01

Career educators appear to be developing an approach to schooling rooted in at least four questionable assumptions about the learning process. Unless these interrelated assumptions are critically examined and rectified, then the most beneficial intended outcomes of career education will be subverted. (Authors)

COAL UTILITY EVIRONMENTAL COST (CUECOST) WORKBOOK USER'S MANUAL

EPA Science Inventory

The document is a user's manual for the Coal Utility Environmental Cost (CUECost) workbook (an interrelated set of spreadsheets) and documents its development and the validity of methods used to estimate installed capital ad annualize costs. The CUECost workbook produces rough-or...

Beyond the Rhetoric of Partnership.

ERIC Educational Resources Information Center

Walling, Donovan R.

1988-01-01

Discusses the growth in four interrelated groups that bear on the school's relationship to the community: elderly citizens, school-age children, nontraditional families, and the underclass of impoverished children. Suggests that schools target business, the elderly, and parents as publics that will offer future support. (MS)

On-Line Retrieval II.

ERIC Educational Resources Information Center

Kurtz, Peter; And Others

This report is concerned with the implementation of two interrelated computer systems: an automatic document analysis and classification package, and an on-line interactive information retrieval system which utilizes the information gathered during the automatic classification phase. Well-known techniques developed by Salton and Dennis have been…

47 CFR 32.9000 - Glossary of terms.

Code of Federal Regulations, 2010 CFR

2010-10-01

... of this system of accounts. Accounting system means the total set of interrelated principles, rules... entity from a financial perspective. An accounting system generally consists of a chart of accounts, various parallel subsystems and subsidiary records. An accounting system is utilized to provide the...

Complexities of Teaching and Implications for Equity

ERIC Educational Resources Information Center

Lee, Carol D.

2011-01-01

Teacher knowledge involves a complex network of inter-related domains, including cognition; differences in learning strengths for primary and secondary school students; social and emotional development across the life course; motivation; language acquisition and socialization; curriculum design and assessment; and classroom management. In…

Modeling as a tool for management of saline soils and irrigation waters

USDA-ARS?s Scientific Manuscript database

Optimal management of saline soils and irrigation waters requires consideration of many interrelated factors including, climate, water applications and timing, water flow, plant water uptake, soil chemical reactions, plant response to salinity and solution composition, soil hydraulic properties and ...

The USSR: Sport and Politics Intertwined

ERIC Educational Resources Information Center

Howell, Reet

1975-01-01

Although sport is supposedly non-political in the Soviet Union, it is used to achieve non-sport objectives such as political socialization, political indoctrination and political integration. Article considered sport in the Soviet Union as it is interrelated with other aspects of society. (Author/RK)

Mileage-based user fees : defining a path toward implementation phase 1, defining a research strategy, final report, November 2009.

DOT National Transportation Integrated Search

2009-11-01

This report documents early activities of a twophase research effort composed of three interrelated : components: 1) a technology assessment, 2) an institutional assessment, and 3) a oneday : implementationfocused symposium. Each component b...

Restructuring for an Interdisciplinary Curriculum.

ERIC Educational Resources Information Center

Jenkins, John M., Ed.; Tanner, Daniel, Ed.

Articles for developing an integrated secondary curriculum are presented in this book. The articles include: "Synthesis Versus Fragmentation: The Way Out of Curriculum Confusion," by Daniel Tanner; "The Interrelated Curriculum," by Steven S. Means; "Integrated Teaching and Learning in Essential Schools," by Richard Lear; "Interdisciplinary Teaming…

Associations of Emotion-Related Regulation with Language Skills, Emotion Knowledge, and Academic Outcomes

ERIC Educational Resources Information Center

Eisenberg, Nancy; Sadovsky, Adrienne; Spinrad, Tracy L.

2005-01-01

Research suggests that the development of emotional regulation in early childhood is interrelated with emotional understanding and language skills. Heuristic models are proposed on how these factors influence children's emerging academic motivation and skills. (Contains 2 figures.)

Avoiding High School Senior Slump

ERIC Educational Resources Information Center

Weil, Henry

1974-01-01

The Freshman Year Program at the New School for Social Research is meant to be an alternative to the disaffection that appears in high school seniors. This freshman year establishes an interrelated approach to knowledge, while introducing students to a variety of educational disciplines. (Author/PG)

Brief Report: Trichotillomania in an Autistic Male.

ERIC Educational Resources Information Center

Hamdan-Allen, Ghada

1991-01-01

This report describes trichotillomania (the irresistible urge to pull one's own body hair) in a young male with autism who was treated successfully with Fluoxetine, a serotonergic antidepressant. The possible etiologic interrelations and treatment implications of this kind of comorbidity are presented. (JDD)

Mild hypothermia alters midazolam pharmacokinetics in normal healthy volunteers.

PubMed

Hostler, David; Zhou, Jiangquan; Tortorici, Michael A; Bies, Robert R; Rittenberger, Jon C; Empey, Philip E; Kochanek, Patrick M; Callaway, Clifton W; Poloyac, Samuel M

2010-05-01

The clinical use of therapeutic hypothermia has been rapidly expanding due to evidence of neuroprotection. However, the effect of hypothermia on specific pathways of drug elimination in humans is relatively unknown. To gain insight into the potential effects of hypothermia on drug metabolism and disposition, we evaluated the pharmacokinetics of midazolam as a probe for CYP3A4/5 activity during mild hypothermia in human volunteers. A second objective of this work was to determine whether benzodiazepines and magnesium administered intravenously would facilitate the induction of hypothermia. Subjects were enrolled in a randomized crossover study, which included two mild hypothermia groups (4 degrees C saline infusions and 4 degrees C saline + magnesium) and two normothermia groups (37 degrees C saline infusions and 37 degrees C saline + magnesium). The lowest temperatures achieved in the 4 degrees C saline + magnesium and 4 degrees C saline infusions were 35.4 +/- 0.4 and 35.8 +/- 0.3 degrees C, respectively. A significant decrease in the formation clearance of the major metabolite 1'-hydroxymidazolam was observed during the 4 degrees C saline + magnesium compared with that in the 37 degrees C saline group (p < 0.05). Population pharmacokinetic modeling identified a significant relationship between temperature and clearance and intercompartmental clearance for midazolam. This model predicted that midazolam clearance decreases 11.1% for each degree Celsius reduction in core temperature from 36.5 degrees C. Midazolam with magnesium facilitated the induction of hypothermia, but shivering was minimally suppressed. These data provided proof of concept that even mild and short-duration changes in body temperature significantly affect midazolam metabolism. Future studies in patients who receive lower levels and a longer duration of hypothermia are warranted.

Population Pharmacokinetics of Vancomycin in Patients Undergoing Allogeneic Hematopoietic Stem-Cell Transplantation.

PubMed

Okada, Akira; Kariya, Misato; Irie, Kei; Okada, Yutaka; Hiramoto, Nobuhiro; Hashimoto, Hisako; Kajioka, Ryosuke; Maruyama, Chika; Kasai, Hidefumi; Hamori, Mami; Nishimura, Asako; Shibata, Nobuhito; Fukushima, Keizo; Sugioka, Nobuyuki

2018-05-15

Vancomycin is a commonly used antimicrobial agent for patients undergoing allogeneic hematopoietic stem-cell transplantation (allo-HSCT). Vancomycin has large inter- and intraindividual pharmacokinetic variability, which is mainly described by renal function; various studies have indicated that vancomycin pharmacokinetics are altered in special populations. However, little is known regarding vancomycin pharmacokinetics in patients undergoing allo-HSCT. Therefore, we aimed to develop a population pharmacokinetic (PopPK) model of vancomycin in patients undergoing allo-HSCT for effective and safe antimicrobial therapy and to develop a vancomycin dosing nomogram for a vancomycin optimal-dosing strategy. In total, 285 observations from 95 patients undergoing allo-HSCT were available. The final PopPK parameter estimates were central volume of distribution (V1, L), 39.2; clearance (L/h), 4.25; peripheral volume of distribution (V2, L), 56.1; and intercompartmental clearance (L/h), 1.95. The developed vancomycin model revealed an increase in V1 and V2 compared with those in the general population that consisted of patients with methicillin-resistant Staphylococcus aureus. Moreover, serum creatinine was reduced because of an increase in the plasma fraction because of destruction of hematopoietic stem cells accompanying allo-HSCT pretreatment, suggesting that the Cockcroft-Gault equation-based creatinine clearance value was overestimated. To our knowledge, this is the first PopPK study to develop a dosing nomogram for vancomycin in patients undergoing allo-HSCT and was proven to be useful in optimizing the dosage and dosing interval of vancomycin in these patients. This strategy will provide more useful information for vancomycin therapy with an evidence-based dose adjustment. © 2018, The American College of Clinical Pharmacology.

Population Pharmacokinetics and Exposure Response Assessment of CC-292, a Potent BTK Inhibitor, in Patients With Chronic Lymphocytic Leukemia.

PubMed

Li, Yan; Ramírez-Valle, Francisco; Xue, Yongjun; Ventura, Judith I; Gouedard, Olivier; Mei, Jay; Takeshita, Kenichi; Palmisano, Maria; Zhou, Simon

2017-10-01

CC-292, a potent Bruton tyrosine kinase inhibitor, is under development for the treatment of B-cell malignancies. An analysis was performed to develop a population pharmacokinetic model of CC-292 and assess the influence of demographics and disease-related covariates on CC-292 exposure and to assess the exposure-response (overall response rate) relationship in patients with chronic lymphocytic leukemia. Population pharmacokinetic analysis was based on a 2-compartment base model conducted in NONMEM. Categorical exposure-response analysis was performed using logistic regression in SAS. The population pharmacokinetic analysis results indicated that CC-292 pharmacokinetic disposition is similar between healthy subjects and patients. CC-292 showed a larger central compartment volume of distribution than the peripheral compartment volume of distribution (158 L and 72 L, respectively) and a faster clearance than intercompartmental clearance (134 L/h and 18.7 L/h, respectively), indicating that for CC-292, clearance from blood occurs faster than distribution into deep tissues and organs. CC-292 clearance is not affected by demographics or baseline clinical lab factors, except for sex. Although sex significantly reduced variation of apparent clearance, the sex effect on apparent clearance is unlikely to be clinically relevant. The exposure-response analysis suggested that higher drug exposure is linearly correlated with higher overall response rate. A twice-daily dose regimen showed higher overall response rate as compared to once-daily dosing, consistent with a threshold concentration of approximately 300 ng/mL, above which the probability of overall response rate significantly increases. © 2017, The Authors. The Journal of Clinical Pharmacology Published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

Does Critical Illness Change Levofloxacin Pharmacokinetics?

PubMed

Roberts, Jason A; Cotta, Menino Osbert; Cojutti, Piergiorgio; Lugano, Manuela; Della Rocca, Giorgio; Pea, Federico

2015-12-14

Levofloxacin is commonly used in critically ill patients for which existing data suggest nonstandard dosing regimens should be used. The objective of this study was to compare the population pharmacokinetics of levofloxacin in critically ill and in non-critically ill patients. Adult patients with a clinical indication for levofloxacin were eligible for participation in this prospective pharmacokinetic study. Patients were given 500 mg or 750 mg daily by intravenous administration with up to 11 blood samples taken on day 1 or 2 of therapy. Plasma samples were analyzed and population pharmacokinetic analysis was undertaken using Pmetrics. Thirty-five patients (18 critically ill) were included. The mean (standard deviation [SD]) age, weight, and Cockcroft-Gault creatinine clearance for the critically ill and for the non-critically ill patients were 60.3 (16.4) and 72.0 (11.6) years, 78.5 (14.8) and 70.9 (15.8) kg, and 71.9 (65.8) and 68.2 (30.1) ml/min, respectively. A two-compartment linear model best described the data. Increasing creatinine clearance was the only covariate associated with increasing drug clearance. The presence of critical illness did not significantly affect any pharmacokinetic parameter. The mean (SD) parameter estimates were as follows: clearance, 8.66 (3.85) liters/h; volume of the central compartment (Vc), 41.5 (24.5) liters; intercompartmental clearance constants from central to peripheral, 2.58 (3.51) liters/h; and peripheral to central compartments, 0.90 (0.58) liters/h. Monte Carlo dosing simulations demonstrated that achievement of therapeutic exposures was dependent on renal function, pathogen, and MIC. Critical illness appears to have no independent effect on levofloxacin pharmacokinetics that cannot be explained by altered renal function. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Does Critical Illness Change Levofloxacin Pharmacokinetics?

PubMed Central

Cotta, Menino Osbert; Cojutti, Piergiorgio; Lugano, Manuela; Rocca, Giorgio Della; Pea, Federico

2015-01-01

Levofloxacin is commonly used in critically ill patients for which existing data suggest nonstandard dosing regimens should be used. The objective of this study was to compare the population pharmacokinetics of levofloxacin in critically ill and in non-critically ill patients. Adult patients with a clinical indication for levofloxacin were eligible for participation in this prospective pharmacokinetic study. Patients were given 500 mg or 750 mg daily by intravenous administration with up to 11 blood samples taken on day 1 or 2 of therapy. Plasma samples were analyzed and population pharmacokinetic analysis was undertaken using Pmetrics. Thirty-five patients (18 critically ill) were included. The mean (standard deviation [SD]) age, weight, and Cockcroft-Gault creatinine clearance for the critically ill and for the non-critically ill patients were 60.3 (16.4) and 72.0 (11.6) years, 78.5 (14.8) and 70.9 (15.8) kg, and 71.9 (65.8) and 68.2 (30.1) ml/min, respectively. A two-compartment linear model best described the data. Increasing creatinine clearance was the only covariate associated with increasing drug clearance. The presence of critical illness did not significantly affect any pharmacokinetic parameter. The mean (SD) parameter estimates were as follows: clearance, 8.66 (3.85) liters/h; volume of the central compartment (Vc), 41.5 (24.5) liters; intercompartmental clearance constants from central to peripheral, 2.58 (3.51) liters/h; and peripheral to central compartments, 0.90 (0.58) liters/h. Monte Carlo dosing simulations demonstrated that achievement of therapeutic exposures was dependent on renal function, pathogen, and MIC. Critical illness appears to have no independent effect on levofloxacin pharmacokinetics that cannot be explained by altered renal function. PMID:26666946

Whole-body fluid distribution in humans during dehydration and recovery, before and after humid-heat acclimation induced using controlled hyperthermia.

PubMed

Patterson, M J; Stocks, J M; Taylor, N A S

2014-04-01

This experiment was designed to test the hypothesis that the plasma volume is not selectively defended during exercise- and heat-induced dehydration following humid-heat acclimation. Eight physically active males were heat acclimated (39.8 °C, relative humidity 59.2%) using 17 days of controlled hyperthermia (core temperature: 38.5 °C). Inter-compartmental fluid losses and movements were tracked (radioisotopes and Evans blue dye) during progressive dehydration (cycling) in these same conditions and also during a resting recovery without fluid replacement (28 °C), before (day 1), during (day 8) and after heat acclimation (day 22). On days 8 and 22, there were significant increases in total body water, interstitial fluid and plasma volume (P < 0.05), but the intracellular compartments did not change (P > 0.05). The baseline plasma volume remained expanded throughout: 43.4 [±2.6 (day 1)], 49.1 [±2.4 (day 8); P < 0.05] and 48.9 mL kg(-1) [±3.0 (day 22); P < 0.05]. During progressive dehydration, plasma reductions of 9.0% (±0.9: day 1), 12.4% (±1.6: day 8) and 13.6% (±1.2: day 22) were observed, with day 8 and 22 losses significantly exceeding day 1 (P < 0.05). During recovery, plasma volume restoration commenced, with the intracellular fluid contribution becoming more pronounced as acclimation progressed. It is concluded that the plasma volume was not defended more vigorously following humid-heat acclimation. Indeed, a greater fluid loss may well underlie the mechanisms for enhancing plasma volume recovery when heat acclimation is induced using the controlled-hyperthermia technique. © 2013 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.

Population Pharmacokinetics of Fentanyl in the Critically Ill

PubMed Central

Choi, Leena; Ferrell, Benjamin A; Vasilevskis, Eduard E; Pandharipande, Pratik P; Heltsley, Rebecca; Ely, E Wesley; Stein, C Michael; Girard, Timothy D

2016-01-01

Objective To characterize fentanyl population pharmacokinetics in patients with critical illness and identify patient characteristics associated with altered fentanyl concentrations. Design Prospective cohort study. Setting Medical and surgical ICUs in a large tertiary care hospital in the United States. Patients Patients with acute respiratory failure and/or shock who received fentanyl during the first five days of their ICU stay. Measurements and Main Results We collected clinical and hourly drug administration data and measured fentanyl concentrations in plasma collected once daily for up to five days after enrollment. Among 337 patients, the mean duration of infusion was 58 hours at a median rate of 100 µg/hr. Using a nonlinear mixed-effects model implemented by NONMEM, we found fentanyl pharmacokinetics were best described by a two-compartment model in which weight, severe liver disease, and congestive heart failure most affected fentanyl concentrations. For a patient population with a mean weight of 92 kg and no history of severe liver disease or congestive heart failure, the final model, which performed well in repeated 10-fold cross-validation, estimated total clearance (CL), intercompartmental clearance (Q), and volumes of distribution for the central (V1) and peripheral compartments (V2) to be 35 (95% confidence interval: 32 to 39) L/hr, 55 (42 to 68) L/hr, 203 (140 to 266) L, and 523 (428 to 618) L, respectively. Severity of illness was marginally associated with fentanyl pharmacokinetics but did not improve the model fit after liver and heart disease were included. Conclusions In this study, fentanyl pharmacokinetics during critical illness were strongly influenced by severe liver disease, congestive heart failure, and weight, factors that should be considered when dosing fentanyl in the ICU. Future studies are needed to determine if data-driven fentanyl dosing algorithms can improve outcomes for ICU patients. PMID:26491862

Role of metabolite transporters in source-sink carbon allocation

PubMed Central

Ludewig, Frank; Flügge, Ulf-Ingo

2013-01-01

Plants assimilate carbon dioxide during photosynthesis in chloroplasts. Assimilated carbon is subsequently allocated throughout the plant. Generally, two types of organs can be distinguished, mature green source leaves as net photoassimilate exporters, and net importers, the sinks, e.g., roots, flowers, small leaves, and storage organs like tubers. Within these organs, different tissue types developed according to their respective function, and cells of either tissue type are highly compartmentalized. Photoassimilates are allocated to distinct compartments of these tissues in all organs, requiring a set of metabolite transporters mediating this intercompartmental transfer. The general route of photoassimilates can be briefly described as follows. Upon fixation of carbon dioxide in chloroplasts of mesophyll cells, triose phosphates either enter the cytosol for mainly sucrose formation or remain in the stroma to form transiently stored starch which is degraded during the night and enters the cytosol as maltose or glucose to be further metabolized to sucrose. In both cases, sucrose enters the phloem for long distance transport or is transiently stored in the vacuole, or can be degraded to hexoses which also can be stored in the vacuole. In the majority of plant species, sucrose is actively loaded into the phloem via the apoplast. Following long distance transport, it is released into sink organs, where it enters cells as source of carbon and energy. In storage organs, sucrose can be stored, or carbon derived from sucrose can be stored as starch in plastids, or as oil in oil bodies, or – in combination with nitrogen – as protein in protein storage vacuoles and protein bodies. Here, we focus on transport proteins known for either of these steps, and discuss the implications for yield increase in plants upon genetic engineering of respective transporters. PMID:23847636

Assessment of micafungin regimens by pharmacokinetic-pharmacodynamic analysis: a dosing strategy for Aspergillus infections.

PubMed

Ikawa, Kazuro; Nomura, Kenichi; Morikawa, Norifumi; Ikeda, Kayo; Taniwaki, Masafumi

2009-10-01

A pharmacokinetic (PK)-pharmacodynamic (PD) analysis was conducted to assess various micafungin regimens for Candida and Aspergillus infections, as appropriate regimens have not been established, especially for Aspergillus infections. Plasma drug concentrations (48 samples from 10 adult patients with haematological malignancies) were determined chromatographically, and used for population PK modelling and Monte Carlo simulation to evaluate the ability of regimens (1 h infusions) to attain genus-dependent PK-PD targets, namely fungistatic and fungicidal targets against Candida spp. [area under the plasma unbound (1%) drug concentration-time curve over 24 h/MIC (fAUC/MIC) = 10 and 20] and an effective concentration target against Aspergillus spp. (plasma unbound drug concentration = 0.05 mg/L). Mean (variance) values for two-compartment PK model parameters were: clearance, 0.762 L/h (15.4%); volume of central compartment, 9.25 L (24.6%); intercompartmental clearance, 7.02 L/h (fixed); and volume of peripheral compartment, 8.86 L (71.8%). The Monte Carlo simulation demonstrated that 50 mg once daily and 100 mg once daily for the fungistatic and fungicidal targets achieved a >95% probability of target attainment against Candida spp. To achieve such probability against Aspergillus spp., 250 mg once daily or 100 mg twice daily was required. These results rationalize the approved micafungin dosages for Candida infections (50 mg once daily for prophylaxis and 100-150 mg once daily for treatment), and on the basis of these results we propose a PK-PD-based dosing strategy for Aspergillus infections. A regimen of 200-250 mg/day should be initiated to ensure the likelihood of a favourable outcome. The regimen can be optimized by decreasing the dosing interval.

Intra- and intercompartmental associations between levels of organochlorines in maternal plasma, cord plasma and breast milk, and lead and cadmium in whole blood, for indigenous peoples of Chukotka, Russia.

PubMed

Eik Anda, E; Nieboer, E; Dudarev, A A; Sandanger, T M; Odland, J Ø

2007-08-01

Long-range transport of pollutants towards circumpolar regions emphasizes the need for up-to-date and reliable biological monitoring data. This paper explores the use, reliability and availability of maternal blood (MB) and plasma (MP), cord blood (CB) and plasma (CP) and mother's milk (MM) in terms of assessing exposure to persistent toxic substances (PTSs). It is concluded that MP has the best combination of availability, sensitivity in terms of number of PTSs, their detection frequency and concentrations, and physiological relevance. The study group consisted of 48 pregnant women of indigenous origin from the Chuchki district in the eastern Russian arctic. Blood, CB and MM specimens were collected from all women and MP, CP and MM were analyzed for the Arctic Monitoring and Assessment Programme (AMAP) suite of organochlorines (OCs) and metals (Pb and Cd in MB and CB). Generally speaking, the levels of PTSs coincided with those indicated in several AMAP publications from Chukotka and other areas of northern Russia. The correlations of PTS concentrations between the three body fluid compartments exceeded the minimum statistical requirements of alpha = 0.05 and beta = 0.20 for most of the compounds, with r > 0.46 except for Cd (r = 0.05); lipid adjustments for the OCs did not affect the r-values to any significant extent. The majority of the inter-OC correlations within compartments also fulfilled the indicated statistical condition. Careful consideration is given to the replacement of concentrations below the detection limit, OC detection frequency, the criteria for log-transformation of the data, analytical uncertainty, and biological variability. Practical implications of the findings are explored.

Botulinum toxin type-A affects mechanics of non-injected antagonistic rat muscles.

PubMed

Ateş, Filiz; Yucesoy, Can A

2018-08-01

Botulinum toxin type A (BTX-A) effects on the mechanics of non-injected antagonistic muscles are unknown. The aim was to test the following hypotheses in a rat model: BTX-A injected into gastrocnemius medialis (GM) and lateralis (GL) (1) decreases forces of the antagonistic tibialis anterior (TA) and extensor digitorum longus (EDL), (2) reduces length range of force exertion and (3) increases passive forces of the TA, and (4) changes inter-antagonistic and inter-synergistic epimuscular myofascial force transmission (EMFT). Two groups of Wistar rats were tested: BTX (0.1 units of BTX-A were injected to the GM and GL, each) and Control (saline injected). Five-days post, TA, EDL, GM-GL, and soleus distal and EDL proximal isometric forces were measured after TA lengthening. BTX-A exposure caused forces of all muscles to decrease significantly. TA and EDL active force drops (maximally by 37.3%) show inter-compartmental spread. Length range of force exertion of the TA did not change, but its passive force increased significantly (by 25%). The percentages of intramuscular connective tissue content of the TA and EDL was higher (BTX: 20.0 ± 4.9% and 19.3 ± 4.1% vs. control: 13.1 ± 5.4% and 14.5 ± 4.0%, respectively). Calf muscles' forces were not affected by TA length changes for both groups indicating lacking inter-antagonistic EMFT. However, BTX-A altered EDL proximo-distal force differences hence, inter-synergistic EMFT. A major novel finding is that BTX-A affects mechanics of non-injected antagonistic muscles in test conditions involving only limited EMFT. The effects indicating a stiffer muscle with no length range increase contradict some treatment aims, which require clinical testing. Copyright © 2018 Elsevier Ltd. All rights reserved.

Population pharmacokinetics of lyophilized recombinant glucagon-like peptide-1 receptor agonist (recombinant exendin-4, rE-4) in Chinese patients with type 2 diabetes mellitus
.

PubMed

Zang, Yan-Nan; Zhang, Min-Jie; Wang, Yi-Tong; Wang, Chen; Wang, Qian; Zheng, Qing-Shan; Ji, Li-Nong; Guo, Wei; Fang, Yi

2017-08-01

To investigate the population pharmacokinetics of lyophilized recombinant glucagon-like peptide-1 receptor agonist (rE-4) in Chinese patients with type 2 diabetes mellitus (T2DM) for plasma concentration estimation and individualized treatment. Twelve patients with T2DM were enrolled to receive subcutaneous injections of rE-4 at 5 µg twice daily for 84 days. Administration dosage was adjusted from 5 µg to 10 µg twice daily at day 29 in case of glycated albumin (GA) ≥ 17%. The population pharmacokinetic model was developed in the nonlinear mixed-effects modeling software NONMEM. The data were best described by a two-compartment model with first-order absorption and elimination. The outcome parameters were as follows: apparent clearance (CL/F) 6.67 L/h, apparent distribution volume of central compartment (V_c/F) 19.4 L, absorption rate constant (K_a) 1.39 h^-1, apparent distribution volume of peripheral compartment (V_p/F) 22.6 L, intercompartmental clearance (Q/F) 1.28 L/h. The interindividual variabilities for CL/F, V_c/F, K_a, and Q/F were 64.4%, 57.7%, 45.5%, and 153.3%, respectively. The intra-individual variability of proportional error model was 41.7%. No covariate was screened out that showed significant influence on the model parameters. The established two-compartment model with first-order absorption and elimination successfully described the pharmacokinetic characteristics of rE-4 in Chinese patients with T2DM.
.

Evaluation of Aztreonam Dosing Regimens in Patients With Normal and Impaired Renal Function: A Population Pharmacokinetic Modeling and Monte Carlo Simulation Analysis.

PubMed

Xu, Hongmei; Zhou, Wangda; Zhou, Diansong; Li, Jianguo; Al-Huniti, Nidal

2017-03-01

Aztreonam is a monocyclic β-lactam antibiotic often used to treat infections caused by Enterobacteriaceae or Pseudomonas aeruginosa. Despite the long history of clinical use, population pharmacokinetic modeling of aztreonam in renally impaired patients is not yet available. The aims of this study were to assess the impact of renal impairment on aztreonam exposure and to evaluate dosing regimens for patients with renal impairment. A population model describing aztreonam pharmacokinetics following intravenous administration was developed using plasma concentrations from 42 healthy volunteers and renally impaired patients from 2 clinical studies. The final pharmacokinetic model was used to predict aztreonam plasma concentrations and evaluate the probability of pharmacodynamic target attainment (PTA) in patients with different levels of renal function. A 2-compartment model with first-order elimination adequately described aztreonam pharmacokinetics. The population mean estimates of aztreonam clearance, intercompartmental clearance, volume of distribution of the central compartment, and volume of distribution of the peripheral compartment were 4.93 L/h, 9.26 L/h, 7.43 L, and 6.44 L, respectively. Creatinine clearance and body weight were the most significant variables to explain patient variability in aztreonam clearance and volume of distribution, respectively. Simulations using the final pharmacokinetic model resulted in a clinical susceptibility break point of 4 and 8 mg/L, respectively, based on the clinical use of 1- and 2-g loading doses with the same or reduced maintenance dose every 8 hours for various renal deficiency patients. The population pharmacokinetic modeling and PTA estimation support adequate PTAs (>90% PTA) from the aztreonam label for dose adjustment of aztreonam in patients with moderate and severe renal impairment. © 2016, The American College of Clinical Pharmacology.

Population Pharmacokinetics and Exploratory Pharmacodynamics of Lorazepam in Pediatric Status Epilepticus.

PubMed

Gonzalez, Daniel; Chamberlain, James M; Guptill, Jeffrey T; Cohen-Wolkowiez, Michael; Harper, Barrie; Zhao, Jian; Capparelli, Edmund V

2017-08-01

Lorazepam is one of the preferred agents used for intravenous treatment of status epilepticus (SE). We combined data from two pediatric clinical trials to characterize the population pharmacokinetics of intravenous lorazepam in infants and children aged 3 months to 17 years with active SE or a history of SE. We developed a population pharmacokinetic model for lorazepam using the NONMEM software. We then assessed exploratory exposure-response relationships using the overall efficacy and safety study endpoints, and performed dosing simulations. A total of 145 patients contributed 439 pharmacokinetic samples. The median (range) age and dose were 5.4 years (0.3-17.8) and 0.10 mg/kg (0.02-0.18), respectively. A two-compartment pharmacokinetic model with allometric scaling described the data well. In addition to total body weight (WT), younger age was associated with slightly higher weight-normalized clearance (CL). The following relationships characterized the typical values for the central compartment volume (V1), CL, peripheral compartment volume (V2), and intercompartmental CL (Q), using individual subject WT (kg) and age (years): V1 (L) = 0.879*WT; CL (L/h) = 0.115*(Age/4.7) 0.133 *WT 0.75 ; V2 (L) = 0.542*V1; Q (L/h) = 1.45*WT 0.75 . No pharmacokinetic parameters were associated with clinical outcomes. Simulations suggest uniform pediatric dosing (0.1 mg/kg, to a maximum of 4 mg) can be used to achieve concentrations of 50-100 ng/mL in children with SE, which have been previously associated with effective seizure control. The population pharmacokinetics of lorazepam were successfully described using a sparse sampling approach and a two-compartment model in pediatric patients with active SE.

Population pharmacokinetics of telapristone (CDB-4124) and its active monodemethylated metabolite CDB-4453, with a mixture model for total clearance.

PubMed

Morris, Denise; Podolski, Joseph; Kirsch, Alan; Wiehle, Ronald; Fleckenstein, Lawrence

2011-12-01

Telapristone is a selective progesterone antagonist that is being developed for the long-term treatment of symptoms associated with endometriosis and uterine fibroids. The population pharmacokinetics of telapristone (CDB-4124) and CDB-4453 was investigated using nonlinear mixed-effects modeling. Data from two clinical studies (n = 32) were included in the analysis. A two-compartment (parent) one compartment (metabolite) mixture model (with two populations for apparent clearance) with first-order absorption and elimination adequately described the pharmacokinetics of telapristone and CDB-4453. Telapristone was rapidly absorbed with an absorption rate constant (Ka) of 1.26 h(-1). Moderate renal impairment resulted in a 74% decrease in Ka. The population estimates for oral clearance (CL/F) for the two populations were 11.6 and 3.34 L/h, respectively, with 25% of the subjects being allocated to the high-clearance group. Apparent volume of distribution for the central compartment (V2/F) was 37.4 L, apparent inter-compartmental clearance (Q/F) was 21.9 L/h, and apparent peripheral volume of distribution for the parent (V4/F) was 120 L. The ratio of the fraction of telapristone converted to CDB-4453 to the distribution volume of CDB-4453 (Fmet(est)) was 0.20/L. Apparent volume of distribution of the metabolite compartment (V3/F) was fixed to 1 L and apparent clearance of the metabolite (CLM/F) was 2.43 L/h. A two-compartment parent-metabolite model adequately described the pharmacokinetics of telapristone and CDB-4453. The clearance of telapristone was separated into two populations and could be the result of metabolism via polymorphic CYP3A5.

Malate valves: Old shuttles with new perspectives.

PubMed

Selinski, Jennifer; Scheibe, Renate

2018-06-22

Malate valves act as powerful systems for balancing the ATP/NAD(P)H ratio required in various subcellular compartments in plant cells. As components of malate valves, isoforms of malate dehydrogenases (MDHs) and dicarboxylate translocators catalyze the reversible interconversion of malate and oxaloacetate and their transport. Depending on the coenzyme specificity of the MDH isoforms, either NADH or NADPH can be transported indirectly. Arabidopsis thaliana possesses nine genes encoding MDH isoenzymes: Activities of NAD-dependent MDHs have been detected in mitochondria, peroxisomes, cytosol and plastids, respectively. In addition, chloroplasts possess a NADP-dependent MDH isoform. The NADP-MDH as part of the "light malate valve" plays an important role as a poising mechanism to adjust the ATP/NADPH ratio in the stroma. Its activity is strictly regulated by post-translational redox-modification mediated via the ferredoxin-thioredoxin system and fine control via the NADP + /NADP(H) ratio, thereby maintaining redox homeostasis under changing conditions. In contrast, the plastid NAD-MDH ("dark malate valve") is constitutively active and its lack leads to failure in early embryo development. While redox regulation of the main cytosolic MDH isoform has been shown, the knowledge about regulation of the other two cytosolic MDHs as well as NAD-MDH isoforms from peroxisomes and mitochondria is still lacking. Knockout mutants lacking the isoforms from chloroplasts, mitochondria, and peroxisomes have been characterized, but not much is known about cytosolic NAD-MDH isoforms and their role in planta. This review updates the current knowledge on MDH isoforms and the shuttle systems for intercompartmental dicarboxylate exchange focusing on the various metabolic functions of these valves. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Pooled population pharmacokinetic model of imipenem in plasma and the lung epithelial lining fluid.

PubMed

van Hasselt, J G Coen; Rizk, Matthew L; Lala, Mallika; Chavez-Eng, Cynthia; Visser, Sandra A G; Kerbusch, Thomas; Danhof, Meindert; Rao, Gauri; van der Graaf, Piet H

2016-06-01

Several clinical trials have confirmed the therapeutic benefit of imipenem for treatment of lung infections. There is however no knowledge of the penetration of imipenem into the lung epithelial lining fluid (ELF), the site of action relevant for lung infections. Furthermore, although the plasma pharmacokinetics (PK) of imipenem has been widely studied, most studies have been based on selected patient groups. The aim of this analysis was to characterize imipenem plasma PK across populations and to quantify imipenem ELF penetration. A population model for imipenem plasma PK was developed using data obtained from healthy volunteers, elderly subjects and subjects with renal impairment, in order to identify predictors for inter-individual variability (IIV) of imipenem PK. Subsequently, a clinical study which measured plasma and ELF concentrations of imipenem was included in order to quantify lung penetration. A two compartmental model best described the plasma PK of imipenem. Creatinine clearance and body weight were included as subject characteristics predictive for IIV on clearance. Typical estimates for clearance, central and peripheral volume, and inter-compartmental clearance were 11.5 l h(-1) , 9.37 l, 6.41 l, 13.7 l h(-1) , respectively (relative standard error (RSE) <8%). The distribution of imipenem into ELF was described using a time-independent penetration coefficient of 0.44 (RSE 14%). The identified lung penetration coefficient confirms the clinical relevance of imipenem for treatment of lung infections, while the population PK model provided insights into predictors of IIV for imipenem PK and may be of relevance to support dose optimization in various subject groups. © 2016 The British Pharmacological Society.

Population Pharmacokinetic-Pharmacodynamic Analysis to Compare the Effect of Moxifloxacin on QT Interval Prolongation Between Healthy Korean and Japanese Subjects.

PubMed

Choi, Hyang-Ki; Jung, Jin Ah; Fujita, Tomoe; Amano, Hideki; Ghim, Jong-Lyul; Lee, Dong-Hwan; Tabata, Kenichi; Song, Il-Dae; Maeda, Mika; Kumagai, Yuji; Mendzelevski, Boaz; Shin, Jae-Gook

2016-12-01

The goal of this study was to evaluate the moxifloxacin-induced QT interval prolongation in healthy male and female Korean and Japanese volunteers to investigate interethnic differences. This multicenter, randomized, double-blind, placebo-controlled, 2-way crossover study was conducted in healthy male and female Korean and Japanese volunteers. In each period, a single dose of moxifloxacin or placebo 400 mg was administered orally under fasting conditions. Triplicate 12-lead ECGs were recorded at defined time points before, up to 24 hours after dosing, and at corresponding time points during baseline. Serial blood sampling was conducted for pharmacokinetic analysis of moxifloxacin. The pharmacokinetic-pharmacodynamic data between the 2 ethnic groups were compared by using a typical analysis based on the intersection-union test and a nonlinear mixed effects method. A total of 39 healthy subjects (Korean, male: 10, female: 10; Japanese, male: 10, female: 9) were included in the analysis. The concentration-effect analysis revealed that there was no change in slope (and confirmed that the difference was caused by a change in the pharmacokinetic model of moxifloxacin). A 2-compartment model with first-order absorption provided the best description of moxifloxacin's pharmacokinetic parameters. Weight and sex were selected as significant covariates for central volume of distribution and intercompartmental clearance, respectively. An E max model (E[C]=[E max ⋅C]/[EC 50 +C]) described the QT interval data of this study well. However, ethnicity was not found to be a significant factor in a pharmacokinetic-pharmacodynamic link model. The drug-induced QTc prolongations evaluated using moxifloxacin as the probe did not seem to be significantly different between these Korean and Japanese subjects. ClinicalTrials.gov identifier: NCT01876316. Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.

Homogeneous and heterogeneous micro-structuring of austenitic stainless steels by the low temperature plasma nitriding

NASA Astrophysics Data System (ADS)

Aizawa, T.; Yoshihara, S.-I.

2018-06-01

The austenitic stainless steels have been widely utilized as a structural component and member as well as a die and mold substrate for stamping. AISI316 dies and molds require for the surface treatment to accommodate the sufficient hardness and wear resistance to them. In addition, the candidate treatment methods must be free from toxicity, energy consumption and inefficiency. The low temperature plasma nitriding process has become one of the most promising methods to make solid-solution hardening by the nitrogen super-saturation. In the present paper, the high density RF/DC plasma nitriding process was applied to form the uniform nitrided layer in the AISI316 matrix and to describe the essential mechanism of inner nitriding in this low temperature nitriding process. In case of the nitrided AISI316 at 673 K for 14.4ks, the nitrided layer thickness became 60 μm with the surface hardness of 1700 HV and the surface nitrogen content of 7 mass %. This inner nitriding process is governed by the synergetic interrelation among the nitrogen super-saturation, the lattice expansion, the phase transformation, the plastic straining, the microstructure refinement and the acceleration of nitrogen diffusion. As far as this interrelation is sustained during the nitriding process, the original austenitic microstructure is homogeneously nitrided to have fine grains with the average size of 0.1 μm and the high crystallographic misorientation angles and to have two phase (γ + α’) structures with the plateau of nitrogen content by 5 mass%. Once this interrelation does not work anymore, the homogeneous microstructure changed itself to the heterogeneous one. The plastic straining took place in the selected coarse grains; they were partially refined into subgrains. This plastic localization accompanied the localized phase transformation.

ESSG-based global spatial reference frame for datasets interrelation

NASA Astrophysics Data System (ADS)

Yu, J. Q.; Wu, L. X.; Jia, Y. J.

2013-10-01

To know well about the highly complex earth system, a large volume of, as well as a large variety of, datasets on the planet Earth are being obtained, distributed, and shared worldwide everyday. However, seldom of existing systems concentrates on the distribution and interrelation of different datasets in a common Global Spatial Reference Frame (GSRF), which holds an invisble obstacle to the data sharing and scientific collaboration. Group on Earth Obeservation (GEO) has recently established a new GSRF, named Earth System Spatial Grid (ESSG), for global datasets distribution, sharing and interrelation in its 2012-2015 WORKING PLAN.The ESSG may bridge the gap among different spatial datasets and hence overcome the obstacles. This paper is to present the implementation of the ESSG-based GSRF. A reference spheroid, a grid subdvision scheme, and a suitable encoding system are required to implement it. The radius of ESSG reference spheroid was set to the double of approximated Earth radius to make datasets from different areas of earth system science being covered. The same paramerters of positioning and orienting as Earth Centred Earth Fixed (ECEF) was adopted for the ESSG reference spheroid to make any other GSRFs being freely transformed into the ESSG-based GSRF. Spheroid degenerated octree grid with radius refiment (SDOG-R) and its encoding method were taken as the grid subdvision and encoding scheme for its good performance in many aspects. A triple (C, T, A) model is introduced to represent and link different datasets based on the ESSG-based GSRF. Finally, the methods of coordinate transformation between the ESSGbased GSRF and other GSRFs were presented to make ESSG-based GSRF operable and propagable.

Dyspnea, chest wall hyperinflation, and rib cage distortion in exercising patients with chronic obstructive pulmonary disease.

PubMed

Bruni, Giulia Innocenti; Gigliotti, Francesco; Binazzi, Barbara; Romagnoli, Isabella; Duranti, Roberto; Scano, Giorgio

2012-06-01

Whether dyspnea, chest wall dynamic hyperinflation, and abnormalities of rib cage motion are interrelated phenomena has not been systematically evaluated in patients with chronic obstructive pulmonary disease (COPD). Our hypothesis that they are not interrelated was based on the following observations: (i) externally imposed expiratory flow limitation is associated with no rib cage distortion during strenuous incremental exercise, with indexes of hyperinflation not being correlated with dyspnea, and (ii) end-expiratory chest wall volume may either increase or decrease during exercise in patients with COPD, with those who hyperinflate being as breathless as those who do not. Sixteen patients breathed either room air or 50% supplemental O2 at 75% of peak exercise in randomized order. We evaluated the volume of chest wall (V(cw)) and its compartments: the upper rib cage (V(rcp)), lower rib cage (V(rca)), and abdomen (V(ab)) using optoelectronic plethysmography; rib cage distortion was assessed by measuring the phase angle shift between V(rcp) and V(rca). Ten patients increased end-expiratory V(cw) (V(cw,ee)) on air. In seven hyperinflators and three non-hyperinflators, the lower rib cage paradoxed inward during inspiration with a phase angle of 63.4° ± 30.7° compared with a normal phase angle of 16.1° ± 2.3° recorded in patients without rib cage distortion. Dyspnea (by Borg scale) averaged 8.2 and 9 at the end of exercise on air in patients with and without rib cage distortion, respectively. At iso-time during exercise with oxygen, decreased dyspnea was associated with a decrease in ventilation regardless of whether patients distorted the rib cage, dynamically hyperinflated, or deflated the chest wall. Dyspnea, chest wall dynamic hyperinflation, and rib cage distortion are not interrelated phenomena.

Activin Signaling Targeted by Insulin/dFOXO Regulates Aging and Muscle Proteostasis in Drosophila

PubMed Central

Bai, Hua; Kang, Ping; Hernandez, Ana Maria; Tatar, Marc

2013-01-01

Reduced insulin/IGF signaling increases lifespan in many animals. To understand how insulin/IGF mediates lifespan in Drosophila, we performed chromatin immunoprecipitation-sequencing analysis with the insulin/IGF regulated transcription factor dFOXO in long-lived insulin/IGF signaling genotypes. Dawdle, an Activin ligand, is bound and repressed by dFOXO when reduced insulin/IGF extends lifespan. Reduced Activin signaling improves performance and protein homeostasis in muscles of aged flies. Activin signaling through the Smad binding element inhibits the transcription of Autophagy-specific gene 8a (Atg8a) within muscle, a factor controlling the rate of autophagy. Expression of Atg8a within muscle is sufficient to increase lifespan. These data reveal how insulin signaling can regulate aging through control of Activin signaling that in turn controls autophagy, representing a potentially conserved molecular basis for longevity assurance. While reduced Activin within muscle autonomously retards functional aging of this tissue, these effects in muscle also reduce secretion of insulin-like peptides at a distance from the brain. Reduced insulin secretion from the brain may subsequently reinforce longevity assurance through decreased systemic insulin/IGF signaling. PMID:24244197

Different redox sensitivity of endoplasmic reticulum associated degradation clients suggests a novel role for disulphide bonds in secretory proteins.

PubMed

Medraño-Fernandez, Iria; Fagioli, Claudio; Mezghrani, Alexandre; Otsu, Mieko; Sitia, Roberto

2014-04-01

To maintain proteostasis in the endoplasmic reticulum (ER), terminally misfolded secretory proteins must be recognized, partially unfolded, and dislocated to the cytosol for proteasomal destruction, in a complex process called ER-associated degradation (ERAD). Dislocation implies reduction of inter-chain disulphide bonds. When in its reduced form, protein disulphide isomerase (PDI) can act not only as a reductase but also as an unfoldase, preparing substrates for dislocation. PDI oxidation by Ero1 favours substrate release and transport across the ER membrane. Here we addressed the redox dependency of ERAD and found that DTT stimulates the dislocation of proteins with DTT-resistant disulphide bonds (i.e., orphan Ig-μ chains) but stabilizes a ribophorin mutant (Ri332) devoid of them. DTT promotes the association of Ri332, but not of Ig-µ, with PDI. This discrepancy may suggest that disulphide bonds in cargo proteins can be utilized to oxidize PDI, hence facilitating substrate detachment and degradation also in the absence of Ero1. Accordingly, Ero1 silencing retards Ri332 degradation, but has little if any effect on Ig-µ. Thus, some disulphides can increase the stability and simultaneously favour quality control of secretory proteins.

Translation Control of Swarming Proficiency in Bacillus subtilis by 5-Amino-pentanolylated Elongation Factor P.

PubMed

Rajkovic, Andrei; Hummels, Katherine R; Witzky, Anne; Erickson, Sarah; Gafken, Philip R; Whitelegge, Julian P; Faull, Kym F; Kearns, Daniel B; Ibba, Michael

2016-05-20

Elongation factor P (EF-P) accelerates diprolyl synthesis and requires a posttranslational modification to maintain proteostasis. Two phylogenetically distinct EF-P modification pathways have been described and are encoded in the majority of Gram-negative bacteria, but neither is present in Gram-positive bacteria. Prior work suggested that the EF-P-encoding gene (efp) primarily supports Bacillus subtilis swarming differentiation, whereas EF-P in Gram-negative bacteria has a more global housekeeping role, prompting our investigation to determine whether EF-P is modified and how it impacts gene expression in motile cells. We identified a 5-aminopentanol moiety attached to Lys(32) of B. subtilis EF-P that is required for swarming motility. A fluorescent in vivo B. subtilis reporter system identified peptide motifs whose efficient synthesis was most dependent on 5-aminopentanol EF-P. Examination of the B. subtilis genome sequence showed that these EF-P-dependent peptide motifs were represented in flagellar genes. Taken together, these data show that, in B. subtilis, a previously uncharacterized posttranslational modification of EF-P can modulate the synthesis of specific diprolyl motifs present in proteins required for swarming motility. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Skeletal muscle-specific eukaryotic translation initiation factor 2α phosphorylation controls amino acid metabolism and fibroblast growth factor 21-mediated non-cell-autonomous energy metabolism.

PubMed

Miyake, Masato; Nomura, Akitoshi; Ogura, Atsushi; Takehana, Kenji; Kitahara, Yoshihiro; Takahara, Kazuna; Tsugawa, Kazue; Miyamoto, Chinobu; Miura, Naoko; Sato, Ryosuke; Kurahashi, Kiyoe; Harding, Heather P; Oyadomari, Miho; Ron, David; Oyadomari, Seiichi

2016-02-01

The eukaryotic translation initiation factor 2α (eIF2α) phosphorylation-dependent integrated stress response (ISR), a component of the unfolded protein response, has long been known to regulate intermediary metabolism, but the details are poorly worked out. We report that profiling of mRNAs of transgenic mice harboring a ligand-activated skeletal muscle-specific derivative of the eIF2α protein kinase R-like ER kinase revealed the expected up-regulation of genes involved in amino acid biosynthesis and transport but also uncovered the induced expression and secretion of a myokine, fibroblast growth factor 21 (FGF21), that stimulates energy consumption and prevents obesity. The link between the ISR and FGF21 expression was further reinforced by the identification of a small-molecule ISR activator that promoted Fgf21 expression in cell-based screens and by implication of the ISR-inducible activating transcription factor 4 in the process. Our findings establish that eIF2α phosphorylation regulates not only cell-autonomous proteostasis and amino acid metabolism, but also affects non-cell-autonomous metabolic regulation by induced expression of a potent myokine. © FASEB.

Characterisation of the biological response of Saccharomyces cerevisiae to the loss of an allele of the eukaryotic initiation factor 4A.

PubMed

Venturi, Veronica; Little, Richard; Bircham, Peter W; Rodigheri Brito, Juliana; Atkinson, Paul H; Maass, David R; Teesdale-Spittle, Paul H

2018-02-19

The translation initiation machinery is emerging as an important target for therapeutic intervention, with potential in the treatment of cancer, viral infections, and muscle wasting. Amongst the targets for pharmacological control of translation initiation is the eukaryotic initiation factor 4A (eIF4A), an RNA helicase that is essential for cap-dependent translation initiation. We set out to explore the system-wide impact of a reduction of functional eIF4A. To this end, we investigated the effect of deletion of TIF1, one of the duplicate genes that produce eIF4A in yeast, through synthetic genetic array interactions and system-wide changes in GFP-tagged protein abundances. We show that there is a biological response to deletion of the TIF1 gene that extends through the proteostasis network. Effects of the deletion are apparent in processes as distributed as chromatin remodelling, ribosome biogenesis, amino acid metabolism, and protein trafficking. The results from this study identify protein complexes and pathways that will make ideal targets for combination therapies with eIF4A inhibitors. Copyright © 2018 Elsevier Inc. All rights reserved.

Saccharomyces cerevisiae KNU5377 stress response during high-temperature ethanol fermentation.

PubMed

Kim, Il-Sup; Kim, Young-Saeng; Kim, Hyun; Jin, Ingnyol; Yoon, Ho-Sung

2013-03-01

Fuel ethanol production is far more costly to produce than fossil fuels. There are a number of approaches to cost-effective fuel ethanol production from biomass. We characterized stress response of thermotolerant Saccharomyces cerevisiae KNU5377 during glucose-based batch fermentation at high temperature (40°C). S. cerevisiae KNU5377 (KNU5377) transcription factors (Hsf1, Msn2/4, and Yap1), metabolic enzymes (hexokinase, glyceraldehyde-3-phosphate dehydrogenase, glucose-6-phosphate dehydrogenase, isocitrate dehydrogenase, and alcohol dehydrogenase), antioxidant enzymes (thioredoxin 3, thioredoxin reductase, and porin), and molecular chaperones and its cofactors (Hsp104, Hsp82, Hsp60, Hsp42, Hsp30, Hsp26, Cpr1, Sti1, and Zpr1) are upregulated during fermentation, in comparison to S. cerevisiae S288C (S288C). Expression of glyceraldehyde-3-phosphate dehydrogenase increased significantly in KNU5377 cells. In addition, cellular hydroperoxide and protein oxidation, particularly lipid peroxidation of triosephosphate isomerase, was lower in KNU5377 than in S288C. Thus, KNU5377 activates various cell rescue proteins through transcription activators, improving tolerance and increasing alcohol yield by rapidly responding to fermentation stress through redox homeostasis and proteostasis.

Amyotrophic lateral sclerosis: recent genetic highlights.

PubMed

White, Matthew A; Sreedharan, Jemeen

2016-10-01

Amyotrophic lateral sclerosis (ALS), like other neurodegenerative diseases, remains incurable, but gene mutations linked to ALS are providing clues as to how to target therapies. It is important for researchers to keep abreast of the rapid influx of new data in ALS, and we aim to summarize the major genetic advances made in the field over the past 2 years. Significant variation in seven genes has recently been found in ALS: TBK1, CCNF, GLE1, MATR3, TUBA4A, CHCHD10 and NEK1. These have mostly been identified through large exome screening studies, though traditional linkage approaches and candidate gene screening remain important. We briefly update C9orf72 research, noting in particular the development of reagents to better understand the normal role of C9orf72 protein. Striking advances in our understanding of the genetic heterogeneity of ALS continue to be made, year on year. These implicate proteostasis, RNA export, nuclear transport, the cytoskeleton, mitochondrial function, the cell cycle and DNA repair. Functional studies to integrate these hits are needed. By building a web of knowledge with interlinked genes and mechanisms, it is hoped we can better understand ALS and work toward effective therapies.

Diabetes Drug Discovery: hIAPP1-37 Polymorphic Amyloid Structures as Novel Therapeutic Targets.

PubMed

Fernández-Gómez, Isaac; Sablón-Carrazana, Marquiza; Bencomo-Martínez, Alberto; Domínguez, Guadalupe; Lara-Martínez, Reyna; Altamirano-Bustamante, Nelly F; Jiménez-García, Luis Felipe; Pasten-Hidalgo, Karina; Castillo-Rodríguez, Rosa Angélica; Altamirano, Perla; Marrero, Suchitil Rivera; Revilla-Monsalve, Cristina; Valdés-Sosa, Peter; Salamanca-Gómez, Fabio; Garrido-Magaña, Eulalia; Rodríguez-Tanty, Chryslaine; Altamirano-Bustamante, Myriam M

2018-03-19

Human islet amyloid peptide (hIAPP 1-37 ) aggregation is an early step in Diabetes Mellitus. We aimed to evaluate a family of pharmaco-chaperones to act as modulators that provide dynamic interventions and the multi-target capacity (native state, cytotoxic oligomers, protofilaments and fibrils of hIAPP 1-37 ) required to meet the treatment challenges of diabetes. We used a cross-functional approach that combines in silico and in vitro biochemical and biophysical methods to study the hIAPP 1-37 aggregation-oligomerization process as to reveal novel potential anti-diabetic drugs. The family of pharmaco-chaperones are modulators of the oligomerization and fibre formation of hIAPP 1-37 . When they interact with the amino acid in the amyloid-like steric zipper zone, they inhibit and/or delay the aggregation-oligomerization pathway by binding and stabilizing several amyloid structures of hIAPP 1-37 . Moreover, they can protect cerebellar granule cells (CGC) from the cytotoxicity produced by the hIAPP 1-37 oligomers. The modulation of proteostasis by the family of pharmaco-chaperones A - F is a promising potential approach to limit the onset and progression of diabetes and its comorbidities.

The Safety Dance: Biophysics of Membrane Protein Folding and Misfolding in a Cellular Context

PubMed Central

Schlebach, Jonathan P.; Sanders, Charles R.

2015-01-01

Most biological processes require the production and degradation of proteins, a task that weighs heavily on the cell. Mutations that compromise the conformational stability of proteins place both specific and general burdens on cellular protein homeostasis (proteostasis) in ways that contribute to numerous diseases. Efforts to elucidate the chain of molecular events responsible for diseases of protein folding address one of the foremost challenges in biomedical science. However, relatively little is known about the processes by which mutations prompt the misfolding of α-helical membrane proteins, which rely on an intricate network of cellular machinery to acquire and maintain their functional structures within cellular membranes. In this review, we summarize the current understanding of the physical principles that guide membrane protein biogenesis and folding in the context of mammalian cells. Additionally, we explore how pathogenic mutations that influence biogenesis may differ from those that disrupt folding and assembly, as well as how this may relate to disease mechanisms and therapeutic intervention. These perspectives indicate an imperative for the use of information from structural, cellular, and biochemical studies of membrane proteins in the design of novel therapeutics and in personalized medicine. PMID:25420508

Molecular Age-Related Changes in the Anterior Segment of the Eye.

PubMed

Hernandez-Zimbron, Luis Fernando; Gulias-Cañizo, Rosario; Golzarri, María F; Martínez-Báez, Blanca Elizabeth; Quiroz-Mercado, Hugo; Gonzalez-Salinas, Roberto

2017-01-01

To examine the current knowledge about the age-related processes in the anterior segment of the eye at a biological, clinical, and molecular level. We reviewed the available published literature that addresses the aging process of the anterior segment of the eye and its associated molecular and physiological events. We performed a search on PubMed, CINAHL, and Embase using the MeSH terms "eye," "anterior segment," and "age." We generated searches to account for synonyms of these keywords and MESH headings as follows: (1) "Eye" AND "ageing process" OR "anterior segment ageing" and (2) "Anterior segment" AND "ageing process" OR "anterior segment" AND "molecular changes" AND "age." Results . Among the principal causes of age-dependent alterations in the anterior segment of the eye, we found the mutation of the TGF- β gene and loss of autophagy in addition to oxidative stress, which contributes to the pathogenesis of degenerative diseases. In this review, we summarize the current knowledge regarding some of the molecular mechanisms related to aging in the anterior segment of the eye. We also introduce and propose potential roles of autophagy, an important mechanism responsible for maintaining homeostasis and proteostasis under stress conditions in the anterior segment during aging.

Conformational analysis of misfolded protein aggregation by FRET and live-cell imaging techniques.

PubMed

Kitamura, Akira; Nagata, Kazuhiro; Kinjo, Masataka

2015-03-16

Cellular homeostasis is maintained by several types of protein machinery, including molecular chaperones and proteolysis systems. Dysregulation of the proteome disrupts homeostasis in cells, tissues, and the organism as a whole, and has been hypothesized to cause neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD). A hallmark of neurodegenerative disorders is formation of ubiquitin-positive inclusion bodies in neurons, suggesting that the aggregation process of misfolded proteins changes during disease progression. Hence, high-throughput determination of soluble oligomers during the aggregation process, as well as the conformation of sequestered proteins in inclusion bodies, is essential for elucidation of physiological regulation mechanism and drug discovery in this field. To elucidate the interaction, accumulation, and conformation of aggregation-prone proteins, in situ spectroscopic imaging techniques, such as Förster/fluorescence resonance energy transfer (FRET), fluorescence correlation spectroscopy (FCS), and bimolecular fluorescence complementation (BiFC) have been employed. Here, we summarize recent reports in which these techniques were applied to the analysis of aggregation-prone proteins (in particular their dimerization, interactions, and conformational changes), and describe several fluorescent indicators used for real-time observation of physiological states related to proteostasis.

Activation of the unfolded protein response promotes axonal regeneration after peripheral nerve injury.

PubMed

Oñate, Maritza; Catenaccio, Alejandra; Martínez, Gabriela; Armentano, Donna; Parsons, Geoffrey; Kerr, Bredford; Hetz, Claudio; Court, Felipe A

2016-02-24

Although protein-folding stress at the endoplasmic reticulum (ER) is emerging as a driver of neuronal dysfunction in models of spinal cord injury and neurodegeneration, the contribution of this pathway to peripheral nerve damage remains poorly explored. Here we targeted the unfolded protein response (UPR), an adaptive reaction against ER stress, in mouse models of sciatic nerve injury and found that ablation of the transcription factor XBP1, but not ATF4, significantly delay locomotor recovery. XBP1 deficiency led to decreased macrophage recruitment, a reduction in myelin removal and axonal regeneration. Conversely, overexpression of XBP1s in the nervous system in transgenic mice enhanced locomotor recovery after sciatic nerve crush, associated to an improvement in key pro-regenerative events. To assess the therapeutic potential of UPR manipulation to axonal regeneration, we locally delivered XBP1s or an shRNA targeting this transcription factor to sensory neurons of the dorsal root ganglia using a gene therapy approach and found an enhancement or reduction of axonal regeneration in vivo, respectively. Our results demonstrate a functional role of specific components of the ER proteostasis network in the cellular changes associated to regeneration and functional recovery after peripheral nerve injury.

Activation of the unfolded protein response promotes axonal regeneration after peripheral nerve injury

PubMed Central

Oñate, Maritza; Catenaccio, Alejandra; Martínez, Gabriela; Armentano, Donna; Parsons, Geoffrey; Kerr, Bredford; Hetz, Claudio; Court, Felipe A.

2016-01-01

Although protein-folding stress at the endoplasmic reticulum (ER) is emerging as a driver of neuronal dysfunction in models of spinal cord injury and neurodegeneration, the contribution of this pathway to peripheral nerve damage remains poorly explored. Here we targeted the unfolded protein response (UPR), an adaptive reaction against ER stress, in mouse models of sciatic nerve injury and found that ablation of the transcription factor XBP1, but not ATF4, significantly delay locomotor recovery. XBP1 deficiency led to decreased macrophage recruitment, a reduction in myelin removal and axonal regeneration. Conversely, overexpression of XBP1s in the nervous system in transgenic mice enhanced locomotor recovery after sciatic nerve crush, associated to an improvement in key pro-regenerative events. To assess the therapeutic potential of UPR manipulation to axonal regeneration, we locally delivered XBP1s or an shRNA targeting this transcription factor to sensory neurons of the dorsal root ganglia using a gene therapy approach and found an enhancement or reduction of axonal regeneration in vivo, respectively. Our results demonstrate a functional role of specific components of the ER proteostasis network in the cellular changes associated to regeneration and functional recovery after peripheral nerve injury. PMID:26906090

Essential function of VCP/p97 in infection cycle of the nucleopolyhedrovirus AcMNPV in Spodoptera frugiperda Sf9 cells.

PubMed

Lyupina, Yulia V; Erokhov, Pavel A; Kravchuk, Oksana I; Finoshin, Alexander D; Abaturova, Svetlana B; Orlova, Olga V; Beljelarskaya, Svetlana N; Kostyuchenko, Margarita V; Mikhailov, Victor S

2018-06-08

The protein VCP/p97 (also named CDC48 and TER94) belongs to a type II subfamily of the AAA+ATPases and controls cellular proteostasis by acting upstream of proteasomes in the ubiquitin-proteasome protein degradation pathway. The function of VCP/p97 in the baculovirus infection cycle in insect cells remains unknown. Here, we identified VCP/p97 in the fall armyworm Spodoptera frugiperda (Sf9) cells and analyzed the replication of the Autographa californica multiple nucleopolyhedrovirus, AcMNPV, in Sf9 cells in which the VCP/p97 function was inhibited. The specific allosteric inhibitor of the VCP/p97 ATPase activity, NMS-873, did not deplete VCP/p97 in infected cells but caused a dose-dependent inhibition of viral DNA synthesis and efficiently suppressed expression of viral proteins and production of budded virions. NMS-873 caused accumulation of ubiquitinated proteins in a manner similar to the inhibitor of proteasome activity, Bortezomib. This suggests the essential function of VCP/p97 in the baculovirus infection cycle might be associated, at least in part, with the ubiquitin-proteasome system. Copyright © 2018 Elsevier B.V. All rights reserved.

Mileage-based user fees : defining a path toward implementation phase 2, an assessment of institutional issues, final report, November 2009

DOT National Transportation Integrated Search

2009-11-01

This report documents the activities of a twophase research effort composed of three interrelated : components: 1) a technology assessment, 2) an institutional assessment, and 3) a oneday implementationfocused : symposium. Each component builds...

The Interrelationships of Mathematical Precursors in Kindergarten

ERIC Educational Resources Information Center

Cirino, Paul T.

2011-01-01

This study evaluated the interrelations among cognitive precursors across quantitative, linguistic, and spatial attention domains that have been implicated for math achievement in young children. The dimensionality of the quantity precursors was evaluated in 286 kindergarteners via latent variable techniques, and the contribution of precursors…

Behavior-Analytic Instruction for Children with Autism: Philosophy Matters.

ERIC Educational Resources Information Center

Kimball, Jonathan W.

2002-01-01

This article describes the philosophical underpinnings of applied behavior analysis (ABA) for children with autism. It discusses the three interrelated levels of behavior analysis (technology, science, and philosophy), and the three pillars of behavioral philosophy: empiricism, pragmatism, and selectionism. The amelioration, rather than…

Alliance through Change

ERIC Educational Resources Information Center

Sebalj, Darlene; Hudson, Susan; Ryan, Jan; Wight-Boycott, Juliet

2007-01-01

Following a landmark organisational change event within the University of Western Sydney, when the university ceased operating as a federation of four distinct, inter-related elements and merged to become a single entity, four foundation College Managers made a strategic decision to form an alliance. This alliance significantly enhanced the…

Assessing Graduate Assistant Teacher Communication Concerns.

ERIC Educational Resources Information Center

Feezel, Jerry D.; Myers, Scott A.

1997-01-01

Finds that graduate teaching assistants (GTAs) experience eight interrelated types of communication concern (self, task, impact, role conflict, teaching, area knowledge, procedural knowledge, and time management). Shows that GTA variables of expected duties, prior teaching experience, newness to area, foreign or domestic birth, and age are likely…

Interrelation of mating, flight, and fecundity in navel orangeworm (Lepidoptera: Pyralidae) females

USDA-ARS?s Scientific Manuscript database

The navel orangeworm Amyelois transitella (Walker) (Lepidoptera: Pyralidae) is an economically important pest of nut crops in California. Improved management will require better understanding of insect dispersal, particularly relative to when mating occurs. A previous study demonstrated a more robus...

An Introduction to Psycholinguistics

ERIC Educational Resources Information Center

Jodai, Hojat

2011-01-01

This paper is written to have a preliminary introduction about psycholinguistics. Psycholinguistics or psychology of language is the study of the interrelation between linguistic factors and psychological aspects. The main subject of research in psycholinguistics is the study of cognitive processes that underlie the comprehension and production of…

Substitution Between Privately and Publicly Supplied Urban Recreational Open Space

ERIC Educational Resources Information Center

Cordell, Harold K.

1976-01-01

Public and private open space should be considered as interrelated components of a singular open-space supply system; ignoring amounts of private space in the development of guidelines for expansion of public open-space supply may lead to inefficiencies in land allocation. (JD)

A Systematic Presentation of Organic Phosphorus and Sulfur Compounds.

ERIC Educational Resources Information Center

Hendrickson, James B.

1985-01-01

Because the names, interrelations, and oxidation levels of the organic compounds of phosphorus and sulfur tend to confuse students, a simple way to organize these compounds has been developed. The system consists of grouping them by oxidation state and extent of carbon substitution. (JN)

Internet Gambling in the Workplace

ERIC Educational Resources Information Center

Griffiths, Mark

2009-01-01

Purpose: This paper seeks to overview the issues, concerns and challenges relating to gambling--and more specifically internet gambling--in the workplace. Design/methodology/approach: Using psychological literature, this paper outlines a number of important and inter-related areas including brief overviews of gambling and problem gambling,…

Sanctions Connected to Dress Code Violations in Secondary School Handbooks

ERIC Educational Resources Information Center

Workman, Jane E.; Freeburg, Elizabeth W.; Lentz-Hees, Elizabeth S.

2004-01-01

This study identifies and evaluates sanctions for dress code violations in secondary school handbooks. Sanctions, or consequences for breaking rules, vary along seven interrelated dimensions: source, formality, retribution, obtrusiveness, magnitude, severity, and pervasiveness. A content analysis of handbooks from 155 public secondary schools…

LIFE CYCLE ASSESSMENT FOR PC BLEND 2 AIRCRAFT RADOME DEPAINTER

EPA Science Inventory

This report describes the life cycle assessment on a potential replacement solvent blend for aircraft radome depainting at the Oklahoma City Air Logistics Center at Tinker Air Force Base. The life cycle assessment is composed of three separate but interrelated components: life cy...

Alternatives for Measuring the Unexplained Wage Gap.

ERIC Educational Resources Information Center

Toutkoushian, Robert K.; Hoffman, Emily P.

2002-01-01

Reviews several different methods that analysts can use to measure gender- and race-based pay differences for academic employees, and how they are interrelated. Discusses the advantages and disadvantages of each method, and shows how they can give rise to different estimates of pay disparity. (EV)

Therapists Value of Interprofessional Collaboration

ERIC Educational Resources Information Center

De Vries, Dawn R.

2012-01-01

The work of occupational (OT), physical (PT), and recreational therapists (RT), as well as speech- language pathologists (SLP), is interrelated and requires effective teamwork and collaboration to optimize patient outcomes and satisfaction. Literature shows that health care professionals are ill prepared to work in an interprofessional manner due…

Synthesis-Spectroscopy Roadmap Problems: Discovering Organic Chemistry

ERIC Educational Resources Information Center

Kurth, Laurie L.; Kurth, Mark J.

2014-01-01

Organic chemistry problems that interrelate and integrate synthesis with spectroscopy are presented. These synthesis-spectroscopy roadmap (SSR) problems uniquely engage second-year undergraduate organic chemistry students in the personal discovery of organic chemistry. SSR problems counter the memorize-or-bust strategy that many students tend to…

Concrete Geometry: Playing with Blocks

ERIC Educational Resources Information Center

Luescher, Andreas

2010-01-01

This article describes a design/build exercise conducted in an Architectural Materials and Methods class to achieve three interrelated objectives: (1) to apply physically the semester's theoretical focus on the constituent process and languages of architecture investigations, (2) to capitalise on the physical and aesthetic properties of concrete…

Tracking a Global Academic Revolution

ERIC Educational Resources Information Center

Altbach, Philip G.; Reisberg, Liz; Rumbley, Laura E.

2010-01-01

A global revolution has been taking place in higher education during the past half-century. In the educators' view, four fundamental and interrelated forces have impelled the current academic revolution: the "massification" of higher education, globalization, the advent of the knowledge society and the importance of research universities…

Research 1970/1971: Annual Progress Report.

ERIC Educational Resources Information Center

Georgia Inst. of Tech., Atlanta. Science Information Research Center.

The report presents a summary of science information research activities of the School of Information and Computer Science, Georgia Institute of Technology. Included are project reports on interrelated studies in science information, information processing and systems design, automata and systems theories, and semiotics and linguistics. Also…

The general deterrence of driving while intoxicated. Volume 1, System analysis and computer-based simulation

DOT National Transportation Integrated Search

1978-01-01

A system analysis was completed of the general deterrence of driving while intoxicated (DWI). Elements which influence DWI decisions were identified and interrelated in a system model; then, potential countermeasures which might be employed in DWI ge...

Addressing the Needs of Diverse Distributed Students

ERIC Educational Resources Information Center

Shimoni, Rena; Barrington, Gail; Wilde, Russ; Henwood, Scott

2013-01-01

Two interrelated studies were undertaken to assist Alberta post-secondary institutions with meeting challenges associated with providing services to diverse distributed students that are of similar quality to services provided to traditional classroom students. The first study identified and assessed best practices in distributed learning; the…

Sustainability in Multi-Religious Societies: An Islamic Perspective

ERIC Educational Resources Information Center

Grine, Fadila; Bensaid, Benaouda; Nor, Mohd Roslan Mohd; Ladjal, Tarek

2013-01-01

The question of sustainability in multi-religious societies underscores interrelating theological, moral and cultural issues affecting the very process of social co-existence, cohesion and development. This article discusses Islam's understanding of the question of sustainability in multi-religious contexts while highlighting the contribution of…

Designing Online Mathematical Investigation

ERIC Educational Resources Information Center

Gadanidis, George; Sedig, Kamran; Liang, Hai-Ning

2004-01-01

In this paper we focus on interactive visualizations that support mathematical investigation. In the context of analyzing and redesigning an interactive visualization from the National Council of Teachers of Mathematics's (NCTM's) Illuminations Web site, we consider two interrelated issues: (1) how the pedagogy of mathematical investigation may be…

Teenage Drinking, Symbolic Capital and Distinction

ERIC Educational Resources Information Center

Jarvinen, Margaretha; Gundelach, Peter

2007-01-01

This article analyses alcohol-related lifestyles among Danish teenagers. Building on Bourdieu's reasoning on symbolic capital and distinction, we analyse three interrelated themes. First, we show that alcohol-related variables (drinking patterns, drinking debut, experience of intoxication, etc.) can be used to identify some very distinctive life…

A Practical Approach to Programmatic Assessment Design

ERIC Educational Resources Information Center

Timmerman, A. A.; Dijkstra, J.

2017-01-01

Assessment of complex tasks integrating several competencies calls for a programmatic design approach. As single instruments do not provide the information required to reach a robust judgment of integral performance, 73 guidelines for programmatic assessment design were developed. When simultaneously applying these interrelated guidelines, it is…

Class Size.

ERIC Educational Resources Information Center

Ellis, Thomas I.

1985-01-01

After a brief introduction identifying current issues and trends in research on class size, this brochure reviews five recent studies bearing on the relationship of class size to educational effectiveness. Part 1 is a review of two interrelated and highly controversial "meta-analyses" or statistical integrations of research findings on…

Teaching Basic Science Environmentally.

ERIC Educational Resources Information Center

Busch, Phyllis S.

1986-01-01

Explains why earthworms are fascinating and important animals whose study should be expanded. Describes how to collect earthworms and their castings and how to demonstrate their tunneling activity. Stresses animal's uniqueness and how it is interrelated with other animals, plants, and non-living parts of the world. (NEC)

Knowledge in the Postmodern University.

ERIC Educational Resources Information Center

Simpson, Evan

2000-01-01

It is essential for higher education to interpret its institutional goals. This essay facilitates that task by clarifying the intellectual rationale of the postmodern challenge, highlighting the success of that rationale, and arguing that the interrelated critiques of rationalism, realism, and foundationalism show that the modern university…

Population Trends and the Implications for Education.

ERIC Educational Resources Information Center

Hauser, Philip M.

There are three developments which have profoundly affected mans' values, attitudes, social institutions, and behaviorisms. These are the population explosion, the population implosion, and population differentiation. These three developments are interrelated and are affected by accelerating rates of technological and social change. By reason of…

Illiteracy, Poverty and Racism: Their Interconnexion.

ERIC Educational Resources Information Center

Harman, David

1978-01-01

Illiteracy, racism, and poverty are clearly interrelated, with perhaps even some elements of cause and effect. But education is not the only factor, according to the author. He notes that it is necessary to approach each cultural group through its own sociocultural and educative mechanisms. (MF)

Innovativeness and the Organizational Attributes of Schools.

ERIC Educational Resources Information Center

Eidell, Terry L.; And Others

Five papers focus on the interrelated themes of school organization and innovation. They report on some preliminary analyses of field studies conducted during 1968 on such structural, sociocultural, and sociopsychological variables as division of labor, performance of organizational functions, decision making studies and processes, hierarchies of…

Effect of the microstructure on electrical properties of high-purity germanium

NASA Astrophysics Data System (ADS)

Podkopaev, O. I.; Shimanskii, A. F.; Molotkovskaya, N. O.; Kulakovskaya, T. V.

2013-05-01

The interrelation between the electrical properties and the microstructure of high-purity germanium crystals has been revealed. The electrical conductivity of polycrystalline samples increases and the life-time of nonequilibrium charge carriers in them decreases with a decrease in the crystallite sizes.

The Female Athlete Triad

ERIC Educational Resources Information Center

Sherman, Roberta Trattner; Thompson, Ron A.

2004-01-01

The Female Athlete Triad is a syndrome of the interrelated components of disordered eating, amenorrhea, and osteoporosis. Sometimes inadvertently, but more often by willful dietary restriction, many female athletes do not ingest sufficient calories to adequately fuel their physical or sport activities, which can disrupt menstrual functioning,…

LANDSCAPE INFLUENCES ON LAKE CHEMISTRY OF SMALL DIMICTIC LAKES IN THE HUMAN DOMINATED SOUTHERN WISCONSIN LANDSCAPE

EPA Science Inventory

Changes in landscape heterogeneity, historic landcover change, and human disturbance regimes are governed by complex interrelated landscape processes that modify lake water quality through the addition of nutrients, sediment, anthropogenic chemicals, and changes in major ion conc...

Individualizing Foreign Language Instruction: New Myths and Old Realities.

ERIC Educational Resources Information Center

Grittner, Frank M.

Three interrelated, principal factors bearing on the concept of "individualized instruction" are critically examined in this study. They include the notions of: (1) "integrity of the discipline," (2) "democratization" of instruction, and (3) academic accountability. Discussion of the growing mythology surrounding individualized instruction reveals…

Couple Infertility: From the Perspective of the Close-Relationship Model.

ERIC Educational Resources Information Center

Higgins, Barbara S.

1990-01-01

Presents Close-Relationship Model as comprehensive framework in which to examine interrelated nature of causes and effects of infertility on marital relationship. Includes these factors: physical and psychological characteristics of both partners; joint, couple characteristics; physical and social environment; and relationship itself. Discusses…

Conceptions of Islamic Education: Pedagogical Framings. Global Studies in Education. Volume 3

ERIC Educational Resources Information Center

Waghid, Yusef

2011-01-01

"Conceptions of Islamic Education: Pedagogical Framings" argues that "madaris" (Muslim schools) cannot exclusively be held responsible for the cultivation of extremism. Islamic education can most appropriately be framed according to three interrelated concepts: "tarbiyyah" (rearing or nurturing), "ta'lim"…

Tantrik influence on sarngadhara.

PubMed

Sharma, P V

1984-01-01

Tantra and Ayurveda are interrelated, particularly during medieval period, Tantra had great impact on the theory and practice of Ayurveda. Hitherto this aspect of history is not sufficiently explored. In this paper, influence of Tantra on Sarngadhara, a representative author of the medieval period, has been vividly brought out.