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Sample records for functional ubiquitin-proteasome system

  1. Ubiquitin-proteasome system and hereditary cardiomyopathies.

    PubMed

    Schlossarek, Saskia; Frey, Norbert; Carrier, Lucie

    2014-06-01

    Adequate protein turnover is essential for cardiac homeostasis. Different protein quality controls are involved in the maintenance of protein homeostasis, including molecular chaperones and co-chaperones, the autophagy-lysosomal pathway, and the ubiquitin-proteasome system (UPS). In the last decade, a series of evidence has underlined a major function of the UPS in cardiac physiology and disease. Particularly, recent studies have shown that dysfunctional proteasomal function leads to cardiac disorders. Hypertrophic and dilated cardiomyopathies are the two most prevalent inherited cardiomyopathies. Both are primarily transmitted as an autosomal-dominant trait and mainly caused by mutations in genes encoding components of the cardiac sarcomere, including a relevant striated muscle-specific E3 ubiquitin ligase. A growing body of evidence indicates impairment of the UPS in inherited cardiomyopathies as determined by measurement of the level of ubiquitinated proteins, the activities of the proteasome and/or the use of fluorescent UPS reporter substrates. The present review will propose mechanisms of UPS impairment in inherited cardiomyopathies, summarize the potential consequences of UPS impairment, including activation of the unfolded protein response, and underline some therapeutic options available to restore proteasome function and therefore cardiac homeostasis and function. This article is part of a Special Issue entitled "Protein Quality Control, the Ubiquitin Proteasome System, and Autophagy".

  2. How the ubiquitin proteasome system regulates the regulators of transcription.

    PubMed

    Ee, Gary; Lehming, Norbert

    2012-01-01

    The ubiquitin proteasome system plays an important role in transcription. Monoubiquitination of activators is believed to aid their function, while the 26S proteasomal degradation of repressors is believed to restrict their function. What remains controversial is the question of whether the degradation of activators aids or restricts their function.

  3. Role of the ubiquitin-proteasome system in nervous system function and disease: using C. elegans as a dissecting tool.

    PubMed

    Baptista, Márcio S; Duarte, Carlos B; Maciel, Patrícia

    2012-08-01

    In addition to its central roles in protein quality control, regulation of cell cycle, intracellular signaling, DNA damage response and transcription regulation, the ubiquitin-proteasome system (UPS) plays specific roles in the nervous system, where it contributes to precise connectivity through development, and later assures functionality by regulating a wide spectrum of neuron-specific cellular processes. Aberrations in this system have been implicated in the etiology of neurodevelopmental and neurodegenerative diseases. In this review, we provide an updated view on the UPS and highlight recent findings concerning its role in normal and diseased nervous systems. We discuss the advantages of the model organism Caenorhabditis elegans as a tool to unravel the major unsolved questions concerning this biochemical pathway and its involvement in nervous system function and dysfunction, and expose the new possibilities, using state-of-the-art techniques, to assess UPS function using this model system.

  4. Ubiquitin proteasome system research in gastrointestinal cancer

    PubMed Central

    Zhong, Jia-Ling; Huang, Chang-Zhi

    2016-01-01

    The ubiquitin proteasome system (UPS) is important for the degradation of proteins in eukaryotic cells. It is involved in nearly every cellular process and plays an important role in maintaining body homeostasis. An increasing body of evidence has linked alterations in the UPS to gastrointestinal malignancies, including esophageal, gastric and colorectal cancers. Here, we summarize the current literature detailing the involvement of the UPS in gastrointestinal cancer, highlighting its role in tumor occurrence and development, providing information for therapeutic targets research and anti-gastrointestinal tumor drug design. PMID:26909134

  5. Ubiquitin proteasome system research in gastrointestinal cancer.

    PubMed

    Zhong, Jia-Ling; Huang, Chang-Zhi

    2016-02-15

    The ubiquitin proteasome system (UPS) is important for the degradation of proteins in eukaryotic cells. It is involved in nearly every cellular process and plays an important role in maintaining body homeostasis. An increasing body of evidence has linked alterations in the UPS to gastrointestinal malignancies, including esophageal, gastric and colorectal cancers. Here, we summarize the current literature detailing the involvement of the UPS in gastrointestinal cancer, highlighting its role in tumor occurrence and development, providing information for therapeutic targets research and anti-gastrointestinal tumor drug design.

  6. Subnormothermic Perfusion in the Isolated Rat Liver Preserves the Antioxidant Glutathione and Enhances the Function of the Ubiquitin Proteasome System

    PubMed Central

    Alva, Norma; Sanchez-Nuño, Sergio; Dewey, Shannamar; Gomes, Aldrin V.

    2016-01-01

    The reduction of oxidative stress is suggested to be one of the main mechanisms to explain the benefits of subnormothermic perfusion against ischemic liver damage. In this study we investigated the early cellular mechanisms induced in isolated rat livers after 15 min perfusion at temperatures ranging from normothermia (37°C) to subnormothermia (26°C and 22°C). Subnormothermic perfusion was found to maintain hepatic viability. Perfusion at 22°C raised reduced glutathione levels and the activity of glutathione reductase; however, lipid and protein oxidation still occurred as determined by malondialdehyde, 4-hydroxynonenal-protein adducts, and advanced oxidation protein products. In livers perfused at 22°C the lysosomal and ubiquitin proteasome system (UPS) were both activated. The 26S chymotrypsin-like (β5) proteasome activity was significantly increased in the 26°C (46%) and 22°C (42%) groups. The increased proteasome activity may be due to increased Rpt6 Ser120 phosphorylation, which is known to enhance 26S proteasome activity. Together, our results indicate that the early events produced by subnormothermic perfusion in the liver can induce oxidative stress concomitantly with antioxidant glutathione preservation and enhanced function of the lysosomal and UPS systems. Thus, a brief hypothermia could trigger antioxidant mechanisms and may be functioning as a preconditioning stimulus. PMID:27800122

  7. Emerging therapies targeting the ubiquitin proteasome system in cancer

    PubMed Central

    Weathington, Nathaniel M.; Mallampalli, Rama K.

    2014-01-01

    The ubiquitin proteasome system (UPS) is an essential metabolic constituent of cellular physiology that tightly regulates cellular protein concentrations with specificity and precision to optimize cellular function. Inhibition of the proteasome has proven very effective in the treatment of multiple myeloma, and this approach is being tested for utility in other malignancies. New pharmaceuticals targeting the proteasome itself or specific proximal pathways of the UPS are in development as antiproliferatives or immunomodulatory agents. In this article, we discuss the biology of UPS-targeting drugs, their use as therapy for neoplasia, and the state of clinical and preclinical development for emerging therapeutics. PMID:24382383

  8. Emerging therapies targeting the ubiquitin proteasome system in cancer.

    PubMed

    Weathington, Nathaniel M; Mallampalli, Rama K

    2014-01-01

    The ubiquitin proteasome system (UPS) is an essential metabolic constituent of cellular physiology that tightly regulates cellular protein concentrations with specificity and precision to optimize cellular function. Inhibition of the proteasome has proven very effective in the treatment of multiple myeloma, and this approach is being tested for utility in other malignancies. New pharmaceuticals targeting the proteasome itself or specific proximal pathways of the UPS are in development as antiproliferatives or immunomodulatory agents. In this article, we discuss the biology of UPS-targeting drugs, their use as therapy for neoplasia, and the state of clinical and preclinical development for emerging therapeutics.

  9. Dysregulation of Ubiquitin-Proteasome System in Neurodegenerative Diseases

    PubMed Central

    Zheng, Qiuyang; Huang, Timothy; Zhang, Lishan; Zhou, Ying; Luo, Hong; Xu, Huaxi; Wang, Xin

    2016-01-01

    The ubiquitin-proteasome system (UPS) is one of the major protein degradation pathways, where abnormal UPS function has been observed in cancer and neurological diseases. Many neurodegenerative diseases share a common pathological feature, namely intracellular ubiquitin-positive inclusions formed by aggregate-prone neurotoxic proteins. This suggests that dysfunction of the UPS in neurodegenerative diseases contributes to the accumulation of neurotoxic proteins and to instigate neurodegeneration. Here, we review recent findings describing various aspects of UPS dysregulation in neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. PMID:28018215

  10. The ubiquitin proteasome system in neuropathology.

    PubMed

    Lehman, Norman L

    2009-09-01

    The ubiquitin proteasome system (UPS) orchestrates the turnover of innumerable cellular proteins. In the process of ubiquitination the small protein ubiquitin is attached to a target protein by a peptide bond. The ubiquitinated target protein is subsequently shuttled to a protease complex known as the 26S proteasome and subjected to degradative proteolysis. The UPS facilitates the turnover of proteins in several settings. It targets oxidized, mutant or misfolded proteins for general proteolytic destruction, and allows for the tightly controlled and specific destruction of proteins involved in development and differentiation, cell cycle progression, circadian rhythms, apoptosis, and other biological processes. In neuropathology, alteration of the UPS, or mutations in UPS target proteins may result in signaling abnormalities leading to the initiation or progression of tumors such as astrocytomas, hemangioblastomas, craniopharyngiomas, pituitary adenomas, and medulloblastomas. Dysregulation of the UPS may also contribute to tumor progression by perturbation of DNA replication and mitotic control mechanisms, leading to genomic instability. In neurodegenerative diseases caused by the expression of mutant proteins, the cellular accumulation of these proteins may overload the UPS, indirectly contributing to the disease process, e.g., sporadic Parkinsonism and prion diseases. In other cases, mutation of UPS components may directly cause pathological accumulation of proteins, e.g., autosomal recessive Parkinsonism and spinocerebellar ataxias. Defects or dysfunction of the UPS may also underlie cognitive disorders such as Angelman syndrome, Rett syndrome and autism, and muscle and nerve diseases, e.g., inclusion body myopathy and giant axon neuropathy. This paper describes the basic biochemical mechanisms comprising the UPS and reviews both its theoretical and proven involvement in neuropathological diseases. The potential for the UPS as a target of pharmacological therapy

  11. Functional alterations of the ubiquitin-proteasome system in motor neurons of a mouse model of familial amyotrophic lateral sclerosis†

    PubMed Central

    Cheroni, Cristina; Marino, Marianna; Tortarolo, Massimo; Veglianese, Pietro; De Biasi, Silvia; Fontana, Elena; Zuccarello, Laura Vitellaro; Maynard, Christa J.; Dantuma, Nico P.; Bendotti, Caterina

    2009-01-01

    In familial and sporadic amyotrophic lateral sclerosis (ALS) and in rodent models of the disease, alterations in the ubiquitin-proteasome system (UPS) may be responsible for the accumulation of potentially harmful ubiquitinated proteins, leading to motor neuron death. In the spinal cord of transgenic mice expressing the familial ALS superoxide dismutase 1 (SOD1) gene mutation G93A (SOD1G93A), we found a decrease in constitutive proteasome subunits during disease progression, as assessed by real-time PCR and immunohistochemistry. In parallel, an increased immunoproteasome expression was observed, which correlated with a local inflammatory response due to glial activation. These findings support the existence of proteasome modifications in ALS vulnerable tissues. To functionally investigate the UPS in ALS motor neurons in vivo, we crossed SOD1G93A mice with transgenic mice that express a fluorescently tagged reporter substrate of the UPS. In double-transgenic UbG76V-GFP /SOD1G93A mice an increase in UbG76V-GFP reporter, indicative of UPS impairment, was detectable in a few spinal motor neurons and not in reactive astrocytes or microglia, at symptomatic stage but not before symptoms onset. The levels of reporter transcript were unaltered, suggesting that the accumulation of UbG76V-GFP was due to deficient reporter degradation. In some motor neurons the increase of UbG76V-GFP was accompanied by the accumulation of ubiquitin and phosphorylated neurofilaments, both markers of ALS pathology. These data suggest that UPS impairment occurs in motor neurons of mutant SOD1-linked ALS mice and may play a role in the disease progression. PMID:18826962

  12. Poxvirus Exploitation of the Ubiquitin-Proteasome System

    PubMed Central

    Barry, Michele; van Buuren, Nicholas; Burles, Kristin; Mottet, Kelly; Wang, Qian; Teale, Alastair

    2010-01-01

    Ubiquitination plays a critical role in many cellular processes. A growing number of viruses have evolved strategies to exploit the ubiquitin-proteasome system, including members of the Poxviridae family. Members of the poxvirus family have recently been shown to encode BTB/kelch and ankyrin/F-box proteins that interact with cullin-3 and cullin-1 based ubiquitin ligases, respectively. Multiple members of the poxvirus family also encode ubiquitin ligases with intrinsic activity. This review describes the numerous mechanisms that poxviruses employ to manipulate the ubiquitin-proteasome system. PMID:21994622

  13. The ubiquitin-proteasome system regulates plant hormone signaling

    PubMed Central

    Santner, Aaron; Estelle, Mark

    2011-01-01

    SUMMARY Plants utilize the ubiquitin-proteasome system (UPS) to modulate nearly every aspect of growth and development. Ubiquitin is covalently attached to target proteins through the action of three enzymes known as E1, E2, and E3. The ultimate outcome of this post-translational modification depends on the nature of the ubiquitin linkage and the extent of polyubiquitination. In most cases, ubiquitination results in degradation of the target protein in the 26S proteasome. During the last 10 years it has become clear that the UPS plays a prominent regulatory role in hormone biology. E3 ubiquitin ligases in particular actively participate in hormone perception, de-repression of hormone signaling pathways, degradation of hormone specific transcription factors, and regulation of hormone biosynthesis. It is certain that additional functions will be discovered as more of the nearly 1200 potential E3s in plants are elucidated. PMID:20409276

  14. Denervation-Induced Activation of the Ubiquitin-Proteasome System Reduces Skeletal Muscle Quantity Not Quality.

    PubMed

    Baumann, Cory W; Liu, Haiming M; Thompson, LaDora V

    2016-01-01

    It is well known that the ubiquitin-proteasome system is activated in response to skeletal muscle wasting and functions to degrade contractile proteins. The loss of these proteins inevitably reduces skeletal muscle size (i.e., quantity). However, it is currently unknown whether activation of this pathway also affects function by impairing the muscle's intrinsic ability to produce force (i.e., quality). Therefore, the purpose of this study was twofold, (1) document how the ubiquitin-proteasome system responds to denervation and (2) identify the physiological consequences of these changes. To induce soleus muscle atrophy, C57BL6 mice underwent tibial nerve transection of the left hindlimb for 7 or 14 days (n = 6-8 per group). At these time points, content of several proteins within the ubiquitin-proteasome system were determined via Western blot, while ex vivo whole muscle contractility was specifically analyzed at day 14. Denervation temporarily increased several key proteins within the ubiquitin-proteasome system, including the E3 ligase MuRF1 and the proteasome subunits 19S, α7 and β5. These changes were accompanied by reductions in absolute peak force and power, which were offset when expressed relative to physiological cross-sectional area. Contrary to peak force, absolute and relative forces at submaximal stimulation frequencies were significantly greater following 14 days of denervation. Taken together, these data represent two keys findings. First, activation of the ubiquitin-proteasome system is associated with reductions in skeletal muscle quantity rather than quality. Second, shortly after denervation, it appears the muscle remodels to compensate for the loss of neural activity via changes in Ca2+ handling.

  15. The role of allostery in the ubiquitin-proteasome system

    PubMed Central

    Liu, Jin; Nussinov, Ruth

    2012-01-01

    The Ubiquitin-Proteasome System is involved in many cellular processes including protein degradation. Degradation of a protein via this system involves two successive steps: ubiquitination and degradation. Ubiquitination tags the target protein with ubiquitin-like proteins, such as ubiquitin, SUMO and NEDD8, via a cascade involving three enzymes: activating enzyme E1, conjugating enzyme E2, and E3 ubiquitin ligases. The proteasomes recognize the ubiquitin-like protein tagged substrate proteins and degrade them. Accumulating evidence indicates that allostery is a central player in the regulation of ubiquitination, as well as deubiquitination and degradation. Here, we provide an overview of the key mechanistic roles played by allostery in all steps of these processes, and highlight allosteric drugs targeting them. Throughout the review, we emphasize the crucial mechanistic role played by linkers in allosterically controlling the Ubiquitin-Proteasome System action by biasing the sampling of the conformational space, which facilitate the catalytic reactions of the ubiquitination and degradation. Finally, we propose that allostery may similarly play key roles in the regulation of molecular machines in the cell, and as such allosteric drugs can be expected to be increasingly exploited in therapeutic regimes. PMID:23234564

  16. Protein oxidative modification in the aging organism and the role of the ubiquitin proteasomal system.

    PubMed

    Kastle, Marc; Grune, Tilman

    2011-12-01

    Living in an oxygen containing environment is automatically connected to oxidative stress. Beside lipids and nucleic acids, especially proteins are very susceptible for oxidative modifications. These oxidative modifications comprise alterations of single amino acids, like the formation of protein carbonyls and methionine sulfoxide, or the aggregation of whole proteins. Due to the ongoing accumulation of protein aggregates during the aging process, the cellular protein quality control system becomes more and more overwhelmed. One essential element of the protein quality control machinery is the ubiquitin proteasomal system which plays therefore a crucial part in the aging process, too. Ubiquitination of proteins is a three step mechanism to tag proteins with a polyubiquitin chain for the proteasome. The proteasome is a regulated, barrel-shaped multi-enzyme complex which is responsible for the degradation of proteins. Although there is no drastic loss of all proteasomal subunits during the aging process, there is a functional decline of the proteasome activity in aging organisms. Impairment of the ubiquitin proteasome system leads to increasing protein aggregation and cellular death. A lot of age related diseases are closely connected to an inhibition of the proteasome and the formation of large protein aggregates. Especially skin aging, atherosclerosis, age-dependent macula degeneration, cataract formation and several neurodegenerative diseases are directly connected to the decline of proteasome function. This review outlines the connections between aging, oxidative stress and protein oxidation, as well as the influence on the ubiquitin proteasomal system and several associated diseases.

  17. Regulation of the retinoblastoma-E2F pathway by the ubiquitin-proteasome system.

    PubMed

    Sengupta, Satyaki; Henry, R William

    2015-10-01

    The retinoblastoma tumor suppressor (RB) and its related family members p107 and p130 regulate cell proliferation through the transcriptional repression of genes involved in cellular G1 to S phase transition. However, RB proteins are functionally versatile, and numerous genetic and biochemical studies point to expansive roles in cellular growth control, pluripotency, and apoptotic response. For the vast majority of genes, RB family members target the E2F family of transcriptional activators as an integral component of its gene regulatory mechanism. These interactions are regulated via reversible phosphorylation by Cyclin/Cyclin-dependent kinase (Cdk) complexes, a major molecular mechanism that regulates transcriptional output of RB/E2F target genes. Recent studies indicate an additional level of regulation involving the ubiquitin-proteasome system that renders pervasive control over each component of the RB pathway. Disruption of the genetic circuitry for proteasome-mediated targeting of the RB pathway has serious consequences on development and cellular transformation, and is associated with several forms of human cancer. In this review, we discuss the role of the ubiquitin-proteasome system in proteolytic control of RB-E2F pathway components, and recent data that points to surprising non-proteolytic roles for the ubiquitin-proteasome system in novel transcriptional regulatory mechanisms.

  18. Targeting the ubiquitin-proteasome system for cancer therapy

    PubMed Central

    Yang, Yili; Kitagaki, Jirouta; Wang, Honghe; Hou, Dexing; Perantoni, Alan O.

    2009-01-01

    Summary The ubiquitin-proteasome system plays a critical role in controlling the level, activity, and location of various cellular proteins. Significant progress has been made in investigating the molecular mechanisms of ubiquitination, particularly in understanding the structure of the ubiquitination machinery and identifying ubiquitin protein ligases, the primary specificity-determining enzymes. Therefore, it is now possible to target specific molecules involved in the ubiquitination and proteasomal degradation to regulate many cellular processes such as signal transduction, proliferation and apoptosis. In particular, alterations in ubiquitination are observed in most, if not all, cancer cells. This is manifested by destabilization of tumor suppressors, such as p53, and overexpression of oncogenes such as c-Myc and c-Jun. In addition to the development and clinical validation of proteasome inhibitor Bortezomib in myeloma therapy, recent studies have demonstrated that it is possible to develop inhibitors for specific ubiquitination and deubiquitination enzymes. With the help of structural studies, rational design, and chemical synthesis, it is conceivable that we will be able to use “druggable” inhibitors of the ubiquitin system to evaluate their effects in animal tumor models in the not-so-distant future. PMID:19037995

  19. Human papillomavirus-induced carcinogenesis and the ubiquitin-proteasome system.

    PubMed

    Scheffner, Martin; Whitaker, Noel J

    2003-02-01

    Certain types of human papillomaviruses have been etiologically associated with malignant lesions, most notably with cervical cancer. The major oncoproteins of these cancer-associated viruses are encoded by the viral E6 and E7 genes. Thorough characterization of these oncoproteins and their interaction with cellular proteins has shown that both E6 and E7 exploit the ubiquitin-proteasome system to degrade and, thus, to functionally inactivate negative cell-regulatory proteins including members of the p110(RB) family and p53. This act of piracy is assumed to contribute to both the efficient propagation of HPVs and HPV-induced carcinogenesis.

  20. Protein Degradation by Ubiquitin-Proteasome System in Formation and Labilization of Contextual Conditioning Memory

    ERIC Educational Resources Information Center

    Fustiñana, María Sol; de la Fuente, Verónica; Federman, Noel; Freudenthal, Ramiro; Romano, Arturo

    2014-01-01

    The ubiquitin-proteasome system (UPS) of protein degradation has been evaluated in different forms of neural plasticity and memory. The role of UPS in such processes is controversial. Several results support the idea that the activation of this system in memory consolidation is necessary to overcome negative constrains for plasticity. In this…

  1. Atrophy, hypertrophy, and hypoxemia induce transcriptional regulators of the ubiquitin proteasome system in the rat heart

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In skeletal muscle, transcript levels of proteins regulating the ubiquitin proteasome system (UPS) increase with atrophy and decrease with hypertrophy. Whether the same is true for heart muscle is not known. We set out to characterize the transcriptional profile of regulators of the UPS during atrop...

  2. The ubiquitin-proteasome system in cardiac proteinopathy: a quality control perspective

    PubMed Central

    Su, Huabo; Wang, Xuejun

    2010-01-01

    Protein quality control (PQC) depends on elegant collaboration between molecular chaperones and targeted proteolysis in the cell. The latter is primarily carried out by the ubiquitin-proteasome system, but recent advances in this area of research suggest a supplementary role for the autophagy-lysosomal pathway in PQC-related proteolysis. The (patho)physiological significance of PQC in the heart is best illustrated in cardiac proteinopathy, which belongs to a family of cardiac diseases caused by expression of aggregation-prone proteins in cardiomyocytes. Cardiac proteasome functional insufficiency (PFI) is best studied in desmin-related cardiomyopathy, a bona fide cardiac proteinopathy. Emerging evidence suggests that many common forms of cardiomyopathy may belong to proteinopathy. This review focuses on examining current evidence, as it relates to the hypothesis that PFI impairs PQC in cardiomyocytes and contributes to the progression of cardiac proteinopathies to heart failure. PMID:19696071

  3. Mitochondrial and Ubiquitin Proteasome System Dysfunction in Ageing and Disease: Two Sides of the Same Coin?

    PubMed Central

    Ross, Jaime M.; Olson, Lars; Coppotelli, Giuseppe

    2015-01-01

    Mitochondrial dysfunction and impairment of the ubiquitin proteasome system have been described as two hallmarks of the ageing process. Additionally, both systems have been implicated in the etiopathogenesis of many age-related diseases, particularly neurodegenerative disorders, such as Alzheimer’s and Parkinson’s disease. Interestingly, these two systems are closely interconnected, with the ubiquitin proteasome system maintaining mitochondrial homeostasis by regulating organelle dynamics, the proteome, and mitophagy, and mitochondrial dysfunction impairing cellular protein homeostasis by oxidative damage. Here, we review the current literature and argue that the interplay of the two systems should be considered in order to better understand the cellular dysfunction observed in ageing and age-related diseases. Such an approach may provide valuable insights into molecular mechanisms underlying the ageing process, and further discovery of treatments to counteract ageing and its associated diseases. Furthermore, we provide a hypothetical model for the heterogeneity described among individuals during ageing. PMID:26287188

  4. Mitochondrial and Ubiquitin Proteasome System Dysfunction in Ageing and Disease: Two Sides of the Same Coin?

    PubMed

    Ross, Jaime M; Olson, Lars; Coppotelli, Giuseppe

    2015-08-17

    Mitochondrial dysfunction and impairment of the ubiquitin proteasome system have been described as two hallmarks of the ageing process. Additionally, both systems have been implicated in the etiopathogenesis of many age-related diseases, particularly neurodegenerative disorders, such as Alzheimer's and Parkinson's disease. Interestingly, these two systems are closely interconnected, with the ubiquitin proteasome system maintaining mitochondrial homeostasis by regulating organelle dynamics, the proteome, and mitophagy, and mitochondrial dysfunction impairing cellular protein homeostasis by oxidative damage. Here, we review the current literature and argue that the interplay of the two systems should be considered in order to better understand the cellular dysfunction observed in ageing and age-related diseases. Such an approach may provide valuable insights into molecular mechanisms underlying the ageing process, and further discovery of treatments to counteract ageing and its associated diseases. Furthermore, we provide a hypothetical model for the heterogeneity described among individuals during ageing.

  5. Sphingosine 1-phosphate lyase ablation disrupts presynaptic architecture and function via an ubiquitin- proteasome mediated mechanism

    PubMed Central

    Mitroi, Daniel N.; Deutschmann, André U.; Raucamp, Maren; Karunakaran, Indulekha; Glebov, Konstantine; Hans, Michael; Walter, Jochen; Saba, Julie; Gräler, Markus; Ehninger, Dan; Sopova, Elena; Shupliakov, Oleg; Swandulla, Dieter; van Echten-Deckert, Gerhild

    2016-01-01

    The bioactive lipid sphingosine 1-phosphate (S1P) is a degradation product of sphingolipids that are particularly abundant in neurons. We have shown previously that neuronal S1P accumulation is toxic leading to ER-stress and an increase in intracellular calcium. To clarify the neuronal function of S1P, we generated brain-specific knockout mouse models in which S1P-lyase (SPL), the enzyme responsible for irreversible S1P cleavage was inactivated. Constitutive ablation of SPL in the brain (SPLfl/fl/Nes) but not postnatal neuronal forebrain-restricted SPL deletion (SPLfl/fl/CaMK) caused marked accumulation of S1P. Hence, altered presynaptic architecture including a significant decrease in number and density of synaptic vesicles, decreased expression of several presynaptic proteins, and impaired synaptic short term plasticity were observed in hippocampal neurons from SPLfl/fl/Nes mice. Accordingly, these mice displayed cognitive deficits. At the molecular level, an activation of the ubiquitin-proteasome system (UPS) was detected which resulted in a decreased expression of the deubiquitinating enzyme USP14 and several presynaptic proteins. Upon inhibition of proteasomal activity, USP14 levels, expression of presynaptic proteins and synaptic function were restored. These findings identify S1P metabolism as a novel player in modulating synaptic architecture and plasticity. PMID:27883090

  6. Nuclear ubiquitin proteasome degradation affects WRKY45 function in the rice defense program.

    PubMed

    Matsushita, Akane; Inoue, Haruhiko; Goto, Shingo; Nakayama, Akira; Sugano, Shoji; Hayashi, Nagao; Takatsuji, Hiroshi

    2013-01-01

    The transcriptional activator WRKY45 plays a major role in the salicylic acid/benzothiadiazole-induced defense program in rice. Here, we show that the nuclear ubiquitin-proteasome system (UPS) plays a role in regulating the function of WRKY45. Proteasome inhibitors induced accumulation of polyubiquitinated WRKY45 and transient up-regulation of WRKY45 target genes in rice cells, suggesting that WRKY45 is constantly degraded by the UPS to suppress defense responses in the absence of defense signals. Mutational analysis of the nuclear localization signal indicated that UPS-dependent WRKY45 degradation occurs in the nuclei. Interestingly, the transcriptional activity of WRKY45 after salicylic acid treatment was impaired by proteasome inhibition. The same C-terminal region in WRKY45 was essential for both transcriptional activity and UPS-dependent degradation. These results suggest that UPS regulation also plays a role in the transcriptional activity of WRKY45. It has been reported that AtNPR1, the central regulator of the salicylic acid pathway in Arabidopsis, is regulated by the UPS. We found that OsNPR1/NH1, the rice counterpart of NPR1, was not stabilized by proteasome inhibition under uninfected conditions. We discuss the differences in post-translational regulation of salicylic acid pathway components between rice and Arabidopsis.

  7. Insulin alleviates degradation of skeletal muscle protein by inhibiting the ubiquitin-proteasome system in septic rats.

    PubMed

    Chen, Qiyi; Li, Ning; Zhu, Weiming; Li, Weiqin; Tang, Shaoqiu; Yu, Wenkui; Gao, Tao; Zhang, Juanjuan; Li, Jieshou

    2011-06-03

    Hypercatabolism is common under septic conditions. Skeletal muscle is the main target organ for hypercatabolism, and this phenomenon is a vital factor in the deterioration of recovery in septic patients. In skeletal muscle, activation of the ubiquitin-proteasome system plays an important role in hypercatabolism under septic status. Insulin is a vital anticatabolic hormone and previous evidence suggests that insulin administration inhibits various steps in the ubiquitin-proteasome system. However, whether insulin can alleviate the degradation of skeletal muscle protein by inhibiting the ubiquitin-proteasome system under septic condition is unclear. This paper confirmed that mRNA and protein levels of the ubiquitin-proteasome system were upregulated and molecular markers of skeletal muscle proteolysis (tyrosine and 3-methylhistidine) simultaneously increased in the skeletal muscle of septic rats. Septic rats were infused with insulin at a constant rate of 2.4 mU.kg-1.min-1 for 8 hours. Concentrations of mRNA and proteins of the ubiquitin-proteasome system and molecular markers of skeletal muscle proteolysis were mildly affected. When the insulin infusion dose increased to 4.8 mU.kg-1.min-1, mRNA for ubiquitin, E2-14 KDa, and the C2 subunit were all sharply downregulated. At the same time, the levels of ubiquitinated proteins, E2-14KDa, and the C2 subunit protein were significantly reduced. Tyrosine and 3-methylhistidine decreased significantly. We concluded that the ubiquitin-proteasome system is important skeletal muscle hypercatabolism in septic rats. Infusion of insulin can reverse the detrimental metabolism of skeletal muscle by inhibiting the ubiquitin-proteasome system, and the effect is proportional to the insulin infusion dose.

  8. Cereblon is recruited to aggresome and shows cytoprotective effect against ubiquitin-proteasome system dysfunction.

    PubMed

    Sawamura, Naoya; Wakabayashi, Satoru; Matsumoto, Kodai; Yamada, Haruka; Asahi, Toru

    2015-09-04

    Cereblon (CRBN) is encoded by a candidate gene for autosomal recessive nonsyndromic intellectual disability (ID). The nonsense mutation, R419X, causes deletion of 24 amino acids at the C-terminus of CRBN, leading to mild ID. Although abnormal CRBN function may be associated with ID disease onset, its cellular mechanism is still unclear. Here, we examine the role of CRBN in aggresome formation and cytoprotection. In the presence of a proteasome inhibitor, exogenous CRBN formed perinuclear inclusions and co-localized with aggresome markers. Endogenous CRBN also formed perinuclear inclusions under the same condition. Treatment with a microtubule destabilizer or an inhibitor of the E3 ubiquitin ligase activity of CRBN blocked formation of CRBN inclusions. Biochemical analysis showed CRBN containing inclusions were high-molecular weight, ubiquitin-positive. CRBN overexpression in cultured cells suppressed cell death induced by proteasome inhibitor. Furthermore, knockdown of endogenous CRBN in cultured cells increased cell death induced by proteasome inhibitor, compared with control cells. Our results show CRBN is recruited to aggresome and has functional roles in cytoprotection against ubiquitin-proteasome system impaired condition.

  9. Dendrite development regulated by the schizophrenia-associated gene FEZ1 involves the ubiquitin proteasome system.

    PubMed

    Watanabe, Yasuhito; Khodosevich, Konstantin; Monyer, Hannah

    2014-04-24

    Downregulation of the schizophrenia-associated gene DISC1 and its interacting protein FEZ1 positively regulates dendrite growth in young neurons. However, little is known about the mechanism that controls these molecules during neuronal development. Here, we identify several components of the ubiquitin proteasome system and the cell-cycle machinery that act upstream of FEZ1. We demonstrate that the ubiquitin ligase cell division cycle 20/anaphase-promoting complex (Cdc20/APC) controls dendrite growth by regulating the degradation of FEZ1. Furthermore, dendrite growth is modulated by BubR1, whose known function so far has been restricted to control Cdc20/APC activity during the cell cycle. The modulatory function of BubR1 is dependent on its acetylation status. We show that BubR1 is deacetylated by Hdac11, thereby disinhibiting the Cdc20/APC complex. Because dendrite growth is affected both in hippocampal dentate granule cells and olfactory bulb neurons upon modifying expression of these genes, we conclude that the proposed mechanism governs neuronal development in a general fashion.

  10. The interplay between autophagy and the ubiquitin-proteasome system in cardiac proteotoxicity

    PubMed Central

    Wang, Changhua; Wang, Xuejun

    2014-01-01

    Proteotoxicity refers to the detrimental effects of damaged/misfolded proteins on the cell. Cardiac muscle is particularly susceptible to proteotoxicity because sustained and severe proteotoxic stress leads to cell death and cardiac muscle has very limited self-renewal capacity. The ubiquitin-proteasome system (UPS) and the autophagic-lysosomal pathway (ALP) are two major pathways responsible for degradation of most cellular proteins. Alterations of UPS and ALP functions are associated with the accumulation of proteotoxic species in the heart, a key pathological feature of common forms of heart disease including idiopathic, ischemic, and pressure-overloaded cardiomyopathies and a large subset of congestive heart failure. Emerging evidence suggests proteasome inhibition or impairment activates autophagy and conversely, acute ALP inhibition may sometimes increase intrinsic proteasome peptidase activities but chronic ALP inhibition hinders UPS performance in ubiquitinated protein degradation. The exact molecular basis on which the two degradative pathways interact remains largely undefined. Here we review current understanding of the roles of the UPS and autophagy in the control of cardiac proteotoxicity, with a specific focus on the crosstalk between the two pathways. PMID:25092168

  11. Ubiquitin-Proteasome System Inhibition Promotes Long-Term Depression and Synaptic Tagging/Capture.

    PubMed

    Li, Qin; Korte, Martin; Sajikumar, Sreedharan

    2016-06-01

    A balance of protein synthesis and degradation is critical for the dynamic regulation and implementation of long-term memory storage. The role of the ubiquitin-proteasome system (UPS) in regulating the plasticity at potentiated synapses is well studied, but its roles in depressed synaptic populations remain elusive. In this study, we probed the possibility of regulating the UPS by inhibiting the proteasome function during the induction of protein synthesis-independent form of hippocampal long-term depression (early-LTD), an important component of synaptic plasticity. Here, we show that protein degradation is involved in early-LTD induction and interfering with this process facilitates early-LTD to late-LTD. We provide evidence here that under the circumstances of proteasome inhibition brain-derived neurotrophic factor is accumulated as plasticity-related protein and it drives the weakly depressed or potentiated synapses to associativity. Thus, UPS inhibition promotes LTD and establishes associativity between weakly depressed or potentiated synapses through the mechanisms of synaptic tagging/capture or cross-capture.

  12. The role of the ubiquitin proteasome system in synapse remodeling and neurodegenerative diseases

    PubMed Central

    Ding, Mei; Shen, Kang

    2011-01-01

    Summary The ubiquitin proteasome system is a potent regulatory mechanism used to control protein stability in numerous cellular processes, including neural development. Many neurodegenerative diseases are featured by the accumulation of UPS-associated proteins, suggesting the UPS dysfunction may be crucial for pathogenesis. Recent experiments have highlighted the UPS as a key player during synaptic development. Here we summarize recent discoveries centered on the role of the UPS in synapse remodeling and draw attention to the potential link between the synaptic UPS dysfunction and the pathology of neurodegenerative diseases. PMID:18937340

  13. The Ubiquitin-Proteasome System: Potential Therapeutic Targets for Alzheimer's Disease and Spinal Cord Injury.

    PubMed

    Gong, Bing; Radulovic, Miroslav; Figueiredo-Pereira, Maria E; Cardozo, Christopher

    2016-01-01

    The ubiquitin-proteasome system (UPS) is a crucial protein degradation system in eukaryotes. Herein, we will review advances in the understanding of the role of several proteins of the UPS in Alzheimer's disease (AD) and functional recovery after spinal cord injury (SCI). The UPS consists of many factors that include E3 ubiquitin ligases, ubiquitin hydrolases, ubiquitin and ubiquitin-like molecules, and the proteasome itself. An extensive body of work links UPS dysfunction with AD pathogenesis and progression. More recently, the UPS has been shown to have vital roles in recovery of function after SCI. The ubiquitin hydrolase (Uch-L1) has been proposed to increase cellular levels of mono-ubiquitin and hence to increase rates of protein turnover by the UPS. A low Uch-L1 level has been linked with Aβ accumulation in AD and reduced neuroregeneration after SCI. One likely mechanism for these beneficial effects of Uch-L1 is reduced turnover of the PKA regulatory subunit and consequently, reduced signaling via CREB. The neuron-specific F-box protein Fbx2 ubiquitinates β-secretase thus targeting it for proteasomal degradation and reducing generation of Aβ. Both Uch-L1 and Fbx2 improve synaptic plasticity and cognitive function in mouse AD models. The role of Fbx2 after SCI has not been examined, but abolishing ß-secretase reduces neuronal recovery after SCI, associated with reduced myelination. UBB+1, which arises through a frame-shift mutation in the ubiquitin gene that adds 19 amino acids to the C-terminus of ubiquitin, inhibits proteasomal function and is associated with increased neurofibrillary tangles in patients with AD, Pick's disease and Down's syndrome. These advances in understanding of the roles of the UPS in AD and SCI raise new questions but, also, identify attractive and exciting targets for potential, future therapeutic interventions.

  14. The ubiquitin-proteasome system and the autophagic-lysosomal system in Alzheimer disease.

    PubMed

    Ihara, Yasuo; Morishima-Kawashima, Maho; Nixon, Ralph

    2012-08-01

    As neurons age, their survival depends on eliminating a growing burden of damaged, potentially toxic proteins and organelles-a capability that declines owing to aging and disease factors. Here, we review the two proteolytic systems principally responsible for protein quality control in neurons and their important contributions to Alzheimer disease pathogenesis. In the first section, the discovery of paired helical filament ubiquitination is described as a backdrop for discussing the importance of the ubiquitin-proteasome system in Alzheimer disease. In the second section, we review the prominent involvement of the lysosomal system beginning with pathological endosomal-lysosomal activation and signaling at the very earliest stages of Alzheimer disease followed by the progressive failure of autophagy. These abnormalities, which result in part from Alzheimer-related genes acting directly on these lysosomal pathways, contribute to the development of each of the Alzheimer neuropathological hallmarks and represent a promising therapeutic target.

  15. The Ubiquitin Proteasome System Plays a Role in Venezuelan Equine Encephalitis Virus Infection

    PubMed Central

    Amaya, Moushimi; Keck, Forrest; Lindquist, Michael; Voss, Kelsey; Scavone, Lauren; Kehn-Hall, Kylene; Roberts, Brian; Bailey, Charles; Schmaljohn, Connie; Narayanan, Aarthi

    2015-01-01

    Many viruses have been implicated in utilizing or modulating the Ubiquitin Proteasome System (UPS) to enhance viral multiplication and/or to sustain a persistent infection. The mosquito-borne Venezuelan equine encephalitis virus (VEEV) belongs to the Togaviridae family and is an important biodefense pathogen and select agent. There are currently no approved vaccines or therapies for VEEV infections; therefore, it is imperative to identify novel targets for therapeutic development. We hypothesized that a functional UPS is required for efficient VEEV multiplication. We have shown that at non-toxic concentrations Bortezomib, a FDA-approved inhibitor of the proteasome, proved to be a potent inhibitor of VEEV multiplication in the human astrocytoma cell line U87MG. Bortezomib inhibited the virulent Trinidad donkey (TrD) strain and the attenuated TC-83 strain of VEEV. Additional studies with virulent strains of Eastern equine encephalitis virus (EEEV) and Western equine encephalitis virus (WEEV) demonstrated that Bortezomib is a broad spectrum inhibitor of the New World alphaviruses. Time-of-addition assays showed that Bortezomib was an effective inhibitor of viral multiplication even when the drug was introduced many hours post exposure to the virus. Mass spectrometry analyses indicated that the VEEV capsid protein is ubiquitinated in infected cells, which was validated by confocal microscopy and immunoprecipitation assays. Subsequent studies revealed that capsid is ubiquitinated on K48 during early stages of infection which was affected by Bortezomib treatment. This study will aid future investigations in identifying host proteins as potential broad spectrum therapeutic targets for treating alphavirus infections. PMID:25927990

  16. The ubiquitin proteasome system plays a role in venezuelan equine encephalitis virus infection.

    PubMed

    Amaya, Moushimi; Keck, Forrest; Lindquist, Michael; Voss, Kelsey; Scavone, Lauren; Kehn-Hall, Kylene; Roberts, Brian; Bailey, Charles; Schmaljohn, Connie; Narayanan, Aarthi

    2015-01-01

    Many viruses have been implicated in utilizing or modulating the Ubiquitin Proteasome System (UPS) to enhance viral multiplication and/or to sustain a persistent infection. The mosquito-borne Venezuelan equine encephalitis virus (VEEV) belongs to the Togaviridae family and is an important biodefense pathogen and select agent. There are currently no approved vaccines or therapies for VEEV infections; therefore, it is imperative to identify novel targets for therapeutic development. We hypothesized that a functional UPS is required for efficient VEEV multiplication. We have shown that at non-toxic concentrations Bortezomib, a FDA-approved inhibitor of the proteasome, proved to be a potent inhibitor of VEEV multiplication in the human astrocytoma cell line U87MG. Bortezomib inhibited the virulent Trinidad donkey (TrD) strain and the attenuated TC-83 strain of VEEV. Additional studies with virulent strains of Eastern equine encephalitis virus (EEEV) and Western equine encephalitis virus (WEEV) demonstrated that Bortezomib is a broad spectrum inhibitor of the New World alphaviruses. Time-of-addition assays showed that Bortezomib was an effective inhibitor of viral multiplication even when the drug was introduced many hours post exposure to the virus. Mass spectrometry analyses indicated that the VEEV capsid protein is ubiquitinated in infected cells, which was validated by confocal microscopy and immunoprecipitation assays. Subsequent studies revealed that capsid is ubiquitinated on K48 during early stages of infection which was affected by Bortezomib treatment. This study will aid future investigations in identifying host proteins as potential broad spectrum therapeutic targets for treating alphavirus infections.

  17. Melatonin-induced temporal up-regulation of gene expression related to ubiquitin/proteasome system (UPS) in the human malaria parasite Plasmodium falciparum.

    PubMed

    Koyama, Fernanda C; Azevedo, Mauro F; Budu, Alexandre; Chakrabarti, Debopam; Garcia, Célia R S

    2014-12-03

    There is an increasing understanding that melatonin and the ubiquitin/ proteasome system (UPS) interact to regulate multiple cellular functions. Post-translational modifications such as ubiquitination are important modulators of signaling processes, cell cycle and many other cellular functions. Previously, we reported a melatonin-induced upregulation of gene expression related to ubiquitin/proteasome system (UPS) in Plasmodium falciparum, the human malaria parasite, and that P. falciparum protein kinase 7 influences this process. This implies a role of melatonin, an indolamine, in modulating intraerythrocytic development of the parasite. In this report we demonstrate by qPCR analysis, that melatonin induces gene upregulation in nine out of fourteen genes of the UPS, consisting of the same set of genes previously reported, between 4 to 5 h after melatonin treatment. We demonstrate that melatonin causes a temporally controlled gene expression of UPS members.

  18. Remodelling of the ubiquitin-proteasome system in response to interferons.

    PubMed

    Seifert, Ulrike; Krüger, Elke

    2008-10-01

    Peptide generation by the UPS (ubiquitin-proteasome system) is rate-limiting in MHC class I-restricted antigen presentation in response to virus-induced IFNs (interferons). In this process, the role of IFN-induced rapid remodelling of the UPS is less defined. IFN-mediated de novo formation of different proteasome compositions as i20S (immunoproteasomes) or m20S (mixed-type proteasomes) essentially supports the rapid adjustment of the mammalian immune system to pathogens. This adjustment is of particular importance for the immune response to rapidly replicating viruses. In agreement, i20S formation has been shown to be an accelerated and transient response. Moreover, i20S and/or PA28 (proteasome activator 28) are essentially required for the generation of certain viral epitopes. In the present paper, we discuss how IFNs consecutively regulate the UPS at different levels, thereby improving the immune responsiveness of target cells.

  19. Effect of ionizing radiation exposure on Trypanosoma cruzi ubiquitin-proteasome system.

    PubMed

    Cerqueira, Paula G; Passos-Silva, Danielle G; Vieira-da-Rocha, João P; Mendes, Isabela Cecilia; de Oliveira, Karla A; Oliveira, Camila F B; Vilela, Liza F F; Nagem, Ronaldo A P; Cardoso, Joseane; Nardelli, Sheila C; Krieger, Marco A; Franco, Glória R; Macedo, Andrea M; Pena, Sérgio D J; Schenkman, Sérgio; Gomes, Dawidson A; Guerra-Sá, Renata; Machado, Carlos R

    2017-03-01

    In recent years, proteasome involvement in the damage response induced by ionizing radiation (IR) became evident. However, whether proteasome plays a direct or indirect role in IR-induced damage response still unclear. Trypanosoma cruzi is a human parasite capable of remarkable high tolerance to IR, suggesting a highly efficient damage response system. Here, we investigate the role of T. cruzi proteasome in the damage response induced by IR. We exposed epimastigotes to high doses of gamma ray and we analyzed the expression and subcellular localization of several components of the ubiquitin-proteasome system. We show that proteasome inhibition increases IR-induced cell growth arrest and proteasome-mediated proteolysis is altered after parasite exposure. We observed nuclear accumulation of 19S and 20S proteasome subunits in response to IR treatments. Intriguingly, the dynamic of 19S particle nuclear accumulation was more similar to the dynamic observed for Rad51 nuclear translocation than the observed for 20S. In the other hand, 20S increase and nuclear translocation could be related with an increase of its regulator PA26 and high levels of proteasome-mediated proteolysis in vitro. The intersection between the opposed peaks of 19S and 20S protein levels was marked by nuclear accumulation of both 20S and 19S together with Ubiquitin, suggesting a role of ubiquitin-proteasome system in the nuclear protein turnover at the time. Our results revealed the importance of proteasome-mediated proteolysis in T. cruzi IR-induced damage response suggesting that proteasome is also involved in T. cruzi IR tolerance. Moreover, our data support the possible direct/signaling role of 19S in DNA damage repair. Based on these results, we speculate that spatial and temporal differences between the 19S particle and 20S proteasome controls proteasome multiple roles in IR damage response.

  20. On the linkage between the ubiquitin-proteasome system and the mitochondria.

    PubMed

    Lehmann, Gilad; Udasin, Ronald G; Ciechanover, Aaron

    2016-04-22

    Several metabolic pathways critical for cellular homeostasis occur in the mitochondria. Because of the evolution of mitochondria and their physical separation, these pathways have traditionally been thought to be free from regulation by the ubiquitin-proteasome system. This perception has recently been challenged by evidence for the presence of ubiquitin system components in the mitochondria. Furthermore, it has been shown that certain mitochondrial proteins are conjugated by ubiquitin, and some of them are degraded by the proteasome. Of particular interest is the finding that some of these proteins are localized to the inner membrane and matrix, which rules out that their targeting is mediated by the cytosolic ubiquitin system. However, the extent of the involvement of the ubiquitin system in mitochondrial regulation is not known. The present study addresses this surprising finding, employing several independent approaches. First, we identified reported ubiquitin conjugates in human and yeast mitochondria and found that a large fraction of the mitochondrial proteome (62% in human) is ubiquitinated, with most proteins localized to the inner membrane and matrix. Next, we searched the literature and found that numerous ubiquitin system components localize to the mitochondria and/or contain mitochondrial targeting sequences. Finally, we identified reported protein-protein interactions between ubiquitin system components and mitochondrial proteins. These unexpected findings suggest that mitochondrial regulation by the ubiquitin system is fundamental and may have broad biomedical implications.

  1. Measuring activity in the ubiquitin-proteasome system: from large scale discoveries to single cells analysis.

    PubMed

    Melvin, Adam T; Woss, Gregery S; Park, Jessica H; Waters, Marcey L; Allbritton, Nancy L

    2013-09-01

    The ubiquitin-proteasome system (UPS) is the primary pathway responsible for the recognition and degradation of misfolded, damaged, or tightly regulated proteins in addition to performing essential roles in DNA repair, cell cycle regulation, cell migration, and the immune response. While traditional biochemical techniques have proven useful in the identification of key proteins involved in this pathway, the implementation of novel reporters responsible for measuring enzymatic activity of the UPS has provided valuable insight into the effectiveness of therapeutics and role of the UPS in various human diseases such as multiple myeloma and Huntington's disease. These reporters, usually consisting of a recognition sequence fused to an analytical handle, are designed to specifically evaluate enzymatic activity of certain members of the UPS including the proteasome, E3 ubiquitin ligases, and deubiquitinating enzymes. This review highlights the more commonly used reporters employed in a variety of scenarios ranging from high-throughput screening of novel inhibitors to single cell microscopy techniques measuring E3 ligase or proteasome activity. Finally, a recent study is presented highlighting the development of a novel degron-based substrate designed to overcome the limitations of current reporting techniques in measuring E3 ligase and proteasome activity in patient samples.

  2. Oxidation matters: the ubiquitin proteasome system connects innate immune mechanisms with MHC class I antigen presentation.

    PubMed

    Warnatsch, Annika; Bergann, Theresa; Krüger, Elke

    2013-09-01

    During innate immune responses the delicate balance of protein synthesis, quality control and degradation is severely challenged by production of radicals and/or the massive synthesis of pathogen proteins. The regulated degradation of ubiquitin-tagged proteins by the ubiquitin proteasome system (UPS) represents one major pathway for the maintenance of cellular proteostasis and regulatory processes under these conditions. In addition, MHC class I antigen presentation is strictly dependent on an appropriate peptide supply by the UPS to efficiently prime CD8(+) T cells and to initiate an adaptive immune response. We here discuss recent efforts in defining the link between innate immune mechanisms like cytokine and ROS production, the induction of an efficient adaptive immune response and the specific involvement of the UPS therein. Cytokines and/or infections induce translation and the production of free radicals, which in turn confer oxidative damage to nascent as well as folded proteins. In parallel, the same signaling cascades are able to accelerate the protein turnover by the concomitantly induced ubiquitin conjugation and degradation of such damaged polypeptides by immunoproteasomes. The ability of immunoproteasomes to efficiently degrade such oxidant-damaged ubiquitylated proteins protects cells from accumulating toxic ubiquitin-rich aggregates. At the same time, this innate immune mechanism facilitates a sufficient peptide supply for MHC class I antigen presentation and connects it to initiation of adaptive immunity.

  3. Novel strategies to target the ubiquitin proteasome system in multiple myeloma

    PubMed Central

    Lub, Susanne; Maes, Ken; Menu, Eline; De Bruyne, Elke; Vanderkerken, Karin; Van Valckenborgh, Els

    2016-01-01

    Multiple myeloma (MM) is a hematological malignancy characterized by the accumulation of plasma cells in the bone marrow (BM). The success of the proteasome inhibitor bortezomib in the treatment of MM highlights the importance of the ubiquitin proteasome system (UPS) in this particular cancer. Despite the prolonged survival of MM patients, a significant amount of patients relapse or become resistant to therapy. This underlines the importance of the development and investigation of novel targets to improve MM therapy. The UPS plays an important role in different cellular processes by targeted destruction of proteins. The ubiquitination process consists of enzymes that transfer ubiquitin to proteins targeting them for proteasomal degradation. An emerging and promising approach is to target more disease specific components of the UPS to reduce side effects and overcome resistance. In this review, we will focus on different components of the UPS such as the ubiquitin activating enzyme E1, the ubiquitin conjugating enzyme E2, the E3 ubiquitin ligases, the deubiquitinating enzymes (DUBs) and the proteasome. We will discuss their role in MM and the implications in drug discovery for the treatment of MM. PMID:26695547

  4. Tripartite degrons confer diversity and specificity on regulated protein degradation in the ubiquitin-proteasome system

    PubMed Central

    Guharoy, Mainak; Bhowmick, Pallab; Sallam, Mohamed; Tompa, Peter

    2016-01-01

    Specific signals (degrons) regulate protein turnover mediated by the ubiquitin-proteasome system. Here we systematically analyse known degrons and propose a tripartite model comprising the following: (1) a primary degron (peptide motif) that specifies substrate recognition by cognate E3 ubiquitin ligases, (2) secondary site(s) comprising a single or multiple neighbouring ubiquitinated lysine(s) and (3) a structurally disordered segment that initiates substrate unfolding at the 26S proteasome. Primary degron sequences are conserved among orthologues and occur in structurally disordered regions that undergo E3-induced folding-on-binding. Posttranslational modifications can switch primary degrons into E3-binding-competent states, thereby integrating degradation with signalling pathways. Degradation-linked lysines tend to be located within disordered segments that also initiate substrate degradation by effective proteasomal engagement. Many characterized mutations and alternative isoforms with abrogated degron components are implicated in disease. These effects result from increased protein stability and interactome rewiring. The distributed nature of degrons ensures regulation, specificity and combinatorial control of degradation. PMID:26732515

  5. Involvement of protein degradation by the ubiquitin proteasome system in opiate addictive behaviors.

    PubMed

    Massaly, Nicolas; Dahan, Lionel; Baudonnat, Mathieu; Hovnanian, Caroline; Rekik, Khaoula; Solinas, Marcello; David, Vincent; Pech, Stéphane; Zajac, Jean-Marie; Roullet, Pascal; Mouledous, Lionel; Frances, Bernard

    2013-03-01

    Plastic changes in the nucleus accumbens (NAcc), a structure occupying a key position in the neural circuitry related to motivation, are among the critical cellular processes responsible for drug addiction. During the last decade, it has been shown that memory formation and related neuronal plasticity may rely not only on protein synthesis but also on protein degradation by the ubiquitin proteasome system (UPS). In this study, we assess the role of protein degradation in the NAcc in opiate-related behaviors. For this purpose, we coupled behavioral experiments to intra-accumbens injections of lactacystin, an inhibitor of the UPS. We show that protein degradation in the NAcc is mandatory for a full range of animal models of opiate addiction including morphine locomotor sensitization, morphine conditioned place preference, intra-ventral tegmental area morphine self-administration and intra-venous heroin self-administration but not for discrimination learning rewarded by highly palatable food. This study provides the first evidence of a specific role of protein degradation by the UPS in addiction.

  6. It Is All about (U)biquitin: Role of Altered Ubiquitin-Proteasome System and UCHL1 in Alzheimer Disease.

    PubMed

    Tramutola, Antonella; Di Domenico, Fabio; Barone, Eugenio; Perluigi, Marzia; Butterfield, D Allan

    2016-01-01

    Free radical-mediated damage to macromolecules and the resulting oxidative modification of different cellular components are a common feature of aging, and this process becomes much more pronounced in age-associated pathologies, including Alzheimer disease (AD). In particular, proteins are particularly sensitive to oxidative stress-induced damage and these irreversible modifications lead to the alteration of protein structure and function. In order to maintain cell homeostasis, these oxidized/damaged proteins have to be removed in order to prevent their toxic accumulation. It is generally accepted that the age-related accumulation of "aberrant" proteins results from both the increased occurrence of damage and the decreased efficiency of degradative systems. One of the most important cellular proteolytic systems responsible for the removal of oxidized proteins in the cytosol and in the nucleus is the proteasomal system. Several studies have demonstrated the impairment of the proteasome in AD thus suggesting a direct link between accumulation of oxidized/misfolded proteins and reduction of this clearance system. In this review we discuss the impairment of the proteasome system as a consequence of oxidative stress and how this contributes to AD neuropathology. Further, we focus the attention on the oxidative modifications of a key component of the ubiquitin-proteasome pathway, UCHL1, which lead to the impairment of its activity.

  7. Mechanisms stimulating muscle wasting in chronic kidney disease: the roles of the ubiquitin-proteasome system and myostatin.

    PubMed

    Thomas, Sandhya S; Mitch, William E

    2013-04-01

    Catabolic conditions including chronic kidney disease (CKD), cancer, and diabetes cause muscle atrophy. The loss of muscle mass worsens the burden of disease because it is associated with increased morbidity and mortality. To avoid these problems or to develop treatment strategies, the mechanisms leading to muscle wasting must be identified. Specific mechanisms uncovered in CKD generally occur in other catabolic conditions. These include stimulation of protein degradation in muscle arising from activation of caspase-3 and the ubiquitin-proteasome system (UPS). These proteases act in a coordinated fashion with caspase-3 initially cleaving the complex structure of proteins in muscle, yielding fragments that are substrates that are degraded by the UPS. Fortunately, the UPS exhibits remarkable specificity for proteins to be degraded because it is the major intracellular proteolytic system. Without a high level of specificity cellular functions would be disrupted. The specificity is accomplished by complex reactions that depend on recognition of a protein substrate by specific E3 ubiquitin ligases. In muscle, the specific ligases are Atrogin-1 and MuRF-1, and their expression has characteristics of a biomarker of accelerated muscle proteolysis. Specific complications of CKD (metabolic acidosis, insulin resistance, inflammation, and angiotensin II) activate caspase-3 and the UPS through mechanisms that include glucocorticoids and impaired insulin or IGF-1 signaling. Mediators activate myostatin, which functions as a negative growth factor in muscle. In models of cancer or CKD, strategies that block myostatin prevent muscle wasting, suggesting that therapies that block myostatin could prevent muscle wasting in catabolic conditions.

  8. Protein degradation by ubiquitin-proteasome system in formation and labilization of contextual conditioning memory.

    PubMed

    Sol Fustiñana, María; de la Fuente, Verónica; Federman, Noel; Freudenthal, Ramiro; Romano, Arturo

    2014-09-01

    The ubiquitin-proteasome system (UPS) of protein degradation has been evaluated in different forms of neural plasticity and memory. The role of UPS in such processes is controversial. Several results support the idea that the activation of this system in memory consolidation is necessary to overcome negative constrains for plasticity. In this case, the inhibition of the UPS during consolidation impairs memory. Similar results were reported for memory reconsolidation. However, in other cases, the inhibition of UPS had no effect on memory consolidation and reconsolidation but impedes the amnesic action of protein synthesis inhibition after retrieval. The last finding suggests a specific action of the UPS inhibitor on memory labilization. However, another interpretation is possible in terms of the synthesis/degradation balance of positive and negative elements in neural plasticity, as was found in the case of long-term potentiation. To evaluate these alternative interpretations, other reconsolidation-interfering drugs than translation inhibitors should be tested. Here we analyzed initially the UPS inhibitor effect in contextual conditioning in crabs. We found that UPS inhibition during consolidation impaired long-term memory. In contrast, UPS inhibition did not affect memory reconsolidation after contextual retrieval but, in fact, impeded memory labilization, blocking the action of drugs that does not affect directly the protein synthesis. To extend these finding to vertebrates, we performed similar experiments in contextual fear memory in mice. We found that the UPS inhibitor in hippocampus affected memory consolidation and blocked memory labilization after retrieval. These findings exclude alternative interpretations to the requirement of UPS in memory labilization and give evidence of this mechanism in both vertebrates and invertebrates.

  9. Multiple Interactions between Peroxisome Proliferators-Activated Receptors and the Ubiquitin-Proteasome System and Implications for Cancer Pathogenesis

    PubMed Central

    Genini, Davide; Carbone, Giuseppina M.; Catapano, Carlo V.

    2008-01-01

    The peroxisome proliferator-activated receptors (PPAR) α, β/δ, and γ are ligand-activated nuclear receptors involved in a number of physiological processes, including lipid and glucose homeostasis, inflammation, cell growth, differentiation, and death. PPAR agonists are used in the treatment of human diseases, like type 2 diabetes and dyslipidemia, and PPARs appear as promising therapeutic targets in other conditions, including cancer. A better understanding of the functions and regulation of PPARs in normal and pathological processes is of primary importance to devise appropriate therapeutic strategies. The ubiquitin-proteasome system (UPS) plays an important role in controlling level and activity of many nuclear receptors and transcription factors. PPARs are subjected to UPS-dependent regulation. Interestingly, the three PPAR isotypes are differentially regulated by the UPS in response to ligand-dependent activation, a phenomenon that may be intrinsically connected to their distinct cellular functions and behaviors. In addition to their effects ongene expression, PPARs appear to affect protein levels and downstream pathways also by modulating the activity of the UPS in target-specific manners. Here we review the current knowledge of the interactions between the UPS and PPARs in light of the potential implications for their effects on cell fate and tumorigenesis. PMID:18551186

  10. Regulation of autophagy and the ubiquitin-proteasome system by the FoxO transcriptional network during muscle atrophy.

    PubMed

    Milan, Giulia; Romanello, Vanina; Pescatore, Francesca; Armani, Andrea; Paik, Ji-Hye; Frasson, Laura; Seydel, Anke; Zhao, Jinghui; Abraham, Reimar; Goldberg, Alfred L; Blaauw, Bert; DePinho, Ronald A; Sandri, Marco

    2015-04-10

    Stresses like low nutrients, systemic inflammation, cancer or infections provoke a catabolic state characterized by enhanced muscle proteolysis and amino acid release to sustain liver gluconeogenesis and tissue protein synthesis. These conditions activate the family of Forkhead Box (Fox) O transcription factors. Here we report that muscle-specific deletion of FoxO members protects from muscle loss as a result of the role of FoxOs in the induction of autophagy-lysosome and ubiquitin-proteasome systems. Notably, in the setting of low nutrient signalling, we demonstrate that FoxOs are required for Akt activity but not for mTOR signalling. FoxOs control several stress-response pathways such as the unfolded protein response, ROS detoxification, DNA repair and translation. Finally, we identify FoxO-dependent ubiquitin ligases including MUSA1 and a previously uncharacterised ligase termed SMART (Specific of Muscle Atrophy and Regulated by Transcription). Our findings underscore the central function of FoxOs in coordinating a variety of stress-response genes during catabolic conditions.

  11. HSF-1 activates the ubiquitin proteasome system to promote non-apoptotic developmental cell death in C. elegans.

    PubMed

    Kinet, Maxime J; Malin, Jennifer A; Abraham, Mary C; Blum, Elyse S; Silverman, Melanie R; Lu, Yun; Shaham, Shai

    2016-03-08

    Apoptosis is a prominent metazoan cell death form. Yet, mutations in apoptosis regulators cause only minor defects in vertebrate development, suggesting that another developmental cell death mechanism exists. While some non-apoptotic programs have been molecularly characterized, none appear to control developmental cell culling. Linker-cell-type death (LCD) is a morphologically conserved non-apoptotic cell death process operating in Caenorhabditis elegans and vertebrate development, and is therefore a compelling candidate process complementing apoptosis. However, the details of LCD execution are not known. Here we delineate a molecular-genetic pathway governing LCD in C. elegans. Redundant activities of antagonistic Wnt signals, a temporal control pathway, and mitogen-activated protein kinase kinase signaling control heat shock factor 1 (HSF-1), a conserved stress-activated transcription factor. Rather than protecting cells, HSF-1 promotes their demise by activating components of the ubiquitin proteasome system, including the E2 ligase LET-70/UBE2D2 functioning with E3 components CUL-3, RBX-1, BTBD-2, and SIAH-1. Our studies uncover design similarities between LCD and developmental apoptosis, and provide testable predictions for analyzing LCD in vertebrates.

  12. HSF-1 activates the ubiquitin proteasome system to promote non-apoptotic developmental cell death in C. elegans

    PubMed Central

    Kinet, Maxime J; Malin, Jennifer A; Abraham, Mary C; Blum, Elyse S; Silverman, Melanie R; Lu, Yun; Shaham, Shai

    2016-01-01

    Apoptosis is a prominent metazoan cell death form. Yet, mutations in apoptosis regulators cause only minor defects in vertebrate development, suggesting that another developmental cell death mechanism exists. While some non-apoptotic programs have been molecularly characterized, none appear to control developmental cell culling. Linker-cell-type death (LCD) is a morphologically conserved non-apoptotic cell death process operating in Caenorhabditis elegans and vertebrate development, and is therefore a compelling candidate process complementing apoptosis. However, the details of LCD execution are not known. Here we delineate a molecular-genetic pathway governing LCD in C. elegans. Redundant activities of antagonistic Wnt signals, a temporal control pathway, and mitogen-activated protein kinase kinase signaling control heat shock factor 1 (HSF-1), a conserved stress-activated transcription factor. Rather than protecting cells, HSF-1 promotes their demise by activating components of the ubiquitin proteasome system, including the E2 ligase LET-70/UBE2D2 functioning with E3 components CUL-3, RBX-1, BTBD-2, and SIAH-1. Our studies uncover design similarities between LCD and developmental apoptosis, and provide testable predictions for analyzing LCD in vertebrates. DOI: http://dx.doi.org/10.7554/eLife.12821.001 PMID:26952214

  13. RAN translation at CGG repeats induces ubiquitin proteasome system impairment in models of fragile X-associated tremor ataxia syndrome.

    PubMed

    Oh, Seok Yoon; He, Fang; Krans, Amy; Frazer, Michelle; Taylor, J Paul; Paulson, Henry L; Todd, Peter K

    2015-08-01

    Fragile X-associated tremor ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by a CGG trinucleotide repeat expansion in the 5' UTR of the Fragile X gene, FMR1. FXTAS is thought to arise primarily from an RNA gain-of-function toxicity mechanism. However, recent studies demonstrate that the repeat also elicits production of a toxic polyglycine protein, FMRpolyG, via repeat-associated non-AUG (RAN)-initiated translation. Pathologically, FXTAS is characterized by ubiquitin-positive intranuclear neuronal inclusions, raising the possibility that failure of protein quality control pathways could contribute to disease pathogenesis. To test this hypothesis, we used Drosophila- and cell-based models of CGG-repeat-associated toxicity. In Drosophila, ubiquitin proteasome system (UPS) impairment led to enhancement of CGG-repeat-induced degeneration, whereas overexpression of the chaperone protein HSP70 suppressed this toxicity. In transfected mammalian cells, CGG repeat expression triggered accumulation of a UPS reporter in a length-dependent fashion. To delineate the contributions from CGG repeats as RNA from RAN translation-associated toxicity, we enhanced or impaired the production of FMRpolyG in these models. Driving expression of FMRpolyG enhanced induction of UPS impairment in cell models, while prevention of RAN translation attenuated UPS impairment in cells and suppressed the genetic interaction with UPS manipulation in Drosophila. Taken together, these findings suggest that CGG repeats induce UPS impairment at least in part through activation of RAN translation.

  14. The Ubiquitin-Proteasome Pathway and Synaptic Plasticity

    ERIC Educational Resources Information Center

    Hegde, Ashok N.

    2010-01-01

    Proteolysis by the ubiquitin-proteasome pathway (UPP) has emerged as a new molecular mechanism that controls wide-ranging functions in the nervous system, including fine-tuning of synaptic connections during development and synaptic plasticity in the adult organism. In the UPP, attachment of a small protein, ubiquitin, tags the substrates for…

  15. The Ubiquitin-Proteasome System: Potential Therapeutic Targets for Alzheimer’s Disease and Spinal Cord Injury

    PubMed Central

    Gong, Bing; Radulovic, Miroslav; Figueiredo-Pereira, Maria E.; Cardozo, Christopher

    2016-01-01

    The ubiquitin-proteasome system (UPS) is a crucial protein degradation system in eukaryotes. Herein, we will review advances in the understanding of the role of several proteins of the UPS in Alzheimer’s disease (AD) and functional recovery after spinal cord injury (SCI). The UPS consists of many factors that include E3 ubiquitin ligases, ubiquitin hydrolases, ubiquitin and ubiquitin-like molecules, and the proteasome itself. An extensive body of work links UPS dysfunction with AD pathogenesis and progression. More recently, the UPS has been shown to have vital roles in recovery of function after SCI. The ubiquitin hydrolase (Uch-L1) has been proposed to increase cellular levels of mono-ubiquitin and hence to increase rates of protein turnover by the UPS. A low Uch-L1 level has been linked with Aβ accumulation in AD and reduced neuroregeneration after SCI. One likely mechanism for these beneficial effects of Uch-L1 is reduced turnover of the PKA regulatory subunit and consequently, reduced signaling via CREB. The neuron-specific F-box protein Fbx2 ubiquitinates β-secretase thus targeting it for proteasomal degradation and reducing generation of Aβ. Both Uch-L1 and Fbx2 improve synaptic plasticity and cognitive function in mouse AD models. The role of Fbx2 after SCI has not been examined, but abolishing ß-secretase reduces neuronal recovery after SCI, associated with reduced myelination. UBB+1, which arises through a frame-shift mutation in the ubiquitin gene that adds 19 amino acids to the C-terminus of ubiquitin, inhibits proteasomal function and is associated with increased neurofibrillary tangles in patients with AD, Pick’s disease and Down’s syndrome. These advances in understanding of the roles of the UPS in AD and SCI raise new questions but, also, identify attractive and exciting targets for potential, future therapeutic interventions. PMID:26858599

  16. Mechanisms Stimulating Muscle Wasting in Chronic Kidney Disease: The Roles of the Ubiquitin-Proteasome System and Myostatin

    PubMed Central

    Thomas, Sandhya S.; Mitch, William E.

    2013-01-01

    Catabolic conditions including chronic kidney disease (CKD), cancer, and diabetes cause muscle atrophy. The loss of muscle mass worsens the burden of disease because it is associated with increased morbidity and mortality. To avoid these problems or to develop treatment strategies, the mechanisms leading to muscle wasting must be identified. Specific mechanisms uncovered in CKD generally occur in other catabolic conditions. These include stimulation of protein degradation in muscle arising from activation of caspase-3 and the ubiquitin-proteasome system (UPS). These proteases act in a coordinated fashion with caspase-3 initially cleaving the complex structure of proteins in muscle yielding fragments that are substrates which are degraded by the UPS. Fortunately, the UPS exhibits remarkable specificity for proteins to be degraded because it is the major intracellular proteolytic system. Without a high level of specificity cellular functions would be disrupted. The specificity is accomplished by complex reactions that depend on recognition of a protein substrate by specific E3 ubiquitin ligases. In muscle, the specific ligases are Atrogin-1 and MuRF1 and their expression has characteristics of a biomarker of accelerated muscle proteolysis. Specific complications of CKD (metabolic acidosis, insulin resistance, inflammation, and angiotensin II) activate caspase-3 and the UPS through mechanisms that include glucocorticoids and impaired insulin or IGF-1 signaling. Mediators activate myostatin which functions as a negative growth factor in muscle. In models of cancer or CKD, strategies that block myostatin prevent muscle wasting suggesting that therapies which block myostatin could prevent muscle wasting in catabolic conditions. PMID:23292175

  17. Prefoldin Subunits Are Protected from Ubiquitin-Proteasome System-mediated Degradation by Forming Complex with Other Constituent Subunits*

    PubMed Central

    Miyazawa, Makoto; Tashiro, Erika; Kitaura, Hirotake; Maita, Hiroshi; Suto, Hiroo; Iguchi-Ariga, Sanae M. M.; Ariga, Hiroyoshi

    2011-01-01

    The molecular chaperone prefoldin (PFD) is a complex comprised of six different subunits, PFD1-PFD6, and delivers newly synthesized unfolded proteins to cytosolic chaperonin TRiC/CCT to facilitate the folding of proteins. PFD subunits also have functions different from the function of the PFD complex. We previously identified MM-1α/PFD5 as a novel c-Myc-binding protein and found that MM-1α suppresses transformation activity of c-Myc. However, it remains unclear how cells regulate protein levels of individual subunits and what mechanisms alter the ratio of their activities between subunits and their complex. In this study, we found that knockdown of one subunit decreased protein levels of other subunits and that transfection of five subunits other than MM-1α into cells increased the level of endogenous MM-1α. We also found that treatment of cells with MG132, a proteasome inhibitor, increased the level of transfected/overexpressed MM-1α but not that of endogenous MM-1α, indicating that overexpressed MM-1α, but not endogenous MM-1α, was degraded by the ubiquitin proteasome system (UPS). Experiments using other PFD subunits showed that the UPS degraded a monomer of PFD subunits, though extents of degradation varied among subunits. Furthermore, the level of one subunit was increased after co-transfection with the respective subunit, indicating that there are specific combinations between subunits to be stabilized. These results suggest mutual regulation of protein levels among PFD subunits and show how individual subunits form the PFD complex without degradation. PMID:21478150

  18. Prefoldin subunits are protected from ubiquitin-proteasome system-mediated degradation by forming complex with other constituent subunits.

    PubMed

    Miyazawa, Makoto; Tashiro, Erika; Kitaura, Hirotake; Maita, Hiroshi; Suto, Hiroo; Iguchi-Ariga, Sanae M M; Ariga, Hiroyoshi

    2011-06-03

    The molecular chaperone prefoldin (PFD) is a complex comprised of six different subunits, PFD1-PFD6, and delivers newly synthesized unfolded proteins to cytosolic chaperonin TRiC/CCT to facilitate the folding of proteins. PFD subunits also have functions different from the function of the PFD complex. We previously identified MM-1α/PFD5 as a novel c-Myc-binding protein and found that MM-1α suppresses transformation activity of c-Myc. However, it remains unclear how cells regulate protein levels of individual subunits and what mechanisms alter the ratio of their activities between subunits and their complex. In this study, we found that knockdown of one subunit decreased protein levels of other subunits and that transfection of five subunits other than MM-1α into cells increased the level of endogenous MM-1α. We also found that treatment of cells with MG132, a proteasome inhibitor, increased the level of transfected/overexpressed MM-1α but not that of endogenous MM-1α, indicating that overexpressed MM-1α, but not endogenous MM-1α, was degraded by the ubiquitin proteasome system (UPS). Experiments using other PFD subunits showed that the UPS degraded a monomer of PFD subunits, though extents of degradation varied among subunits. Furthermore, the level of one subunit was increased after co-transfection with the respective subunit, indicating that there are specific combinations between subunits to be stabilized. These results suggest mutual regulation of protein levels among PFD subunits and show how individual subunits form the PFD complex without degradation.

  19. Contribution of the autophagy-lysosomal and ubiquitin-proteasomal proteolytic systems to total proteolysis in rainbow trout (Oncorhynchus mykiss) myotubes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Two major proteolytic systems are thought to (co-) operate in the skeletal muscle of vertebrates, the ubiquitin-proteasomal system (UPS) and the autophagic/lysosomal system (ALS). While their relative contribution to muscle loss has been already well documented in mammals, little is known in fish sp...

  20. Effects of titanium dioxide nanoparticles on α-synuclein aggregation and the ubiquitin-proteasome system in dopaminergic neurons.

    PubMed

    Wu, Jie; Xie, Hongjun

    2016-01-01

    Dopaminergic neurons (PC12 cells) were treated with different doses of titanium dioxide nanoparticles (TiO2-NPs), to investigate their effects on α-Synuclein (α-Syn) aggregation and their mechanism of action. Western blotting and immunofluorescent staining were performed. Exposure to TiO2-NPs increased α-Syn expression (p < 0.05) and induced dose-dependent α-Syn aggregation. Pretreatment with N-acetylcysteine partially inhibited α-Syn expression induced by a 200 μg/ml dose of TiO2-NPs. TiO2-NPs reduced the expressions of parkin and ubiquitin C-terminal hydrolase protein, and were associated with oxidative stress in PC12 cells. Dysfunction of the ubiquitin-proteasome system also contributed to α-Syn aggregation. The potentially neurotoxic TiO2-NPs may cause Parkinson's disease.

  1. Eukaryotic Cells Producing Ribosomes Deficient in Rpl1 Are Hypersensitive to Defects in the Ubiquitin-Proteasome System

    PubMed Central

    McIntosh, Kerri B.; Bhattacharya, Arpita; Willis, Ian M.; Warner, Jonathan R.

    2011-01-01

    It has recently become clear that the misassembly of ribosomes in eukaryotic cells can have deleterious effects that go far beyond a simple shortage of ribosomes. In this work we find that cells deficient in ribosomal protein L1 (Rpl1; Rpl10a in mammals) produce ribosomes lacking Rpl1 that are exported to the cytoplasm and that can be incorporated into polyribosomes. The presence of such defective ribosomes leads to slow growth and appears to render the cells hypersensitive to lesions in the ubiquitin-proteasome system. Several genes that were reasonable candidates for degradation of 60S subunits lacking Rpl1 fail to do so, suggesting that key players in the surveillance of ribosomal subunits remain to be found. Interestingly, in spite of rendering the cells hypersensitive to the proteasome inhibitor MG132, shortage of Rpl1 partially suppresses the stress-invoked temporary repression of ribosome synthesis caused by MG132. PMID:21858174

  2. Eukaryotic cells producing ribosomes deficient in Rpl1 are hypersensitive to defects in the ubiquitin-proteasome system.

    PubMed

    McIntosh, Kerri B; Bhattacharya, Arpita; Willis, Ian M; Warner, Jonathan R

    2011-01-01

    It has recently become clear that the misassembly of ribosomes in eukaryotic cells can have deleterious effects that go far beyond a simple shortage of ribosomes. In this work we find that cells deficient in ribosomal protein L1 (Rpl1; Rpl10a in mammals) produce ribosomes lacking Rpl1 that are exported to the cytoplasm and that can be incorporated into polyribosomes. The presence of such defective ribosomes leads to slow growth and appears to render the cells hypersensitive to lesions in the ubiquitin-proteasome system. Several genes that were reasonable candidates for degradation of 60S subunits lacking Rpl1 fail to do so, suggesting that key players in the surveillance of ribosomal subunits remain to be found. Interestingly, in spite of rendering the cells hypersensitive to the proteasome inhibitor MG132, shortage of Rpl1 partially suppresses the stress-invoked temporary repression of ribosome synthesis caused by MG132.

  3. Role of the Ubiquitin-Proteasome Systems in the Biology and Virulence of Protozoan Parasites.

    PubMed

    Muñoz, Christian; San Francisco, Juan; Gutiérrez, Bessy; González, Jorge

    2015-01-01

    In eukaryotic cells, proteasomes perform crucial roles in many cellular pathways by degrading proteins to enforce quality control and regulate many cellular processes such as cell cycle progression, signal transduction, cell death, immune responses, metabolism, protein-quality control, and development. The catalytic heart of these complexes, the 20S proteasome, is highly conserved in bacteria, yeast, and humans. However, until a few years ago, the role of proteasomes in parasite biology was completely unknown. Here, we summarize findings about the role of proteasomes in protozoan parasites biology and virulence. Several reports have confirmed the role of proteasomes in parasite biological processes such as cell differentiation, cell cycle, proliferation, and encystation. Proliferation and cell differentiation are key steps in host colonization. Considering the importance of proteasomes in both processes in many different parasites such as Trypanosoma, Leishmania, Toxoplasma, and Entamoeba, parasite proteasomes might serve as virulence factors. Several pieces of evidence strongly suggest that the ubiquitin-proteasome pathway is also a viable parasitic therapeutic target. Research in recent years has shown that the proteasome is a valid drug target for sleeping sickness and malaria. Then, proteasomes are a key organelle in parasite biology and virulence and appear to be an attractive new chemotherapeutic target.

  4. Role of the Ubiquitin-Proteasome Systems in the Biology and Virulence of Protozoan Parasites

    PubMed Central

    Muñoz, Christian; San Francisco, Juan; Gutiérrez, Bessy; González, Jorge

    2015-01-01

    In eukaryotic cells, proteasomes perform crucial roles in many cellular pathways by degrading proteins to enforce quality control and regulate many cellular processes such as cell cycle progression, signal transduction, cell death, immune responses, metabolism, protein-quality control, and development. The catalytic heart of these complexes, the 20S proteasome, is highly conserved in bacteria, yeast, and humans. However, until a few years ago, the role of proteasomes in parasite biology was completely unknown. Here, we summarize findings about the role of proteasomes in protozoan parasites biology and virulence. Several reports have confirmed the role of proteasomes in parasite biological processes such as cell differentiation, cell cycle, proliferation, and encystation. Proliferation and cell differentiation are key steps in host colonization. Considering the importance of proteasomes in both processes in many different parasites such as Trypanosoma, Leishmania, Toxoplasma, and Entamoeba, parasite proteasomes might serve as virulence factors. Several pieces of evidence strongly suggest that the ubiquitin-proteasome pathway is also a viable parasitic therapeutic target. Research in recent years has shown that the proteasome is a valid drug target for sleeping sickness and malaria. Then, proteasomes are a key organelle in parasite biology and virulence and appear to be an attractive new chemotherapeutic target. PMID:26090380

  5. Ubiquitin-proteasome system controls ciliogenesis at the initial step of axoneme extension.

    PubMed

    Kasahara, Kousuke; Kawakami, Yoshitaka; Kiyono, Tohru; Yonemura, Shigenobu; Kawamura, Yoshifumi; Era, Saho; Matsuzaki, Fumio; Goshima, Naoki; Inagaki, Masaki

    2014-10-01

    Primary cilia are microtubule-based sensory organelles that organize numerous key signals during developments and tissue homeostasis. Ciliary microtubule doublet, named axoneme, is grown directly from the distal end of mother centrioles through a multistep process upon cell cycle exit; however, the instructive signals that initiate these events are poorly understood. Here we show that ubiquitin-proteasome machinery removes trichoplein, a negative regulator of ciliogenesis, from mother centrioles and thereby causes Aurora-A inactivation, leading to ciliogenesis. Ciliogenesis is blocked if centriolar trichoplein is stabilized by treatment with proteasome inhibitors or by expression of non-ubiquitylatable trichoplein mutant (K50/57R). Started from two-stepped global E3 screening, we have identified KCTD17 as a substrate-adaptor for Cul3-RING E3 ligases (CRL3s) that polyubiquitylates trichoplein. Depletion of KCTD17 specifically arrests ciliogenesis at the initial step of axoneme extension through aberrant trichoplein-Aurora-A activity. Thus, CRL3-KCTD17 targets trichoplein to proteolysis to initiate the axoneme extension during ciliogenesis.

  6. Ubiquitin-proteasome pathway components as therapeutic targets for CNS maladies.

    PubMed

    Upadhya, Sudarshan C; Hegde, Ashok N

    2005-01-01

    In the central nervous system (CNS), abnormal deposition of insoluble protein aggregates or inclusion bodies within nerve cells is commonly observed in association with several neurodegenerative diseases. The ubiquitinated protein aggregates are believed to result from malfunction or overload of the ubiquitin-proteasome pathway or from structural changes in the protein substrates which prevent their recognition and degradation by the ubiquitin-proteasome pathway. Impaired proteolysis might also contribute to the synaptic dysfunction seen early in neurodegenerative diseases because the ubiquitin-proteasome pathway is known to play a role in normal functioning of synapses. Because specificity of the ubiquitin proteasome mediated proteolysis is determined by specific ubiquitin ligases (E3s), identification of specific E3s and their allosteric modulators are likely to provide effective therapeutic targets for the treatment of several CNS disorders. Another unexplored area for the discovery of drug targets is the proteasome. Although many inhibitors of the proteasome are available, no effective drugs exist that can stimulate the proteasome. Since abnormal protein aggregation is a common feature of different neurodegenerative diseases, enhancement of proteasome activity might be an efficient way to remove the aggregates that accumulate in the brain. In this review, we discuss how the components of the ubiquitin-proteasome pathway could be potential targets for therapy of CNS diseases and disorders.

  7. Sent to destroy: the ubiquitin proteasome system regulates cell signaling and protein quality control in cardiovascular development and disease.

    PubMed

    Willis, Monte S; Townley-Tilson, W H Davin; Kang, Eunice Y; Homeister, Jonathon W; Patterson, Cam

    2010-02-19

    The ubiquitin proteasome system (UPS) plays a crucial role in biological processes integral to the development of the cardiovascular system and cardiovascular diseases. The UPS prototypically recognizes specific protein substrates and places polyubiquitin chains on them for subsequent destruction by the proteasome. This system is in place to degrade not only misfolded and damaged proteins, but is essential also in regulating a host of cell signaling pathways involved in proliferation, adaptation to stress, regulation of cell size, and cell death. During the development of the cardiovascular system, the UPS regulates cell signaling by modifying transcription factors, receptors, and structural proteins. Later, in the event of cardiovascular diseases as diverse as atherosclerosis, cardiac hypertrophy, and ischemia/reperfusion injury, ubiquitin ligases and the proteasome are implicated in protecting and exacerbating clinical outcomes. However, when misfolded and damaged proteins are ubiquitinated by the UPS, their destruction by the proteasome is not always possible because of their aggregated confirmations. Recent studies have discovered how these ubiquitinated misfolded proteins can be destroyed by alternative "specific" mechanisms. The cytosolic receptors p62, NBR, and histone deacetylase 6 recognize aggregated ubiquitinated proteins and target them for autophagy in the process of "selective autophagy." Even the ubiquitination of multiple proteins within whole organelles that drive the more general macro-autophagy may be due, in part, to similar ubiquitin-driven mechanisms. In summary, the crosstalk between the UPS and autophagy highlight the pivotal and diverse roles the UPS plays in maintaining protein quality control and regulating cardiovascular development and disease.

  8. Regulation of mitochondrial genome inheritance by autophagy and ubiquitin-proteasome system: implications for health, fitness, and fertility.

    PubMed

    Song, Won-Hee; Ballard, John William Oman; Yi, Young-Joo; Sutovsky, Peter

    2014-01-01

    Mitochondria, the energy-generating organelles, play a role in numerous cellular functions including adenosine triphosphate (ATP) production, cellular homeostasis, and apoptosis. Maternal inheritance of mitochondria and mitochondrial DNA (mtDNA) is universally observed in humans and most animals. In general, high levels of mitochondrial heteroplasmy might contribute to a detrimental effect on fitness and disease resistance. Therefore, a disposal of the sperm-derived mitochondria inside fertilized oocytes assures normal preimplantation embryo development. Here we summarize the current research and knowledge concerning the role of autophagic pathway and ubiquitin-proteasome-dependent proteolysis in sperm mitophagy in mammals, including humans. Current data indicate that sperm mitophagy inside the fertilized oocyte could occur along multiple degradation routes converging on autophagic clearance of paternal mitochondria. The influence of assisted reproductive therapies (ART) such as intracytoplasmic sperm injection (ICSI), mitochondrial replacement (MR), and assisted fertilization of oocytes from patients of advanced reproductive age on mitochondrial function, inheritance, and fitness and for the development and health of ART babies will be of particular interest to clinical audiences. Altogether, the study of sperm mitophagy after fertilization has implications in the timing of evolution and developmental and reproductive biology and in human health, fitness, and management of mitochondrial disease.

  9. The Differential Profiling of Ubiquitin-Proteasome and Autophagy Systems in Different Tissues before the Onset of Huntington's Disease Models.

    PubMed

    Her, Lu-Shiun; Lin, Jian-Yu; Fu, Mu-Hui; Chang, Yu-Fan; Li, Chia-Ling; Tang, Ting-Yu; Jhang, Yu-Ling; Chang, Chih-Yi; Shih, Meng-Chi; Cheng, Pei-Hsun; Yang, Shang-Hsun

    2015-07-01

    Huntington's disease (HD) is a genetic and neurodegenerative disease, leading to motor and cognitive dysfunction in HD patients. At cellular level, this disease is caused by the accumulation of mutant huntingtin (HTT) in different cells, and finally results in the dysfunction of different cells. To clean these mutant proteins, ubiquitin-proteasome system (UPS) and autophagy system are two critical pathways in the brain; however, little is known in other peripheral tissues. As mutant HTT affects different tissues progressively and might influence the UPS and autophagy pathways at early stages, we attempted to examine two clearance systems in HD models before the onset. Here, in vitro results showed that the accumulation of UPS signals with time was observed obviously in neuroblastoma and kidney cells, not in other cells. In HD transgenic mice, we observed the impairment of UPS, but not autophagy, over time in the cortex and striatum. In heart and muscle tissues, disturbance of autophagy was observed, whereas dysfunction of UPS was displayed in liver and lung. These results suggest that two protein clearance pathways are disturbed differentially in different tissues before the onset of HD, and enhancement of protein clearance at early stages might provide a potential stratagem to alleviate the progression of HD.

  10. Myostatin Activates the Ubiquitin-Proteasome and Autophagy-Lysosome Systems Contributing to Muscle Wasting in Chronic Kidney Disease

    PubMed Central

    Wang, Dong-Tao; Yang, Ya-Jun; Huang, Ren-Hua; Zhang, Zhi-Hua; Lin, Xin

    2015-01-01

    Our evidence demonstrated that CKD upregulated the expression of myostatin, TNF-α, and p-IkBa and downregulated the phosphorylation of PI3K, Akt, and FoxO3a, which were also associated with protein degradation and muscle atrophy. The autophagosome formation and protein expression of autophagy-related genes were increased in muscle of CKD rats. The mRNA level and protein expression of MAFbx and MuRF-1 were also upregulated in CKD rats, as well as proteasome activity of 26S. Moreover, activation of myostatin elicited by TNF-α induces C2C12 myotube atrophy via upregulating the expression of autophagy-related genes, including MAFbx and MuRF1 and proteasome subunits. Inactivation of FoxO3a triggered by PI3K inhibitor LY294002 prevented the myostatin-induced increase of expression of MuRF1, MAFbx, and LC3-II protein in C2C12 myotubes. The findings were further consolidated by using siRNA interference and overexpression of myostatin. Additionally, expression of myostatin was activated by TNF-α via a NF-κB dependent pathway in C2C12 myotubes, while inhibition of NF-κB activity suppressed myostatin and improved myotube atrophy. Collectively, myostatin mediated CKD-induced muscle catabolism via coordinate activation of the autophagy and the ubiquitin-proteasome systems. PMID:26448817

  11. Sent to Destroy: The Ubiquitin Proteasome System Regulates Cell Signaling and Protein Quality Control in Cardiovascular Development and Disease

    PubMed Central

    Willis, Monte S.; Townley-Tilson, W.H. Davin; Kang, Eunice Y.; Homeister, Jonathon W.; Patterson, Cam

    2010-01-01

    The ubiquitin proteasome system (UPS) plays a crucial role in biological processes integral to the development of the cardiovascular system and cardiovascular diseases. The UPS prototypically recognizes specific protein substrates and places polyubiquitin chains on them for subsequent destruction by the proteasome. This system is in place to degrade not only misfolded and damaged proteins, but is essential also in regulating a host of cell signaling pathways involved in proliferation, adaptation to stress, regulation of cell size, and cell death. During the development of the cardiovascular system, the UPS regulates cell signaling by modifying transcription factors, receptors, and structural proteins. Later, in the event of cardiovascular diseases as diverse as atherosclerosis, cardiac hypertrophy, and ischemia reperfusion injury, ubiquitin ligases and the proteasome are implicated in protecting and exacerbating clinical outcomes. However, when misfolded and damaged proteins are ubiquitinated by the UPS, their destruction by the proteasome is not always possible due to their aggregated confirmations. Recent studies have discovered how these ubiquitinated misfolded proteins can be destroyed by alternative “specific” mechanisms. The cytosolic receptors p62, NBR, and HDAC6 recognize aggregated ubiquitinated proteins and target them for autophagy in the process of “selective autophagy”. Even the ubiquitination of multiple proteins within whole organelles that drive the more general macro-autophagy may be due, in part, to similar ubiquitin-driven mechanisms. In summary, the cross-talk between the UPS and autophagy highlight the pivotal and diverse roles the UPS plays in maintaining protein quality control and regulating cardiovascular development and disease. PMID:20167943

  12. Response of the Ubiquitin-Proteasome System to Memory Retrieval After Extended-Access Cocaine or Saline Self-Administration.

    PubMed

    Werner, Craig T; Milovanovic, Mike; Christian, Daniel T; Loweth, Jessica A; Wolf, Marina E

    2015-12-01

    The ubiquitin-proteasome system (UPS) has been implicated in the retrieval-induced destabilization of cocaine- and fear-related memories in Pavlovian paradigms. However, nothing is known about its role in memory retrieval after self-administration of cocaine, an operant paradigm, or how the length of withdrawal from cocaine may influence retrieval mechanisms. Here, we examined UPS activity after an extended-access cocaine self-administration regimen that leads to withdrawal-dependent incubation of cue-induced cocaine craving. Controls self-administered saline. In initial experiments, memory retrieval was elicited via a cue-induced seeking/retrieval test on withdrawal day (WD) 50-60, when craving has incubated. We found that retrieval of cocaine- and saline-associated memories produced similar increases in polyubiquitinated proteins in the nucleus accumbens (NAc), compared with rats that did not undergo a seeking/retrieval test. Measures of proteasome catalytic activity confirmed similar activation of the UPS after retrieval of saline and cocaine memories. However, in a subsequent experiment in which testing was conducted on WD1, proteasome activity in the NAc was greater after retrieval of cocaine memory than saline memory. Analysis of other brain regions confirmed that effects of cocaine memory retrieval on proteasome activity, relative to saline memory retrieval, depend on withdrawal time. These results, combined with prior studies, suggest that the relationship between UPS activity and memory retrieval depends on training paradigm, brain region, and time elapsed between training and retrieval. The observation that mechanisms underlying cocaine memory retrieval change depending on the age of the memory has implications for development of memory destabilization therapies for cue-induced relapse in cocaine addicts.

  13. Metabolomic Quantitative Trait Loci (mQTL) Mapping Implicates the Ubiquitin Proteasome System in Cardiovascular Disease Pathogenesis

    PubMed Central

    Kraus, William E.; Muoio, Deborah M.; Stevens, Robert; Craig, Damian; Bain, James R.; Grass, Elizabeth; Haynes, Carol; Kwee, Lydia; Qin, Xuejun; Slentz, Dorothy H.; Krupp, Deidre; Muehlbauer, Michael; Hauser, Elizabeth R.; Gregory, Simon G.; Newgard, Christopher B.; Shah, Svati H.

    2015-01-01

    Levels of certain circulating short-chain dicarboxylacylcarnitine (SCDA), long-chain dicarboxylacylcarnitine (LCDA) and medium chain acylcarnitine (MCA) metabolites are heritable and predict cardiovascular disease (CVD) events. Little is known about the biological pathways that influence levels of most of these metabolites. Here, we analyzed genetics, epigenetics, and transcriptomics with metabolomics in samples from a large CVD cohort to identify novel genetic markers for CVD and to better understand the role of metabolites in CVD pathogenesis. Using genomewide association in the CATHGEN cohort (N = 1490), we observed associations of several metabolites with genetic loci. Our strongest findings were for SCDA metabolite levels with variants in genes that regulate components of endoplasmic reticulum (ER) stress (USP3, HERC1, STIM1, SEL1L, FBXO25, SUGT1) These findings were validated in a second cohort of CATHGEN subjects (N = 2022, combined p = 8.4x10-6–2.3x10-10). Importantly, variants in these genes independently predicted CVD events. Association of genomewide methylation profiles with SCDA metabolites identified two ER stress genes as differentially methylated (BRSK2 and HOOK2). Expression quantitative trait loci (eQTL) pathway analyses driven by gene variants and SCDA metabolites corroborated perturbations in ER stress and highlighted the ubiquitin proteasome system (UPS) arm. Moreover, culture of human kidney cells in the presence of levels of fatty acids found in individuals with cardiometabolic disease, induced accumulation of SCDA metabolites in parallel with increases in the ER stress marker BiP. Thus, our integrative strategy implicates the UPS arm of the ER stress pathway in CVD pathogenesis, and identifies novel genetic loci associated with CVD event risk. PMID:26540294

  14. Nuclear protein quality is regulated by the ubiquitin-proteasome system through the activity of Ubc4 and San1 in fission yeast.

    PubMed

    Matsuo, Yuzy; Kishimoto, Hayafumi; Tanae, Katsuhiro; Kitamura, Kenji; Katayama, Satoshi; Kawamukai, Makoto

    2011-04-15

    Eukaryotic cells monitor and maintain protein quality through a set of protein quality control (PQC) systems whose role is to minimize the harmful effects of the accumulation of aberrant proteins. Although these PQC systems have been extensively studied in the cytoplasm, nuclear PQC systems are not well understood. The present work shows the existence of a nuclear PQC system mediated by the ubiquitin-proteasome system in the fission yeast Schizosaccharomyces pombe. Asf1-30, a mutant form of the histone chaperone Asf1, was used as a model substrate for the study of the nuclear PQC. A temperature-sensitive Asf1-30 protein localized to the nucleus was selectively degraded by the ubiquitin-proteasome system. The Asf1-30 mutant protein was highly ubiquitinated at higher temperatures, and it remained stable in an mts2-1 mutant, which lacks proteasome activity. The E2 enzyme Ubc4 was identified among 11 candidate proteins as the ubiquitin-conjugating enzyme in this system, and San1 was selected among 100 candidates as the ubiquitin ligase (E3) targeting Asf1-30 for degradation. San1, but not other nuclear E3s, showed specificity for the mutant nuclear Asf1-30, but did not show activity against wild-type Asf1. These data clearly showed that the aberrant nuclear protein was degraded by a defined set of E1-E2-E3 enzymes through the ubiquitin-proteasome system. The data also show, for the first time, the presence of a nuclear PQC system in fission yeast.

  15. Supplementation with l-carnitine downregulates genes of the ubiquitin proteasome system in the skeletal muscle and liver of piglets.

    PubMed

    Keller, J; Ringseis, R; Koc, A; Lukas, I; Kluge, H; Eder, K

    2012-01-01

    Supplementation of carnitine has been shown to improve performance characteristics such as protein accretion in growing pigs. The molecular mechanisms underlying this phenomenon are largely unknown. Based on recent results from DNA microchip analysis, we hypothesized that carnitine supplementation leads to a downregulation of genes of the ubiquitin proteasome system (UPS). The UPS is the most important system for protein breakdown in tissues, which in turn could be an explanation for increased protein accretion. To test this hypothesis, we fed sixteen male, four-week-old piglets either a control diet or the same diet supplemented with carnitine and determined the expression of several genes involved in the UPS in the liver and skeletal muscle. To further determine whether the effects of carnitine on the expression of genes of the UPS are mediated directly or indirectly, we also investigated the effect of carnitine on the expression of genes of the UPS in cultured C2C12 myotubes and HepG2 liver cells. In the liver of piglets fed the carnitine-supplemented diet, the relative mRNA levels of atrogin-1, E214k and Psma1 were lower than in those of the control piglets (P < 0.05). In skeletal muscle, the relative mRNA levels of atrogin-1, MuRF1, E214k, Psma1 and ubiquitin were lower in piglets fed the carnitine-supplemented diet than that in control piglets (P < 0.05). Incubating C2C12 myotubes and HepG2 liver cells with increasing concentrations of carnitine had no effect on basal and/or hydrocortisone-stimulated mRNA levels of genes of the UPS. In conclusion, this study shows that dietary carnitine decreases the transcript levels of several genes involved in the UPS in skeletal muscle and liver of piglets, whereas carnitine has no effect on the transcript levels of these genes in cultivated HepG2 liver cells and C2C12 myotubes. These data suggest that the inhibitory effect of carnitine on the expression of genes of the UPS is mediated indirectly, probably via modulating

  16. The Regulation of Tumor Suppressor p63 by the Ubiquitin-Proteasome System

    PubMed Central

    Armstrong, Stephen R.; Wu, Hong; Wang, Benfan; Abuetabh, Yasser; Sergi, Consolato; Leng, Roger P.

    2016-01-01

    The protein p63 has been identified as a homolog of the tumor suppressor protein p53 and is capable of inducing apoptosis, cell cycle arrest, or senescence. p63 has at least six isoforms, which can be divided into two major groups: the TAp63 variants that contain the N-terminal transactivation domain and the ΔNp63 variants that lack the N-terminal transactivation domain. The TAp63 variants are generally considered to be tumor suppressors involved in activating apoptosis and suppressing metastasis. ΔNp63 variants cannot induce apoptosis but can act as dominant negative inhibitors to block the function of TAp53, TAp73, and TAp63. p63 is rarely mutated in human tumors and is predominately regulated at the post-translational level by phosphorylation and ubiquitination. This review focuses primarily on regulation of p63 by the ubiquitin E-3 ligase family of enzymes via ubiquitination and proteasome-mediated degradation, and introduces a new key regulator of the p63 protein. PMID:27929429

  17. The role of the ubiquitin proteasome system in cerebellar development and medulloblastoma.

    PubMed

    Vriend, Jerry; Ghavami, Saeid; Marzban, Hassan

    2015-10-17

    Cerebellar granule cells precursors are derived from the upper rhombic lip and migrate tangentially independent of glia along the subpial stream pathway to form the external germinal zone. Postnatally, granule cells migrate from the external germinal zone radially through the Purkinje cell layer, guided by Bergmann glia fibers, to the internal granular cell layer.Medulloblastomas (MBs) are the most common malignant childhood brain tumor. Many of these tumors develop from precursor cells of the embryonic rhombic lips. Four main groups of MB are recognized. The WNT group of MBs arise primarily from the lower rhombic lip and embryonic brainstem. The SHH group of MBs originate from cerebellar granule cell precursors in the external germinal zone of the embryonic cerebellum. The cellular origins of type 3 and type 4 MBs are not clear.Several ubiquitin ligases are revealed to be significant factors in development of the cerebellum as well as in the initiation and maintenance of MBs. Proteasome dysfunction at a critical stage of development may be a major factor in determining whether progenitor cells which are destined to become granule cells differentiate normally or become MB cells. We propose the hypothesis that proteasomal activity is essential to regulate the critical transition between proliferating granule cells and differentiated granule cells and that proteasome dysfunction may lead to MB. Proteasome dysfunction could also account for various mutations in MBs resulting from deficiencies in DNA checkpoint and repair mechanisms prior to development of MBs.Data showing a role for the ubiquitin ligases β-TrCP, FBW7, Huwe1, and SKP2 in MBs suggest the possibility of a classification of MBs based on the expression (over expression or under expression) of specific ubiquitin ligases which function as oncogenes, tumor suppressors or cell cycle regulators.

  18. The role of the ubiquitin-proteasome system in the response of the ligninolytic fungus Trametes versicolor to nitrogen deprivation.

    PubMed

    Staszczak, Magdalena

    2008-03-01

    The white rot fungus Trametes versicolor is an efficient lignin degrader with ecological significance and industrial applications. Lignin-modifying enzymes of white rot fungi are mainly produced during secondary metabolism triggered in these microorganisms by nutrient deprivation. Selective ubiquitin/proteasome-mediated proteolysis is known to play a crucial role in the response of cells to various stresses such as nutrient limitation, heat shock, and heavy metal exposure. Previous studies from our laboratory demonstrated that proteasomal degradation of intracellular proteins is involved in the regulation of laccase, a major ligninolytic enzyme of T. versicolor, in response to cadmium. In the present study, it was found that the 6-h nitrogen starvation leads to depletion of intracellular free ubiquitin pool in T. versicolor. The difference in the intracellular level of free monomeric ubiquitin observed between the mycelium extract from the nitrogen-deprived and that from the nitrogen-sufficient culture was accompanied by the different pattern of ubiquitin-dependent degradation. Furthermore, it was found that nitrogen deprivation affected 26S proteasome activities of T. versicolor. Proteasome inhibition by lactacystin beta-lactone, a highly specific agent, increased laccase activity in nitrogen-deprived cultures, but not in nitrogen-sufficient cultures. The present study implicates the ubiquitin/proteasome-mediated proteolytic pathway in the response of T. versicolor to nitrogen deprivation.

  19. Cap-dependent mRNA translation and the ubiquitin-proteasome system cooperate to promote ERBB2-dependent esophageal cancer phenotype.

    PubMed

    Issaenko, O A; Bitterman, P B; Polunovsky, V A; Dahlberg, P S

    2012-09-01

    Pathological post-transcriptional control of the proteome composition is a central feature of malignancy. Two steps in this pathway, eIF4F-driven cap-dependent mRNA translation and the ubiquitin-proteasome system (UPS), are deregulated in most if not all cancers. We tested a hypothesis that eIF4F is aberrantly activated in human esophageal adenocarcinoma (EAC) and requires elevated rates of protein turnover and proteolysis and thereby activated UPS for its pro-neoplastic function. Here, we show that 80% of tumors and cell lines featuring amplified ERBB2 display an aberrantly activated eIF4F. Direct genetic targeting of the eIF4F in ERBB2-amplified EAC cells with a constitutively active form of the eIF4F repressor 4E-BP1 decreased colony formation and proliferation and triggered apoptosis. In contrast, suppression of m-TOR-kinase activity towards 4E-BP1with rapamycin only modestly inhibited eIF4F-driven cap-dependent translation and EAC malignant phenotype; and promoted feedback activation of other cancer pathways. Our data show that co-treatment with 2 FDA-approved agents, the m-TOR inhibitor rapamycin and the proteasome inhibitor bortezomib, leads to strong synergistic growth-inhibitory effects. Moreover, direct targeting of eIF4F with constitutively active 4E-BP1 is significantly more potent in collaboration with bortezomib than rapamycin. These data support the hypothesis that a finely tuned balance between eIF4F-driven protein synthesis and proteasome-mediated protein degradation is required for the maintenance of ERBB2-mediated EAC malignant phenotype. Altogether, our study supports the development of pharmaceuticals to directly target eIF4F as most efficient strategy; and provides a clear rationale for the clinical evaluation of combination therapy with m-TOR inhibitors and bortezomib for EAC treatment.

  20. Proteomic Profiling of Cranial (Superior) Cervical Ganglia Reveals Beta-Amyloid and Ubiquitin Proteasome System Perturbations in an Equine Multiple System Neuropathy.

    PubMed

    McGorum, Bruce C; Pirie, R Scott; Eaton, Samantha L; Keen, John A; Cumyn, Elizabeth M; Arnott, Danielle M; Chen, Wenzhang; Lamont, Douglas J; Graham, Laura C; Llavero Hurtado, Maica; Pemberton, Alan; Wishart, Thomas M

    2015-11-01

    Equine grass sickness (EGS) is an acute, predominantly fatal, multiple system neuropathy of grazing horses with reported incidence rates of ∼2%. An apparently identical disease occurs in multiple species, including but not limited to cats, dogs, and rabbits. Although the precise etiology remains unclear, ultrastructural findings have suggested that the primary lesion lies in the glycoprotein biosynthetic pathway of specific neuronal populations. The goal of this study was therefore to identify the molecular processes underpinning neurodegeneration in EGS. Here, we use a bottom-up approach beginning with the application of modern proteomic tools to the analysis of cranial (superior) cervical ganglion (CCG, a consistently affected tissue) from EGS-affected patients and appropriate control cases postmortem. In what appears to be the proteomic application of modern proteomic tools to equine neuronal tissues and/or to an inherent neurodegenerative disease of large animals (not a model of human disease), we identified 2,311 proteins in CCG extracts, with 320 proteins increased and 186 decreased by greater than 20% relative to controls. Further examination of selected proteomic candidates by quantitative fluorescent Western blotting (QFWB) and subcellular expression profiling by immunohistochemistry highlighted a previously unreported dysregulation in proteins commonly associated with protein misfolding/aggregation responses seen in a myriad of human neurodegenerative conditions, including but not limited to amyloid precursor protein (APP), microtubule associated protein (Tau), and multiple components of the ubiquitin proteasome system (UPS). Differentially expressed proteins eligible for in silico pathway analysis clustered predominantly into the following biofunctions: (1) diseases and disorders, including; neurological disease and skeletal and muscular disorders and (2) molecular and cellular functions, including cellular assembly and organization, cell

  1. Proteomic Profiling of Cranial (Superior) Cervical Ganglia Reveals Beta-Amyloid and Ubiquitin Proteasome System Perturbations in an Equine Multiple System Neuropathy*

    PubMed Central

    McGorum, Bruce C.; Pirie, R. Scott; Eaton, Samantha L.; Keen, John A.; Cumyn, Elizabeth M.; Arnott, Danielle M.; Chen, Wenzhang; Lamont, Douglas J.; Graham, Laura C.; Llavero Hurtado, Maica; Pemberton, Alan; Wishart, Thomas M.

    2015-01-01

    Equine grass sickness (EGS) is an acute, predominantly fatal, multiple system neuropathy of grazing horses with reported incidence rates of ∼2%. An apparently identical disease occurs in multiple species, including but not limited to cats, dogs, and rabbits. Although the precise etiology remains unclear, ultrastructural findings have suggested that the primary lesion lies in the glycoprotein biosynthetic pathway of specific neuronal populations. The goal of this study was therefore to identify the molecular processes underpinning neurodegeneration in EGS. Here, we use a bottom-up approach beginning with the application of modern proteomic tools to the analysis of cranial (superior) cervical ganglion (CCG, a consistently affected tissue) from EGS-affected patients and appropriate control cases postmortem. In what appears to be the proteomic application of modern proteomic tools to equine neuronal tissues and/or to an inherent neurodegenerative disease of large animals (not a model of human disease), we identified 2,311 proteins in CCG extracts, with 320 proteins increased and 186 decreased by greater than 20% relative to controls. Further examination of selected proteomic candidates by quantitative fluorescent Western blotting (QFWB) and subcellular expression profiling by immunohistochemistry highlighted a previously unreported dysregulation in proteins commonly associated with protein misfolding/aggregation responses seen in a myriad of human neurodegenerative conditions, including but not limited to amyloid precursor protein (APP), microtubule associated protein (Tau), and multiple components of the ubiquitin proteasome system (UPS). Differentially expressed proteins eligible for in silico pathway analysis clustered predominantly into the following biofunctions: (1) diseases and disorders, including; neurological disease and skeletal and muscular disorders and (2) molecular and cellular functions, including cellular assembly and organization, cell

  2. Intracellular Protein Degradation: From a Vague Idea through the Lysosome and the Ubiquitin-Proteasome System and onto Human Diseases and Drug Targeting

    PubMed Central

    Ciechanover, Aaron

    2012-01-01

    Between the 1950s and 1980s, scientists were focusing mostly on how the genetic code was transcribed to RNA and translated to proteins, but how proteins were degraded had remained a neglected research area. With the discovery of the lysosome by Christian de Duve it was assumed that cellular proteins are degraded within this organelle. Yet, several independent lines of experimental evidence strongly suggested that intracellular proteolysis was largely non-lysosomal, but the mechanisms involved have remained obscure. The discovery of the ubiquitin-proteasome system resolved the enigma. We now recognize that degradation of intracellular proteins is involved in regulation of a broad array of cellular processes, such as cell cycle and division, regulation of transcription factors, and assurance of the cellular quality control. Not surprisingly, aberrations in the system have been implicated in the pathogenesis of human disease, such as malignancies and neurodegenerative disorders, which led subsequently to an increasing effort to develop mechanism-based drugs. PMID:23908826

  3. What do we really know about the ubiquitin-proteasome pathway in muscle atrophy?

    NASA Technical Reports Server (NTRS)

    Jagoe, R. T.; Goldberg, A. L.

    2001-01-01

    Studies of many different rodent models of muscle wasting have indicated that accelerated proteolysis via the ubiquitin-proteasome pathway is the principal cause of muscle atrophy induced by fasting, cancer cachexia, metabolic acidosis, denervation, disuse, diabetes, sepsis, burns, hyperthyroidism and excess glucocorticoids. However, our understanding about how muscle proteins are degraded, and how the ubiquitin-proteasome pathway is activated in muscle under these conditions, is still very limited. The identities of the important ubiquitin-protein ligases in skeletal muscle, and the ways in which they recognize substrates are still largely unknown. Recent in-vitro studies have suggested that one set of ubquitination enzymes, E2(14K) and E3(alpha), which are responsible for the 'N-end rule' system of ubiquitination, plays an important role in muscle, especially in catabolic states. However, their functional significance in degrading different muscle proteins is still unclear. This review focuses on the many gaps in our understanding of the functioning of the ubiquitin-proteasome pathway in muscle atrophy, and highlights the strengths and limitations of the different experimental approaches used in such studies.

  4. Overview of Proteasome Inhibitor-Based Anti-cancer Therapies: Perspective on Bortezomib and Second Generation Proteasome Inhibitors versus Future Generation Inhibitors of Ubiquitin-Proteasome System

    PubMed Central

    Dou, Q. Ping; Zonder, Jeffrey A.

    2014-01-01

    Over the past ten years, proteasome inhibition has emerged as an effective therapeutic strategy for treating multiple myeloma (MM) and some lymphomas. In 2003, Bortezomib (BTZ) became the first proteasome inhibitor approved by the U.S. Food and Drug Administration (FDA). BTZ-based therapies have become a staple for the treatment of MM at all stages of the disease. The survival rate of MM patients has improved significantly since clinical introduction of BTZ and other immunomodulatory drugs. However, BTZ has several limitations. Not all patients respond to BTZ-based therapies and relapse occurs in many patients who initially responded. Solid tumors, in particular, are often resistant to BTZ. Furthermore, BTZ can induce dose-limiting peripheral neuropathy (PN). The second generation proteasome inhibitor Carfizomib (CFZ; U.S. FDA approved in August 2012) induces responses in a minority of MM patients relapsed from or refractory to BTZ. There is less PN compared to BTZ. Four other second-generation proteasome inhibitors (Ixazomib, Delanzomib, Oprozomib and Marizomib) with different pharmacologic properties and broader anticancer activities, have also shown some clinical activity in bortezomib-resistant cancers. While the mechanism of resistance to bortezomib in human cancers still remains to be fully understood, targeting the immunoproteasome, ubiquitin E3 ligases, the 19S proteasome and deubiquitinases in pre-clinical studies represents possible directions for future generation inhibitors of ubiquitin-proteasome system in the treatment of MM and other cancers. PMID:25092212

  5. Pyrrolidine Dithiocarbamate Inhibits Herpes Simplex Virus 1 and 2 Replication, and Its Activity May Be Mediated through Dysregulation of the Ubiquitin-Proteasome System

    PubMed Central

    Qiu, Min; Chen, Yu; Cheng, Lin; Chu, Ying; Song, Hong-Yong

    2013-01-01

    Pyrrolidine dithiocarbamate (PDTC) is widely used as an antioxidant or an NF-κB inhibitor. It has been reported to inhibit the replication of human rhinoviruses, poliovirus, coxsackievirus, and influenza virus. In this paper, we report that PDTC could inhibit the replication of herpes simplex virus 1 and 2 (HSV-1 and HSV-2). PDTC suppressed the expression of HSV-1 and HSV-2 viral immediate early (IE) and late (membrane protein gD) genes and the production of viral progeny. This antiviral property was mediated by the dithiocarbamate moiety of PDTC and required the presence of Zn2+. Although PDTC could potently block reactive oxygen species (ROS) generation, it was found that this property did not contribute to its anti-HSV activity. PDTC showed no activity in disrupting the mitogen-activated protein kinase (MAPK) pathway activation induced by viral infection that was vital for the virus's propagation. We found that PDTC modulated cellular ubiquitination and, furthermore, influenced HSV-2-induced IκB-α degradation to inhibit NF-κB activation and enhanced PML stability in the nucleus, resulting in the inhibition of viral gene expression. These results suggested that the antiviral activity of PDTC might be mediated by its dysregulation of the cellular ubiquitin-proteasome system (UPS). PMID:23740985

  6. The regulation of glucose on milk fat synthesis is mediated by the ubiquitin-proteasome system in bovine mammary epithelial cells.

    PubMed

    Liu, Lily; Jiang, Li; Ding, Xiang-dong; Liu, Jian-feng; Zhang, Qin

    2015-09-11

    Glucose as one of the nutrition factors plays a vital role in the regulation of milk fat synthesis. Ubiquitin-proteasome system (UPS) is a vital proteolytic pathway in all eukaryotic cells through timely marking, recognizing and degrading the poly-ubiquitinated protein substrates. Previous studies indicated that UPS plays a considerable role in controlling the triglyceride (TG) synthesis. Therefore, the aim of this study is to confirm the link between high-glucose and UPS and its regulation mechanism on milk fat synthesis in BMEC (bovine mammary epithelial cells). We incubated BMEC with normal (17.5 mm/L) and high-glucose (25 mm/L) with and without proteasome inhibitor epoxomicin and found that, compared with the control (normal glucose and without proteasome inhibitor), both high-glucose concentration and proteasome inhibitor epoxomicin could increase the accumulation of TG and poly-ubiquitinated proteins, and reduce significantly three proteasome activities (chymotrypsin-like, caspase-like, and trypsin-like). In addition, high-glucose concentration combined with proteasome inhibitor further enhanced the increase of the poly-ubiquitinated protein level and the decrease of proteasome activities. Our results suggest that the regulation of high-glucose on milk fat synthesis is mediated by UPS in BMEC, and high-glucose exposure could lead to a hypersensitization of BMEC to UPS inhibition which in turn results in increased milk fat synthesis.

  7. Treatment of Plasmodium chabaudi Parasites with Curcumin in Combination with Antimalarial Drugs: Drug Interactions and Implications on the Ubiquitin/Proteasome System

    PubMed Central

    Neto, Zoraima; Machado, Marta; Lindeza, Ana; do Rosário, Virgílio; Gazarini, Marcos L.; Lopes, Dinora

    2013-01-01

    Antimalarial drug resistance remains a major obstacle in malaria control. Evidence from Southeast Asia shows that resistance to artemisinin combination therapy (ACT) is inevitable. Ethnopharmacological studies have confirmed the efficacy of curcumin against Plasmodium spp. Drug interaction assays between curcumin/piperine/chloroquine and curcumin/piperine/artemisinin combinations and the potential of drug treatment to interfere with the ubiquitin proteasome system (UPS) were analyzed. In vivo efficacy of curcumin was studied in BALB/c mice infected with Plasmodium chabaudi clones resistant to chloroquine and artemisinin, and drug interactions were analyzed by isobolograms. Subtherapeutic doses of curcumin, chloroquine, and artemisinin were administered to mice, and mRNA was collected following treatment for RT-PCR analysis of genes encoding deubiquitylating enzymes (DUBs). Curcumin was found be nontoxic in BALB/c mice. The combination of curcumin/chloroquine/piperine reduced parasitemia to 37% seven days after treatment versus the control group's 65%, and an additive interaction was revealed. Curcumin/piperine/artemisinin combination did not show a favorable drug interaction in this murine model of malaria. Treatment of mice with subtherapeutic doses of the drugs resulted in a transient increase in genes encoding DUBs indicating UPS interference. If curcumin is to join the arsenal of available antimalarial drugs, future studies exploring suitable drug partners would be of interest. PMID:23691276

  8. Archaeal Tuc1/Ncs6 Homolog Required for Wobble Uridine tRNA Thiolation Is Associated with Ubiquitin-Proteasome, Translation, and RNA Processing System Homologs

    PubMed Central

    Chavarria, Nikita E.; Hwang, Sungmin; Cao, Shiyun; Fu, Xian; Holman, Mary; Elbanna, Dina; Rodriguez, Suzanne; Arrington, Deanna; Englert, Markus; Uthandi, Sivakumar; Söll, Dieter; Maupin-Furlow, Julie A.

    2014-01-01

    While cytoplasmic tRNA 2-thiolation protein 1 (Tuc1/Ncs6) and ubiquitin-related modifier-1 (Urm1) are important in the 2-thiolation of 5-methoxycarbonylmethyl-2-thiouridine (mcm5s2U) at wobble uridines of tRNAs in eukaryotes, the biocatalytic roles and properties of Ncs6/Tuc1 and its homologs are poorly understood. Here we present the first report of an Ncs6 homolog of archaea (NcsA of Haloferax volcanii) that is essential for maintaining cellular pools of thiolated tRNALysUUU and for growth at high temperature. When purified from Hfx. volcanii, NcsA was found to be modified at Lys204 by isopeptide linkage to polymeric chains of the ubiquitin-fold protein SAMP2. The ubiquitin-activating E1 enzyme homolog of archaea (UbaA) was required for this covalent modification. Non-covalent protein partners that specifically associated with NcsA were also identified including UbaA, SAMP2, proteasome activating nucleotidase (PAN)-A/1, translation elongation factor aEF-1α and a β-CASP ribonuclease homolog of the archaeal cleavage and polyadenylation specificity factor 1 family (aCPSF1). Together, our study reveals that NcsA is essential for growth at high temperature, required for formation of thiolated tRNALysUUU and intimately linked to homologs of ubiquitin-proteasome, translation and RNA processing systems. PMID:24906001

  9. Exposure to Melan-A/MART-126-35 tumor epitope specific CD8(+)T cells reveals immune escape by affecting the ubiquitin-proteasome system (UPS).

    PubMed

    Ebstein, Frédéric; Keller, Martin; Paschen, Annette; Walden, Peter; Seeger, Michael; Bürger, Elke; Krüger, Elke; Schadendorf, Dirk; Kloetzel, Peter-M; Seifert, Ulrike

    2016-05-04

    Efficient processing of target antigens by the ubiquitin-proteasome-system (UPS) is essential for treatment of cancers by T cell therapies. However, immune escape due to altered expression of IFN-γ-inducible components of the antigen presentation machinery and consequent inefficient processing of HLA-dependent tumor epitopes can be one important reason for failure of such therapies. Here, we show that short-term co-culture of Melan-A/MART-1 tumor antigen-expressing melanoma cells with Melan-A/MART-126-35-specific cytotoxic T lymphocytes (CTL) led to resistance against CTL-induced lysis because of impaired Melan-A/MART-126-35 epitope processing. Interestingly, deregulation of p97/VCP expression, which is an IFN-γ-independent component of the UPS and part of the ER-dependent protein degradation pathway (ERAD), was found to be essentially involved in the observed immune escape. In support, our data demonstrate that re-expression of p97/VCP in Melan-A/MART-126-35 CTL-resistant melanoma cells completely restored immune recognition by Melan-A/MART-126-35 CTL. In conclusion, our experiments show that impaired expression of IFN-γ-independent components of the UPS can exert rapid immune evasion of tumor cells and suggest that tumor antigens processed by distinct UPS degradation pathways should be simultaneously targeted in T cell therapies to restrict the likelihood of immune evasion due to impaired antigen processing.

  10. Exposure to Melan-A/MART-126-35 tumor epitope specific CD8+T cells reveals immune escape by affecting the ubiquitin-proteasome system (UPS)

    PubMed Central

    Ebstein, Frédéric; Keller, Martin; Paschen, Annette; Walden, Peter; Seeger, Michael; Bürger, Elke; Krüger, Elke; Schadendorf, Dirk; Kloetzel, Peter-M.; Seifert, Ulrike

    2016-01-01

    Efficient processing of target antigens by the ubiquitin-proteasome-system (UPS) is essential for treatment of cancers by T cell therapies. However, immune escape due to altered expression of IFN-γ-inducible components of the antigen presentation machinery and consequent inefficient processing of HLA-dependent tumor epitopes can be one important reason for failure of such therapies. Here, we show that short-term co-culture of Melan-A/MART-1 tumor antigen-expressing melanoma cells with Melan-A/MART-126-35-specific cytotoxic T lymphocytes (CTL) led to resistance against CTL-induced lysis because of impaired Melan-A/MART-126-35 epitope processing. Interestingly, deregulation of p97/VCP expression, which is an IFN-γ-independent component of the UPS and part of the ER-dependent protein degradation pathway (ERAD), was found to be essentially involved in the observed immune escape. In support, our data demonstrate that re-expression of p97/VCP in Melan-A/MART-126-35 CTL-resistant melanoma cells completely restored immune recognition by Melan-A/MART-126-35 CTL. In conclusion, our experiments show that impaired expression of IFN-γ-independent components of the UPS can exert rapid immune evasion of tumor cells and suggest that tumor antigens processed by distinct UPS degradation pathways should be simultaneously targeted in T cell therapies to restrict the likelihood of immune evasion due to impaired antigen processing. PMID:27143649

  11. Pesticides that inhibit the ubiquitin-proteasome system: effect measure modification by genetic variation in SKP1 in Parkinson׳s disease.

    PubMed

    Rhodes, Shannon L; Fitzmaurice, Arthur G; Cockburn, Myles; Bronstein, Jeff M; Sinsheimer, Janet S; Ritz, Beate

    2013-10-01

    Cytoplasmic inclusions known as Lewy bodies, a hallmark of Parkinson's disease (PD) pathology, may protect against cytotoxic proteins. Since the ubiquitin-proteasome system (UPS) degrades cytotoxic proteins, dysfunction in the UPS may contribute to PD etiology. Our goal in this study was to screen pesticides for proteasome inhibition and investigate (i) whether ambient exposures to pesticides that inhibit the UPS increase PD risk and (ii) whether genetic variation in candidate genes of the UPS pathway modify those increased risks. We assessed 26S UPS activity in SK-N-MC(u) cells by fluorescence. We recruited idiopathic PD cases (n=360) and population-based controls (n=816) from three counties in California with considerable commercial agriculture. We determined ambient pesticide exposure by our validated GIS-based model utilizing residential and workplace address histories. We limited effect measure modification assessment to Caucasians (287 cases, 453 controls). Eleven of 28 pesticides we screened inhibited 26S UPS activity at 10 µM. Benomyl, cyanazine, dieldrin, endosulfan, metam, propargite, triflumizole, and ziram were associated with increased PD risk. We estimated an odds ratio of 2.14 (95% CI: 1.42, 3.22) for subjects with ambient exposure to any UPS-inhibiting pesticide at both residential and workplace addresses; this association was modified by genetic variation in the s-phase kinase-associated protein 1 gene (SKP1; interaction p-value=0.005). Our results provide evidence that UPS-inhibiting pesticides play a role in the etiology of PD and suggest that genetic variation in candidate genes involved in the UPS pathway might exacerbate the toxic effects of pesticide exposures.

  12. Administration of haloperidol with biperiden reduces mRNAs related to the ubiquitin-proteasome system in mice.

    PubMed

    Iwata, Shin-Ichi; Morioka, Hirofumi; Iwabuchi, Mika; Shinohara, Kazuya; Maeda, Maki; Shimizu, Takao; Miyata, Atsuro

    2005-06-15

    In order to find molecules affected by administration of an antipsychotic drug with an antimuscarinic drug, which is a common prescription used to prevent extrapyramidal adverse effects caused by the antipsychotic drugs, gene expression profiling in the frontal cortex was studied in mice. After 14 days of administration with 2 mg/kg haloperidol, a typical antipsychotic drug, and 2 mg/kg biperiden, a high-affinity antagonist for muscarinic receptors in the brain, approximately 500 mRNAs related to synaptic function were investigated. The levels of the mRNAs related to the ubiquitin-related systems were significantly reduced after the combined administration. However, the separate administration of either haloperidol or biperiden had little effect on the levels of the mRNAs. This result suggests that coadministration of haloperidol and biperiden specifically affects the ubiquitin-related system.

  13. Plant ubiquitin-proteasome pathway and its role in gibberellin signaling

    PubMed Central

    Wang, Feng; Deng, Xing Wang

    2011-01-01

    The ubiquitin-proteasome system (UPS) in plants, like in other eukaryotes, targets numerous intracellular regulators and thus modulates almost every aspect of growth and development. The well-known and best-characterized outcome of ubiquitination is mediating target protein degradation via the 26S proteasome, which represents the major selective protein degradation pathway conserved among eukaryotes. In this review, we will discuss the molecular composition, regulation and function of plant UPS, with a major focus on how DELLA protein degradation acts as a key in gibberellin signal transduction and its implication in the regulation of plant growth. PMID:21788985

  14. Muscle wasting in chronic kidney disease: the role of the ubiquitin proteasome system and its clinical impact

    PubMed Central

    Rajan, Vik R.

    2007-01-01

    Muscle wasting in chronic kidney disease (CKD) and other catabolic diseases (e.g. sepsis, diabetes, cancer) can occur despite adequate nutritional intake. It is now known that complications of these various disorders, including acidosis, insulin resistance, inflammation, and increased glucocorticoid and angiotensin II production, all activate the ubiquitin–proteasome system (UPS) to degrade muscle proteins. The initial step in this process is activation of caspase-3 to cleave the myofibril into its components (actin, myosin, troponin, and tropomyosin). Caspase-3 is required because the UPS minimally degrades the myofibril but rapidly degrades its component proteins. Caspase-3 activity is easily detected because it leaves a characteristic 14kD actin fragment in muscle samples. Preliminary evidence from several experimental models of catabolic diseases, as well as from studies in patients, indicates that this fragment could be a useful biomarker because it correlates well with the degree of muscle degradation in dialysis patients and in other catabolic conditions. PMID:17987322

  15. Ubiquitin, Proteasomes and Proteolytic Mechanisms Activated by Kidney Disease

    PubMed Central

    Rajan, Vik; Mitch, William E.

    2008-01-01

    Summary The ubiquitin-proteasome system (UPS) includes 3 enzymes that conjugate ubiquitin to intracellular proteins that are then recognized and degraded in the proteasome. The process participates in the regulation of cell metabolism. In the kidney, the UPS regulates the turnover of transporters and signaling proteins and its activity is down regulated in acidosis-induced proximal tubular cell hypertrophy. In chronic kidney disease (CKD), muscle wasting occurs because complications of CKD including acidosis, insulin resistance, inflammation, and increased angiotensin II levels stimulate the UPS to degrade muscle proteins. This response also includes caspase-3 and calpains which act to cleave muscle proteins to provide substrates for the UPS. For example, caspase-3 degrades actomyosin, leaving a 14kD fragment of actin in muscle. The 14 kD actin fragment is increased in muscle of patient with kidney disease, burn injury and surgery. In addition, acidosis, insulin resistance, inflammation and angiotensin II stimulate glucocorticoid production. Glucocorticoids are also required for the muscle wasting that occurs in CKD. Thus, the UPS is involved in regulating kidney function and participates in highly organized responses that degrade muscle protein in response to loss of kidney function. PMID:18723090

  16. Morphine Induces Ubiquitin-Proteasome Activity and Glutamate Transporter Degradation*

    PubMed Central

    Yang, Liling; Wang, Shuxing; Sung, Backil; Lim, Grewo; Mao, Jianren

    2008-01-01

    Glutamate transporters play a crucial role in physiological glutamate homeostasis, neurotoxicity, and glutamatergic regulation of opioid tolerance. However, how the glutamate transporter turnover is regulated remains poorly understood. Here we show that chronic morphine exposure induced posttranscriptional down-regulation of the glutamate transporter EAAC1 in C6 glioma cells with a concurrent decrease in glutamate uptake and increase in proteasome activity, which were blocked by the selective proteasome inhibitor MG-132 or lactacystin but not the lysosomal inhibitor chloroquin. At the cellular level, chronic morphine induced the PTEN (phosphatase and tensin homolog deleted on chromosome Ten)-mediated up-regulation of the ubiquitin E3 ligase Nedd4 via cAMP/protein kinase A signaling, leading to EAAC1 ubiquitination and proteasomal degradation. Either Nedd4 or PTEN knockdown with small interfering RNA prevented the morphine-induced EAAC1 degradation and decreased glutamate uptake. These data indicate that cAMP/protein kinase A signaling serves as an intracellular regulator upstream to the activation of the PTEN/Nedd4-mediated ubiquitin-proteasome system activity that is critical for glutamate transporter turnover. Under an in vivo condition, chronic morphine exposure also induced posttranscriptional down-regulation of the glutamate transporter EAAC1, which was prevented by MG-132, and transcriptional up-regulation of PTEN and Nedd4 within the spinal cord dorsal horn. Thus, inhibition of the ubiquitin-proteasome-mediated glutamate transporter degradation may be an important mechanism for preventing glutamate overexcitation and may offer a new strategy for treating certain neurological disorders and improving opioid therapy in chronic pain management. PMID:18539596

  17. Autophagy maintains ubiquitination-proteasomal degradation of Sirt3 to limit oxidative stress in K562 leukemia cells

    PubMed Central

    Xu, Li; Cao, Yan; Xu, Fei; Yan, Lili; Nie, Meilan; Yuan, Na; Zhang, Suping; Zhao, Ruijin; Wang, Hongbin; Wu, Mengyin; Zhang, Xiaoying; Wang, Jianrong

    2016-01-01

    Sirtuin protein family member 3 (Sirt3) has been suggested as a positive regulator in alleviating oxidative stress by acting on the mitochondrial antioxidant machinery in solid tumors; however, its role and regulation in hematological malignancies has been poorly understood. Here, we show that contrary to what has been reported in solid tumors, in K562 leukemia cells elevated Sirt3 was associated with mitochondrial stress, and depletion of Sirt3 decreased reactive oxygen species (ROS) generation and lipid oxidation, but increased the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG), suggesting an opposite role of Sirt3 in regulating oxidative stress in the leukemia cells. Notably, loss of autophagy by deletion of autophagy essential gene or by pharmacological inhibition on autophagic degradation caused a significant accumulation of Sirt3. However, induced activation of autophagy did not cause autophagic degradation of Sirt3. Furthermore, inhibiting proteasome activity accumulated Sirt3 in autophagy-intact but not autophagy-defective cells, and disrupting functional autophagy either genetically or pharmacologically caused significantly less ubiquitination of Sirt3. Therefore, our data suggest that basal but not enhanced autophagy activity maintains ubiquitination-proteasomal degradation of Sirt3 to limit lipid oxidative stress, representing an adaptive mechanism by which autophagy, in collaboration with the ubiquitination-proteasomal system, controls oxidative stress by controlling the levels of certain proteins in K562 leukemia cells. PMID:27232755

  18. Exploring the Ubiquitin-Proteasome Protein Degradation Pathway in Yeast

    ERIC Educational Resources Information Center

    Will, Tamara J.; McWatters, Melissa K.; McQuade, Kristi L.

    2006-01-01

    This article describes an undergraduate biochemistry laboratory investigating the ubiquitin-proteasome pathway in yeast. In this exercise, the enzyme beta-galactosidase (beta-gal) is expressed in yeast under the control of a stress response promoter. Following exposure to heat stress to induce beta-gal expression, cycloheximide is added to halt…

  19. Ubiquitin-proteasome pathway and cellular responses to oxidative stress

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The ubiquitin-proteasome pathway (UPP) is the primary cytosolic proteolytic machinery for the selective degradation of various forms of damaged proteins. Thus, the UPP is an important protein quality control mechanism. In the canonical UPP, both ubiquitin and the 26S proteasome are involved. Subs...

  20. Recognition and Cleavage of Related to Ubiquitin 1 (Rub1) and Rub1-Ubiquitin Chains by Components of the Ubiquitin-Proteasome System*

    PubMed Central

    Singh, Rajesh K.; Zerath, Sylvia; Kleifeld, Oded; Scheffner, Martin; Glickman, Michael H.; Fushman, David

    2012-01-01

    Of all ubiquitin-like proteins, Rub1 (Nedd8 in mammals) is the closest kin of ubiquitin. We show via NMR that structurally, Rub1 and ubiquitin are fundamentally similar as well. Despite these profound similarities, the prevalence of Rub1/Nedd8 and of ubiquitin as modifiers of the proteome is starkly different, and their attachments to specific substrates perform different functions. Recently, some proteins, including p53, p73, EGFR, caspase-7, and Parkin, have been shown to be modified by both Rub1/Nedd8 and ubiquitin within cells. To understand whether and how it might be possible to distinguish among the same target protein modified by Rub1 or ubiquitin or both, we examined whether ubiquitin receptors can differentiate between Rub1 and ubiquitin. Surprisingly, Rub1 interacts with proteasome ubiquitin-shuttle proteins comparably to ubiquitin but binds more weakly to a proteasomal ubiquitin receptor Rpn10. We identified Rub1-ubiquitin heteromers in yeast and Nedd8-Ub heteromers in human cells. We validate that in human cells and in vitro, human Rub1 (Nedd8) forms chains with ubiquitin where it acts as a chain terminator. Interestingly, enzymatically assembled K48-linked Rub1-ubiquitin heterodimers are recognized by various proteasomal ubiquitin shuttles and receptors comparably to K48-linked ubiquitin homodimers. Furthermore, these heterologous chains are cleaved by COP9 signalosome or 26S proteasome. A derubylation function of the proteasome expands the repertoire of its enzymatic activities. In contrast, Rub1 conjugates may be somewhat resilient to the actions of other canonical deubiquitinating enzymes. Taken together, these findings suggest that once Rub1/Nedd8 is channeled into ubiquitin pathways, it is recognized essentially like ubiquitin. PMID:23105008

  1. Regulation of Bovine Papillomavirus Replicative Helicase E1 by the Ubiquitin-Proteasome Pathway

    PubMed Central

    Malcles, Marie-Helene; Cueille, Nathalie; Mechali, Francisca; Coux, Olivier; Bonne-Andrea, Catherine

    2002-01-01

    Papillomaviruses maintain their genomes in a relatively constant copy number as stable extrachromosomal plasmids in the nuclei of dividing host cells. The viral initiator of replication, E1, is not detected in papillomavirus-infected cells. Here, we present evidence that E1 encoded by bovine papillomavirus type 1 is an unstable protein that is degraded through the ubiquitin-proteasome pathway. In a cell-free system derived from Xenopus egg extracts, E1 degradation is regulated by both cyclin E/Cdk2 binding and E1 replication activity. Free E1 is readily ubiquitinated and degraded by the proteasome, while it becomes resistant to this degradation pathway when bound to cyclin E/Cdk2 complexes before the start of DNA synthesis. This stabilization is reversed in a process involving E1-dependent replication activity. In transiently transfected cells, E1 is also polyubiquitinated and accumulates when proteasome activity is inhibited. Thus, the establishment and maintenance of a stable number of papillomavirus genomes in latently infected cells are in part a function of regulated ubiquitin-mediated degradation of E1. PMID:12388695

  2. The Ubiquitin-Proteasome Pathway and Proteasome Inhibitors

    PubMed Central

    Myung, Jayhyuk; Kim, Kyung Bo

    2008-01-01

    The ubiquitin-proteasome pathway has emerged as a central player in the regulation of several diverse cellular processes. Here, we describe the important components of this complex biochemical machinery as well as several important cellular substrates targeted by this pathway and examples of human diseases resulting from defects in various components of the ubiquitin-proteasome pathway. In addition, this review covers the chemistry of synthetic and natural proteasome inhibitors, emphasizing their mode of actions toward the 20S proteasome. Given the importance of proteasome-mediated protein degradation in various intracellular processes, inhibitors of this pathway will continue to serve as both molecular probes of major cellular networks as well as potential therapeutic agents for various human diseases. PMID:11410931

  3. Colorectal Carcinogenesis, Radiation Quality, and the Ubiquitin-Proteasome Pathway

    PubMed Central

    Datta, Kamal; Suman, Shubhankar; Kumar, Santosh; Fornace, Albert J

    2016-01-01

    Adult colorectal epithelium undergoes continuous renewal and maintains homeostatic balance through regulated cellular proliferation, differentiation, and migration. The canonical Wnt signaling pathway involving the transcriptional co-activator β-catenin is important for colorectal development and normal epithelial maintenance, and deregulated Wnt/β-catenin signaling has been implicated in colorectal carcinogenesis. Colorectal carcinogenesis has been linked to radiation exposure, and radiation has been demonstrated to alter Wnt/β-catenin signaling, as well as the proteasomal pathway involved in the degradation of the signaling components and thus regulation of β-catenin. The current review discusses recent progresses in our understanding of colorectal carcinogenesis in relation to different types of radiation and roles that radiation quality plays in deregulating β-catenin and ubiquitin-proteasome pathway (UPP) for colorectal cancer initiation and progression. PMID:26819641

  4. Ubiquitin-Proteasome Dependent Regulation of the GOLDEN2-LIKE 1 Transcription Factor in Response to Plastid Signals1[OPEN

    PubMed Central

    Tokumaru, Mitsuaki; Adachi, Fumi; Toda, Makoto; Yazu, Fumiko; Hirosawa, Yoshihiro

    2017-01-01

    Arabidopsis (Arabidopsis thaliana) GOLDEN2-LIKE (GLK) transcription factors promote chloroplast biogenesis by regulating the expression of photosynthesis-related genes. Arabidopsis GLK1 is also known to participate in retrograde signaling from chloroplasts to the nucleus. To elucidate the mechanism by which GLK1 is regulated in response to plastid signals, we biochemically characterized Arabidopsis GLK1 protein. Expression analysis of GLK1 protein indicated that GLK1 accumulates in aerial tissues. Both tissue-specific and Suc-dependent accumulation of GLK1 were regulated primarily at the transcriptional level. In contrast, norflurazon- or lincomycin-treated gun1-101 mutant expressing normal levels of GLK1 mRNA failed to accumulate GLK1 protein, suggesting that plastid signals directly regulate the accumulation of GLK1 protein in a GUN1-independent manner. Treatment of the glk1glk2 mutant expressing functional GFP-GLK1 with a proteasome inhibitor, MG-132, induced the accumulation of polyubiquitinated GFP-GLK1. Furthermore, the level of endogenous GLK1 in plants with damaged plastids was partially restored when those plants were treated with MG-132. Collectively, these data indicate that the ubiquitin-proteasome system participates in the degradation of Arabidopsis GLK1 in response to plastid signals. PMID:27821720

  5. Ubiquitin-proteasome dependent degradation of GABAAα1 in autism spectrum disorder

    PubMed Central

    2014-01-01

    was found in the middle frontal gyrus of ASD subjects. Conclusions SYVN1 plays a critical role as an E3 ligase in the ubiquitin proteasome system (UPS)-mediated GABAAα1 degradation. Thus, inhibition of the ubiquitin-proteasome-mediated GABAAα1 degradation may be an important mechanism for preventing GABAAα1 turnover to maintain GABAAα1 levels and GABA signaling in ASD. PMID:25392730

  6. Degradation of the Neurospora circadian clock protein FREQUENCY through the ubiquitin-proteasome pathway.

    PubMed

    He, Q; Liu, Y

    2005-11-01

    Phosphorylation of the Neurospora circadian clock protein FREQUENCY (FRQ) promotes its degradation through the ubiquitin-proteasome pathway. Ubiquitination of FRQ requires FWD-1 (F-box/WD-40 repeat-containing protein-1), which is the substrate-recruiting subunit of an SCF (SKP/Cullin/F-box)-type ubiquitin ligase. In the fwd-1 mutant strains, FRQ degradation is defective, resulting in the accumulation of hyperphosphorylated FRQ and the loss of the circadian rhythmicities. The CSN (COP9 signalosome) promotes the function of SCF complexes in vivo. But in vitro, deneddylation of cullins by CSN inhibits SCF activity. In Neurospora, the disruption of the csn-2 subunit impairs FRQ degradation and compromises the normal circadian functions. These defects are due to the dramatically reduced levels of FWD-1 in the csn-2 mutant, a result of its rapid degradation. Other components of the SCF(FWD-1) complex, SKP-1 and CUL-1 are also unstable in the mutant. These results establish important roles for SCF(FWD-1) and CSN in the circadian clock of Neurospora and suggest that they are conserved components of the eukaryotic circadian clocks. In addition, these findings resolve the CSN paradox and suggest that the major function of CSN is to maintain the stability of SCF ubiquitin ligases in vivo.

  7. Neuroinflammation and J2 prostaglandins: linking impairment of the ubiquitin-proteasome pathway and mitochondria to neurodegeneration

    PubMed Central

    Figueiredo-Pereira, Maria E.; Rockwell, Patricia; Schmidt-Glenewinkel, Thomas; Serrano, Peter

    2015-01-01

    The immune response of the CNS is a defense mechanism activated upon injury to initiate repair mechanisms while chronic over-activation of the CNS immune system (termed neuroinflammation) may exacerbate injury. The latter is implicated in a variety of neurological and neurodegenerative disorders such as Alzheimer and Parkinson diseases, amyotrophic lateral sclerosis, multiple sclerosis, traumatic brain injury, HIV dementia, and prion diseases. Cyclooxygenases (COX-1 and COX-2), which are key enzymes in the conversion of arachidonic acid into bioactive prostanoids, play a central role in the inflammatory cascade. J2 prostaglandins are endogenous toxic products of cyclooxygenases, and because their levels are significantly increased upon brain injury, they are actively involved in neuronal dysfunction induced by pro-inflammatory stimuli. In this review, we highlight the mechanisms by which J2 prostaglandins (1) exert their actions, (2) potentially contribute to the transition from acute to chronic inflammation and to the spreading of neuropathology, (3) disturb the ubiquitin-proteasome pathway and mitochondrial function, and (4) contribute to neurodegenerative disorders such as Alzheimer and Parkinson diseases, and amyotrophic lateral sclerosis, as well as stroke, traumatic brain injury (TBI), and demyelination in Krabbe disease. We conclude by discussing the therapeutic potential of targeting the J2 prostaglandin pathway to prevent/delay neurodegeneration associated with neuroinflammation. In this context, we suggest a shift from the traditional view that cyclooxygenases are the most appropriate targets to treat neuroinflammation, to the notion that J2 prostaglandin pathways and other neurotoxic prostaglandins downstream from cyclooxygenases, would offer significant benefits as more effective therapeutic targets to treat chronic neurodegenerative diseases, while minimizing adverse side effects. PMID:25628533

  8. New insights to the ubiquitin-proteasome pathway (UPP) mechanism during spermatogenesis.

    PubMed

    Hou, Cong-Cong; Yang, Wan-Xi

    2013-04-01

    Spermatogenesis is a complicated and highly ordered process which begins with the differentiation of spermatogonial stem cells and ends with the formation of mature sperm. After meiosis, several morphological changes occur during spermatogenesis. During spermatogenesis, many proteins and organelles are degraded, and the ubiquitin-proteasome pathway (UPP) plays a key role in the process which facilitates the formation of condensed sperm. UPP contains various indispensable components: ubiquitin, ubiquitin-activating enzyme E1, ubiquitin-conjugating enzyme E2, ubiquitin ligase enzyme E3 and proteasomes. At some key stages of spermatogenesis, such as meiosis, acrosome biogenesis, and spermatozoa maturation, the ubiquitin-related components (including deubiquitination enzymes) exert positive and active functions. Generally speaking, deficient UPP will block spermatogenesis which may induce infertility at various degrees. Although ubiquitination during spermatogenesis has been widely investigated, further detailed aspects such as the mechanism of ubiquitination during the formation of midpiece and acrosome morphogenesis still remains unknown. The present review will overview current progress on ubiquitination during spermatogenesis, and will provide some suggestions for future studies on the functions of UPP components during spermatogenesis.

  9. New insights into the role of the ubiquitin-proteasome pathway in the regulation of apoptosis.

    PubMed

    Liu, Cui-Hua; Goldberg, Alfred L; Qiu, Xiao-Bo

    2007-01-01

    The ubiquitin-proteasome pathway (UPP) is the major system responsible for degradation of intracellular proteins in eukaryotes. By controlling the levels of key proteins, it regulates almost all of the cellular activities, including cell cycle progression, DNA replication and repair, transcription, protein quality control, immune response, and apoptosis. UPP is composed of the ubiquitination system that marks proteins for degradation and the proteasome which degrades the ubiquitinated proteins. The 26S proteasome is a 2400 kDa complex consisting of more than 40 subunits. Following ubiquitination catalyzed by the ubiquitin activating enzyme (El), a ubiquitin-carrier protein (E2), and one of the cell's many ubiquitin-protein ligases (E3s), the protein substrates are targeted to the proteasome for degradation into small peptides. E3s regulate the degradation of protein substrates indirectly by determining both the specificity and timing of substrate ubiquitination, whereas the deubiquitinating enzymes can inhibit this process by releasing ubiquitin from substrates. In this review, we attempt to highlight the recent progress in research on UPP and its role in the regulation of apoptosis by focusing on several of its important components, including the ubiqutin ligase Nrdp 1, which regulates ErbB/EGFR family of receptor tyrosine kinases, the ubiquitin-carrier protein BRUCE/Apollon (an Inhibitor of Apoptosis Protein), and the novel proteasome subunit hRpnl3 (a binding site for the deubiquitinating enzyme, UCH37).

  10. Contributions of the ubiquitin-proteasome pathway and apoptosis to human skeletal muscle wasting with age.

    PubMed

    Whitman, Samantha A; Wacker, Michael J; Richmond, Scott R; Godard, Michael P

    2005-09-01

    The primary mechanism that contributes to decreasing skeletal muscle strength and size with healthy aging is not presently known. This study examined the contribution of the ubiquitin-proteasome pathway and apoptosis to skeletal muscle wasting in older adults (n = 21; mean age = 72.76 +/- 8.31 years) and young controls (n = 21; mean age = 21.48 +/- 2.93 years). Subjects underwent a percutaneous muscle biopsy of the vastus lateralis to determine: (1) ubiquitin ligase gene expression (MAFbx and MuRF1); (2) frequency of apoptosis; and (3) individual fiber type and cross-sectional area. In addition, a whole muscle strength test was also performed. A one-way ANOVA revealed significant increases in the number of positive TUNEL cells in older adults (87%; p < 0.05), although no significant increase in caspase-3/7 activity was detected. Additionally, ubiquitin ligase gene expression, individual muscle fiber type and CSA were not different between old and young subjects. Muscle strength was also significantly lower in old compared to young subjects (p < 0.05). In conclusion, this study indicates a preferential role for apoptosis contributing to decreases in muscle function with age.

  11. Formation of distinct inclusion bodies by inhibition of ubiquitin-proteasome and autophagy-lysosome pathways

    SciTech Connect

    Lee, Junho; Yang, Kyu-Hwan; Joe, Cheol O.; Kang, Seok-Seong

    2011-01-14

    Research highlights: {yields} Distinct inclusion bodies are developed by inhibition of UPP and ALP. {yields} The inclusion bodies differ in morphology, localization and formation process. {yields} The inclusion bodies are distinguishable by the localization of TSC2. {yields} Inhibition of both UPP and ALP simultaneously induces those inclusion bodies. -- Abstract: Accumulation of misfolded proteins is caused by the impairment of protein quality control systems, such as ubiquitin-proteasome pathway (UPP) and autophagy-lysosome pathway (ALP). In this study, the formation of inclusion bodies was examined after the blockade of UPP and/or ALP in A549 cells. UPP inhibition induced a single and large inclusion body localized in microtubule-organizing center. Interestingly, however, ALP inhibition generated dispersed small inclusion bodies in the cytoplasm. Tuberous sclerosis complex 2 was selectively accumulated in the inclusion bodies of UPP-inhibited cells, but not those of ALP-inhibited cells. Blockade of transcription and translation entirely inhibited the formation of inclusion body induced by UPP inhibition, but partially by ALP inhibition. Moreover, the simultaneous inhibition of two protein catabolic pathways independently developed two distinct inclusion bodies within a single cell. These findings clearly demonstrated that dysfunction of each catabolic pathway induced formation and accumulation of unique inclusion bodies on the basis of morphology, localization and formation process in A549 cells.

  12. Formation of distinct inclusion bodies by inhibition of ubiquitin-proteasome and autophagy-lysosome pathways.

    PubMed

    Lee, Junho; Yang, Kyu-Hwan; Joe, Cheol O; Kang, Seok-Seong

    2011-01-14

    Accumulation of misfolded proteins is caused by the impairment of protein quality control systems, such as ubiquitin-proteasome pathway (UPP) and autophagy-lysosome pathway (ALP). In this study, the formation of inclusion bodies was examined after the blockade of UPP and/or ALP in A549 cells. UPP inhibition induced a single and large inclusion body localized in microtubule-organizing center. Interestingly, however, ALP inhibition generated dispersed small inclusion bodies in the cytoplasm. Tuberous sclerosis complex 2 was selectively accumulated in the inclusion bodies of UPP-inhibited cells, but not those of ALP-inhibited cells. Blockade of transcription and translation entirely inhibited the formation of inclusion body induced by UPP inhibition, but partially by ALP inhibition. Moreover, the simultaneous inhibition of two protein catabolic pathways independently developed two distinct inclusion bodies within a single cell. These findings clearly demonstrated that dysfunction of each catabolic pathway induced formation and accumulation of unique inclusion bodies on the basis of morphology, localization and formation process in A549 cells.

  13. Plant Virus Infection and the Ubiquitin Proteasome Machinery: Arms Race along the Endoplasmic Reticulum

    PubMed Central

    Verchot, Jeanmarie

    2016-01-01

    The endoplasmic reticulum (ER) is central to plant virus replication, translation, maturation, and egress. Ubiquitin modification of ER associated cellular and viral proteins, alongside the actions of the 26S proteasome, are vital for the regulation of infection. Viruses can arrogate ER associated ubiquitination as well as cytosolic ubiquitin ligases with the purpose of directing the ubiquitin proteasome system (UPS) to new targets. Such targets include necessary modification of viral proteins which may stabilize certain complexes, or modification of Argonaute to suppress gene silencing. The UPS machinery also contributes to the regulation of effector triggered immunity pattern recognition receptor immunity. Combining the results of unrelated studies, many positive strand RNA plant viruses appear to interact with cytosolic Ub-ligases to provide novel avenues for controlling the deleterious consequences of disease. Viral interactions with the UPS serve to regulate virus infection in a manner that promotes replication and movement, but also modulates the levels of RNA accumulation to ensure successful biotrophic interactions. In other instances, the UPS plays a central role in cellular immunity. These opposing roles are made evident by contrasting studies where knockout mutations in the UPS can either hamper viruses or lead to more aggressive diseases. Understanding how viruses manipulate ER associated post-translational machineries to better manage virus–host interactions will provide new targets for crop improvement. PMID:27869775

  14. Ubiquitin proteasome pathway-mediated degradation of proteins: effects due to site-specific substrate deamidation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The accumulation, aggregation, and precipitation of proteins are etiologic for age-related diseases, particularly cataract, because the precipitates cloud the lens. Deamidation of crystallins is associated with protein precipitation, aging, and cataract. Among the roles of the ubiquitin proteasome p...

  15. High-throughput bioluminescence screening of ubiquitin-proteasome pathway inhibitors from chemical and natural sources.

    PubMed

    Ausseil, Frederic; Samson, Arnaud; Aussagues, Yannick; Vandenberghe, Isabelle; Creancier, Laurent; Pouny, Isabelle; Kruczynski, Anna; Massiot, Georges; Bailly, Christian

    2007-02-01

    To discover original inhibitors of the ubiquitin-proteasome pathway, the authors have developed a cell-based bioluminescent assay and used it to screen collections of plant extracts and chemical compounds. They first established a DLD-1 human colon cancer cell line that stably expresses a 4Ubiquitin-Luciferase (4Ub-Luc) reporter protein, efficiently targeted to the ubiquitin-proteasome degradation pathway. The assay was then adapted to 96- and 384-well plate formats and calibrated with reference proteasome inhibitors. Assay robustness was carefully assessed, particularly cell toxicity, and the statistical Z factor value was calculated to 0.83, demonstrating a good performance level of the assay. A total of 18,239 molecules and 15,744 plant extracts and fractions thereof were screened for their capacity to increase the luciferase activity in DLD-1 4Ub-Luc cells, and 21 molecules and 66 extracts inhibiting the ubiquitin-proteasome pathway were identified. The fractionation of an active methanol extract of Physalis angulata L. aerial parts was performed to isolate 2 secosteroids known as physalin B and C. In a cell-based Western blot assay, the ubiquitinated protein accumulation was confirmed after a physalin treatment confirming the accuracy of the screening process. The method reported here thus provides a robust approach to identify novel ubiquitin-proteasome pathway inhibitors in large collections of chemical compounds and natural products.

  16. Impairment of the ubiquitin-proteasome pathway in RPE alters the expression of inflammation related genes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The ubiquitin-proteasome pathway (UPP) plays an important role in regulating gene expression. Retinal pigment epithelial cells (RPE) are a major source of ocular inflammatory cytokines. In this work we determined the relationship between impairment of the UPP and expression of inflammation-related f...

  17. Heat Shock Protein 70 Regulates Degradation of the Mumps Virus Phosphoprotein via the Ubiquitin-Proteasome Pathway

    PubMed Central

    Kubota, Toru; Kita, Shunsuke; Nakatsu, Yuichiro; Aoki, Natsuko; Mori, Yoshio; Maenaka, Katsumi; Takeda, Makoto; Kidokoro, Minoru

    2014-01-01

    ABSTRACT Mumps virus (MuV) infection induces formation of cytoplasmic inclusion bodies (IBs). Growing evidence indicates that IBs are the sites where RNA viruses synthesize their viral RNA. However, in the case of MuV infection, little is known about the viral and cellular compositions and biological functions of the IBs. In this study, pulldown purification and N-terminal amino acid sequencing revealed that stress-inducible heat shock protein 70 (Hsp72) was a binding partner of MuV phosphoprotein (P protein), which was an essential component of the IB formation. Immunofluorescence and immunoblotting analyses revealed that Hsp72 was colocalized with the P protein in the IBs, and its expression was increased during MuV infection. Knockdown of Hsp72 using small interfering RNAs (siRNAs) had little, if any, effect on viral propagation in cultured cells. Knockdown of Hsp72 caused accumulation of ubiquitinated P protein and delayed P protein degradation. These results show that Hsp72 is recruited to IBs and regulates the degradation of MuV P protein through the ubiquitin-proteasome pathway. IMPORTANCE Formation of cytoplasmic inclusion bodies (IBs) is a common characteristic feature in mononegavirus infections. IBs are considered to be the sites of viral RNA replication and transcription. However, there have been few studies focused on host factors recruited to the IBs and their biological functions. Here, we identified stress-inducible heat shock protein 70 (Hsp72) as the first cellular partner of mumps virus (MuV) phosphoprotein (P protein), which is an essential component of the IBs and is involved in viral RNA replication/transcription. We found that the Hsp72 mobilized to the IBs promoted degradation of the MuV P protein through the ubiquitin-proteasome pathway. Our data provide new insight into the role played by IBs in mononegavirus infection. PMID:25552722

  18. The PML-nuclear inclusion of human supraoptic neurons: a new compartment with SUMO-1- and ubiquitin-proteasome-associated domains.

    PubMed

    Villagra, Nuria T; Navascues, Joaquin; Casafont, Iñigo; Val-Bernal, J Fernando; Lafarga, Miguel; Berciano, Maria T

    2006-01-01

    It is well known that the cell nucleus is organized in structural and functional compartments involved in transcription, RNA processing and protein modifications such as conjugation with SUMO-1 and proteolysis. Promyelocytic leukaemia (PML) bodies are dynamic nuclear structures that concentrate PML protein, SUMO-1 and several sumoylated and non-sumoylated protein regulators of nuclear functions. PML bodies and their associated CBP has been involved in neuronal survival. By light and electron microscopy immunocytochemistry and in situ hybridization we reported the presence, in non-pathological conditions, of a large PML-nuclear inclusion (PML-NI) in human supraoptic neurons. This inclusion appears as a single nuclear structure composed of a capsule enriched in PML, SUMO-1 and CBP proteins and a central lattice of filaments immunoreactive for class III beta-tubulin, ubiquitinated proteins and proteasomes. Furthermore, the PML-NI concentrates the SUMO-conjugating enzyme E2 (UBC9). The PML-NI may be considered a nuclear factory involved in sumoylation and proteolysis via ubiquitin-proteasome system, two nuclear pathways engaged in the control of the nucleoplasmic concentration of active transcriptional regulators. Interestingly, the structural and molecular organization of the PML-NI is related to the Marinesco bodies, age-associated ubiquitinated intranuclear inclusions, and to the intranuclear rodlets enriched in class III beta-tubulin, which are nuclear structures markedly decreased in Alzheimer's disease.

  19. Degradation Signals for Ubiquitin-Proteasome Dependent Cytosolic Protein Quality Control (CytoQC) in Yeast.

    PubMed

    Maurer, Matthew J; Spear, Eric D; Yu, Allen T; Lee, Evan J; Shahzad, Saba; Michaelis, Susan

    2016-07-07

    Cellular protein quality control (PQC) systems selectively target misfolded or otherwise aberrant proteins for degradation by the ubiquitin-proteasome system (UPS). How cells discern abnormal from normal proteins remains incompletely understood, but involves in part the recognition between ubiquitin E3 ligases and degradation signals (degrons) that are exposed in misfolded proteins. PQC is compartmentalized in the cell, and a great deal has been learned in recent years about ER-associated degradation (ERAD) and nuclear quality control. In contrast, a comprehensive view of cytosolic quality control (CytoQC) has yet to emerge, and will benefit from the development of a well-defined set of model substrates. In this study, we generated an isogenic "degron library" in Saccharomyces cerevisiae consisting of short sequences appended to the C-terminus of a reporter protein, Ura3 About half of these degron-containing proteins are substrates of the integral membrane E3 ligase Doa10, which also plays a pivotal role in ERAD and some nuclear protein degradation. Notably, some of our degron fusion proteins exhibit dependence on the E3 ligase Ltn1/Rkr1 for degradation, apparently by a mechanism distinct from its known role in ribosomal quality control of translationally paused proteins. Ubr1 and San1, E3 ligases involved in the recognition of some misfolded CytoQC substrates, are largely dispensable for the degradation of our degron-containing proteins. Interestingly, the Hsp70/Hsp40 chaperone/cochaperones Ssa1,2 and Ydj1, are required for the degradation of all constructs tested. Taken together, the comprehensive degron library presented here provides an important resource of isogenic substrates for testing candidate PQC components and identifying new ones.

  20. Degradation Signals for Ubiquitin-Proteasome Dependent Cytosolic Protein Quality Control (CytoQC) in Yeast

    PubMed Central

    Maurer, Matthew J.; Spear, Eric D.; Yu, Allen T.; Lee, Evan J.; Shahzad, Saba; Michaelis, Susan

    2016-01-01

    Cellular protein quality control (PQC) systems selectively target misfolded or otherwise aberrant proteins for degradation by the ubiquitin-proteasome system (UPS). How cells discern abnormal from normal proteins remains incompletely understood, but involves in part the recognition between ubiquitin E3 ligases and degradation signals (degrons) that are exposed in misfolded proteins. PQC is compartmentalized in the cell, and a great deal has been learned in recent years about ER-associated degradation (ERAD) and nuclear quality control. In contrast, a comprehensive view of cytosolic quality control (CytoQC) has yet to emerge, and will benefit from the development of a well-defined set of model substrates. In this study, we generated an isogenic “degron library” in Saccharomyces cerevisiae consisting of short sequences appended to the C-terminus of a reporter protein, Ura3. About half of these degron-containing proteins are substrates of the integral membrane E3 ligase Doa10, which also plays a pivotal role in ERAD and some nuclear protein degradation. Notably, some of our degron fusion proteins exhibit dependence on the E3 ligase Ltn1/Rkr1 for degradation, apparently by a mechanism distinct from its known role in ribosomal quality control of translationally paused proteins. Ubr1 and San1, E3 ligases involved in the recognition of some misfolded CytoQC substrates, are largely dispensable for the degradation of our degron-containing proteins. Interestingly, the Hsp70/Hsp40 chaperone/cochaperones Ssa1,2 and Ydj1, are required for the degradation of all constructs tested. Taken together, the comprehensive degron library presented here provides an important resource of isogenic substrates for testing candidate PQC components and identifying new ones. PMID:27172186

  1. Regulating the ubiquitin/proteasome pathway via cAMP-signaling: neuroprotective potential

    PubMed Central

    Huang, He; Wang, Hu; Figueiredo-Pereira, Maria E.

    2013-01-01

    The cAMP-signaling pathway has been under intensive investigation for decades. It is a wonder that such a small simple molecule like cAMP can modulate a vast number of diverse processes in different types of cells. The ubiquitous involvement of cAMP-signaling in a variety of cellular events requires tight spatial and temporal control of its generation, propagation, compartmentalization, and elimination. Among the various steps of the cAMP-signaling pathway, G-protein coupled receptors, adenylate cyclases, phosphodiesterases, the two major cAMP targets, i.e. protein kinase A and exchange protein activated by cAMP, as well as the A-kinase anchoring proteins, are potential targets for drug development. Herein we review the recent progress on the regulation and manipulation of different steps of the cAMP-signaling pathway. We end by focusing on the emerging role of cAMP-signaling in modulating protein degradation via the ubiquitin/proteasome pathway. New discoveries on the regulation of the ubiquitin/proteasome pathway by cAMP-signaling support the development of new therapeutic approaches to prevent proteotoxicity in chronic neurodegenerative disorders and other human disease conditions associated with impaired protein turnover by the ubiquitin/proteasome pathway and the accumulation of ubiquitin-protein aggregates. PMID:23686612

  2. High Fat Diet-Induced Skeletal Muscle Wasting Is Decreased by Mesenchymal Stem Cells Administration: Implications on Oxidative Stress, Ubiquitin Proteasome Pathway Activation, and Myonuclear Apoptosis.

    PubMed

    Abrigo, Johanna; Rivera, Juan Carlos; Aravena, Javier; Cabrera, Daniel; Simon, Felipe; Ezquer, Fernando; Ezquer, Marcelo; Cabello-Verrugio, Claudio

    2016-01-01

    Obesity can lead to skeletal muscle atrophy, a pathological condition characterized by the loss of strength and muscle mass. A feature of muscle atrophy is a decrease of myofibrillar proteins as a result of ubiquitin proteasome pathway overactivation, as evidenced by increased expression of the muscle-specific ubiquitin ligases atrogin-1 and MuRF-1. Additionally, other mechanisms are related to muscle wasting, including oxidative stress, myonuclear apoptosis, and autophagy. Stem cells are an emerging therapy in the treatment of chronic diseases such as high fat diet-induced obesity. Mesenchymal stem cells (MSCs) are a population of self-renewable and undifferentiated cells present in the bone marrow and other mesenchymal tissues of adult individuals. The present study is the first to analyze the effects of systemic MSC administration on high fat diet-induced skeletal muscle atrophy in the tibialis anterior of mice. Treatment with MSCs reduced losses of muscle strength and mass, decreases of fiber diameter and myosin heavy chain protein levels, and fiber type transitions. Underlying these antiatrophic effects, MSC administration also decreased ubiquitin proteasome pathway activation, oxidative stress, and myonuclear apoptosis. These results are the first to indicate that systemically administered MSCs could prevent muscle wasting associated with high fat diet-induced obesity and diabetes.

  3. High Fat Diet-Induced Skeletal Muscle Wasting Is Decreased by Mesenchymal Stem Cells Administration: Implications on Oxidative Stress, Ubiquitin Proteasome Pathway Activation, and Myonuclear Apoptosis

    PubMed Central

    Aravena, Javier; Cabrera, Daniel; Simon, Felipe; Ezquer, Fernando

    2016-01-01

    Obesity can lead to skeletal muscle atrophy, a pathological condition characterized by the loss of strength and muscle mass. A feature of muscle atrophy is a decrease of myofibrillar proteins as a result of ubiquitin proteasome pathway overactivation, as evidenced by increased expression of the muscle-specific ubiquitin ligases atrogin-1 and MuRF-1. Additionally, other mechanisms are related to muscle wasting, including oxidative stress, myonuclear apoptosis, and autophagy. Stem cells are an emerging therapy in the treatment of chronic diseases such as high fat diet-induced obesity. Mesenchymal stem cells (MSCs) are a population of self-renewable and undifferentiated cells present in the bone marrow and other mesenchymal tissues of adult individuals. The present study is the first to analyze the effects of systemic MSC administration on high fat diet-induced skeletal muscle atrophy in the tibialis anterior of mice. Treatment with MSCs reduced losses of muscle strength and mass, decreases of fiber diameter and myosin heavy chain protein levels, and fiber type transitions. Underlying these antiatrophic effects, MSC administration also decreased ubiquitin proteasome pathway activation, oxidative stress, and myonuclear apoptosis. These results are the first to indicate that systemically administered MSCs could prevent muscle wasting associated with high fat diet-induced obesity and diabetes. PMID:27579157

  4. Reproductive Cytotoxicity Is Predicted by Magnetic Resonance Microscopy and Confirmed by Ubiquitin Proteasome Immunohistochemistry in a Theophylline-Induced Model of Rat Testicular and Epididymal Toxicity

    NASA Astrophysics Data System (ADS)

    Tengowski, M. W.; Sutovsky, P.; Hedlund, L. W.; Guyot, D. J.; Burkhardt, J. E.; Thompson, W. E.; Sutovsky, M.; Johnson, G. A.

    2005-08-01

    This study investigated the testicular changes in the rat induced by the nonspecific phosphodiesterase inhibitor, theophylline using magnetic resonance microscopy (MRM) and ubiquitin immunostaining techniques. In vivo T1- and T2-weighted images were acquired at 2 T under anesthesia. Increased signal observed in the theophylline-treated rats suggests that leakage of MRM contrast was occurring. In vivo MRM results indicate that day 16 testis displayed an increased T1-weighted water signal in the area of the seminiferous tubule that decreased by day 32. These findings were validated by histopathology, suggesting that in vivo MRM has the sensitivity to predict changes in testis and epididymal tissues. The participation of the ubiquitin system was investigated, using probes for various markers of the ubiquitin-proteasome pathway. MRM can be used to detect subtle changes in the vascular perfusion of organ systems, and the up-regulation/mobilization of ubiquitin-proteasome pathway may be one of the mechanisms used in theophylline-treated epididymis to remove damaged cells before storage in the cauda epididymis. The combined use of in vivo MRM and subsequent tissue or seminal analysis for the presence of ubiquitin in longitudinal studies may become an important biomarker for assessing testis toxicities drug studies.

  5. The acidosis of chronic renal failure activates muscle proteolysis in rats by augmenting transcription of genes encoding proteins of the ATP-dependent ubiquitin-proteasome pathway.

    PubMed Central

    Bailey, J L; Wang, X; England, B K; Price, S R; Ding, X; Mitch, W E

    1996-01-01

    Chronic renal failure (CRF) is associated with negative nitrogen balance and loss of lean body mass. To identify specific proteolytic pathways activated by CRF, protein degradation was measured in incubated epitrochlearis muscles from CRF and sham-operated, pair-fed rats. CRF stimulated muscle proteolysis, and inhibition of lysosomal and calcium-activated proteases did not eliminate this increase. When ATP production was blocked, proteolysis in CRF muscles fell to the same level as that in control muscles. Increased proteolysis was also prevented by feeding CRF rats sodium bicarbonate, suggesting that activation depends on acidification. Evidence that the ATP-dependent ubiquitin-proteasome pathway is stimulated by the acidemia of CRF includes the following findings: (a) An inhibitor of the proteasome eliminated the increase in muscle proteolysis; and (b) there was an increase in mRNAs encoding ubiquitin (324%) and proteasome subunits C3 (137%) and C9 (251%) in muscle. This response involved gene activation since transcription of mRNAs for ubiquitin and the C3 subunit were selectively increased in muscle of CRF rats. We conclude that CRF stimulates muscle proteolysis by activating the ATP-ubiquitin-proteasome-dependent pathway. The mechanism depends on acidification and increased expression of genes encoding components of the system. These responses could contribute to the loss of muscle mass associated with CRF. PMID:8617877

  6. Inhibition of PCSK9 transcription by berberine involves down-regulation of hepatic HNF1α protein expression through the ubiquitin-proteasome degradation pathway.

    PubMed

    Dong, Bin; Li, Hai; Singh, Amar Bahadur; Cao, Aiqin; Liu, Jingwen

    2015-02-13

    Our previous in vitro studies have identified hepatocyte nuclear factor 1α (HNF1α) as an obligated trans-activator for PCSK9 gene expression and demonstrated its functional involvement in the suppression of PCSK9 expression by berberine (BBR), a natural cholesterol-lowering compound. In this study, we investigated the mechanism underlying the inhibitory effect of BBR on HNF1α-mediated PCSK9 transcription. Administration of BBR to hyperlipidemic mice and hamsters lowered circulating PCSK9 concentrations and hepatic PCSK9 mRNA levels without affecting the gene expression of HNF1α. However, hepatic HNF1α protein levels were markedly reduced in BBR-treated animals as compared with the control. Using HepG2 cells as a model system, we obtained evidence that BBR treatment let to accelerated degradation of HNF1α protein. By applying inhibitors to selectively block the ubiquitin proteasome system (UPS) and autophagy-lysosomal pathway, we show that HNF1α protein content in HepG2 cells was not affected by bafilomycin A1 treatment, but it was dose-dependently increased by UPS inhibitors bortezomib and MG132. Bortezomib treatment elevated HNF1α and PCSK9 cellular levels with concomitant reductions of LDL receptor protein. Moreover, HNF1α protein displayed a multiubiquitination ladder pattern in cells treated with BBR or overexpressing ubiquitin. By expressing GFP-HNF1α fusion protein in cells, we observed that blocking UPS resulted in accumulation of GFP-HNF1α in cytoplasm. Importantly, we show that the BBR reducing effects on HNF1α protein and PCSK9 gene transcription can be eradicated by proteasome inhibitors. Altogether, our studies using BBR as a probe uncovered a new aspect of PCSK9 regulation by ubiquitin-induced proteasomal degradation of HNF1α.

  7. Reactive center loop moiety is essential for the maspin activity on cellular invasion and ubiquitin-proteasome level.

    PubMed

    Khanaree, Chakkrit; Chairatvit, Kongthawat; Roytrakul, Sittiruk; Wongnoppavich, Ariyaphong

    2013-01-01

    Maspin, a tumor suppressor (SERPINB5), inhibits cancer migration, invasion, and metastasis in vitro and in vivo. The tumor-suppressing effects of maspin depend in part on its ability to enhance cell adhesion to extracellular matrix. Although the molecular mechanism of maspin's action is still unclear, its functional domain is believed to be located at the reactive center loop (RCL). We have elucidated the role of maspin RCL on adhesion, migration, and invasion by transfecting the highly invasive human breast carcinoma MDA-MB-231 cell line with pcDNA3.1-His/FLAG containing wild-type maspin, ovalbumin, or maspin/ovalbumin RCL chimeric mutants in which maspin RCL is replaced by ovalbumin (MOM) and vice versa (OMO). MDA-MB-231 cells transfected with maspin- or OMO-containing recombinant expression plasmid manifested significant increase in adhesion to fibronectin and reduction in in vitro migration and invasion through Matrigel compared with mock transfection or cells transfected with ovalbumin or MOM. Proteomics analysis of maspin- or OMO-transfected MDA-MB-231 cells revealed reduction in contents of proteins known to promote cancer metastasis and those of ubiquitin-proteasome pathway, while those with tumor-suppressing properties were increased. Furthermore, MDA-MB-231 cells containing maspin or OMO transgene have significantly higher levels of ubiquitin and ubiquitinated conjugates, but reduced 20S proteasome chymotrypsin-like activity. These results clearly demonstrate that the tumor-suppressive properties of maspin reside in its RCL domain.

  8. Cancer cell death induced by novel small molecules degrading the TACC3 protein via the ubiquitin-proteasome pathway.

    PubMed

    Ohoka, N; Nagai, K; Hattori, T; Okuhira, K; Shibata, N; Cho, N; Naito, M

    2014-11-06

    The selective degradation of target proteins with small molecules is a novel approach to the treatment of various diseases, including cancer. We have developed a protein knockdown system with a series of hybrid small compounds that induce the selective degradation of target proteins via the ubiquitin-proteasome pathway. In this study, we designed and synthesized novel small molecules called SNIPER(TACC3)s, which target the spindle regulatory protein transforming acidic coiled-coil-3 (TACC3). SNIPER(TACC3)s induce poly-ubiquitylation and proteasomal degradation of TACC3 and reduce the TACC3 protein level in cells. Mechanistic analysis indicated that the ubiquitin ligase APC/C(CDH1) mediates the SNIPER(TACC3)-induced degradation of TACC3. Intriguingly, SNIPER(TACC3) selectively induced cell death in cancer cells expressing a larger amount of TACC3 protein than normal cells. These results suggest that protein knockdown of TACC3 by SNIPER(TACC3) is a potential strategy for treating cancers overexpressing the TACC3 protein.

  9. Skeletal muscle myotubes of the severely obese exhibit altered ubiquitin-proteasome and autophagic/lysosomal proteolytic flux

    PubMed Central

    Bollinger, Lance M.; Powell, Jonathan J. S.; Houmard, Joseph A.; Witczak, Carol A.; Brault, Jeffrey J.

    2015-01-01

    Objective Whole-body protein metabolism is dysregulated with obesity. Our goal was to determine if activity and expression of major protein degradation pathways are compromised specifically in human skeletal muscle with obesity. Methods We utilized primary Human Skeletal Muscle cell (HSkM) cultures since cellular mechanisms can be studied absent of hormones and contractile activity that could independently influence metabolism. HSkM from 10 lean (BMI ≤ 26.0 kg/m2) and 8 severely obese (BMI ≥ 39.0) women were examined basally and when stimulated to atrophy (serum and amino acid starvation). Results HSkM from obese donors had a lower proportion of type I myosin heavy chain and slower flux through the autophagic/lysosomal pathway. During starvation, flux through the ubiquitin-proteasome system diverged according to obesity status, with a decrease in the lean and an increase in HSkM from obese subjects. HSkMC from the obese also displayed elevated proteasome activity despite no difference in proteasome content. Atrophy-related gene expression and myotube area were similar in myotubes derived from lean and obese individuals under basal and starved conditions. Conclusions Our data indicate that muscle cells of the lean and severely obese have innate differences in management of protein degradation, which may explain their metabolic differences. PMID:26010327

  10. Oxidative stress, NF-κB and the ubiquitin proteasomal pathway in the pathology of calpainopathy.

    PubMed

    Rajakumar, Dhanarajan; Alexander, Mathew; Oommen, Anna

    2013-10-01

    The neuromuscular disorder, calpainopathy (LGMD 2A), is a major muscular dystrophy classified under limb girdle muscular dystrophies. Genetic mutations of the enzyme calpain 3 cause LGMD 2A. Calpainopathy is phenotypically observed as progressive muscle wasting and weakness. Pathomechanisms of muscle wasting of calpainopathy remain poorly understood. Oxidative stress, NF-κB and the ubiquitin proteasomal pathway underlie the pathology of several muscle wasting conditions but their role in calpainopathic dystrophy is not known. Oxidative and nitrosative stress, the source of reactive oxygen species, NF-κB signaling and protein ubiquitinylation were studied in 15 calpainopathic and 8 healthy control human muscle biopsies. Oxidative stress and NF-κB/IKK β signaling were increased in calpainopathic muscle and may contribute to increased protein ubiquitinylation and muscle protein loss. Preventing oxidative stress or inhibition of NF-κB signaling could be considered for treatment of LGMD 2A.

  11. A Sporadic Parkinson Disease Model via Silencing of the Ubiquitin-Proteasome/E3 Ligase Component SKP1A*

    PubMed Central

    Fishman-Jacob, Tali; Reznichenko, Lydia; Youdim, Moussa B. H.; Mandel, Silvia A.

    2009-01-01

    The aim of this study was to develop a new model of sporadic Parkinson disease (PD) based on silencing of the SKP1A gene, a component of the ubiquitin-proteasome/E3 ligase complex, Skp1, Cullin 1, F-box protein, which was found to be highly decreased in the substantia nigra of sporadic PD patients. Initially, an embryonic mouse substantia nigra-derived cell line (SN4741 cells) was infected with short hairpin RNA lentiviruses encoding the murine transcript of the SKP1A gene or with scrambled vector. SKP1A silencing resulted in increased susceptibility to neuronal damages induced by the parkinsonism-inducing neurotoxin 1-methyl-4-phenylpyridinium ion and serum starvation, in parallel with a decline in the expression of the dopaminergic markers, dopamine transporter and vesicular monoamine transporter-2. SKP1A-deficient cells presented a delay in completion of the cell cycle and the inability to arrest at the G0/G1 phase when induced to differentiate. Instead, the cells progressed through S phase, developing rounded aggregates with characteristics of aggresomes including immunoreactivity for γ-tubulin, α-synuclein, ubiquitin, tyrosine hydroxylase, Hsc-70 (70-kDa heat shock cognate protein), and proteasome subunit, and culminating in a lethal phenotype. Conversely, stably enforced expression of wild type SKP1A duplicated the survival index of naïve SN4741 cells under proteasomal inhibition injury, suggesting a new structural role of SKP1 in dopaminergic neuronal function, besides its E3 ligase activity. These results link, for the first time, SKP1 to dopamine neuronal function and survival, suggesting an essential role in sporadic PD. In summary, this new model has reproduced to a significant extent the molecular alterations described in sporadic PD at the cellular level, implicating Skp1 as a potential modifier in sporadic PD neurodegeneration. PMID:19748892

  12. A sporadic Parkinson disease model via silencing of the ubiquitin-proteasome/E3 ligase component SKP1A.

    PubMed

    Fishman-Jacob, Tali; Reznichenko, Lydia; Youdim, Moussa B H; Mandel, Silvia A

    2009-11-20

    The aim of this study was to develop a new model of sporadic Parkinson disease (PD) based on silencing of the SKP1A gene, a component of the ubiquitin-proteasome/E3 ligase complex, Skp1, Cullin 1, F-box protein, which was found to be highly decreased in the substantia nigra of sporadic PD patients. Initially, an embryonic mouse substantia nigra-derived cell line (SN4741 cells) was infected with short hairpin RNA lentiviruses encoding the murine transcript of the SKP1A gene or with scrambled vector. SKP1A silencing resulted in increased susceptibility to neuronal damages induced by the parkinsonism-inducing neurotoxin 1-methyl-4-phenylpyridinium ion and serum starvation, in parallel with a decline in the expression of the dopaminergic markers, dopamine transporter and vesicular monoamine transporter-2. SKP1A-deficient cells presented a delay in completion of the cell cycle and the inability to arrest at the G(0)/G(1) phase when induced to differentiate. Instead, the cells progressed through S phase, developing rounded aggregates with characteristics of aggresomes including immunoreactivity for gamma-tubulin, alpha-synuclein, ubiquitin, tyrosine hydroxylase, Hsc-70 (70-kDa heat shock cognate protein), and proteasome subunit, and culminating in a lethal phenotype. Conversely, stably enforced expression of wild type SKP1A duplicated the survival index of naïve SN4741 cells under proteasomal inhibition injury, suggesting a new structural role of SKP1 in dopaminergic neuronal function, besides its E3 ligase activity. These results link, for the first time, SKP1 to dopamine neuronal function and survival, suggesting an essential role in sporadic PD. In summary, this new model has reproduced to a significant extent the molecular alterations described in sporadic PD at the cellular level, implicating Skp1 as a potential modifier in sporadic PD neurodegeneration.

  13. Regulation of HTLV-1 tax stability, cellular trafficking and NF-κB activation by the ubiquitin-proteasome pathway.

    PubMed

    Lavorgna, Alfonso; Harhaj, Edward William

    2014-10-23

    Human T-cell leukemia virus type 1 (HTLV-1) is a complex retrovirus that infects CD4+ T cells and causes adult T-cell leukemia/lymphoma (ATLL) in 3%-5% of infected individuals after a long latent period. HTLV-1 Tax is a trans-activating protein that regulates viral gene expression and also modulates cellular signaling pathways to enhance T-cell proliferation and cell survival. The Tax oncoprotein promotes T-cell transformation, in part via constitutive activation of the NF-κB transcription factor; however, the underlying mechanisms remain unknown. Ubiquitination is a type of post-translational modification that occurs in a three-step enzymatic cascade mediated by E1, E2 and E3 enzymes and regulates protein stability as well as signal transduction, protein trafficking and the DNA damage response. Emerging studies indicate that Tax hijacks the ubiquitin machinery to activate ubiquitin-dependent kinases and downstream NF-κB signaling. Tax interacts with the E2 conjugating enzyme Ubc13 and is conjugated on C-terminal lysine residues with lysine 63-linked polyubiquitin chains. Tax K63-linked polyubiquitination may serve as a platform for signaling complexes since this modification is critical for interactions with NEMO and IKK. In addition to NF-κB signaling, mono- and polyubiquitination of Tax also regulate its subcellular trafficking and stability. Here, we review recent advances in the diverse roles of ubiquitin in Tax function and how Tax usurps the ubiquitin-proteasome pathway to promote oncogenesis.

  14. Small acidic protein 1 and SCF(TIR)(1) ubiquitin proteasome pathway act in concert to induce 2,4-dichlorophenoxyacetic acid-mediated alteration of actin in Arabidopsis roots.

    PubMed

    Takahashi, Maho; Umetsu, Kana; Oono, Yutaka; Higaki, Takumi; Blancaflor, Elison B; Rahman, Abidur

    2017-03-01

    2,4-Dichlorophenoxyacetic acid (2,4-D), a functional analogue of auxin, is used as an exogenous source of auxin as it evokes physiological responses like the endogenous auxin, indole-3-acetic acid (IAA). Previous molecular analyses of the auxin response pathway revealed that IAA and 2,4-D share a common mode of action to elicit downstream physiological responses. However, recent findings with 2,4-D-specific mutants suggested that 2,4-D and IAA might also use distinct pathways to modulate root growth in Arabidopsis. Using genetic and cellular approaches, we demonstrate that the distinct effects of 2,4-D and IAA on actin filament organization partly dictate the differential responses of roots to these two auxin analogues. 2,4-D but not IAA altered the actin structure in long-term and short-term assays. Analysis of the 2,4-D-specific mutant aar1-1 revealed that small acidic protein 1 (SMAP1) functions positively to facilitate the 2,4-D-induced depolymerization of actin. The ubiquitin proteasome mutants tir1-1 and axr1-12, which show enhanced resistance to 2,4-D compared with IAA for inhibition of root growth, were also found to have less disrupted actin filament networks after 2,4-D exposure. Consistently, a chemical inhibitor of the ubiquitin proteasome pathway mitigated the disrupting effects of 2,4-D on the organization of actin filaments. Roots of the double mutant aar1-1 tir1-1 also showed enhanced resistance to 2,4-D-induced inhibition of root growth and actin degradation compared with their respective parental lines. Collectively, these results suggest that the effects of 2,4-D on actin filament organization and root growth are mediated through synergistic interactions between SMAP1 and SCF(TIR)(1) ubiquitin proteasome components.

  15. Production of Infectious Dengue Virus in Aedes aegypti Is Dependent on the Ubiquitin Proteasome Pathway

    PubMed Central

    Choy, Milly M.; Sessions, October M.; Gubler, Duane J.; Ooi, Eng Eong

    2015-01-01

    Dengue virus (DENV) relies on host factors to complete its life cycle in its mosquito host for subsequent transmission to humans. DENV first establishes infection in the midgut of Aedes aegypti and spreads to various mosquito organs for lifelong infection. Curiously, studies have shown that infectious DENV titers peak and decrease thereafter in the midgut despite relatively stable viral genome levels. However, the mechanisms that regulate this decoupling of infectious virion production from viral RNA replication have never been determined. We show here that the ubiquitin proteasome pathway (UPP) plays an important role in regulating infectious DENV production. Using RNA interference studies, we show in vivo that knockdown of selected UPP components reduced infectious virus production without altering viral RNA replication in the midgut. Furthermore, this decoupling effect could also be observed after RNAi knockdown in the head/thorax of the mosquito, which otherwise showed direct correlation between infectious DENV titer and viral RNA levels. The dependence on the UPP for successful DENV production is further reinforced by the observed up-regulation of key UPP molecules upon DENV infection that overcome the relatively low expression of these genes after a blood meal. Collectively, our findings indicate an important role for the UPP in regulating DENV production in the mosquito vector. PMID:26566123

  16. Regulation of ubiquitin proteasome pathway molecular markers in response to endurance and resistance exercise and training.

    PubMed

    Stefanetti, Renae J; Lamon, Séverine; Wallace, Marita; Vendelbo, Mikkel H; Russell, Aaron P; Vissing, Kristian

    2015-07-01

    Knowledge on the effects of divergent exercise on ostensibly protein degradation pathways may be valuable for counteracting muscle wasting and for understanding muscle remodelling. This study examined mRNA and/or protein levels of molecular markers of the ubiquitin proteasome pathway (UPP), including FBXO32 (atrogin-1), MURF-1, FBXO40, FOXO1 and FOXO3. Protein substrates of atrogin-1-including EIF3F, MYOG and MYOD1-and of MURF-1-including PKM and MHC-were also measured. Subjects completed 10 weeks of endurance training (ET) or resistance training (RT) followed by a single-bout of endurance exercise (EE) or resistance exercise (RE). Following training, atrogin-1, FBXO40, FOXO1 and FOXO3 mRNA increased independently of exercise mode, whereas MURF-1 mRNA and FOXO3 protein increased following ET only. No change in other target proteins occurred post-training. In the trained state, single-bout EE, but not RE, increased atrogin-1, MURF-1, FBXO40, FOXO1, FOXO3 mRNA and FOXO3 protein. In contrast to EE, FBXO40 mRNA and protein decreased following single-bout RE. MURF-1 and FOXO1 protein levels as well as the protein substrates of atrogin-1 and MURF-1 were unchanged following training and single-bout exercise. This study demonstrates that the intracellular signals elicited by ET and RT result in an upregulation of UPP molecular markers, with a greater increase following ET. However, in the trained state, the expression levels of UPP molecular markers are increased following single-bout EE, but are less responsive to single-bout RE. This suggests that adaptations following endurance exercise training are more reliant on protein UPP degradation processes than adaptations following resistance exercise training.

  17. Analysis of the Protein Kinase A-Regulated Proteome of Cryptococcus neoformans Identifies a Role for the Ubiquitin-Proteasome Pathway in Capsule Formation

    PubMed Central

    Geddes, J. M. H.; Caza, M.; Croll, D.; Stoynov, N.; Foster, L. J.

    2016-01-01

    ABSTRACT The opportunistic fungal pathogen Cryptococcus neoformans causes life-threatening meningitis in immunocompromised individuals. The expression of virulence factors, including capsule and melanin, is in part regulated by the cyclic-AMP/protein kinase A (cAMP/PKA) signal transduction pathway. In this study, we investigated the influence of PKA on the composition of the intracellular proteome to obtain a comprehensive understanding of the regulation that underpins virulence. Through quantitative proteomics, enrichment and bioinformatic analyses, and an interactome study, we uncovered a pattern of PKA regulation for proteins associated with translation, the proteasome, metabolism, amino acid biosynthesis, and virulence-related functions. PKA regulation of the ubiquitin-proteasome pathway in C. neoformans showed a striking parallel with connections between PKA and protein degradation in chronic neurodegenerative disorders and other human diseases. Further investigation of proteasome function with the inhibitor bortezomib revealed an impact on capsule production as well as hypersusceptibility for strains with altered expression or activity of PKA. Parallel studies with tunicamycin also linked endoplasmic reticulum stress with capsule production and PKA. Taken together, the data suggest a model whereby expression of PKA regulatory and catalytic subunits and the activation of PKA influence proteostasis and the function of the endoplasmic reticulum to control the elaboration of the polysaccharide capsule. Overall, this study revealed both broad and conserved influences of the cAMP/PKA pathway on the proteome and identified proteostasis as a potential therapeutic target for the treatment of cryptococcosis. PMID:26758180

  18. Stimulation of ubiquitin-proteasome pathway through the expression of amidohydrolase for N-terminal asparagine (Ntan1) in cultured rat hippocampal neurons exposed to static magnetism.

    PubMed

    Hirai, Takao; Taniura, Hideo; Goto, Yasuaki; Ogura, Masato; Sng, Judy C G; Yoneda, Yukio

    2006-03-01

    In order to elucidate mechanisms underlying modulation by static magnetism of the cellular functionality and/or integrity in the brain, we screened genes responsive to brief magnetism in cultured rat hippocampal neurons using differential display analysis. We have for the first time cloned and identified Ntan1 (amidohydrolase for N-terminal asparagine) as a magnetism responsive gene in rat brain. Ntan1 is an essential component of a protein degradation signal, which is a destabilizing N-terminal residue of a protein, in the N-end rule. In situ hybridization histochemistry revealed abundant expression of Ntan1 mRNA in hippocampal neurons in vivo. Northern blot analysis showed that Ntan1 mRNA was increased about three-fold after 3 h in response to brief magnetism. Brief magnetism also increased the transcriptional activity of Ntan1 promoter by luciferase reporter assay. Brief magnetism induced degradation of microtubule-associated protein 2 (MAP2) without affecting cell morphology and viability, which was prevented by a selective inhibitor of 26S proteasome in hippocampal neurons. Overexpression of Ntan1 using recombinant Ntan1 adenovirus vector resulted in a marked decrease in the MAP2 protein expression in hippocampal neurons. Our results suggest that brief magnetism leads to the induction of Ntan1 responsible for MAP2 protein degradation through ubiquitin-proteasome pathway in rat hippocampal neurons.

  19. Progressive skeletal muscle weakness in transgenic mice expressing CTG expansions is associated with the activation of the ubiquitin-proteasome pathway.

    PubMed

    Vignaud, Alban; Ferry, Arnaud; Huguet, Aline; Baraibar, Martin; Trollet, Capucine; Hyzewicz, Janek; Butler-Browne, Gillian; Puymirat, Jack; Gourdon, Genevieve; Furling, Denis

    2010-05-01

    Myotonic dystrophy type 1 (DM1) is a neuromuscular disease caused by the expansion of a CTG repeat in the DMPK gene and characterised by progressive skeletal muscle weakness and wasting. To investigate the effects of the CTG expansion on the physiological function of the skeletal muscles, we have used a transgenic mouse model carrying the human DM1 region with 550 expanded CTG repeats. Maximal force is reduced in the skeletal muscles of 10-month-old but not in 3-month-old DM1 mice when compared to age-matched non-transgenic littermates. The progressive weakness observed in the DM1 mice is directly related to the reduced muscle mass and muscle fibre size. A significant increase in trypsin-like proteasome activity and Fbxo32 expression is also measured in the DM1 muscles indicating that an atrophic process mediated by the ubiquitin-proteasome pathway may contribute to the progressive muscle wasting and weakness in the DM1 mice.

  20. Decreased rate of protein synthesis, caspase-3 activity, and ubiquitin-proteasome proteolysis in soleus muscles from growing rats fed a low-protein, high-carbohydrate diet.

    PubMed

    Batistela, Emanuele; Pereira, Mayara Peron; Siqueira, Juliany Torres; Paula-Gomes, Silvia; Zanon, Neusa Maria; Oliveira, Eduardo Brandt; Navegantes, Luiz Carlos Carvalho; Kettelhut, Isis C; Andrade, Claudia Marlise Balbinotti; Kawashita, Nair Honda; Baviera, Amanda Martins

    2014-06-01

    The aim of this study was to investigate the changes in the rates of both protein synthesis and breakdown, and the activation of intracellular effectors that control these processes in soleus muscles from growing rats fed a low-protein, high-carbohydrate (LPHC) diet for 15 days. The mass and the protein content, as well as the rate of protein synthesis, were decreased in the soleus from LPHC-fed rats. The availability of amino acids was diminished, since the levels of various essential amino acids were decreased in the plasma of LPHC-fed rats. Overall rate of proteolysis was also decreased, explained by reductions in the mRNA levels of atrogin-1 and MuRF-1, ubiquitin conjugates, proteasome activity, and in the activity of caspase-3. Soleus muscles from LPHC-fed rats showed increased insulin sensitivity, with increased levels of insulin receptor and phosphorylation levels of AKT, which probably explains the inhibition of both the caspase-3 activity and the ubiquitin-proteasome system. The fall of muscle proteolysis seems to represent an adaptive response that contributes to spare proteins in a condition of diminished availability of dietary amino acids. Furthermore, the decreased rate of protein synthesis may be the driving factor to the lower muscle mass gain in growing rats fed the LPHC diet.

  1. CDK11{sup p58} represses vitamin D receptor-mediated transcriptional activation through promoting its ubiquitin-proteasome degradation

    SciTech Connect

    Chi, Yayun; Hong, Yi; Zong, Hongliang; Wang, Yanlin; Zou, Weiying; Yang, Junwu; Kong, Xiangfei; Yun, Xiaojing; Gu, Jianxin

    2009-08-28

    Vitamin D receptor (VDR) is a member of the nuclear receptor superfamily and regulates transcription of target genes. In this study, we identified CDK11{sup p58} as a novel protein involved in the regulation of VDR. CDK11{sup p58}, a member of the large family of p34cdc2-related kinases, is associated with cell cycle progression, tumorigenesis, and apoptotic signaling. Our study demonstrated that CDK11{sup p58} interacted with VDR and repressed VDR-dependent transcriptional activation. Furthermore, overexpression of CDK11{sup p58} decreased the stability of VDR through promoting its ubiquitin-proteasome-mediated degradation. Taken together, these results suggest that CDK11{sup p58} is involved in the negative regulation of VDR.

  2. Akt Phosphorylates Wnt Coactivator and Chromatin Effector Pygo2 at Serine 48 to Antagonize Its Ubiquitin/Proteasome-mediated Degradation*

    PubMed Central

    Li, Qiuling; Li, Yuewei; Gu, Bingnan; Fang, Lei; Zhou, Pengbo; Bao, Shilai; Huang, Lan; Dai, Xing

    2015-01-01

    Pygopus 2 (Pygo2/PYGO2) is an evolutionarily conserved coactivator and chromatin effector in the Wnt/β-catenin signaling pathway that regulates cell growth and differentiation in various normal and malignant tissues. Although PYGO2 is highly overexpressed in a number of human cancers, the molecular mechanism underlying its deregulation is largely unknown. Here we report that Pygo2 protein is degraded through the ubiquitin/proteasome pathway and is posttranslationally stabilized through phosphorylation by activated phosphatidylinositol 3-kinase/Akt signaling. Specifically, Pygo2 is stabilized upon inhibition of the proteasome, and its intracellular level is regulated by Cullin 4 (Cul4) and DNA damage-binding protein 1 (DDB1), components of the Cul4-DDB1 E3 ubiquitin ligase complex. Furthermore, Pygo2 is phosphorylated at multiple residues, and Akt-mediated phosphorylation at serine 48 leads to its decreased ubiquitylation and increased stability. Finally, we provide evidence that Akt and its upstream growth factors act in parallel with Wnt to stabilize Pygo2. Taken together, our findings highlight chromatin regulator Pygo2 as a common node downstream of oncogenic Wnt and Akt signaling pathways and underscore posttranslational modification, particularly phosphorylation and ubiquitylation, as a significant mode of regulation of Pygo2 protein expression. PMID:26170450

  3. Cell-cycle-dependent PC-PLC regulation by APC/C(Cdc20)-mediated ubiquitin-proteasome pathway.

    PubMed

    Fu, Da; Ma, Yushui; Wu, Wei; Zhu, Xuchao; Jia, Chengyou; Zhao, Qianlei; Zhang, Chunyi; Wu, Xing Zhong

    2009-07-01

    Phosphatidylcholine-specific phospholipase C (PC-PLC) is involved in the cell signal transduction, cell proliferation, and apoptosis. The mechanism of its action, however, has not been fully understood, particularly, the role of PC-PLC in the cell cycle. In the present study, we found that cell division cycle 20 homolog (Cdc20) and PC-PLC were co-immunoprecipitated reciprocally by either antibody in rat hepatoma cells CBRH-7919 as well as in rat liver tissue. Using confocal microscopy, we found that PC-PLC and Cdc20 were co-localized in the perinuclear endoplasmic reticulum region (the "juxtanuclear quality control" compartment, JUNQ). The expression level and activities of PC-PLC changed in a cell-cycle-dependent manner and were inversely correlated with the expression of Cdc20. Intriguingly, Cdc20 overexpression altered the subcellular localization and distribution of PC-PLC, and caused PC-PLC degradation by the ubiquitin proteasome pathway (UPP). Taken together, our data indicate that PC-PLC regulation in cell cycles is controlled by APC/C(Cdc20)-mediated UPP.

  4. Protein Phosphatase Methyl-Esterase PME-1 Protects Protein Phosphatase 2A from Ubiquitin/Proteasome Degradation.

    PubMed

    Yabe, Ryotaro; Miura, Akane; Usui, Tatsuya; Mudrak, Ingrid; Ogris, Egon; Ohama, Takashi; Sato, Koichi

    2015-01-01

    Protein phosphatase 2A (PP2A) is a conserved essential enzyme that is implicated as a tumor suppressor based on its central role in phosphorylation-dependent signaling pathways. Protein phosphatase methyl esterase (PME-1) catalyzes specifically the demethylation of the C-terminal Leu309 residue of PP2A catalytic subunit (PP2Ac). It has been shown that PME-1 affects the activity of PP2A by demethylating PP2Ac, but also by directly binding to the phosphatase active site, suggesting loss of PME-1 in cells would enhance PP2A activity. However, here we show that PME-1 knockout mouse embryonic fibroblasts (MEFs) exhibit lower PP2A activity than wild type MEFs. Loss of PME-1 enhanced poly-ubiquitination of PP2Ac and shortened the half-life of PP2Ac protein resulting in reduced PP2Ac levels. Chemical inhibition of PME-1 and rescue experiments with wild type and mutated PME-1 revealed methyl-esterase activity was necessary to maintain PP2Ac protein levels. Our data demonstrate that PME-1 methyl-esterase activity protects PP2Ac from ubiquitin/proteasome degradation.

  5. Time course of ubiquitin-proteasome and macroautophagy-lysosome pathways in skeletal muscle in rats with heart failure.

    PubMed

    Fujita, Naoto; Fujino, Hidemi; Sakamoto, Hiroki; Takegaki, Jyunya; Deie, Masataka

    2015-01-01

    Patients with heart failure have limited exercise capacity due to not only the myocardial dysfunction but also skeletal muscle atrophy. However, the mechanisms and time course of protein degradation in skeletal muscle during heart failure remain unclear, and there is no established standard treatment. The purpose of the present study was to investigate the time course of major protein degradation pathways in skeletal muscle during heart failure. Four-week-old male Wistar rats were randomly assigned to heart failure induced by monocrotaline or control groups. At 14 and 21 days after monocrotaline injection, the lungs, heart, and gastrocnemius and soleus muscles were removed and analyzed. There was no significant difference in body weight between the groups at 14 days after monocrotaline injection. Although there were no morphological changes in the skeletal muscle of the monocrotaline group at this time point, ubiquitin-proteasome and macroautophagylysosome pathways were activated in the monocrotaline group. Additionally, the pathways were less strongly activated in the soleus muscle than in the gastrocnemius muscle. These results suggest that physical exercise that shifts to slow muscle characteristics should begin when there is no indication of skeletal muscle atrophy to prevent exercise intolerance with heart failure.

  6. Ubiquitin/proteasome-mediated proteolysis is involved in the response to flooding stress in soybean roots, independent of oxygen limitation.

    PubMed

    Yanagawa, Yuki; Komatsu, Setsuko

    2012-04-01

    Ubiquitin/proteasome-mediated proteolysis plays an important role in the response to several environmental stresses. Here, we described the relationship of the proteolysis in the flooding stress in soybean (Glycine max L. cultivar Enrei). Immunoblot analyses were performed using antibodies against two subunits of 26S proteasome, Rpt5 and Rpn10, 20S proteasome and two subunits of COP9 signalosome (CSN), CSN4 and CSN5, to compare between flooded and untreated roots. We also examined their protein amounts in the condition of low oxygen. Moreover, crude extracts from flooded or untreated roots incubated with or without a proteasome inhibitor MG132 were analyzed by proteomics technique. We revealed that the amount of ubiquitinated proteins in soybean roots decreased after flooding treatment and increased to levels similar to controls after de-submergence. Both CSN4 and CSN5 accumulated following flooding treatment, although no significant difference was observed in proteasome. Low oxygen had no effect on the amount of ubiquitinated proteins or CSN4. By 2D-PAGE, the amount of 6 proteins changed significantly following MG132 treatment in flooding stressed plants. We conclude that the accumulation of CSN proteins might enhance the degradation of ubiquitinated proteins independent of hypoxia caused by flooding, thereby lowering their abundance during flooding stress.

  7. The ubiquitin-proteasome system regulates focal adhesions at the leading edge of migrating cells

    PubMed Central

    Teckchandani, Anjali; Cooper, Jonathan A

    2016-01-01

    Cell migration requires the cyclical assembly and disassembly of focal adhesions. Adhesion induces phosphorylation of focal adhesion proteins, including Cas (Crk-associated substrate/p130Cas/BCAR1). However, Cas phosphorylation stimulates adhesion turnover. This raises the question of how adhesion assembly occurs against opposition from phospho-Cas. Here we show that suppressor of cytokine signaling 6 (SOCS6) and Cullin 5, two components of the CRL5SOCS6 ubiquitin ligase, inhibit Cas-dependent focal adhesion turnover at the front but not rear of migrating epithelial cells. The front focal adhesions contain phospho-Cas which recruits SOCS6. If SOCS6 cannot access focal adhesions, or if cullins or the proteasome are inhibited, adhesion disassembly is stimulated. This suggests that the localized targeting of phospho-Cas within adhesions by CRL5SOCS6 and concurrent cullin and proteasome activity provide a negative feedback loop, ensuring that adhesion assembly predominates over disassembly at the leading edge. By this mechanism, ubiquitination provides a new level of spatio-temporal control over cell migration. DOI: http://dx.doi.org/10.7554/eLife.17440.001 PMID:27656905

  8. Damage control: DNA repair, transcription, and the ubiquitin-proteasome system.

    PubMed

    Daulny, Anne; Tansey, William P

    2009-04-05

    The presence of DNA damage within an actively transcribed gene poses an immediate threat to cellular viability. Bulky DNA adducts, such as those induced by ultraviolet light, can profoundly influence patterns of gene expression by causing the irreversible arrest of RNA polymerase II at sites of DNA damage. It is critical that processes exist to either specifically repair transcribed genes or clear stalled RNA polymerase, so that general repair can occur and transcription resume. A growing body of evidence indicates that clearance of stalled polymerase is achieved, in part, by ubiquitin-mediated destruction of the largest subunit of RNA polymerase II. In this review, we shall discuss how an intimate connection between RNA polymerase II and the ubiquitylation machinery acts to restore normal transcription after DNA damage, and other forms of transcriptional arrest, has occurred.

  9. Characteristics of the turnover of uncoupling protein 3 by the ubiquitin proteasome system in isolated mitochondria.

    PubMed

    Mookerjee, Shona A; Brand, Martin D

    2011-11-01

    Uncoupling protein 3 (UCP3) is implicated in mild uncoupling and the regulation of mitochondrial ROS production. We previously showed that UCP3 turns over rapidly in C2C12 myoblasts, with a half-life of 0.5-4h, and that turnover can be reconstituted in vitro. We show here that rapid degradation of UCP3 in vitro in isolated brown adipose tissue mitochondria required the 26S proteasome, ubiquitin, ATP, succinate to generate a high membrane potential, and a pH of 7.4 or less. Ubiquitin containing lysine-48 was both necessary and sufficient to support UCP3 degradation, implying a requirement for polyubiquitylation at this residue. The 20S proteasome did not support degradation. UCP3 degradation was prevented by simultaneously blocking matrix ATP generation and import, showing that ATP in the mitochondrial matrix was required. Degradation did not appear to require a transmembrane pH gradient, but was very sensitive to membrane potential: degradation was halved when membrane potential decreased 10-20mV from its resting value, and was not significant below about 120mV. We propose that matrix ATP and a high membrane potential are needed for UCP3 to be polyubiquitylated through lysine-48 of ubiquitin and exported to the cytosolic 26S proteasome, where it is de-ubiquitylated and degraded.

  10. A Homozygous Mutation in KCTD7 Links Neuronal Ceroid Lipofuscinosis to the Ubiquitin-Proteasome System

    PubMed Central

    Staropoli, John F.; Karaa, Amel; Lim, Elaine T.; Kirby, Andrew; Elbalalesy, Naser; Romansky, Stephen G.; Leydiker, Karen B.; Coppel, Scott H.; Barone, Rosemary; Xin, Winnie; MacDonald, Marcy E.; Abdenur, Jose E.; Daly, Mark J.; Sims, Katherine B.; Cotman, Susan L.

    2012-01-01

    Neuronal ceroid lipofuscinosis (NCL) is a genetically heterogeneous group of lysosomal diseases that collectively compose the most common Mendelian form of childhood-onset neurodegeneration. It is estimated that ∼8% of individuals diagnosed with NCL by conservative clinical and histopathologic criteria have been ruled out for mutations in the nine known NCL-associated genes, suggesting that additional genes remain unidentified. To further understand the genetic underpinnings of the NCLs, we performed whole-exome sequencing on DNA samples from a Mexican family affected by a molecularly undefined form of NCL characterized by infantile-onset progressive myoclonic epilepsy (PME), vision loss, cognitive and motor regression, premature death, and prominent NCL-type storage material. Using a recessive model to filter the identified variants, we found a single homozygous variant, c.550C>T in KCTD7, that causes a p.Arg184Cys missense change in potassium channel tetramerization domain-containing protein 7 (KCTD7) in the affected individuals. The mutation was predicted to be deleterious and was absent in over 6,000 controls. The identified variant altered the localization pattern of KCTD7 and abrogated interaction with cullin-3, a ubiquitin-ligase component and known KCTD7 interactor. Intriguingly, murine cerebellar cells derived from a juvenile NCL model (CLN3) showed enrichment of endogenous KCTD7. Whereas KCTD7 mutations have previously been linked to PME without lysosomal storage, this study clearly demonstrates that KCTD7 mutations also cause a rare, infantile-onset NCL subtype designated as CLN14. PMID:22748208

  11. Ageing has no effect on the regulation of the ubiquitin proteasome-related genes and proteins following resistance exercise

    PubMed Central

    Stefanetti, Renae J.; Zacharewicz, Evelyn; Della Gatta, Paul; Garnham, Andrew; Russell, Aaron P.; Lamon, Séverine

    2014-01-01

    Skeletal muscle atrophy is a critical component of the ageing process. Age-related muscle wasting is due to disrupted muscle protein turnover, a process mediated in part by the ubiquitin proteasome pathway (UPP). Additionally, older subjects have been observed to have an attenuated anabolic response, at both the molecular and physiological levels, following a single-bout of resistance exercise (RE). We investigated the expression levels of the UPP-related genes and proteins involved in muscle protein degradation in 10 older (60–75 years) vs. 10 younger (18–30 years) healthy male subjects at basal as well as 2 h after a single-bout of RE. MURF1, atrogin-1 and FBXO40, their substrate targets PKM2, myogenin, MYOD, MHC and EIF3F as well as MURF1 and atrogin-1 transcriptional regulators FOXO1 and FOXO3 gene and/or protein expression levels were measured via real time PCR and western blotting, respectively. At basal, no age-related difference was observed in the gene/protein levels of atrogin-1, MURF1, myogenin, MYOD and FOXO1/3. However, a decrease in FBXO40 mRNA and protein levels was observed in older subjects, while PKM2 protein was increased. In response to RE, MURF1, atrogin-1 and FBXO40 mRNA were upregulated in both the younger and older subjects, with changes observed in protein levels. In conclusion, UPP-related gene/protein expression is comparably regulated in healthy young and old male subjects at basal and following RE. These findings suggest that UPP signaling plays a limited role in the process of age-related muscle wasting. Future studies are required to investigate additional proteolytic mechanisms in conjunction with skeletal muscle protein breakdown (MPB) measurements following RE in older vs. younger subjects. PMID:24550841

  12. Down-regulation of types I, II and III inositol 1,4,5-trisphosphate receptors is mediated by the ubiquitin/proteasome pathway.

    PubMed Central

    Oberdorf, J; Webster, J M; Zhu, C C; Luo, S G; Wojcikiewicz, R J

    1999-01-01

    Activation of certain phosphoinositidase-C-linked cell-surface receptors is known to cause an acceleration of the proteolysis of inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] receptors and, thus, lead to Ins(1,4,5)P3-receptor down-regulation. In the current study we have sought to determine whether the ubiquitin/proteasome pathway is involved in this adaptive response. The data presented show (i) that activation of phosphoinositidase-C-linked receptors causes Ins(1,4,5)P3-receptor ubiquitination in a range of cell types (AR4-2J cells, INS-1 cells and rat cerebellar granule cells), (ii) that the Ins(1,4,5)P3-receptor down-regulation induced by activation of these receptors is blocked by proteasome inhibitors, (iii) that all known Ins(1,4,5)P3 receptors (types I, II and III) are substrates for ubiquitination, (iv) that ubiquitination occurs while Ins(1,4,5)P3 receptors are membrane-bound, (v) that Ins(1,4, 5)P3-receptor ubiquitination and down-regulation are stimulated only by those agonists that elevate Ins(1,4,5)P3 concentration persistently, and (vi) that a portion of cellular Ins(1,4,5)P3 receptors (those that are not type-I-receptor-associated) can be resistant to ubiquitination and degradation. In total these data indicate that the ubiquitin/proteasome pathway mediates Ins(1,4, 5)P3-receptor down-regulation and suggest that ubiquitination is stimulated by the binding of Ins(1,4,5)P3 to its receptor. PMID:10191279

  13. A leucine-rich diet modulates the tumor-induced down-regulation of the MAPK/ERK and PI3K/Akt/mTOR signaling pathways and maintains the expression of the ubiquitin-proteasome pathway in the placental tissue of NMRI mice.

    PubMed

    Viana, Laís Rosa; Gomes-Marcondes, Maria Cristina Cintra

    2015-02-01

    Placental tissue injury is concomitant with tumor development. We investigated tumor-driven placental damage by tracing certain steps of the protein synthesis and degradation pathways under leucine-rich diet supplementation in MAC16 tumor-bearing mice. Cell signaling and ubiquitin-proteasome pathways were assessed in the placental tissues of pregnant mice, which were distributed into three groups on a control diet (pregnant control, tumor-bearing pregnant, and pregnant injected with MAC-ascitic fluid) and three other groups on a leucine-rich diet (pregnant, tumor-bearing pregnant, and pregnant injected with MAC-ascitic fluid). MAC tumor growth down-regulated the cell-signaling pathways of the placental tissue and decreased the levels of IRS-1, Akt/PKB, Erk/MAPK, mTOR, p70S6K, STAT3, and STAT6 phosphorylated proteins, as assessed by the multiplex Millipore Luminex assay. Leucine supplementation maintained the levels of these proteins within the established cell-signaling pathways. In the tumor-bearing group (MAC) only, the placental tissue showed increased PC5 mRNA expression, as assessed by quantitative RT-PCR, decreased 19S and 20S protein expression, as assessed by Western blot analysis, and decreased placental tyrosine levels, likely reflecting up-regulation of the ubiquitin-proteasome pathway. Similar effects were found in the pregnant injected with MAC-ascitic fluid group, confirming that the effects of the tumor were mimicked by MAC-ascitic fluid injection. Although tumor progression occurred, the degradation pathway-related protein levels were modulated under leucine-supplementation conditions. In conclusion, tumor evolution reduced the protein expression of the cell-signaling pathway associated with elevated protein degradation, thereby jeopardizing placental activity. Under the leucine-rich diet, the impact of cancer on placental function could be minimized by improving the cell-signaling activity and reducing the proteolytic process.

  14. Dopamine 5 receptor mediates Ang II type 1 receptor degradation via a ubiquitin-proteasome pathway in mice and human cells.

    PubMed

    Li, Hewang; Armando, Ines; Yu, Peiying; Escano, Crisanto; Mueller, Susette C; Asico, Laureano; Pascua, Annabelle; Lu, Quansheng; Wang, Xiaoyan; Villar, Van Anthony M; Jones, John E; Wang, Zheng; Periasamy, Ammasi; Lau, Yuen-Sum; Soares-da-Silva, Patricio; Creswell, Karen; Guillemette, Gaétan; Sibley, David R; Eisner, Gilbert; Gildea, John J; Felder, Robin A; Jose, Pedro A

    2008-06-01

    Hypertension is a multigenic disorder in which abnormal counterregulation between dopamine and Ang II plays a role. Recent studies suggest that this counterregulation results, at least in part, from regulation of the expression of both the antihypertensive dopamine 5 receptor (D5R) and the prohypertensive Ang II type 1 receptor (AT1R). In this report, we investigated the in vivo and in vitro interaction between these GPCRs. Disruption of the gene encoding D5R in mice increased both blood pressure and AT1R protein expression, and the increase in blood pressure was reversed by AT1R blockade. Activation of D5R increased the degradation of glycosylated AT1R in proteasomes in HEK cells and human renal proximal tubule cells heterologously and endogenously expressing human AT1R and D5R. Confocal microscopy, Förster/fluorescence resonance energy transfer microscopy, and fluorescence lifetime imaging microscopy revealed that activation of D5R initiated ubiquitination of the glycosylated AT1R at the plasma membrane. The regulated degradation of AT1R via a ubiquitin/proteasome pathway by activation of D5R provides what we believe to be a novel mechanism whereby blood pressure can be regulated by the interaction of 2 counterregulatory GPCRs. Our results therefore suggest that treatments for hypertension might be optimized by designing compounds that can target the AT1R and the D5R.

  15. The mechanism and physiological function of macroautophagy.

    PubMed

    Klionsky, Daniel J; Codogno, Patrice

    2013-01-01

    With regard to cell biology, one area of focus that has shifted back and forth over the years has been the relative emphasis on catabolic versus anabolic processes: the breakdown of glucose, the synthesis of DNA, the oxidation of pyruvate, the biogenesis of membranes, protein degradation, and protein synthesis. Historically, the majority of studies concerned with degradation dealt with the production of energy; however, the analysis of the ubiquitin-proteasome system revealed the importance of protein degradation for controlling various aspects of cell physiology. The ubiquitin-proteasome system is limited primarily to targeting individual proteins for destruction, but cells also have to deal with larger structures that are damaged, potentially toxic or superfluous, and these substrates, including entire organelles, are the purview of autophagy. As a general definition, autophagy encompasses a range of processes in which the cell degrades parts of itself within the lysosome (or the analogous organelle, the vacuole, in yeast and plants), followed by the release and reuse of the breakdown products. Thus, autophagy is in part a mechanism for cellular recycling, but such a definition belies the importance of the different autophagic processes in cell and organismal function and homeostasis. Indeed, defects in autophagy are associated with many human diseases and metabolic disorders. Here, we provide a brief overview of the mechanism of autophagy and some of the physiological roles in which this process is involved.

  16. L166P MUTANT DJ-1, CAUSATIVE FOR RECESSIVE PARKINSON'S DISEASE IS DEGRADED THROUGH THE UBIQUITIN-PROTEASOME SYSTEM

    EPA Science Inventory

    Abstract

    Mutations in a gene on chromosome 1, DJ-1, have been reported recently to be associated with recessive, early-onset Parkinson's disease. Whilst one mutation is a large deletion that is predicted to produce an effective knockout of the gene, the second is a point ...

  17. Fucoidan inhibition of lung cancer in vivo and in vitro : role of the Smurf2-dependent ubiquitin proteasome pathway in TGFβ receptor degradation.

    PubMed

    Hsu, Hsien-Yeh; Lin, Tung-Yi; Wu, Yu-Chung; Tsao, Shu-Ming; Hwang, Pai-An; Shih, Yu-Wei; Hsu, Jason

    2014-09-15

    Fucoidan, a polysaccharide extracted from brown seaweeds, reduces tumor cell proliferation. In this study, we demonstrate that fucoidan reduces tumor size in LLC1-xenograft male C57BL/6 mice. Moreover, we found that LLC1-bearing mice continuously fed fucoidan showed greater antitumor activity than mice with discontinuous feeding. Fucoidan inhibited the in vitro growth of lung cancer cells. Transforming growth factor β (TGFβ) receptors (TGFRs) play important roles in the regulation of proliferation and progression, and high TGFRI expression in lung cancer specimens is associated with a worse prognosis. Herein, using lung cancer cells, we found that fucoidan effectively reduces TGFRI and TGFRII protein levels in vivo and in vitro. Moreover, fucoidan reduces TGFR downstream signaling events, including those in Smad2/3 and non-Smad pathways: Akt, Erk1/2, and FAK phosphorylation. Furthermore, fucoidan suppresses lung cancer cell mobility upon TGFβ stimulation. To elucidate how fucoidan decreases TGFR proteins in lung cancer cells, we found that fucoidan enhances the ubiquitination proteasome pathway (UPP)-mediated degradation of TGFRs in A549 and CL1-5 cells. Mechanistically, fucoidan promotes Smurf2 and Smad7 to conjugate TGFRs, resulting in TGF degradation; however, Smurf2-shRNA abolishes fucoidan-enhanced UPP-mediated TGFR degradation. Our study is the first to identify a novel mechanism for the antitumor activity of fucoidan, namely decreasing tumor growth by modulating the TGFR/Smad7/Smurf2-dependent axis, leading to TGFR protein degradation and inhibition of lung cancer cell progression in vitro and in vivo. Our current findings indicate that fucoidan is a potential therapeutic agent or dietary supplementation for lung cancer, acting via the Smurf2-dependent ubiquitin degradation of TGFβ receptors.

  18. Activation of the ATP-ubiquitin-proteasome pathway in skeletal muscle of cachectic rats bearing a hepatoma

    NASA Technical Reports Server (NTRS)

    Baracos, V. E.; DeVivo, C.; Hoyle, D. H.; Goldberg, A. L.

    1995-01-01

    Rats implanted with Yoshida ascites hepatoma (YAH) show a rapid and selective loss of muscle protein due mainly to a marked increase (63-95%) in the rate of protein degradation (compared with rates in muscles of pair-fed controls). To define which proteolytic pathways contribute to this increase, epitrochlearis muscles from YAH-bearing and control rats were incubated under conditions that modify different proteolytic systems. Overall proteolysis in either group of rats was not affected by removal of Ca2+ or by blocking the Ca(2+)-dependent proteolytic system. Inhibition of lysosomal function with methylamine reduced proteolysis (-12%) in muscles from YAH-bearing rats, but not in muscles of pair-fed rats. When ATP production was also inhibited, the remaining accelerated proteolysis in muscles of tumor-bearing rats fell to control levels. Muscles of YAH-bearing rats showed increased levels of ubiquitin-conjugated proteins and a 27-kDa proteasome subunit in Western blot analysis. Levels of mRNA encoding components of proteolytic systems were quantitated using Northern hybridization analysis. Although their total RNA content decreased 20-38%, pale muscles of YAH-bearing rats showed increased levels of ubiquitin mRNA (590-880%) and mRNA for multiple subunits of the proteasome (100-215%). Liver, kidney, heart, and brain showed no weight loss and no change in these mRNA species. Muscles of YAH-bearing rats also showed small increases (30-40%) in mRNA for cathepsins B and D, but not for calpain I or heat shock protein 70. Our findings suggest that accelerated muscle proteolysis and muscle wasting in tumor-bearing rats result primarily from activation of the ATP-dependent pathway involving ubiquitin and the proteasome.

  19. 17-DMAG ameliorates polyglutamine-mediated motor neuron degeneration through well-preserved proteasome function in an SBMA model mouse.

    PubMed

    Tokui, Keisuke; Adachi, Hiroaki; Waza, Masahiro; Katsuno, Masahisa; Minamiyama, Makoto; Doi, Hideki; Tanaka, Keiji; Hamazaki, Jun; Murata, Shigeo; Tanaka, Fumiaki; Sobue, Gen

    2009-03-01

    The ubiquitin-proteasome system (UPS) is the principal protein degradation system that tags and targets short-lived proteins, as well as damaged or misfolded proteins, for destruction. In spinal and bulbar muscular atrophy (SBMA), the androgen receptor (AR), an Hsp90 client protein, is such a misfolded protein that tends to aggregate in neurons. Hsp90 inhibitors promote the degradation of Hsp90 client proteins via the UPS. In a transgenic mouse model of SBMA, we examined whether a functioning UPS is preserved, if it was capable of degrading polyglutamine-expanded mutant AR, and what might be the therapeutic effects of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG), an oral Hsp90 inhibitor. Ubiquitin-proteasomal function was well preserved in SBMA mice and was even increased during advanced stages when the mice developed severe phenotypes. Administration of 17-DMAG markedly ameliorated motor impairments in SBMA mice without detectable toxicity and reduced amounts of monomeric and nuclear-accumulated mutant AR. Mutant AR was preferentially degraded in the presence of 17-DMAG in both SBMA cell and mouse models when compared with wild-type AR. 17-DMAG also significantly induced Hsp70 and Hsp40. Thus, 17-DMAG would exert a therapeutic effect on SBMA via preserved proteasome function.

  20. Role of ubiquitin-proteasome in protein quality control and signaling: implication in the pathogenesis of eye diseases

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The ubiquitin–proteasome pathway (UPP) plays important roles in many cellular functions, such as protein quality control, cell cycle control, and signal transduction. The selective degradation of aberrant proteins by the UPP is essential for the timely removal of potential cytotoxic damaged or other...

  1. Physalin B not only inhibits the ubiquitin-proteasome pathway but also induces incomplete autophagic response in human colon cancer cells in vitro

    PubMed Central

    Ma, Yi-ming; Han, Wei; Li, Jia; Hu, Li-hong; Zhou, Yu-bo

    2015-01-01

    Aim: To investigate the effects of physalin B insolated from Physalis divericata on human colon cancer cells in vitro and its anticancer mechanisms. Methods: Human HCT116 colon cancer cell line was tested. Cell viability and apoptosis were detected, and relevant proteins were measured using Western blot analyses. Autophagosomes were observed in stable GFP-LC3 HCT116 cells. Localization of autophagosomes and lysosomes was evaluated in GFP-LC3/RFP-LAMP1-co-transfected cells. Microtubules and F-actin microfilaments were observed with confocal microscope. Mitochondrial ROS (mito-ROS) was detected with flow cytometry in the cells stained with MitoSox dye. Results: Physalin B inhibited the viability of HCT116 cells with an IC50 value of 1.35 μmol/L. Treatment of the cells with physalin B (2.5–10 μmol/L) induced apoptosis and the cleavage of PARP and caspase-3. Meanwhile, physalin B treatment induced autophagosome formation, and accumulation of LC3-II and p62, but decreased Beclin 1 protein level. Marked changes of microtubules and F-actin microfilaments were observed in physalin B-treated cells, which led to the blockage of co-localization of autophagosomes and lysosomes. Physalin B treatment dose-dependently increased the phosphorylation of p38, ERK and JNK in the cells, whereas the p38 inhibitor SB202190, ERK inhibitor U0126 or JNK inhibitor SP600125 could partially reduce physalin B-induced PARP cleavage and p62 accumulation. Moreover, physalin B treatment dose-dependently increased mito-ROS production in the cells, whereas the ROS scavenger NAC could reverse physalin B-induced effects, including incomplete autophagic response, accumulation of ubiquitinated proteins, changes of microtubules and F-actin, activation of p38, ERK and JNK, as well as cell death and apoptosis. Conclusion: Physalin B induces mito-ROS, which not only inhibits the ubiquitin-proteasome pathway but also induces incomplete autophagic response in HCT116 cells in vitro. PMID:25832431

  2. Role of the ubiquitin-proteasome pathway and some peptidases during seed germination and copper stress in bean cotyledons.

    PubMed

    Karmous, Inès; Chaoui, Abdelilah; Jaouani, Khadija; Sheehan, David; El Ferjani, Ezzedine; Scoccianti, Valeria; Crinelli, Rita

    2014-03-01

    The role of the ubiquitin (Ub)-proteasome pathway and some endo- and aminopeptidases (EPs and APs, respectively) was studied in cotyledons of germinating bean seeds (Phaseolus vulgaris L.). The Ub system appeared to be important both in the early (3 days) and late (9 days) phases of germination. In the presence of copper, an increase in protein carbonylation and a decrease in reduced -SH pool occurred, indicating protein damage. This was associated with an enhancement in accumulation of malondialdehyde, a major product of lipid peroxidation, and an increase in content of hydrogen peroxide (H2O2), showing oxidative stress generation. Moreover, copper induced inactivation of the Ub-proteasome (EC 3.4.25) pathway and inhibition of leucine and proline aminopeptidase activities (EC 3.4.11.1 and EC 3.4.11.5, respectively), thus limiting their role in modulating essential metabolic processes, such as the removal of regulatory and oxidatively-damaged proteins. By contrast, total trypsin and chymotrypsin-like activities (EC 3.4.21.4 and EC 3.4.21.1, respectively) increased after copper exposure, in parallel with a decrease in their inhibitor capacities (i.e. trypsin inhibitor and chymotrypsin inhibitor activity), suggesting that these endoproteases are part of the protective mechanisms against copper stress.

  3. Structural insights into the functional cycle of the ATPase module of the 26S proteasome.

    PubMed

    Wehmer, Marc; Rudack, Till; Beck, Florian; Aufderheide, Antje; Pfeifer, Günter; Plitzko, Jürgen M; Förster, Friedrich; Schulten, Klaus; Baumeister, Wolfgang; Sakata, Eri

    2017-02-07

    In eukaryotic cells, the ubiquitin-proteasome system (UPS) is responsible for the regulated degradation of intracellular proteins. The 26S holocomplex comprises the core particle (CP), where proteolysis takes place, and one or two regulatory particles (RPs). The base of the RP is formed by a heterohexameric AAA(+) ATPase module, which unfolds and translocates substrates into the CP. Applying single-particle cryo-electron microscopy (cryo-EM) and image classification to samples in the presence of different nucleotides and nucleotide analogs, we were able to observe four distinct conformational states (s1 to s4). The resolution of the four conformers allowed for the construction of atomic models of the AAA(+) ATPase module as it progresses through the functional cycle. In a hitherto unobserved state (s4), the gate controlling access to the CP is open. The structures described in this study allow us to put forward a model for the 26S functional cycle driven by ATP hydrolysis.

  4. A decade of the anaphase-promoting complex in the nervous system.

    PubMed

    Huang, Ju; Bonni, Azad

    2016-03-15

    Control of protein abundance by the ubiquitin-proteasome system is essential for normal brain development and function. Just over a decade ago, the first post-mitotic function of the anaphase-promoting complex, a major cell cycle-regulated E3 ubiquitin ligase, was discovered in the control of axon growth and patterning in the mammalian brain. Since then, a large number of studies have identified additional novel roles for the anaphase-promoting complex in diverse aspects of neuronal connectivity and plasticity in the developing and mature nervous system. In this review, we discuss the functions and mechanisms of the anaphase-promoting complex in neurogenesis, glial differentiation and migration, neuronal survival and metabolism, neuronal morphogenesis, synapse formation and plasticity, and learning and memory. We also provide a perspective on future investigations of the anaphase-promoting complex in neurobiology.

  5. The new function of two ubiquitin C-terminal hydrolase isozymes as reciprocal modulators of germ cell apoptosis.

    PubMed

    Kwon, Jungkee

    2007-04-01

    Ubiquitination is required throughout all developmental stages of mammalian spermatogenesis. The two ubiquitin C-terminal hydrolase (UCH) enzymes, UCH-L1 and UCH-L3, deubiquitinate ubiquitin-protein conjugates and control the cellular balance of ubiquitin. These two UCH isozymes have 52% amino acid identity and share significant structural similarity. A new function of these two closely related UCH enzymes during spermatogenesis which is associated with germ cell apoptosis has been analyzed. Apoptosis, in general, is thought to be partly regulated by the ubiquitin-proteasome system. During spermatogenesis, apoptosis controls germ cell numbers and eliminates defective germ cells to facilitate testicular homeostasis. In this paper, I review the distinct function of the two UCH isozymes in the testis of gad and Uchl3 knockout mice, which are strongly but reciprocally expressed during spermatogenesis. In addition, the importance of UCHL1-dependent apoptosis for normal spermatogenesis and sperm quality control is discussed.

  6. Quality control of a cytoplasmic protein complex: chaperone motors and the ubiquitin-proteasome system govern the fate of orphan fatty acid synthase subunit Fas2 of yeast.

    PubMed

    Scazzari, Mario; Amm, Ingo; Wolf, Dieter H

    2015-02-20

    For the assembly of protein complexes in the cell, the presence of stoichiometric amounts of the respective protein subunits is of utmost importance. A surplus of any of the subunits may trigger unspecific and harmful protein interactions and has to be avoided. A stoichiometric amount of subunits must finally be reached via transcriptional, translational, and/or post-translational regulation. Synthesis of saturated 16 and 18 carbon fatty acids is carried out by fatty acid synthase: in yeast Saccharomyces cerevisiae, a 2.6-MDa molecular mass assembly containing six protomers each of two different subunits, Fas1 (β) and Fas2 (α). The (α)6(β)6 complex carries six copies of all eight enzymatic activities required for fatty acid synthesis. The FAS1 and FAS2 genes in yeast are unlinked and map on two different chromosomes. Here we study the fate of the α-subunit of the complex, Fas2, when its partner, the β-subunit Fas1, is absent. Individual subunits of fatty acid synthase are proteolytically degraded when the respective partner is missing. Elimination of Fas2 is achieved by the proteasome. Here we show that a ubiquitin transfer machinery is required for Fas2 elimination. The major ubiquitin ligase targeting the superfluous Fas2 subunit to the proteasome is Ubr1. The ubiquitin-conjugating enzymes Ubc2 and Ubc4 assist the degradation process. The AAA-ATPase Cdc48 and the Hsp70 chaperone Ssa1 are crucially involved in the elimination of Fas2.

  7. Activation of Both the Calpain and Ubiquitin-Proteasome Systems Contributes to Septic Cardiomyopathy through Dystrophin Loss/Disruption and mTOR Inhibition

    PubMed Central

    Freitas, Ana Caroline Silva; Figueiredo, Maria Jose; Campos, Erica Carolina; Soave, Danilo Figueiredo; Ramos, Simone Gusmao; Tanowitz, Herbert B.

    2016-01-01

    Cardiac dysfunction caused by the impairment of myocardial contractility has been recognized as an important factor contributing to the high mortality in sepsis. Calpain activation in the heart takes place in response to increased intracellular calcium influx resulting in proteolysis of structural and contractile proteins with subsequent myocardial dysfunction. The purpose of the present study was to test the hypothesis that increased levels of calpain in the septic heart leads to disruption of structural and contractile proteins and that administration of calpain inhibitor-1 (N-acetyl-leucinyl-leucinyl-norleucinal (ALLN)) after sepsis induced by cecal ligation and puncture prevents cardiac protein degradation. We also tested the hypothesis that calpain plays a role in the modulation of protein synthesis/degradation through the activation of proteasome-dependent proteolysis and inhibition of the mTOR pathway. Severe sepsis significantly increased heart calpain-1 levels and promoted ubiquitin and Pa28β over-expression with a reduction in the mTOR levels. In addition, sepsis reduced the expression of structural proteins dystrophin and β-dystroglycan as well as the contractile proteins actin and myosin. ALLN administration prevented sepsis-induced increases in calpain and ubiquitin levels in the heart, which resulted in decreased of structural and contractile proteins degradation and basal mTOR expression levels were re-established. Our results support the concept that increased calpain concentrations may be part of an important mechanism of sepsis-induced cardiac muscle proteolysis. PMID:27880847

  8. Endophilin-A Deficiency Induces the Foxo3a-Fbxo32 Network in the Brain and Causes Dysregulation of Autophagy and the Ubiquitin-Proteasome System.

    PubMed

    Murdoch, John D; Rostosky, Christine M; Gowrisankaran, Sindhuja; Arora, Amandeep S; Soukup, Sandra-Fausia; Vidal, Ramon; Capece, Vincenzo; Freytag, Siona; Fischer, Andre; Verstreken, Patrik; Bonn, Stefan; Raimundo, Nuno; Milosevic, Ira

    2016-10-18

    Endophilin-A, a well-characterized endocytic adaptor essential for synaptic vesicle recycling, has recently been linked to neurodegeneration. We report here that endophilin-A deficiency results in impaired movement, age-dependent ataxia, and neurodegeneration in mice. Transcriptional analysis of endophilin-A mutant mice, complemented by proteomics, highlighted ataxia- and protein-homeostasis-related genes and revealed upregulation of the E3-ubiquitin ligase FBXO32/atrogin-1 and its transcription factor FOXO3A. FBXO32 overexpression triggers apoptosis in cultured cells and neurons but, remarkably, coexpression of endophilin-A rescues it. FBXO32 interacts with all three endophilin-A proteins. Similarly to endophilin-A, FBXO32 tubulates membranes and localizes on clathrin-coated structures. Additionally, FBXO32 and endophilin-A are necessary for autophagosome formation, and both colocalize transiently with autophagosomes. Our results point to a role for endophilin-A proteins in autophagy and protein degradation, processes that are impaired in their absence, potentially contributing to neurodegeneration and ataxia.

  9. Rapid degradation of mutant SLC25A46 by the ubiquitin-proteasome system results in MFN1/2-mediated hyperfusion of mitochondria.

    PubMed

    Steffen, Janos; Vashisht, Ajay A; Wan, Jijun; Jen, Joanna C; Claypool, Steven M; Wohlschlegel, James A; Koehler, Carla M

    2017-03-01

    SCL25A46 is a mitochondrial carrier protein that surprisingly localizes to the outer membrane and is distantly related to Ugo1. Here we show that a subset of SLC25A46 interacts with mitochondrial dynamics components and the MICOS complex. Decreased expression of SLC25A46 results in increased stability and oligomerization of MFN1 and MFN2 on mitochondria, promoting mitochondrial hyperfusion. A mutation at L341P causes rapid degradation of SLC25A46, which manifests as a rare disease, pontocerebellar hypoplasia. The E3 ubiquitin ligases MULAN and MARCH5 coordinate ubiquitylation of SLC25A46 L341P, leading to degradation by organized activities of P97 and the proteasome. Whereas outer mitochondrial membrane-associated degradation is typically associated with apoptosis or a specialized type of autophagy termed mitophagy, SLC25A46 degradation operates independently of activation of outer membrane stress pathways. Thus SLC25A46 is a new component in mitochondrial dynamics that serves as a regulator for MFN1/2 oligomerization. Moreover, SLC25A46 is selectively degraded from the outer membrane independently of mitophagy and apoptosis, providing a framework for mechanistic studies in the proteolysis of outer membrane proteins.

  10. Development of a functional food or drug against unloading-mediated muscle atrophy

    NASA Astrophysics Data System (ADS)

    Nikawa, Takeshi; Nakao, Reiko; Kagawa, Sachiko; Yamada, Chiharu; Abe, Manami; Tamura, Seiko; Kohno, Shohei; Sukeno, Akiko; Hirasaka, Katsuya; Okumura, Yuushi; Ishidoh, Kazumi

    The ubiquitin-proteasome pathway is a primary regulator of muscle protein turnover, providing a mechanism for selective degradation of regulatory and structural proteins. This pathway is constitutively active in muscle fibers and mediates both intracellular signaling events and normal muscle protein turnover. However, conditions of decreased muscle use, so called unloading, remarkably stimulate activity of this pathway, resulting in loss of muscle protein. In fact, we previously reported that expression of several ubiquitin ligase genes, such as MuRF-1, Cbl-b, and Siah-1A, which are rate-limiting enzymes of the ubiquitin-proteasome proteolytic pathway, are significantly up-regulated in rat skeletal muscle during spaceflight. Moreover, we found that Cbl-b-mediated ubiquitination and degradation of IRS-1, an important intermediates of IGF-1 signal transduction, contributes to muscle atrophy during unloading. Therefore, we hypothesized that inhibition of Cbl-b-mediated ubiquitination and degradation of IRS-1 leads to prevention of muscle atrophy during unloading. In this study, we aimed to evaluate oligopeptide as an inhibitor against ubiquitination of IRS-1 by Cbl-b. We synthesized various oligopeptides that may competitively inhibit the binding of Cbl-b to IRS-1 on the basis of their structures and screened inhibitory effects of these synthesized oligopeptides on Cbl-b-mediated ubiquitination of IRS-1 using in vitro ubiquitination systems. We found that two synthetic oligopeptides with specific amino acid sequences effectively inhibited interaction with Cbl-b and IRS-1, resulting in decreased ubiquitination and degradation of IRS-1 (Patent pending). In contrast, we also found inhibitory activity against Cbl-b-mediated ubiquitination of IRS-1 in soy protein-derived oligopeptides, whereas their inhibitory effects were weaker than those of synthetic oligopeptides. Our results suggest that specific oligopeptides may be available as a functional food against the muscle

  11. cAMP signaling increases histone deacetylase 8 expression by inhibiting JNK-dependent degradation via autophagy and the proteasome system in H1299 lung cancer cells.

    PubMed

    Park, Ji-Yeon; Juhnn, Yong-Sung

    2016-02-05

    This study aimed to investigate the roles of autophagy and the ubiquitin-proteasome system in the degradation of histone deacetylase 8 (HDAC8) and to clarify the mechanism by which cAMP signaling regulates this degradation. cAMP signaling was activated by treating H1299 non-small cell lung cancer cells with isoproterenol or forskolin/3-isobutyl-1-methylxanthine, and HDAC8 expression was assessed by western blot analysis. The inhibition of autophagy and ubiquitin-proteasome-dependent degradation increased HDAC8 expression. cAMP signaling inhibited JNK activation, which decreased the phosphorylation of Bcl-2, thereby reducing autophagy, and the phosphorylation of Itch, thereby reducing ubiquitination. These results suggest that the HDAC8 protein is degraded via autophagy and the ubiquitin-proteasome system and that cAMP signaling increases HDAC8 protein levels by reducing JNK-mediated autophagy and ubiquitin-proteasome-dependent degradation of the HDAC8 protein in H1299 lung cancer cells.

  12. Amyloid Precursor Protein (APP) May Act as a Substrate and a Recognition Unit for CRL4CRBN and Stub1 E3 Ligases Facilitating Ubiquitination of Proteins Involved in Presynaptic Functions and Neurodegeneration.

    PubMed

    Del Prete, Dolores; Rice, Richard C; Rajadhyaksha, Anjali M; D'Adamio, Luciano

    2016-08-12

    The amyloid precursor protein (APP), whose mutations cause Alzheimer disease, plays an important in vivo role and facilitates transmitter release. Because the APP cytosolic region (ACR) is essential for these functions, we have characterized its brain interactome. We found that the ACR interacts with proteins that regulate the ubiquitin-proteasome system, predominantly with the E3 ubiquitin-protein ligases Stub1, which binds the NH2 terminus of the ACR, and CRL4(CRBN), which is formed by Cul4a/b, Ddb1, and Crbn, and interacts with the COOH terminus of the ACR via Crbn. APP shares essential functions with APP-like protein-2 (APLP2) but not APP-like protein-1 (APLP1). Noteworthy, APLP2, but not APLP1, interacts with Stub1 and CRL4(CRBN), pointing to a functional pathway shared only by APP and APLP2. In vitro ubiquitination/ubiquitome analysis indicates that these E3 ligases are enzymatically active and ubiquitinate the ACR residues Lys(649/650/651/676/688) Deletion of Crbn reduces ubiquitination of Lys(676) suggesting that Lys(676) is physiologically ubiquitinated by CRL4(CRBN) The ACR facilitated in vitro ubiquitination of presynaptic proteins that regulate exocytosis, suggesting a mechanism by which APP tunes transmitter release. Other dementia-related proteins, namely Tau and apoE, interact with and are ubiquitinated via the ACR in vitro This, and the evidence that CRBN and CUL4B are linked to intellectual disability, prompts us to hypothesize a pathogenic mechanism, in which APP acts as a modulator of E3 ubiquitin-protein ligase(s), shared by distinct neuronal disorders. The well described accumulation of ubiquitinated protein inclusions in neurodegenerative diseases and the link between the ubiquitin-proteasome system and neurodegeneration make this concept plausible.

  13. Aging and Immune Function: Molecular Mechanisms to Interventions

    PubMed Central

    Ponnappan, Subramaniam

    2011-01-01

    Abstract The immune system of an organism is an essential component of the defense mechanism aimed at combating pathogenic stress. Age-associated immune dysfunction, also dubbed “immune senescence,” manifests as increased susceptibility to infections, increased onset and progression of autoimmune diseases, and onset of neoplasia. Over the years, extensive research has generated consensus in terms of the phenotypic and functional defects within the immune system in various organisms, including humans. Indeed, age-associated alterations such as thymic involution, T cell repertoire skewing, decreased ability to activate naïve T cells and to generate robust memory responses, have been shown to have a causative role in immune decline. Further, understanding the molecular mechanisms underlying the generation of proteotoxic stress, DNA damage response, modulation of ubiquitin proteasome pathway, and regulation of transcription factor NFκB activation, in immune decline, have paved the way to delineating signaling pathways that cross-talk and impact immune senescence. Given the role of the immune system in combating infections, its effectiveness with age may well be a marker of health and a predictor of longevity. It is therefore believed that a better understanding of the mechanisms underlying immune senescence will lead to an effective interventional strategy aimed at improving the health span of individuals. Antioxid. Redox Signal. 14, 1551–1585. PMID:20812785

  14. Fast axonal transport of the proteasome complex depends on membrane interaction and molecular motor function.

    PubMed

    Otero, Maria G; Alloatti, Matías; Cromberg, Lucas E; Almenar-Queralt, Angels; Encalada, Sandra E; Pozo Devoto, Victorio M; Bruno, Luciana; Goldstein, Lawrence S B; Falzone, Tomás L

    2014-04-01

    Protein degradation by the ubiquitin-proteasome system in neurons depends on the correct delivery of the proteasome complex. In neurodegenerative diseases, aggregation and accumulation of proteins in axons link transport defects with degradation impairments; however, the transport properties of proteasomes remain unknown. Here, using in vivo experiments, we reveal the fast anterograde transport of assembled and functional 26S proteasome complexes. A high-resolution tracking system to follow fluorescent proteasomes revealed three types of motion: actively driven proteasome axonal transport, diffusive behavior in a viscoelastic axonema and proteasome-confined motion. We show that active proteasome transport depends on motor function because knockdown of the KIF5B motor subunit resulted in impairment of the anterograde proteasome flux and the density of segmental velocities. Finally, we reveal that neuronal proteasomes interact with intracellular membranes and identify the coordinated transport of fluorescent proteasomes with synaptic precursor vesicles, Golgi-derived vesicles, lysosomes and mitochondria. Taken together, our results reveal fast axonal transport as a new mechanism of proteasome delivery that depends on membrane cargo 'hitch-hiking' and the function of molecular motors. We further hypothesize that defects in proteasome transport could promote abnormal protein clearance in neurodegenerative diseases.

  15. Sirtuins and Proteolytic Systems: Implications for Pathogenesis of Synucleinopathies

    PubMed Central

    Sampaio-Marques, Belém; Ludovico, Paula

    2015-01-01

    Insoluble and fibrillar forms of α-synuclein are the major components of Lewy bodies, a hallmark of several sporadic and inherited neurodegenerative diseases known as synucleinopathies. α-Synuclein is a natural unfolded and aggregation-prone protein that can be degraded by the ubiquitin-proteasomal system and the lysosomal degradation pathways. α-Synuclein is a target of the main cellular proteolytic systems, but it is also able to alter their function further, contributing to the progression of neurodegeneration. Aging, a major risk for synucleinopathies, is associated with a decrease activity of the proteolytic systems, further aggravating this toxic looping cycle. Here, the current literature on the basic aspects of the routes for α-synuclein clearance, as well as the consequences of the proteolytic systems collapse, will be discussed. Finally, particular focus will be given to the sirtuins’s role on proteostasis regulation, since their modulation emerged as a promising therapeutic strategy to rescue cells from α-synuclein toxicity. The controversial reports on the potential role of sirtuins in the degradation of α-synuclein will be discussed. Connection between sirtuins and proteolytic systems is definitely worth of further studies to increase the knowledge that will allow its proper exploration as new avenue to fight synucleinopathies. PMID:25946078

  16. Nopaline-type Ti plasmid of Agrobacterium encodes a VirF-like functional F-box protein.

    PubMed

    Lacroix, Benoît; Citovsky, Vitaly

    2015-11-20

    During Agrobacterium-mediated genetic transformation of plants, several bacterial virulence (Vir) proteins are translocated into the host cell to facilitate infection. One of the most important of such translocated factors is VirF, an F-box protein produced by octopine strains of Agrobacterium, which presumably facilitates proteasomal uncoating of the invading T-DNA from its associated proteins. The presence of VirF also is thought to be involved in differences in host specificity between octopine and nopaline strains of Agrobacterium, with the current dogma being that no functional VirF is encoded by nopaline strains. Here, we show that a protein with homology to octopine VirF is encoded by the Ti plasmid of the nopaline C58 strain of Agrobacterium. This protein, C58VirF, possesses the hallmarks of functional F-box proteins: it contains an active F-box domain and specifically interacts, via its F-box domain, with SKP1-like (ASK) protein components of the plant ubiquitin/proteasome system. Thus, our data suggest that nopaline strains of Agrobacterium have evolved to encode a functional F-box protein VirF.

  17. DNA damage in germ cells induces an innate immune response that triggers systemic stress resistance.

    PubMed

    Ermolaeva, Maria A; Segref, Alexandra; Dakhovnik, Alexander; Ou, Hui-Ling; Schneider, Jennifer I; Utermöhlen, Olaf; Hoppe, Thorsten; Schumacher, Björn

    2013-09-19

    DNA damage responses have been well characterized with regard to their cell-autonomous checkpoint functions leading to cell cycle arrest, senescence and apoptosis. In contrast, systemic responses to tissue-specific genome instability remain poorly understood. In adult Caenorhabditis elegans worms germ cells undergo mitotic and meiotic cell divisions, whereas somatic tissues are entirely post-mitotic. Consequently, DNA damage checkpoints function specifically in the germ line, whereas somatic tissues in adult C. elegans are highly radio-resistant. Some DNA repair systems such as global-genome nucleotide excision repair (GG-NER) remove lesions specifically in germ cells. Here we investigated how genome instability in germ cells affects somatic tissues in C. elegans. We show that exogenous and endogenous DNA damage in germ cells evokes elevated resistance to heat and oxidative stress. The somatic stress resistance is mediated by the ERK MAP kinase MPK-1 in germ cells that triggers the induction of putative secreted peptides associated with innate immunity. The innate immune response leads to activation of the ubiquitin-proteasome system (UPS) in somatic tissues, which confers enhanced proteostasis and systemic stress resistance. We propose that elevated systemic stress resistance promotes endurance of somatic tissues to allow delay of progeny production when germ cells are genomically compromised.

  18. Localization of ubiquitin C-terminal hydrolase L1 in mouse ova and its function in the plasma membrane to block polyspermy.

    PubMed

    Sekiguchi, Satoshi; Kwon, Jungkee; Yoshida, Etsuko; Hamasaki, Hiroko; Ichinose, Shizuko; Hideshima, Makoto; Kuraoka, Mutsuki; Takahashi, Akio; Ishii, Yoshiyuki; Kyuwa, Shigeru; Wada, Keiji; Yoshikawa, Yasuhiro

    2006-11-01

    Protein degradation is essential for oogenesis and embryogenesis. The ubiquitin-proteasome system regulates many cellular processes via the rapid degradation of specific proteins. Ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) is exclusively expressed in neurons, testis, ovary, and placenta, each of which has unique biological activities. However, the functional role of UCH-L1 in mouse oocytes remains unknown. Here, we report the expression pattern of UCH-L1 and its isozyme UCH-L3 in mouse ovaries and embryos. Using immunocytochemistry, UCH-L1 was selectively detected on the plasma membrane, whereas UCH-L3 was mainly detected in the cytoplasm, suggesting that these isozymes have distinct functions in mouse eggs. To further investigate the functional role of UCH-L1 in mouse eggs, we analyzed the fertilization rate of UCH-L1-deficient ova of gad female mice. Female gad mice had a significantly increased rate of polyspermy in in vitro fertilization assays, although the rate of fertilization did not differ significantly from wild-type mice. In addition, the litter size of gad female mice was significantly reduced compared with wild-type mice. These results may identify UCH-L1 as a candidate for a sperm-oocyte interactive binding or fusion protein on the plasma membrane that functions during the block to polyspermy in mouse oocytes.

  19. Modulation of protein quality control systems by food phytochemicals.

    PubMed

    Murakami, Akira

    2013-05-01

    There is compelling evidence showing that dietary phytochemicals have exhibited pronounced bioactivities in a number of experimental models. In addition, a variety of epidemiological surveys have demonstrated that frequent ingestion of vegetables and fruits, which contain abundant phytochemicals, lowers the risk of onset of some diseases. However, the action mechanisms by which dietary phytochemicals show bioactivity remain to be fully elucidated and a fundamental question is why this class of chemicals has great potential for regulating health. Meanwhile, maintenance and repair of biological proteins by molecular chaperones, such as heat shock proteins, and clearance of abnormal proteins by the ubiquitin-proteasome system and autophagy play central roles in health, some disease prevention, and longevity. Interestingly, several recent studies have revealed that phytochemicals, including curcumin (yellow pigment in turmeric), resveratrol (phytoalexin in grapes), quercetin (general flavonol in onions and others), and isothiocyanates (preferentially present in cruciferous vegetables, such as broccoli and cabbage), are remarkable regulators of protein quality control systems, suggesting that their physiological and biological functions are exerted, at least in part, through activation of such unique mechanisms. This review article highlights recent findings regarding the effects of representative phytochemicals on protein quality control systems and their possible molecular mechanisms.

  20. Structure, function and networks of transcription factors involved in abiotic stress responses.

    PubMed

    Lindemose, Søren; O'Shea, Charlotte; Jensen, Michael Krogh; Skriver, Karen

    2013-03-13

    Transcription factors (TFs) are master regulators of abiotic stress responses in plants. This review focuses on TFs from seven major TF families, known to play functional roles in response to abiotic stresses, including drought, high salinity, high osmolarity, temperature extremes and the phytohormone ABA. Although ectopic expression of several TFs has improved abiotic stress tolerance in plants, fine-tuning of TF expression and protein levels remains a challenge to avoid crop yield loss. To further our understanding of TFs in abiotic stress responses, emerging gene regulatory networks based on TFs and their direct targets genes are presented. These revealed components shared between ABA-dependent and independent signaling as well as abiotic and biotic stress signaling. Protein structure analysis suggested that TFs hubs of large interactomes have extended regions with protein intrinsic disorder (ID), referring to their lack of fixed tertiary structures. ID is now an emerging topic in plant science. Furthermore, the importance of the ubiquitin-proteasome protein degradation systems and modification by sumoylation is also apparent from the interactomes. Therefore; TF interaction partners such as E3 ubiquitin ligases and TF regions with ID represent future targets for engineering improved abiotic stress tolerance in crops.

  1. Gene therapy by proteasome activator, PA28γ, improves motor coordination and proteasome function in Huntington's disease YAC128 mice.

    PubMed

    Jeon, J; Kim, W; Jang, J; Isacson, O; Seo, H

    2016-06-02

    Huntington's disease (HD) is neurologically characterized by involuntary movements, associated with degeneration of the medium-sized spiny neurons (MSNs) and ubiquitin-positive neuronal intranuclear inclusions (NIIs). It has been reported that the proteolytic activities of the ubiquitin-proteasome system (UPS) are generally inhibited in HD patient's brain. We previously discovered that a proteasome activator (PA), PA28γ enhances proteasome activities and cell survival in in vitro HD model. In this study, we aimed to find whether PA28γ gene transfer improves the proteasome activities and pathological symptoms in in vivo HD model. We stereotaxically injected lenti-PA28γ virus into the striatum of mutant (MT) YAC128 HD mice and littermate (LM) controls at 14-18months of age, and validated their behavioral and biochemical changes at 12weeks after the injection. YAC128 mice showed a significant increase in their peptidyl-glutamyl preferring hydrolytic (PGPH) proteasome activity and the mRNA or protein levels of brain-derived neurotrophic factor (BDNF) and pro-BDNF after lenti-PA28γ injection. The number of ubiquitin-positive inclusion bodies was reduced in the striatum of YAC128 mice after lenti-PA28γ injection. YAC128 mice showed significant improvement of latency to fall on the rota-rod test after lenti-PA28γ injection. These data demonstrate that the gene therapy with PA, PA28γ can improve UPS function as well as behavioral abnormalities in HD model mice.

  2. Negatively Charged Metal Oxide Nanoparticles Interact with the 20S Proteasome and Differentially Modulate Its Biologic Functional Effects

    PubMed Central

    Falaschetti, Christine A.; Paunesku, Tatjana; Kurepa, Jasmina; Nanavati, Dhaval; Chou, Stanley S.; De, Mrinmoy; Song, MinHa; Jang, Jung-tak; Wu, Aiguo; Dravid, Vinayak P.; Cheon, Jinwoo; Smalle, Jan; Woloschak, Gayle E.

    2013-01-01

    The multicatalytic ubiquitin-proteasome system (UPS) carries out proteolysis in a highly orchestrated way and regulates a large number of cellular processes. Deregulation of the UPS in many disorders has been documented. In some cases, e.g. carcinogenesis, elevated proteasome activity has been implicated in disease development, while the etiology of other diseases, e.g. neurodegeneration, includes decreased UPS activity. Therefore, agents that alter proteasome activity could suppress as well as enhance a multitude of diseases. Metal oxide nanoparticles, often developed as diagnostic tools, have not previously been tested as modulators of proteasome activity. Here, several types of metal oxide nanoparticles were found to adsorb to the proteasome and show variable preferential binding for particular proteasome subunits with several peptide binding “hotspots” possible. These interactions depend on the size, charge, and concentration of the nanoparticles and affect proteasome activity in a time-dependent manner. Should metal oxide nanoparticles increase proteasome activity in cells, as they do in vitro, unintended effects related to changes in proteasome function can be expected. PMID:23930940

  3. In silico functional analyses and discovery of survival-associated microRNA signatures in pediatric osteosarcoma

    PubMed Central

    Sanchez-Diaz, Patricia C.; Hsiao, Tzu-Hung; Zou, Yi; Sugalski, Aaron J.; Heim-Hall, Josefine; Chen, Yidong; Langevin, Anne-Marie; Hung, Jaclyn Y.

    2014-01-01

    Purpose Osteosarcoma is the most common bone tumor in children, adolescents, and young adults. In contrast to other childhood malignancies, no biomarkers have been consistently identified as predictors of outcome. This study was conducted to assess the microRNAs(miRs) expression signatures in pre-treatment osteosarcoma specimens and correlate with outcome to identify biomarkers for disease relapse. Results A 42-miRs signature whose expression levels were associated with overall and relapse-free survival waas identified. There were 8 common miRs between the two sets of survival-associated miRs. Bioinformatic analyses of these survival-associated miRs suggested that they might regulate genes involved in ubiquitin proteasome system, TGFb, IGF, PTEN/AKT/mTOR, MAPK, PDGFR/RAF/MEK/ERK, and ErbB/HER pathways. Methods The cohort consisted of 27 patients of 70% Mexican-American ethnicity. High-throughput RT-qPCR approach was used to generate quantitative expression of 754 miRs in the human genome. We examined tumor recurrence status, survival time and their association with miR expression levels by Cox proportional hazard regression analysis. TargetScan was used to predict miR/genes interactions, and functional analyses using KEGG, BioCarta, Gene Ontology were applied to these potential targets to predict deregulated pathways. Conclusions Our findings suggested that these miRs might be potentially useful as prognostic biomarkers and therapeutic targets in pediatric osteosarcoma. PMID:25594070

  4. [Role of intracellular degradation system in regulation of innate immune response].

    PubMed

    Saitoh, Tatsuya

    2014-01-01

    Innate immunity is induced after sensing microbial components by pattern-recognition receptors and functions as a first line of host defense against microbes. However, innate immunity is also induced after sensing host-derived stimulatory substances such as monosodium urate crystals and causes the development of inflammatory diseases, such as gout. Therefore, a better understanding of innate immunity is required for the development of effective therapeutic treatments for infectious and inflammatory diseases. This paper summarizes recent findings on regulation of the innate immune response. Accumulating evidence has shown that the intracellular degradation system is critically involved in various cellular processes. We focused on the intracellular degradation system and have revealed the molecular mechanisms underlying regulation of the innate immune response. Ubiquitin-proteasome, autophagy and phagocyte-specific proteases most certainly regulate the innate immune response induced by infection of microbes and exposure to host-derived stimulatory substances. Therefore, intracellular degradation systems would be attractive therapeutic targets for the treatment of immune-related diseases.

  5. Drugging the undruggables: exploring the ubiquitin system for drug development

    PubMed Central

    Huang, Xiaodong; Dixit, Vishva M

    2016-01-01

    Dynamic modulation of protein levels is tightly controlled in response to physiological cues. In mammalian cells, much of the protein degradation is carried out by the ubiquitin-proteasome system (UPS). Similar to kinases, components of the ubiquitin system are often dysregulated, leading to a variety of diseases, including cancer and neurodegeneration, making them attractive drug targets. However, so far there are only a handful of drugs targeting the ubiquitin system that have been approved by the FDA. Here, we review possible therapeutic intervention nodes in the ubiquitin system, analyze the challenges, and highlight the most promising strategies to target the UPS. PMID:27002218

  6. The F-box protein Fbp1 functions in the invasive growth and cell wall integrity mitogen-activated protein kinase (MAPK) pathways in Fusarium oxysporum.

    PubMed

    Miguel-Rojas, Cristina; Hera, Concepcion

    2016-01-01

    F-box proteins determine substrate specificity of the ubiquitin-proteasome system. Previous work has demonstrated that the F-box protein Fbp1, a component of the SCF(Fbp1) E3 ligase complex, is essential for invasive growth and virulence of the fungal plant pathogen Fusarium oxysporum. Here, we show that, in addition to invasive growth, Fbp1 also contributes to vegetative hyphal fusion and fungal adhesion to tomato roots. All of these functions have been shown previously to require the mitogen-activated protein kinase (MAPK) Fmk1. We found that Fbp1 is required for full phosphorylation of Fmk1, indicating that Fbp1 regulates virulence and invasive growth via the Fmk1 pathway. Moreover, the Δfbp1 mutant is hypersensitive to sodium dodecylsulfate (SDS) and calcofluor white (CFW) and shows reduced phosphorylation levels of the cell wall integrity MAPK Mpk1 after SDS treatment. Collectively, these results suggest that Fbp1 contributes to both the invasive growth and cell wall integrity MAPK pathways of F. oxysporum.

  7. Destabilizing LSD1 by Jade-2 promotes neurogenesis: an antibraking system in neural development.

    PubMed

    Han, Xiao; Gui, Bin; Xiong, Cong; Zhao, Linnan; Liang, Jing; Sun, Luyang; Yang, Xiaohan; Yu, Wenhua; Si, Wenzhe; Yan, Ruorong; Yi, Xia; Zhang, Di; Li, Wanjin; Li, Lifang; Yang, Jianguo; Wang, Yan; Sun, Yi Eve; Zhang, Dai; Meng, Anming; Shang, Yongfeng

    2014-08-07

    Histone H3K4 demethylase LSD1 plays an important role in stem cell biology, especially in the maintenance of the silencing of differentiation genes. However, how the function of LSD1 is regulated and the differentiation genes are derepressed are not understood. Here, we report that elimination of LSD1 promotes embryonic stem cell (ESC) differentiation toward neural lineage. We showed that the destabilization of LSD1 occurs posttranscriptionally via the ubiquitin-proteasome pathway by an E3 ubiquitin ligase, Jade-2. We demonstrated that Jade-2 is a major LSD1 negative regulator during neurogenesis in vitro and in vivo in both mouse developing cerebral cortices and zebra fish embryos. Apparently, Jade-2-mediated degradation of LSD1 acts as an antibraking system and serves as a quick adaptive mechanism for re-establishing epigenetic landscape without more laborious transcriptional regulations. As a potential anticancer strategy, Jade-2-mediated LSD1 degradation could potentially be used in neuroblastoma cells to induce differentiation toward postmitotic neurons.

  8. Phosphorylation of ezrin-radixin-moesin-binding phosphoprotein 50 (EBP50) by Akt promotes stability and mitogenic function of S-phase kinase-associated protein-2 (Skp2).

    PubMed

    Song, Gyun Jee; Leslie, Kristen L; Barrick, Stacey; Mamonova, Tatyana; Fitzpatrick, Jeremy M; Drombosky, Kenneth W; Peyser, Noah; Wang, Bin; Pellegrini, Maria; Bauer, Philip M; Friedman, Peter A; Mierke, Dale F; Bisello, Alessandro

    2015-01-30

    The regulation of the cell cycle by the ubiquitin-proteasome system is dependent on the activity of E3 ligases. Skp2 (S-phase kinase associated protein-2) is the substrate recognition subunit of the E3 ligase that ubiquitylates the cell cycle inhibitors p21(cip1) and p27(kip1) thus promoting cell cycle progression. Increased expression of Skp2 is frequently observed in diseases characterized by excessive cell proliferation, such as cancer and neointima hyperplasia. The stability and cellular localization of Skp2 are regulated by Akt, but the molecular mechanisms underlying these effects remain only partly understood. The scaffolding protein Ezrin-Binding Phosphoprotein of 50 kDa (EBP50) contains two PDZ domains and plays a critical role in the development of neointimal hyperplasia. Here we report that EBP50 directly binds Skp2 via its first PDZ domain. Moreover, EBP50 is phosphorylated by Akt on Thr-156 within the second PDZ domain, an event that allosterically promotes binding to Skp2. The interaction with EBP50 causes cytoplasmic localization of Skp2, increases Skp2 stability and promotes proliferation of primary vascular smooth muscle cells. Collectively, these studies define a novel regulatory mechanism contributing to aberrant cell growth and highlight the importance of scaffolding function of EBP50 in Akt-dependent cell proliferation.

  9. Functional asymmetries of proteasome translocase pore.

    PubMed

    Erales, Jenny; Hoyt, Martin A; Troll, Fabian; Coffino, Philip

    2012-05-25

    Degradation by proteasomes involves coupled translocation and unfolding of its protein substrates. Six distinct but paralogous proteasome ATPase proteins, Rpt1 to -6, form a heterohexameric ring that acts on substrates. An axially positioned loop (Ar-Φ loop) moves in concert with ATP hydrolysis, engages substrate, and propels it into a proteolytic chamber. The aromatic (Ar) residue of the Ar-Φ loop in all six Rpts of S. cerevisiae is tyrosine; this amino acid is thought to have important functional contacts with substrate. Six yeast strains were constructed and characterized in which Tyr was individually mutated to Ala. The mutant cells were viable and had distinct phenotypes. rpt3, rpt4, and rpt5 Tyr/Ala mutants, which cluster on one side of the ATPase hexamer, were substantially impaired in their capacity to degrade substrates. In contrast, rpt1, rpt2, and rpt6 mutants equaled or exceeded wild type in degradation activity. However, rpt1 and rpt6 mutants had defects that limited cell growth or viability under conditions that stressed the ubiquitin proteasome system. In contrast, the rpt3 mutant grew faster than wild type and to a smaller size, a defect that has previously been associated with misregulation of G1 cyclins. This rpt3 phenotype probably results from altered degradation of cell cycle regulatory proteins. Finally, mutation of five of the Rpt subunits increased proteasome ATPase activity, implying bidirectional coupling between the Ar-Φ loop and the ATP hydrolysis site. The present observations assign specific functions to individual Rpt proteins and provide insights into the diverse roles of the axial loops of individual proteasome ATPases.

  10. Posttranslational regulation of coordinated enzyme activities in the Pup-proteasome system

    PubMed Central

    Elharar, Yifat; Roth, Ziv; Hecht, Nir; Rotkopf, Ron; Khalaila, Isam; Gur, Eyal

    2016-01-01

    The proper functioning of any biological system depends on the coordinated activity of its components. Regulation at the genetic level is, in many cases, effective in determining the cellular levels of system components. However, in cases where regulation at the genetic level is insufficient for attaining harmonic system function, posttranslational regulatory mechanisms are often used. Here, we uncover posttranslational regulatory mechanisms in the prokaryotic ubiquitin-like protein (Pup)-proteasome system (PPS), the bacterial equivalent of the eukaryotic ubiquitin-proteasome system. Pup, a ubiquitin analog, is conjugated to proteins through the activities of two enzymes, Dop (deamidase of Pup) and PafA (proteasome accessory factor A), the Pup ligase. As Dop also catalyzes depupylation, it was unclear how PPS function could be maintained without Dop and PafA canceling the activity of the other, and how the two activities of Dop are balanced. We report that tight Pup binding and the limited degree of Dop interaction with high-molecular-weight pupylated proteins results in preferred Pup deamidation over protein depupylation by this enzyme. Under starvation conditions, when accelerated protein pupylation is required, this bias is intensified by depletion of free Dop molecules, thereby minimizing the chance of depupylation. We also find that, in contrast to Dop, PafA presents a distinct preference for high-molecular-weight protein substrates. As such, PafA and Dop act in concert, rather than canceling each other's activity, to generate a high-molecular-weight pupylome. This bias in pupylome molecular weight distribution is consistent with the proposed nutritional role of the PPS under starvation conditions. PMID:26951665

  11. Current topics of functional links between primary cilia and cell cycle.

    PubMed

    Izawa, Ichiro; Goto, Hidemasa; Kasahara, Kousuke; Inagaki, Masaki

    2015-01-01

    Primary cilia, microtubule-based sensory structures, orchestrate various critical signals during development and tissue homeostasis. In view of the rising interest into the reciprocal link between ciliogenesis and cell cycle, we discuss here several recent advances to understand the molecular link between the individual step of ciliogenesis and cell cycle control. At the onset of ciliogenesis (the transition from centrosome to basal body), distal appendage proteins have been established as components indispensable for the docking of vesicles at the mother centriole. In the initial step of axonemal extension, CP110, Ofd1, and trichoplein, key negative regulators of ciliogenesis, are found to be removed by a kinase-dependent mechanism, autophagy, and ubiquitin-proteasome system, respectively. Of note, their disposal functions as a restriction point to decide that the axonemal nucleation and extension begin. In the elongation step, Nde1, a negative regulator of ciliary length, is revealed to be ubiquitylated and degraded by CDK5-SCF(Fbw7) in a cell cycle-dependent manner. With regard to ciliary length control, it has been uncovered in flagellar shortening of Chlamydomonas that cilia itself transmit a ciliary length signal to cytoplasm. At the ciliary resorption step upon cell cycle re-entry, cilia are found to be disassembled not only by Aurora A-HDAC6 pathway but also by Nek2-Kif24 and Plk1-Kif2A pathways through their microtubule-depolymerizing activity. On the other hand, it is becoming evident that the presence of primary cilia itself functions as a structural checkpoint for cell cycle re-entry. These data suggest that ciliogenesis and cell cycle intimately link each other, and further elucidation of these mechanisms will contribute to understanding the pathology of cilia-related disease including cancer and discovering targets of therapeutic interventions.

  12. The Mammalian Endoplasmic Reticulum-Associated Degradation System

    PubMed Central

    Olzmann, James A.; Kopito, Ron R.; Christianson, John C.

    2013-01-01

    The endoplasmic reticulum (ER) is the site of synthesis for nearly one-third of the eukaryotic proteome and is accordingly endowed with specialized machinery to ensure that proteins deployed to the distal secretory pathway are correctly folded and assembled into native oligomeric complexes. Proteins failing to meet this conformational standard are degraded by ER-associated degradation (ERAD), a complex process through which folding-defective proteins are selected and ultimately degraded by the ubiquitin-proteasome system. ERAD proceeds through four tightly coupled steps involving substrate selection, dislocation across the ER membrane, covalent conjugation with polyubiquitin, and proteasomal degradation. The ERAD machinery shows a modular organization with central ER membrane-embedded ubiquitin ligases linking components responsible for recognition in the ER lumen to the ubiquitin-proteasome system in the cytoplasm. The core ERAD machinery is highly conserved among eukaryotes and much of our basic understanding of ERAD organization has been derived from genetic and biochemical studies of yeast. In this article we discuss how the core ERAD machinery is organized in mammalian cells. PMID:23232094

  13. Protein-protein interactions involving voltage-gated sodium channels: Post-translational regulation, intracellular trafficking and functional expression.

    PubMed

    Shao, Dongmin; Okuse, Kenji; Djamgoz, Mustafa B A

    2009-07-01

    Voltage-gated sodium channels (VGSCs), classically known to play a central role in excitability and signalling in nerves and muscles, have also been found to be expressed in a range of 'non-excitable' cells, including lymphocytes, fibroblasts and endothelia. VGSC abnormalities are associated with various diseases including epilepsy, long-QT syndrome 3, Brugada syndrome, sudden infant death syndrome and, more recently, various human cancers. Given their pivotal role in a wide range of physiological and pathophysiological processes, regulation of functional VGSC expression has been the subject of intense study. An emerging theme is post-translational regulation and macro-molecular complexing by protein-protein interactions and intracellular trafficking, leading to changes in functional VGSC expression in plasma membrane. This partially involves endoplasmic reticulum associated degradation and ubiquitin-proteasome system. Several proteins have been shown to associate with VGSCs. Here, we review the interactions involving VGSCs and the following proteins: p11, ankyrin, syntrophin, beta-subunit of VGSC, papin, ERM and Nedd4 proteins. Protein kinases A and C, as well as Ca(2+)-calmodulin dependent kinase II that have also been shown to regulate intracellular trafficking of VGSCs by changing the balance of externalization vs. internalization, and an effort is made to separate these effects from the short-term phosphorylation of mature proteins in plasma membrane. Two further modulatory mechanisms are reciprocal interactions with the cytoskeleton and, late-stage, activity-dependent regulation. Thus, the review gives an updated account of the range of post-translational molecular mechanisms regulating functional VGSC expression. However, many details of VGSC subtype-specific regulation and pathophysiological aspects remain unknown and these are highlighted throughout for completeness.

  14. Mitochondria, metabolic disturbances, oxidative stress and the kynurenine system, with focus on neurodegenerative disorders.

    PubMed

    Sas, Katalin; Robotka, Hermina; Toldi, József; Vécsei, László

    2007-06-15

    normal protein homeostasis of the cell. In the event of a dysfunction of the endoplasmic reticulum, unfolded proteins aggregate in it, forming potentially toxic deposits which tend to be resistant to degradation. Cells possess adaptive mechanisms with which to avoid the accumulation of incorrectly folded proteins. These involve molecular chaperones that fold proteins correctly, and the ubiquitin proteasome system which degrades misfolded, unwanted proteins. Both the endoplasmic reticulum and the ubiquitin proteasome system fulfill cellular protein quality control functions. The kynurenine system: Tryptophan is metabolized via several pathways, the main one being the kynurenine pathway. A central compound of the pathway is kynurenine (KYN), which can be metabolized in two separate ways: one branch furnishing kynurenic acid, and the other 3-hydroxykynurenine and quinolinic acid, the precursors of NAD. An important feature of kynurenic acid is the fact that it is one of the few known endogenous excitatory amino acid receptor blockers with a broad spectrum of antagonistic properties in supraphysiological concentrations. One of its recently confirmed sites of action is the alpha7-nicotinic acetylcholine receptor and interestingly, a more recently identified one is a higher affinity positive modulatory binding site at the AMPA receptor. Kynurenic acid has proven to be neuroprotective in several experimental settings. On the other hand, quinolinic acid is a specific agonist at the N-methyl-d-aspartate receptors, and a potent neurotoxin with an additional and marked free radical-producing property. There are a number of neurodegenerative disorders whose pathogenesis has been demonstrated to involve multiple imbalances of the kynurenine pathway metabolism. These changes may disturb normal brain function and can add to the pathomechanisms of the diseases. In certain disorders, there is a quinolinic acid overproduction, while in others the alterations in brain kynurenic acid levels

  15. Cross-functional systems

    NASA Technical Reports Server (NTRS)

    Lee, Mark

    1991-01-01

    Many companies, including Xerox and Texas Instruments, are using cross functional systems to deal with the increasingly complex and competitive business environment. However, few firms within the aerospace industry appear to be aware of the significant benefits that cross functional systems can provide. Those benefits are examined and a flexible methodology is discussed that companies can use to identify and develop cross functional systems that will help improve organizational performance. In addition, some of the managerial issues are addressed that cross functional systems may raise and specific examples are used to explore networking's contributions to cross functional systems.

  16. Newborn mouse lens proteome and its alteration by lysine 6 mutant ubiquitin

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ubiquitin is a tag that often initiates degradation of proteins by the proteasome in the ubiquitin proteasome system. Targeted expression of K6W mutant ubiquitin (K6W-Ub) in the lens results in defects in lens development and cataract formation, suggesting critical functions for ubiquitin in lens. T...

  17. Identification and functional analysis of Joka2, a tobacco member of the family of selective autophagy cargo receptors.

    PubMed

    Zientara-Rytter, Katarzyna; Lukomska, Jolanta; Moniuszko, Grzegorz; Gwozdecki, Rafał; Surowiecki, Przemysław; Lewandowska, Małgorzata; Liszewska, Frantz; Wawrzyńska, Anna; Sirko, Agnieszka

    2011-10-01

    Two main mechanisms of protein turnover exist in eukaryotic cells: the ubiquitin-proteasome system and the autophagy-lysosomal pathway. Autophagy is an emerging important constituent of many physiological and pathological processes, such as response to nutrient deficiency, programmed cell death and innate immune response. In mammalian cells the selectivity of autophagy is ensured by the presence of cargo receptors, such as p62/SQSTM1 and NBR1, responsible for sequestration of the ubiquitinated proteins. In plants no selective cargo receptors have been identified yet. The present report indicates that structural and functional homologs of p62 and NBR1 proteins exist in plants. The tobacco protein, named Joka2, has been identified in yeast two-hybrid search as a binding partner of a small coiled-coil protein, a member of UP9/LSU family of unknown function, encoded by the UP9C gene strongly and specifically induced during sulfur deficiency. The typical domains of p62 and NBR1 are conserved in Joka2. Similarly to p62, Joka2-YFP has dual localization (cytosolic speckles and the nucleus); it forms homodimers and interacts with a member of the ATG8 family. Increased expression of Joka2 and ATG8f was observed in roots of tobacco plants grown for two days in nutrient-deficient conditions. Constitutive ectopic expression of Joka2-YFP in tobacco resulted in attenuated response (manifested by lesser yellowing of the leaves) to nutrient deficiency. In conclusion, Joka2, and presumably the process of selective autophagy, might constitute an important part of plant response to environmental stresses.

  18. Identification and functional analysis of Joka2, a tobacco member of the family of selective autophagy cargo receptors

    PubMed Central

    Zientara-Rytter, Katarzyna; Łukomska, Jolanta; Moniuszko, Grzegorz; Gwozdecki, Rafał; Surowiecki, Przemysław; Lewandowska, Małgorzata; Liszewska, Frantz; Wawrzyńska, Anna

    2011-01-01

    Two main mechanisms of protein turnover exist in eukaryotic cells: the ubiquitin-proteasome system and the autophagy-lysosomal pathway. Autophagy is an emerging important constituent of many physiological and pathological processes, such as response to nutrient deficiency, programmed cell death and innate immune response. In mammalian cells the selectivity of autophagy is ensured by the presence of cargo receptors, such as p62/SQSTM1 and NBR1, responsible for sequestration of the ubiquitinated proteins. In plants no selective cargo receptors have been identified yet. The present report indicates that structural and functional homologs of p62 and NBR1 proteins exist in plants. The tobacco protein, named Joka2, has been identified in yeast two-hybrid search as a binding partner of a small coiled-coil protein, a member of UP9/LSU family of unknown function, encoded by the UP9C gene strongly and specifically induced during sulfur deficiency. The typical domains of p62 and NBR1 are conserved in Joka2. Similarly to p62, Joka2-YFP has dual localization (cytosolic speckles and the nucleus); it forms homodimers and interacts with a member of the ATG8 family. Increased expression of Joka2 and ATG8f was observed in roots of tobacco plants grown for two days in nutrient-deficient conditions. Constitutive ectopic expression of Joka2-YFP in tobacco resulted in attenuated response (manifested by lesser yellowing of the leaves) to nutrient deficiency. In conclusion, Joka2, and presumably the process of selective autophagy, might constitute an important part of plant response to environmental stresses. PMID:21670587

  19. Antigravitational Functional System

    NASA Astrophysics Data System (ADS)

    Dorogovtsev, V. N.

    2008-06-01

    The purpose of this paper is the description of the main components and basic functioning principles of the antigravitational functional system (AFS). Methods: literary review and theoretical analysis of the neurogenic regulation functional system. The concept of a functional system was formulated in the beginning of the 20th century. Functional system was described as dynamic, self-organizing, central-peripheral functional integration structures of the nervous system whose activity was aiming at achieving adaptive useful results. The main difference between functional system and proposed regulating principles is the physiological mechanism presence of the prospective result prediction (action result acceptor). Action is programmed for defined result receiving. This is anticipatory regulation principle. Using this principle AFS provides timely cardiovascular system preparing for its impending functional conditions changes. It seems that gravity intolerance in the beginning and after space flight is related with AFS regulation peculiarities. There is a necessity for the AFS advanced study. It is very important to create safe and comfort conditions for astronauts adaptation during gravitational loading changes as well as for certain diseases prophylaxis on the Earth.

  20. Proteomic Analysis of the Ubiquitin Landscape in the Drosophila Embryonic Nervous System and the Adult Photoreceptor Cells

    PubMed Central

    Ramirez, Juanma; Martinez, Aitor; Lectez, Benoit; Lee, So Young; Franco, Maribel; Barrio, Rosa; Dittmar, Gunnar; Mayor, Ugo

    2015-01-01

    Background Ubiquitination is known to regulate physiological neuronal functions as well as to be involved in a number of neuronal diseases. Several ubiquitin proteomic approaches have been developed during the last decade but, as they have been mostly applied to non-neuronal cell culture, very little is yet known about neuronal ubiquitination pathways in vivo. Methodology/Principal Findings Using an in vivo biotinylation strategy we have isolated and identified the ubiquitinated proteome in neurons both for the developing embryonic brain and for the adult eye of Drosophila melanogaster. Bioinformatic comparison of both datasets indicates a significant difference on the ubiquitin substrates, which logically correlates with the processes that are most active at each of the developmental stages. Detection within the isolated material of two ubiquitin E3 ligases, Parkin and Ube3a, indicates their ubiquitinating activity on the studied tissues. Further identification of the proteins that do accumulate upon interference with the proteasomal degradative pathway provides an indication of the proteins that are targeted for clearance in neurons. Last, we report the proof-of-principle validation of two lysine residues required for nSyb ubiquitination. Conclusions/Significance These data cast light on the differential and common ubiquitination pathways between the embryonic and adult neurons, and hence will contribute to the understanding of the mechanisms by which neuronal function is regulated. The in vivo biotinylation methodology described here complements other approaches for ubiquitome study and offers unique advantages, and is poised to provide further insight into disease mechanisms related to the ubiquitin proteasome system. PMID:26460970

  1. Ubiquitin-Like Proteasome System Represents a Eukaryotic-Like Pathway for Targeted Proteolysis in Archaea

    PubMed Central

    Fu, Xian; Liu, Rui; Sanchez, Iona; Silva-Sanchez, Cecilia; Hepowit, Nathaniel L.; Cao, Shiyun; Chen, Sixue

    2016-01-01

    ABSTRACT The molecular mechanisms of targeted proteolysis in archaea are poorly understood, yet they may have deep evolutionary roots shared with the ubiquitin-proteasome system of eukaryotic cells. Here, we demonstrate in archaea that TBP2, a TATA-binding protein (TBP) modified by ubiquitin-like isopeptide bonds, is phosphorylated and targeted for degradation by proteasomes. Rapid turnover of TBP2 required the functions of UbaA (the E1/MoeB/ThiF homolog of archaea), AAA ATPases (Cdc48/p97 and Rpt types), a type 2 JAB1/MPN/MOV34 metalloenzyme (JAMM/MPN+) homolog (JAMM2), and 20S proteasomes. The ubiquitin-like protein modifier small archaeal modifier protein 2 (SAMP2) stimulated the degradation of TBP2, but SAMP2 itself was not degraded. Analysis of the TBP2 fractions that were not modified by ubiquitin-like linkages revealed that TBP2 had multiple N termini, including Met1-Ser2, Ser2, and Met1-Ser2(p) [where (p) represents phosphorylation]. The evidence suggested that the Met1-Ser2(p) form accumulated in cells that were unable to degrade TBP2. We propose a model in archaea in which the attachment of ubiquitin-like tags can target proteins for degradation by proteasomes and be controlled by N-terminal degrons. In support of a proteolytic mechanism that is energy dependent and recycles the ubiquitin-like protein tags, we find that a network of AAA ATPases and a JAMM/MPN+ metalloprotease are required, in addition to 20S proteasomes, for controlled intracellular proteolysis. PMID:27190215

  2. Functional diversity and structural disorder in the human ubiquitination pathway.

    PubMed

    Bhowmick, Pallab; Pancsa, Rita; Guharoy, Mainak; Tompa, Peter

    2013-01-01

    The ubiquitin-proteasome system plays a central role in cellular regulation and protein quality control (PQC). The system is built as a pyramid of increasing complexity, with two E1 (ubiquitin activating), few dozen E2 (ubiquitin conjugating) and several hundred E3 (ubiquitin ligase) enzymes. By collecting and analyzing E3 sequences from the KEGG BRITE database and literature, we assembled a coherent dataset of 563 human E3s and analyzed their various physical features. We found an increase in structural disorder of the system with multiple disorder predictors (IUPred - E1: 5.97%, E2: 17.74%, E3: 20.03%). E3s that can bind E2 and substrate simultaneously (single subunit E3, ssE3) have significantly higher disorder (22.98%) than E3s in which E2 binding (multi RING-finger, mRF, 0.62%), scaffolding (6.01%) and substrate binding (adaptor/substrate recognition subunits, 17.33%) functions are separated. In ssE3s, the disorder was localized in the substrate/adaptor binding domains, whereas the E2-binding RING/HECT-domains were structured. To demonstrate the involvement of disorder in E3 function, we applied normal modes and molecular dynamics analyses to show how a disordered and highly flexible linker in human CBL (an E3 that acts as a regulator of several tyrosine kinase-mediated signalling pathways) facilitates long-range conformational changes bringing substrate and E2-binding domains towards each other and thus assisting in ubiquitin transfer. E3s with multiple interaction partners (as evidenced by data in STRING) also possess elevated levels of disorder (hubs, 22.90% vs. non-hubs, 18.36%). Furthermore, a search in PDB uncovered 21 distinct human E3 interactions, in 7 of which the disordered region of E3s undergoes induced folding (or mutual induced folding) in the presence of the partner. In conclusion, our data highlights the primary role of structural disorder in the functions of E3 ligases that manifests itself in the substrate/adaptor binding functions as well

  3. Formation of nucleoplasmic protein aggregates impairs nuclear function in response to SiO{sub 2} nanoparticles

    SciTech Connect

    Chen Min; Mikecz, Anna von . E-mail: mikecz@uni-duesseldorf.de

    2005-04-15

    Despite of their exponentially growing use, little is known about cell biological effects of nanoparticles. Here, we report uptake of silica (SiO{sub 2}) nanoparticles to the cell nucleus where they induce aberrant clusters of topoisomerase I (topo I) in the nucleoplasm that additionally contain signature proteins of nuclear domains, and protein aggregation such as ubiquitin, proteasomes, cellular glutamine repeat (polyQ) proteins, and huntingtin. Formation of intranuclear protein aggregates (1) inhibits replication, transcription, and cell proliferation; (2) does not significantly alter proteasomal activity or cell viability; and (3) is reversible by Congo red and trehalose. Since SiO{sub 2} nanoparticles trigger a subnuclear pathology resembling the one occurring in expanded polyglutamine neurodegenerative disorders, we suggest that integrity of the functional architecture of the cell nucleus should be used as a read out for cytotoxicity and considered in the development of safe nanotechnology.

  4. Therapeutic intervention at cellular quality control systems in Alzheimer's and Parkinson's diseases.

    PubMed

    Arduino, Daniela M; Esteves, A Raquel; Silva, Diana F F; Martins-Branco, Diogo; Santos, Daniel; Pimentel, Diana F Gomes; Cardoso, Sandra M

    2011-01-01

    Cellular homeostasis relies on quality control systems so that damaged biologic structures are either repaired or degraded and entirely replaced by newly formed proteins or even organelles. The clearance of dysfunctional cellular structures in long-lived postmitotic cells, like neurons, is essential to eliminate, per example, defective mitochondria, lipofuscin-loaded lysosomes and oxidized proteins. Short-lived proteins are degraded mainly by proteases and proteasomes whether most long-lived proteins and all organelles are digested by autophagy in the lysosomes. Recently, it an interplay was established between the ubiquitin-proteasome system and macroautophagy, so that both degradative mechanisms compensate for each other. In this article we describe each of these clearance systems and their contribution to neuronal quality control. We will highlight some of the findings that provide evidence for the dysfunction of these systems in Alzheimer's and Parkinson's diseases. Ultimately, we provide an outline on potential therapeutic interventions based on the modulation of cellular degradative systems.

  5. Endolysosomal trafficking of viral G protein-coupled receptor functions in innate immunity and control of viral oncogenesis.

    PubMed

    Dong, Xiaonan; Cheng, Adam; Zou, Zhongju; Yang, Yih-Sheng; Sumpter, Rhea M; Huang, Chou-Long; Bhagat, Govind; Virgin, Herbert W; Lira, Sergio A; Levine, Beth

    2016-03-15

    The ubiquitin-proteasome system degrades viral oncoproteins and other microbial virulence factors; however, the role of endolysosomal degradation pathways in these processes is unclear. Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma, and a constitutively active viral G protein-coupled receptor (vGPCR) contributes to the pathogenesis of KSHV-induced tumors. We report that a recently discovered autophagy-related protein, Beclin 2, interacts with KSHV GPCR, facilitates its endolysosomal degradation, and inhibits vGPCR-driven oncogenic signaling. Furthermore, monoallelic loss of Becn2 in mice accelerates the progression of vGPCR-induced lesions that resemble human Kaposi's sarcoma. Taken together, these findings indicate that Beclin 2 is a host antiviral molecule that protects against the pathogenic effects of KSHV GPCR by facilitating its endolysosomal degradation. More broadly, our data suggest a role for host endolysosomal trafficking pathways in regulating viral pathogenesis and oncogenic signaling.

  6. The proteasome and the degradation of oxidized proteins: Part III—Redox regulation of the proteasomal system

    PubMed Central

    Höhn, Tobias Jung Annika; Grune, Tilman

    2014-01-01

    Here, we review shortly the current knowledge on the regulation of the proteasomal system during and after oxidative stress. After addressing the components of the proteasomal system and the degradation of oxidatively damaged proteins in part I and II of this series, we address here which changes in activity undergo the proteasome and the ubiquitin-proteasomal system itself under oxidative conditions. While several components of the proteasomal system undergo direct oxidative modification, a number of redox-regulated events are modulating the proteasomal activity in a way it can address the major tasks in an oxidative stress situation: the removal of oxidized proteins and the adaptation of the cellular metabolism to the stress situation. PMID:24563857

  7. THE RENIN-ANGIOTENSIN SYSTEM AND THE BIOLOGY OF SKELETAL MUSCLE: MECHANISMS OF MUSCLE WASTING IN CHRONIC DISEASE STATES.

    PubMed

    Delafontaine, Patrice; Yoshida, Tadashi

    2016-01-01

    Sarcopenia and cachexia are muscle-wasting syndromes associated with aging and with many chronic diseases such as congestive heart failure, diabetes, cancer, chronic obstructive pulmonary disease, and renal failure. While mechanisms are complex, these conditions are often accompanied by elevated angiotensin II (Ang II). We found that Ang II infusion in rodents leads to skeletal muscle wasting via alterations in insulin-like growth factor-1 signaling, increased apoptosis, enhanced muscle protein breakdown via the ubiquitin-proteasome system, and decreased appetite resulting from downregulation of hypothalamic orexigenic neuropeptides orexin and neuropeptide Y. Furthermore, Ang II inhibits skeletal muscle stem cell proliferation, leading to lowered muscle regenerative capacity. Distinct stem cell Ang II receptor subtypes are critical for regulation of muscle regeneration. In ischemic mouse congestive heart failure model skeletal muscle wasting and attenuated muscle regeneration are Ang II dependent. These data suggest that the renin-angiotensin system plays a critical role in mechanisms underlying cachexia in chronic disease states.

  8. Oxidative Stress and Protein Quality Control Systems in the Aged Canine Brain as a Model for Human Neurodegenerative Disorders

    PubMed Central

    2015-01-01

    Aged dogs are considered the most suitable spontaneous animal model for studying normal aging and neurodegenerative diseases. Elderly canines naturally develop cognitive dysfunction and neuropathological hallmarks similar to those seen in humans, especially Alzheimer's disease-like pathology. Pet dogs also share similar living conditions and diets to humans. Oxidative damage accumulates in the canine brain during aging, making dogs a valid model for translational antioxidant treatment/prevention studies. Evidence suggests the presence of detective protein quality control systems, involving ubiquitin-proteasome system (UPS) and Heat Shock Proteins (HSPs), in the aged canine brain. Further studies on the canine model are needed to clarify the role of age-related changes in UPS activity and HSP expression in neurodegeneration in order to design novel treatment strategies, such as HSP-based therapies, aimed at improving chaperone defences against proteotoxic stress affecting brain during aging. PMID:26078824

  9. Endoplasmic reticulum stress caused by aggregate-prone proteins containing homopolymeric amino acids.

    PubMed

    Uchio, Naohiro; Oma, Yoko; Toriumi, Kazuya; Sasagawa, Noboru; Tanida, Isei; Fujita, Eriko; Kouroku, Yoriko; Kuroda, Reiko; Momoi, Takashi; Ishiura, Shoichi

    2007-11-01

    Many human proteins have homopolymeric amino acid (HPAA) tracts, but their physiological functions or cellular effects are not well understood. Previously, we expressed 20 HPAAs in mammalian cells and showed characteristic intracellular localization, in that hydrophobic HPAAs aggregated strongly and caused high cytotoxicity in proportion to their hydrophobicity. In the present study, we investigated the cytotoxicity of these aggregate-prone hydrophobic HPAAs, assuming that the ubiquitin proteasome system is impaired in the same manner as other well-known aggregate-prone polyglutamine-containing proteins. Some highly hydrophobic HPAAs caused a deficiency in the ubiquitin proteasome system and excess endoplasmic reticulum stress, leading to apoptosis. These results indicate that the property of causing excess endoplasmic reticulum stress by proteasome impairment may contribute to the strong cytotoxicity of highly hydrophobic HPAAs, and proteasome impairment and the resulting excess endoplasmic reticulum stress is not a common cytotoxic effect of aggregate-prone proteins such as polyglutamine.

  10. Characterization of the 26S proteasome network in Plasmodium falciparum.

    PubMed

    Wang, Lihui; Delahunty, Claire; Fritz-Wolf, Karin; Rahlfs, Stefan; Helena Prieto, Judith; Yates, John R; Becker, Katja

    2015-12-07

    In eukaryotic cells, the ubiquitin-proteasome system as a key regulator of protein quality control is an excellent drug target. We therefore aimed to analyze the 26S proteasome complex in the malaria parasite Plasmodium falciparum, which still threatens almost half of the world's population. First, we established an affinity purification protocol allowing for the isolation of functional 26S proteasome complexes from the parasite. Subunit composition of the proteasome and component stoichiometry were studied and physiologic interacting partners were identified via in situ protein crosslinking. Furthermore, intrinsic ubiquitin receptors of the plasmodial proteasome were determined and their roles in proteasomal substrate recognition were analyzed. Notably, PfUSP14 was characterized as a proteasome-associated deubiquitinase resulting in the concept that targeting proteasomal deubiquitinating activity in P. falciparum may represent a promising antimalarial strategy. The data provide insights into a profound network orchestrated by the plasmodial proteasome and identified novel drug target candidates in the ubiquitin-proteasome system.

  11. Coxsackievirus B5 induced apoptosis of HeLa cells: Effects on p53 and SUMO

    SciTech Connect

    Gomes, Rogerio; Guerra-Sa, Renata; Arruda, Eurico

    2010-01-20

    Coxsackievirus B5 (CVB5), a human enterovirus of the family Picornaviridae, is a frequent cause of acute and chronic human diseases. The pathogenesis of enteroviral infections is not completely understood, and the fate of the CVB5-infected cell has a pivotal role in this process. We have investigated the CVB5-induced apoptosis of HeLa cells and found that it happens by the intrinsic pathway by a mechanism dependent on the ubiquitin-proteasome system, associated with nuclear aggregation of p53. Striking redistribution of both SUMO and UBC9 was noted at 4 h post-infection, simultaneously with a reduction in the levels of the ubiquitin-ligase HDM2. Taken together, these results suggest that CVB5 infection of HeLa cells elicit the intrinsic pathway of apoptosis by MDM2 degradation and p53 activation, destabilizing protein sumoylation, by a mechanism that is dependent on a functional ubiquitin-proteasome system.

  12. NEDD8 protein is involved in ubiquitinated inclusion bodies.

    PubMed

    Dil Kuazi, Afroz; Kito, Katsumi; Abe, Yasuhito; Shin, Ryong-Woon; Kamitani, Tetsu; Ueda, Norifumi

    2003-02-01

    Proteolysis by the ubiquitin-proteasome system is considered to play a pathological role in several degenerative diseases that involve ubiquitinated inclusion bodies. In recent years, several ubiquitin-like proteins have been isolated, but it is uncertain whether their roles are associated with protein degradation through the ubiquitin-proteasome system. NEDD8 (neural precursor cell-expressed and developmentally down-regulated gene), which consists of 81 amino acid residues, possesses the highest sequence similarity to ubiquitin. Recent studies have indicated that NEDD8 is covalently ligated to cullin family proteins, which are components of certain ubiquitin E3 ligases, by a pathway analogous to that of ubiquitin. Thus, by focusing on the structural and functional association between NEDD8 and ubiquitin, it would be of interest to know whether the NEDD8 system is involved in pathological disorders of the ubiquitin-proteasome system. This study has examined the immunohistochemical distribution of NEDD8 protein by using a highly purified antibody in normal tissues and in tissues known to contain ubiquitinated inclusions. NEDD8 protein expression was widely observed in most types of tissues. Furthermore, accumulation of the NEDD8 protein was commonly observed in ubiquitinated inclusion bodies, including Lewy bodies in Parkinson's disease, Mallory bodies in alcoholic liver disease, and Rosenthal fibres in astrocytoma. Two of ten cases of neurofibrillary tangles and senile plaques from patients with Alzheimer's disease showed intense staining for NEDD8 as well as for ubiquitin. These findings suggest the possibility that the NEDD8 system is involved in the metabolism of these inclusion bodies via the ubiquitin-proteasome system.

  13. Assessing Respiratory System Mechanical Function.

    PubMed

    Restrepo, Ruben D; Serrato, Diana M; Adasme, Rodrigo

    2016-12-01

    The main goals of assessing respiratory system mechanical function are to evaluate the lung function through a variety of methods and to detect early signs of abnormalities that could affect the patient's outcomes. In ventilated patients, it has become increasingly important to recognize whether respiratory function has improved or deteriorated, whether the ventilator settings match the patient's demand, and whether the selection of ventilator parameters follows a lung-protective strategy. Ventilator graphics, esophageal pressure, intra-abdominal pressure, and electric impedance tomography are some of the best-known monitoring tools to obtain measurements and adequately evaluate the respiratory system mechanical function.

  14. Apigenin: Selective CK2 inhibitor increases Ikaros expression and improves T cell homeostasis and function in murine pancreatic cancer

    PubMed Central

    Nelson, Nadine; Szekeres, Karoly; Iclozan, Cristina; Rivera, Ivannie Ortiz; McGill, Andrew; Johnson, Gbemisola; Nwogu, Onyekachi

    2017-01-01

    Pancreatic cancer (PC) evades immune destruction by favoring the development of regulatory T cells (Tregs) that inhibit effector T cells. The transcription factor Ikaros is critical for lymphocyte development, especially T cells. We have previously shown that downregulation of Ikaros occurs as a result of its protein degradation by the ubiquitin-proteasome system in our Panc02 tumor-bearing (TB) mouse model. Mechanistically, we observed a deregulation in the balance between Casein Kinase II (CK2) and protein phosphatase 1 (PP1), which suggested that increased CK2 activity is responsible for regulating Ikaros’ stability in our model. We also showed that this loss of Ikaros expression is associated with a significant decrease in CD4+ and CD8+ T cell percentages but increased CD4+CD25+ Tregs in TB mice. In this study, we evaluated the effects of the dietary flavonoid apigenin (API), on Ikaros expression and T cell immune responses. Treatment of splenocytes from naïve mice with (API) stabilized Ikaros expression and prevented Ikaros downregulation in the presence of murine Panc02 cells in vitro, similar to the proteasome inhibitor MG132. In vivo treatment of TB mice with apigenin (TB-API) improved survival, reduced tumor weights and prevented splenomegaly. API treatment also restored protein expression of some Ikaros isoforms, which may be attributed to its moderate inhibition of CK2 activity from splenocytes of TB-API mice. This partial restoration of Ikaros expression was accompanied by a significant increase in CD4+ and CD8+ T cell percentages and a reduction in Treg percentages in TB-API mice. In addition, CD8+ T cells from TB-API mice produced more IFN-γ and their splenocytes were better able to prime allogeneic CD8+ T cell responses compared to TB mice. These results provide further evidence that Ikaros is regulated by CK2 in our pancreatic cancer model. More importantly, our findings suggest that API may be a possible therapeutic agent for stabilizing Ikaros

  15. The effect of temperature adaptation on the ubiquitin-proteasome pathway in notothenioid fishes.

    PubMed

    Todgham, Anne E; Crombie, Timothy A; Hofmann, Gretchen E

    2017-02-01

    There is an accumulating body of evidence suggesting that the sub-zero Antarctic marine environment places physiological constraints on protein homeostasis. Levels of ubiquitin (Ub)-conjugated proteins, 20S proteasome activity and mRNA expression of many proteins involved in both the Ub tagging of damaged proteins as well as the different complexes of the 26S proteasome were measured to examine whether there is thermal compensation of the Ub-proteasome pathway in Antarctic fishes to better understand the efficiency of the protein degradation machinery in polar species. Both Antarctic (Trematomus bernacchii, Pagothenia borchgrevinki) and non-Antarctic (Notothenia angustata, Bovichtus variegatus) notothenioids were included in this study to investigate the mechanisms of cold adaptation of this pathway in polar species. Overall, there were significant differences in the levels of Ub-conjugated proteins between the Antarctic notothenioids and B. variegatus, with N. angustata possessing levels very similar to those of the Antarctic fishes. Proteasome activity in the gills of Antarctic fishes demonstrated a high degree of temperature compensation such that activity levels were similar to activities measured in their temperate relatives at ecologically relevant temperatures. A similar level of thermal compensation of proteasome activity was not present in the liver of two Antarctic fishes. Higher gill proteasome activity is likely due in part to higher cellular levels of proteins involved in the Ub-proteasome pathway, as evidenced by high mRNA expression of relevant genes. Reduced activity of the Ub-proteasome pathway does not appear to be the mechanism responsible for elevated levels of denatured proteins in Antarctic fishes, at least in the gills.

  16. The Role of the Ubiquitin Proteasome Pathway in Keratin Intermediate Filament Protein Degradation

    PubMed Central

    Rogel, Micah R.; Jaitovich, Ariel; Ridge, Karen M.

    2010-01-01

    Lung injury, whether caused by hypoxic or mechanical stresses, elicits a variety of responses at the cellular level. Alveolar epithelial cells respond and adapt to such injurious stimuli by reorganizing the cellular cytoskeleton, mainly accomplished through modification of the intermediate filament (IF) network. The structural and mechanical integrity in epithelial cells is maintained through this adaptive reorganization response. Keratin, the predominant IF expressed in epithelial cells, displays highly dynamic properties in response to injury, sometimes in the form of degradation of the keratin IF network. Post-translational modification, such as phosphorylation, targets keratin proteins for degradation in these circumstances. As with other structural and regulatory proteins, turnover of keratin is regulated by the ubiquitin (Ub)-proteasome pathway. The degradation process begins with activation of Ub by the Ub-activating enzyme (E1), followed by the exchange of Ub to the Ub-conjugating enzyme (E2). E2 shuttles the Ub molecule to the substrate-specific Ub ligase (E3), which then delivers the Ub to the substrate protein, thereby targeting it for degradation. In some cases of injury and IF-related disease, aggresomes form in epithelial cells. The mechanisms that regulate aggresome formation are currently unknown, although proteasome overload may play a role. Therefore, a more complete understanding of keratin degradation—causes, mechanisms, and consequences—will allow for a greater understanding of epithelial cell biology and lung pathology alike. PMID:20160151

  17. CD4 Glycoprotein Degradation Induced by Human Immunodeficiency Virus Type 1 Vpu Protein Requires the Function of Proteasomes and the Ubiquitin-Conjugating Pathway

    PubMed Central

    Schubert, Ulrich; Antón, Luis C.; Bačík, Igor; Cox, Josephine H.; Bour, Stéphane; Bennink, Jack R.; Orlowski, Marian; Strebel, Klaus; Yewdell, Jonathan W.

    1998-01-01

    The human immunodeficiency virus type 1 (HIV-1) vpu gene encodes a type I anchored integral membrane phosphoprotein with two independent functions. First, it regulates virus release from a post-endoplasmic reticulum (ER) compartment by an ion channel activity mediated by its transmembrane anchor. Second, it induces the selective down regulation of host cell receptor proteins (CD4 and major histocompatibility complex class I molecules) in a process involving its phosphorylated cytoplasmic tail. In the present work, we show that the Vpu-induced proteolysis of nascent CD4 can be completely blocked by peptide aldehydes that act as competitive inhibitors of proteasome function and also by lactacystin, which blocks proteasome activity by covalently binding to the catalytic β subunits of proteasomes. The sensitivity of Vpu-induced CD4 degradation to proteasome inhibitors paralleled the inhibition of proteasome degradation of a model ubiquitinated substrate. Characterization of CD4-associated oligosaccharides indicated that CD4 rescued from Vpu-induced degradation by proteasome inhibitors is exported from the ER to the Golgi complex. This finding suggests that retranslocation of CD4 from the ER to the cytosol may be coupled to its proteasomal degradation. CD4 degradation mediated by Vpu does not require the ER chaperone calnexin and is dependent on an intact ubiquitin-conjugating system. This was demonstrated by inhibition of CD4 degradation (i) in cells expressing a thermally inactivated form of the ubiquitin-activating enzyme E1 or (ii) following expression of a mutant form of ubiquitin (Lys48 mutated to Arg48) known to compromise ubiquitin targeting by interfering with the formation of polyubiquitin complexes. CD4 degradation was also prevented by altering the four Lys residues in its cytosolic domain to Arg, suggesting a role for ubiquitination of one or more of these residues in the process of degradation. The results clearly demonstrate a role for the cytosolic

  18. [Features of immune proteasome expression in the development of rat central nervous system].

    PubMed

    Orlova, A Sh; Liupina, Iu V; Abaturova, S B; Sharova, N P

    2014-01-01

    Formation of the central nervous system in ontogeny and function in adult mammals are controlled by universal ubiquitin-proteasome proteolytic system. The aim of this work was to study the dynamics of expression of immune proteasomes in comparison with the dynamics of ChLA and CLA proteasome and expression of the transcription factor Zif268 in the structures of the brain (cortex, hippocampus, and brainstem) in embryonic (E19, E21 days of embryonic development) and early postnatal (P1, P3, P4, P5, P7, P15 days of post-natal development) development in rats. ChLA and CLA in clarified homogenates of rat brain structures were determined by hydrolysis of fluorogenic commercial oligopeptides Suc-LLVY-AMC and Z-LLG-AMC, respectively. In the cortex and hippocampus of the brain was observed upregulation of immune subunits LMP7 during the active formation of biochemical mediatory structure and efferent neuronal projections at the period P7-P15. In the cerebral cortex during this period ChLA and CLA also are increased. In all structures of the brain the LMP2 immune subunits content was significantly increased at the period P7-P15. Contents of proteolytic constitutive subunit β1 in all structures decreased by P4 compare to P1 levels and was increased on P15 relative to the P1 levels. However, the level of expression of proteolytic constitutive subunit β5 increased in cortex, hippocampus and brainstem from E21 and reached maximum values on P3, P5 and P1, respectively with a sharp decrease to P7 in all studied structures. In all structures expression of LM P2 immune subunits and β1 constitutive subunits increased simultaneously with LMP7 immune subunits and sharply on P15. Also shown a positive correlation of increased expression regulator PA28 and constitutive β5 subunits in the hippocampus during the period P3-P5 and in the brainstem at the period P1-P5. The peculiarity of the studied brain regions during P7-P15 of rat early development is a correlation of expression of

  19. Transcriptomics of the interaction between the monopartite phloem-limited geminivirus tomato yellow leaf curl Sardinia virus and Solanum lycopersicum highlights a role for plant hormones, autophagy and plant immune system fine tuning during infection.

    PubMed

    Miozzi, Laura; Napoli, Chiara; Sardo, Luca; Accotto, Gian Paolo

    2014-01-01

    Tomato yellow leaf curl Sardinia virus (TYLCSV), a DNA virus belonging to the genus Begomovirus, causes severe losses in tomato crops. It infects only a limited number of cells in the vascular tissues, making difficult to detect changes in host gene expression linked to its presence. Here we present the first microarray study of transcriptional changes induced by the phloem-limited geminivirus TYLCSV infecting tomato, its natural host. The analysis was performed on the midrib of mature leaves, a material naturally enriched in vascular tissues. A total of 2206 genes were up-regulated and 1398 were down-regulated in infected plants, with an overrepresentation of genes involved in hormone metabolism and responses, nucleic acid metabolism, regulation of transcription, ubiquitin-proteasome pathway and autophagy among those up-regulated, and in primary and secondary metabolism, phosphorylation, transcription and methylation-dependent chromatin silencing among those down-regulated. Our analysis showed a series of responses, such as the induction of GA- and ABA-responsive genes, the activation of the autophagic process and the fine tuning of the plant immune system, observed only in TYLCSV-tomato compatible interaction so far. On the other hand, comparisons with transcriptional changes observed in other geminivirus-plant interactions highlighted common host responses consisting in the deregulation of biotic stress responsive genes, key enzymes in the ethylene biosynthesis and methylation cycle, components of the ubiquitin proteasome system and DNA polymerases II. The involvement of conserved miRNAs and of solanaceous- and tomato-specific miRNAs in geminivirus infection, investigated by integrating differential gene expression data with miRNA targeting data, is discussed.

  20. Isoform-Specific SCFFbw7 Ubiquitination Mediates Differential Regulation of PGC-1α

    PubMed Central

    Trausch-Azar, Julie S.; Abed, Mona; Orian, Amir; Schwartz, Alan L.

    2015-01-01

    The E3 ubiquitin ligase and tumor suppressor SCFFbw7 exists as three isoforms that govern the degradation of a host of critical cell regulators, including c-Myc, cyclin E, and PGC-1α. Peroxisome proliferator activated receptor-gamma coactivator 1α (PGC-1α) is a transcriptional coactivator with broad effects on cellular energy metabolism. Cellular PGC-1α levels are tightly controlled in a dynamic state by the balance of synthesis and rapid degradation via the ubiquitin-proteasome system. Yet, isoform-specific functions of SCFFbw7 are yet to be determined. Here, we show that the E3 ubiquitin ligase, SCFFbw7, regulates cellular PGC-1α levels via two independent, isoform specific, mechanisms. The cytoplasmic isoform (SCFFbw7β) reduces cellular PGC-1α levels via accelerated ubiquitin-proteasome degradation. In contrast, the nuclear isoform (SCFFbw7α) increases cellular PGC-1α levels and protein stability via inhibition of ubiquitin-proteasomal degradation. When nuclear Fbw7α proteins are redirected to the cytoplasm, cellular PGC-1α protein levels are reduced through accelerated ubiquitin-proteasomal degradation. We find that SCFFbw7β catalyzes high molecular weight PGC-1α-ubiquitin conjugation, whereas SCFFbw7α produces low molecular weight PGC-1α-ubiquitin conjugates that are not effective degradation signals. Thus, selective ubiquitination by specific Fbw7 isoforms represents a novel mechanism that tightly regulates cellular PGC-1α levels. Fbw7 isoforms mediate degradation of a host of regulatory proteins. The E3 ubiquitin ligase, Fbw7, mediates PGC-1α levels via selective isoform-specific ubiquitination. Fbw7β reduces cellular PGC-1α via ubiquitin-mediated degradation, whereas Fbw7α increases cellular PGC-1α via ubiquitin-mediated stabilization. PMID:25204433

  1. Caspase activation inhibits proteasome function during apoptosis.

    PubMed

    Sun, Xiao-Ming; Butterworth, Michael; MacFarlane, Marion; Dubiel, Wolfgang; Ciechanover, Aaron; Cohen, Gerald M

    2004-04-09

    The ubiquitin/proteasome system regulates protein turnover by degrading polyubiquitinated proteins. To date, all studies on the relationship of apoptosis and the proteasome have emphasized the key role of the proteasome in the regulation of apoptosis, by virtue of its ability to degrade regulatory molecules involved in apoptosis. We now demonstrate how induction of apoptosis may regulate the activity of the proteasome. During apoptosis, caspase activation results in the cleavage of three specific subunits of the 19S regulatory complex of the proteasome: S6' (Rpt5) and S5a (Rpn10), whose role is to recognize polyubiquitinated substrates of the proteasome, and S1 (Rpn2), which with S5a and S2 (Rpn1) holds together the lid and base of the 19S regulatory complex. This caspase-mediated cleavage inhibits the proteasomal degradation of ubiquitin-dependent and -independent cellular substrates, including proapoptotic molecules such as Smac, so facilitating the execution of the apoptotic program by providing a feed-forward amplification loop.

  2. Disordered holographic systems: Functional renormalization

    NASA Astrophysics Data System (ADS)

    Adams, Allan; Yaida, Sho

    2015-12-01

    We study quenched disorder in strongly correlated systems via holography, focusing on the thermodynamic effects of mild electric disorder. Disorder is introduced through a random potential which is assumed to self-average on macroscopic scales. Studying the flow of this distribution with energy scale leads us to develop a holographic functional renormalization scheme. We test this scheme by computing thermodynamic quantities and confirming that the Harris criterion for relevance, irrelevance, or marginality of quenched disorder holds.

  3. SUMOylation at K707 of DGCR8 controls direct function of primary microRNA

    PubMed Central

    Zhu, Changhong; Chen, Cheng; Huang, Jian; Zhang, Hailong; Zhao, Xian; Deng, Rong; Dou, Jinzhuo; Jin, Hui; Chen, Ran; Xu, Ming; Chen, Qin; Wang, Yanli; Yu, Jianxiu

    2015-01-01

    DGCR8 (DiGeorge syndrome critical region gene 8) is essential for primary microRNA (pri-miRNA) processing in the cell nucleus. It specifically combines with Drosha, a nuclear RNase III enzyme, to form the Microprocessor complex (MC) that cleaves pri-miRNA to precursor miRNA (pre-miRNA), which is further processed to mature miRNA by Dicer, a cytoplasmic RNase III enzyme. Increasing evidences suggest that pri-/pre-miRNAs have direct functions in regulation of gene expression, however the underlying mechanism how it is fine-tuned remains unclear. Here we find that DGCR8 is modified by SUMO1 at the major site K707, which can be promoted by its ERK-activated phosphorylation. SUMOylation of DGCR8 enhances the protein stability by preventing the degradation via the ubiquitin proteasome pathway. More importantly, SUMOylation of DGCR8 does not alter its association with Drosha, the MC activity and miRNA biogenesis, but rather influences its affinity with pri-miRNAs. This altered affinity of DGCR8 with pri-miRNAs seems to control the direct functions of pri-miRNAs in recognition and repression of the target mRNAs, which is evidently linked to the DGCR8 function in regulation of tumorigenesis and cell migration. Collectively, our data suggest a novel mechanism that SUMOylation of DGCR8 controls direct functions of pri-miRNAs in gene silencing. PMID:26202964

  4. Phytochrome from Green Plants: Properties and biological Function

    SciTech Connect

    Quail, Peter H.

    2014-07-25

    Pfr conformer reverses this activity upon initial light exposure, inducing the switch to photomorphogenic development. This reversal involves light-triggered translocation of the photoactivated phy molecule into the nucleus where it interacts with PIF-family members, inducing rapid phosphorylation and degradation of the PIFs via the ubiquitin-proteasome system. This degradation in turn elicits rapid alterations in gene expression that drive the deetiolation transition. This project has made considerable progress in defining phy-PIF signaling activity in controlling the SAR. The biological functions of the multiple PIF-family members in controlling the SAR, including dissection of the relative contributions of the individual PIFs to this process, as well as to diurnal growth-control oscillations, have been investigated using higher-order pif-mutant combinations. Using microarray analysis of a quadruple pif mutant we have defined the shade-induced, PIF-regulated transcriptional network genome-wide. This has revealed that a dynamic antagonism between the phys and PIFs generates selective reciprocal responses during deetiolation and the SAR in a rapidly light-responsive transcriptional network. Using integrated RNA-seq and ChIP-seq analysis of higher order pif-mutant combinations, we have defined the direct gene-targets of PIF transcriptional regulation, and have obtained evidence that this regulation involves differential direct targeting of rapidly light-responsive genes by the individual PIF-family members. This project has provided significant advances in our understanding of the molecular mechanisms by which the phy-PIF photosensory signaling pathway regulates an important bioenergy-related plant response to the light environment. The identification of molecular targets in the primary transcriptional-regulatory circuitry of this pathway has the potential to enable genetic or reverse-genetic manipulation of the partitioning of carbon between reproductive and

  5. Functional Microgels and Microgel Systems.

    PubMed

    Plamper, Felix A; Richtering, Walter

    2017-02-21

    Microgels are macromolecular networks swollen by the solvent in which they are dissolved. They are unique systems that are distinctly different from common colloids, such as, e.g., rigid nanoparticles, flexible macromolecules, micelles, or vesicles. The size of the microgel networks is in the range of several micrometers down to nanometers (then sometimes called "nanogels"). In a collapsed state, they might resemble hard colloids but they can still contain significant amounts of solvent. When swollen, they are soft and have a fuzzy surface with dangling chains. The presence of cross-links provides structural integrity, in contrast to linear and (hyper)branched polymers. Obviously, the cross-linker content will allow control of whether microgels behave more "colloidal" or "macromolecular". The combination of being soft and porous while still having a stable structure through the cross-linked network allows for designing microgels that have the same total chemical composition, but different properties due to a different architecture. Microgels based, e.g., on two monomers but have either statistical spatial distribution, or a core-shell or hollow-two-shell morphology will display very different properties. Microgels provide the possibility to introduce chemical functionality at different positions. Combining architectural diversity and compartmentalization of reactive groups enables thus short-range coexistence of otherwise instable combinations of chemical reactivity. The open microgel structure is beneficial for uptake-release purposes of active substances. In addition, the openness allows site-selective integration of active functionalities like reactive groups, charges, or markers by postmodification processes. The unique ability of microgels to retain their colloidal stability and swelling degree both in water and in many organic solvents allows use of different chemistries for the modification of microgel structure. The capability of microgels to adjust both

  6. Fukui function and response function for nonlocal and fractional systems

    NASA Astrophysics Data System (ADS)

    Peng, Degao; Yang, Weitao

    2013-05-01

    We present extensions to our previous work on Fukui functions and linear-response functions [W. Yang, A. J. Cohen, F. D. Proft, and P. Geerlings, J. Chem. Phys. 136, 144110 (2012), 10.1063/1.3701562]. Viewed as energy derivatives with respect to the number of electrons and the external potential, all second-order derivatives (the linear-response function, the Fukui function, and the chemical hardness) are extended to fractional systems, and all third-order derivatives (the second-order response function, the Fukui response function, the dual descriptor, and the hyperhardness) for integer systems are also obtained. These analytical derivatives are verified by finite difference numerical derivatives. In the context of the exact linearity condition and the constancy condition, these analytical derivatives enrich greatly the information of the exact conditions on the energy functional through establishing real-space dependency. The introduction of an external nonlocal potential defines the nonlocal Fukui function and the nonlocal linear-response function. The nonlocal linear-response function so defined also provides the precise meaning for the time-dependent linear-response density-functional theory calculations with generalized Kohn-Sham functionals. These extensions will be useful to conceptual density-functional theory and density functional development.

  7. Dss1 associating with the proteasome functions in selective nuclear mRNA export in yeast

    SciTech Connect

    Mannen, Taro; Andoh, Tomoko; Tani, Tokio

    2008-01-25

    Dss1p is an evolutionarily conserved small protein that interacts with BRCA2, a tumor suppressor protein, in humans. The Schizosaccharomyces pombe strain lacking the dss1{sup +} gene ({delta}dss1) shows a temperature-sensitive growth defect and accumulation of bulk poly(A){sup +} RNA in the nucleus at a nonpermissive temperature. In situ hybridization using probes for several specific mRNAs, however, revealed that the analyzed mRNAs were exported normally to the cytoplasm in {delta}dss1, suggesting that Dss1p is required for export of some subsets of mRNAs. We identified the pad1{sup +} gene, which encodes a component of the 26S proteasome, as a suppressor for the ts{sup -} phenotype of {delta}dss1. Unexpectedly, overexpression of Pad1p could suppress neither the defect in nuclear mRNA export nor a defect in proteasome function. In addition, loss of proteasome functions does not cause defective nuclear mRNA export. Dss1p seems to be a multifunctional protein involved in nuclear export of specific sets of mRNAs and the ubiquitin-proteasome pathway in fission yeast.

  8. Berberine bioisostere Q8 compound stimulates osteoblast differentiation and function in vitro.

    PubMed

    Han, Younho; Jin, Yifeng; Lee, Sung Ho; Khadka, Daulat Bikram; Cho, Won-Jea; Lee, Kwang Youl

    2017-03-07

    The Q8 compound is a unique derivative of berberine. The present study investigated the functional role of Q8 to evaluate its potential for use in bone regeneration, especially in osteoblast differentiation. The safe concentration of Q8 increased BMP4-induced alkaline phosphatase (ALP) activity, and induced RNA expression of ALP, bone sialoprotein (BSP), and osteocalcin (OC). The activities of ALP-, BSP- and OC-luciferase reporters were also increased by Q8. During osteoblast differentiation, Q8 stabilized the Runx2 and Osterix protein abundance by blocking the ubiquitin-proteasome pathway, which in turn promoted Runx2 and Osterix induced transcriptional activity and subsequently increased the osteoblast differentiation. Meanwhile, depletion of Runx2 and Osterix markedly abolished the bone anabolic effect of Q8 on osteoblast differentiation. To evaluate the signal transduction pathway involved in the Q8-mediated regulation of Runx2 and Osterix, we examined the reporter assay using various kinase inhibitors. Treatment with a protein kinase A (PKA) inhibitor, H89 inhibited the Q8-mediated regulation of Runx2 and Osterix. Based on these findings, this study demonstrates that Q8 promotes the osteoblast differentiation by stabilization of Runx2/Osterix through the increased activation of PKA signaling. The enhancement of osteoblast function by Q8 may contribute to the prevention for osteoporosis.

  9. Control of cell growth by the SCF and APC/C ubiquitin ligases

    PubMed Central

    Skaar, Jeffrey R.; Pagano, Michele

    2009-01-01

    The ubiquitin-proteasome system plays key roles in the control of cell growth. The cell cycle in particular is highly regulated by the functions of the SCF and APC/C ubiquitin ligases, and perturbation of their function can result in tumorigenesis. Although the SCF and APC/C complexes are well-established in growth control pathways, many aspects of their function remain unknown. Recent studies have shed light on the mechanism of SCF-mediated ubiquitination and new functions for the SCF complex and APC/C. Our expanding understanding of the roles of the SCF and APC/C complexes highlight the potential for targeted molecular therapies. PMID:19775879

  10. Software Systems: Consequence versus Functionality

    SciTech Connect

    Berg, Ray; Winter, Victor L.

    1999-08-05

    The purpose of this panel is to present different perspectives and opinions regarding the issues surrounding why software should or shouldn't be entrusted with critical (high consequence) functionality.

  11. Functional roles of PC-PLC and Cdc20 in the cell cycle, proliferation, and apoptosis.

    PubMed

    Chen, Zhiwei; Yu, Yongfeng; Fu, Da; Li, Ziming; Niu, Xiaoming; Liao, Meilin; Lu, Shun

    2010-06-01

    Phosphatidylcholine-specific phospholipase C (PC-PLC) is the major enzyme in the Phosphatidylcholine (PC) cycle and is involved in many long-term cellular responses such as activation, proliferation, and differentiation events. Cell division cycle 20 homolog (Cdc20) is an essential cell-cycle regulator required for the completion of mitosis. Our previous studies identified the interaction between PC-PLC and Cdc20. Through the interaction, Cdc20 could mediate the degradation of PC-PLC by Cdc20-mediated ubiquitin proteasome pathway (UPP). In this study, we found that PC-PLC might not be involved in cancer metastasis. Inhibition of PC-PLC by D609 could cause cell proliferation inhibition and apoptosis inhibition in CBRH-7919 cells. Inhibition of PC-PLC could also influence the cell cycle by arresting the cells in G1 phase, and Cdc20 might be involved in these processes. Taken together, in this report, we provided new evidence for the functional roles of PC-PLC and Cdc20 in the cell cycle, proliferation, and apoptosis in CBRH-7919 cells.

  12. Iterated Function Systems on Functions of Bounded Variation

    NASA Astrophysics Data System (ADS)

    La Torre, Davide; Mendivil, Franklin; Vrscay, Edward R.

    2016-04-01

    We show that under certain hypotheses, an iterated function system on mappings (IFSM) is a contraction on the complete space of functions of bounded variation (BV). It then possesses a unique attractor of BV. Some BV-based inverse problems based on the Collage Theorem for contraction maps are considered.

  13. Transfer function characteristics of super resolving systems

    NASA Technical Reports Server (NTRS)

    Milster, Tom D.; Curtis, Craig H.

    1992-01-01

    Signal quality in an optical storage device greatly depends on the optical system transfer function used to write and read data patterns. The problem is similar to analysis of scanning optical microscopes. Hopkins and Braat have analyzed write-once-read-many (WORM) optical data storage devices. Herein, transfer function analysis of magnetooptic (MO) data storage devices is discussed with respect to improving transfer-function characteristics. Several authors have described improving the transfer function as super resolution. However, none have thoroughly analyzed the MO optical system and effects of the medium. Both the optical system transfer function and effects of the medium of this development are discussed.

  14. [Functional anatomy of the central nervous system].

    PubMed

    Krainik, A; Feydy, A; Colombani, J M; Hélias, A; Menu, Y

    2003-03-01

    The central nervous system (CNS) has a particular regional functional anatomy. The morphological support of cognitive functions can now be depicted using functional imaging. Lesions of the central nervous system may be responsible of specific symptoms based on their location. Current neuroimaging techniques are able to show and locate precisely macroscopic lesions. Therefore, the knowledge of functional anatomy of the central nervous system is useful to link clinical disorders to symptomatic lesions. Using radio-clinical cases, we present the functional neuro-anatomy related to common cognitive impairments.

  15. Writing to Persuade: A Systemic Functional View

    ERIC Educational Resources Information Center

    Schulze, Joshua

    2011-01-01

    This study explores how a genre-based approach to writing instruction influenced by both genre theory and systemic functional linguistics supported the academic writing development of English language learners (ELLs) transitioning to middle school. Drawing on Systemic Functional Linguistics (SFL) as a tool for pedagogy and linguistic analysis, the…

  16. The Keap1-Nrf2 system and diabetes mellitus.

    PubMed

    Uruno, Akira; Yagishita, Yoko; Yamamoto, Masayuki

    2015-01-15

    Nrf2 (NF-E2-related factor 2) plays a key role in the protection of vertebrates against environmental stress by contributing to the inducible expression of detoxification and antioxidant enzymes. Keap1 (Kelch-like ECH-associated protein 1) is a sensor for oxidative and electrophilic stresses. Keap1 also acts as an E3 ubiquitin ligase substrate-recognition subunit that specifically targets Nrf2. Keap1 causes Nrf2 to be degraded through the ubiquitin-proteasome pathway and thus ensures that Nrf2 is constitutively suppressed under unstressed conditions. Upon exposure to oxidative or electrophilic stress, Keap1 loses its ability to ubiquitinate Nrf2. Many lines of evidence have recently clarified that the Keap1-Nrf2 system also plays critical roles in the maintenance of cellular homeostasis. One of the most salient examples is the contribution of Keap1-Nrf2 to metabolic and energy-balance regulation. In particular, how the Keap1-Nrf2 system protects the body against diabetes mellitus and how perturbations in this system provoke the disease condition are now under intense investigation. This review will summarize the recent progress made in this area.

  17. Functional Risk Modeling for Lunar Surface Systems

    NASA Technical Reports Server (NTRS)

    Thomson, Fraser; Mathias, Donovan; Go, Susie; Nejad, Hamed

    2010-01-01

    We introduce an approach to risk modeling that we call functional modeling , which we have developed to estimate the capabilities of a lunar base. The functional model tracks the availability of functions provided by systems, in addition to the operational state of those systems constituent strings. By tracking functions, we are able to identify cases where identical functions are provided by elements (rovers, habitats, etc.) that are connected together on the lunar surface. We credit functional diversity in those cases, and in doing so compute more realistic estimates of operational mode availabilities. The functional modeling approach yields more realistic estimates of the availability of the various operational modes provided to astronauts by the ensemble of surface elements included in a lunar base architecture. By tracking functional availability the effects of diverse backup, which often exists when two or more independent elements are connected together, is properly accounted for.

  18. Spinocerebellar ataxia-13 Kv3.3 potassium channels: arginine-to-histidine mutations affect both functional and protein expression on the cell surface.

    PubMed

    Zhao, Jian; Zhu, Jing; Thornhill, William B

    2013-09-01

    The voltage-gated potassium channel Kv3.3 is the causative gene of SCA13 (spinocerebellar ataxia type 13), an autosomal dominant neurological disorder. The four dominant mutations identified to date cause Kv3.3 channels to be non-functional or have altered gating properties in Xenopus oocytes. In the present paper, we report that SCA13 mutations affect functional as well as protein expression of Kv3.3 channels in a mammalian cell line. The reduced protein level of SCA13 mutants is caused by a shorter protein half-life, and blocking the ubiquitin-proteasome pathway increases the total protein of SCA13 mutants more than wild-type. SCA13 mutated amino acids are highly conserved, and the side chains of these residues play a critical role in the stable expression of Kv3.3 proteins. In addition, we show that mutant Kv3.3 protein levels could be partially rescued by treatment with the chemical chaperone TMAO (trimethylamine N-oxide) and to a lesser extent with co-expression of Kv3.1b. Thus our results suggest that amino acid side chains of SCA13 positions affect the protein half-life and/or function of Kv3.3, and the adverse effect on protein expression cannot be fully rescued.

  19. Function Analysis and Decomposistion using Function Analysis Systems Technique

    SciTech Connect

    J. R. Wixson

    1999-06-01

    The "Father of Value Analysis", Lawrence D. Miles, was a design engineer for General Electric in Schenectady, New York. Miles developed the concept of function analysis to address difficulties in satisfying the requirements to fill shortages of high demand manufactured parts and electrical components during World War II. His concept of function analysis was further developed in the 1960s by Charles W. Bytheway, a design engineer at Sperry Univac in Salt Lake City, Utah. Charles Bytheway extended Mile's function analysis concepts and introduced the methodology called Function Analysis Systems Techniques (FAST) to the Society of American Value Engineers (SAVE) at their International Convention in 1965 (Bytheway 1965). FAST uses intuitive logic to decompose a high level, or objective function into secondary and lower level functions that are displayed in a logic diagram called a FAST model. Other techniques can then be applied to allocate functions to components, individuals, processes, or other entities that accomplish the functions. FAST is best applied in a team setting and proves to be an effective methodology for functional decomposition, allocation, and alternative development.

  20. Function Analysis and Decomposistion using Function Analysis Systems Technique

    SciTech Connect

    Wixson, James Robert

    1999-06-01

    The "Father of Value Analysis", Lawrence D. Miles, was a design engineer for General Electric in Schenectady, New York. Miles developed the concept of function analysis to address difficulties in satisfying the requirements to fill shortages of high demand manufactured parts and electrical components during World War II. His concept of function analysis was further developed in the 1960s by Charles W. Bytheway, a design engineer at Sperry Univac in Salt Lake City, Utah. Charles Bytheway extended Mile's function analysis concepts and introduced the methodology called Function Analysis Systems Technique (FAST) to the Society of American Value Engineers (SAVE) at their International Convention in 1965 (Bytheway 1965). FAST uses intuitive logic to decompose a high level, or objective function into secondary and lower level functions that are displayed in a logic diagram called a FAST model. Other techniques can then be applied to allocate functions to components, individuals, processes, or other entities that accomplish the functions. FAST is best applied in a team setting and proves to be an effective methodology for functional decomposition, allocation, and alternative development.

  1. The Nervous System and Gastrointestinal Function

    ERIC Educational Resources Information Center

    Altaf, Muhammad A.; Sood, Manu R.

    2008-01-01

    The enteric nervous system is an integrative brain with collection of neurons in the gastrointestinal tract which is capable of functioning independently of the central nervous system (CNS). The enteric nervous system modulates motility, secretions, microcirculation, immune and inflammatory responses of the gastrointestinal tract. Dysphagia,…

  2. A pragmatic approach to biochemical systems theory applied to an alpha-synuclein-based model of Parkinson's disease.

    PubMed

    Sass, Matthew B; Lorenz, Alyson N; Green, Robert L; Coleman, Randolph A

    2009-04-15

    This paper presents a detailed systems model of Parkinson's disease (PD), developed utilizing a pragmatic application of biochemical systems theory (BST) intended to assist experimentalists in the study of system behavior. This approach utilizes relative values as a reasonable initial estimate for BST and provides a theoretical means of applying numerical solutions to qualitative and semi-quantitative understandings of cellular pathways and mechanisms. The approach allows for the simulation of human disease through its ability to organize and integrate existing information about metabolic pathways without having a full quantitative description of those pathways, so that hypotheses about individual processes may be tested in a systems environment. Incorporating this method, the PD model describes alpha-synuclein aggregation as mediated by dopamine metabolism, the ubiquitin-proteasome system, and lysosomal degradation, allowing for the examination of dynamic pathway interactions and the evaluation of possible toxic mechanisms in the aggregation process. Four system perturbations: elevated alpha-synuclein aggregation, impaired dopamine packaging, increased neurotoxins, and alpha-synuclein overexpression, were analyzed for correlation to qualitative PD system hypotheses present in the literature, with the model demonstrating a high level of agreement with these hypotheses. Additionally, various PD treatment methods, including levadopa and monoamine oxidase inhibition (MAOI) therapy, were applied to the disease models to examine their effects on the system. Future additions and refinements to the model may further the understanding of the emergent behaviors of the disease, helping in the identification of system sensitivities and possible therapeutic targets.

  3. Form and function in systems neuroscience.

    PubMed

    Kristan, William B; Katz, Paul

    2006-10-10

    'Form follows function' is an architectural philosophy attributed to the great American architect Louis Sullivan, and later taken up by the Bauhaus movement. It stresses that the form of a building should reflect its function. Neuroscientists have used the converse of this dictum to learn the functions of neural circuits, believing that if we study neural architecture, it will lead us to an understanding of how neural systems function. New tools for studying the structure of neural circuits are being developed, so it is important to discuss what the old techniques have taught us about how to derive function from the form of a neural circuit.

  4. Functional characterization of EI24-induced autophagy in the degradation of RING-domain E3 ligases

    PubMed Central

    Devkota, Sushil; Jeong, Hyobin; Kim, Yunmi; Ali, Muhammad; Roh, Jae-il; Hwang, Daehee; Lee, Han-Woong

    2016-01-01

    ABSTRACT Historically, the ubiquitin-proteasome system (UPS) and autophagy pathways were believed to be independent; however, recent data indicate that these pathways engage in crosstalk. To date, the players mediating this crosstalk have been elusive. Here, we show experimentally that EI24 (EI24, autophagy associated transmembrane protein), a key component of basal macroautophagy/autophagy, degrades 14 physiologically important E3 ligases with a RING (really interesting new gene) domain, whereas 5 other ligases were not degraded. Based on the degradation results, we built a statistical model that predicts the RING E3 ligases targeted by EI24 using partial least squares discriminant analysis. Of 381 RING E3 ligases examined computationally, our model predicted 161 EI24 targets. Those targets are primarily involved in transcription, proteolysis, cellular bioenergetics, and apoptosis and regulated by TP53 and MTOR signaling. Collectively, our work demonstrates that EI24 is an essential player in UPS-autophagy crosstalk via degradation of RING E3 ligases. These results indicate a paradigm shift regarding the fate of E3 ligases. PMID:27541728

  5. An siRNA-based functional genomics screen for the identification of regulators of ciliogenesis and ciliopathy genes

    PubMed Central

    Racher, Hilary; Phelps, Ian G.; Toedt, Grischa; Kennedy, Julie; Wunderlich, Kirsten A.; Sorusch, Nasrin; Abdelhamed, Zakia A.; Natarajan, Subaashini; Herridge, Warren; van Reeuwijk, Jeroen; Horn, Nicola; Boldt, Karsten; Parry, David A.; Letteboer, Stef J.F.; Roosing, Susanne; Adams, Matthew; Bell, Sandra M.; Bond, Jacquelyn; Higgins, Julie; Morrison, Ewan E.; Tomlinson, Darren C.; Slaats, Gisela G.; van Dam, Teunis J. P.; Huang, Lijia; Kessler, Kristin; Giessl, Andreas; Logan, Clare V.; Boyle, Evan A.; Shendure, Jay; Anazi, Shamsa; Aldahmesh, Mohammed; Al Hazzaa, Selwa; Hegele, Robert A.; Ober, Carole; Frosk, Patrick; Mhanni, Aizeddin A.; Chodirker, Bernard N.; Chudley, Albert E.; Lamont, Ryan; Bernier, Francois P.; Beaulieu, Chandree L.; Gordon, Paul; Pon, Richard T.; Donahue, Clem; Barkovich, A. James; Wolf, Louis; Toomes, Carmel; Thiel, Christian T.; Boycott, Kym M.; McKibbin, Martin; Inglehearn, Chris F.; Stewart, Fiona; Omran, Heymut; Huynen, Martijn A.; Sergouniotis, Panagiotis I.; Alkuraya, Fowzan S.; Parboosingh, Jillian S.; Innes, A Micheil; Willoughby, Colin E.; Giles, Rachel H.; Webster, Andrew R.; Ueffing, Marius; Blacque, Oliver; Gleeson, Joseph G.; Wolfrum, Uwe; Beales, Philip L.; Gibson, Toby

    2015-01-01

    Defects in primary cilium biogenesis underlie the ciliopathies, a growing group of genetic disorders. We describe a whole genome siRNA-based reverse genetics screen for defects in biogenesis and/or maintenance of the primary cilium, obtaining a global resource. We identify 112 candidate ciliogenesis and ciliopathy genes, including 44 components of the ubiquitin-proteasome system, 12 G-protein-coupled receptors, and three pre-mRNA processing factors (PRPF6, PRPF8 and PRPF31) mutated in autosomal dominant retinitis pigmentosa. The PRPFs localise to the connecting cilium, and PRPF8- and PRPF31-mutated cells have ciliary defects. Combining the screen with exome sequencing data identified recessive mutations in PIBF1/CEP90 and C21orf2/LRRC76 as causes of the ciliopathies Joubert and Jeune syndromes. Biochemical approaches place C21orf2 within key ciliopathy-associated protein modules, offering an explanation for the skeletal and retinal involvement observed in individuals with C21orf2-variants. Our global, unbiased approaches provide insights into ciliogenesis complexity and identify roles for unanticipated pathways in human genetic disease. PMID:26167768

  6. Zinc ionophores pyrithione inhibits herpes simplex virus replication through interfering with proteasome function and NF-κB activation.

    PubMed

    Qiu, Min; Chen, Yu; Chu, Ying; Song, Siwei; Yang, Na; Gao, Jie; Wu, Zhiwei

    2013-10-01

    Pyrithione (PT), known as a zinc ionophore, is effective against several pathogens from the Streptococcus and Staphylococcus genera. The antiviral activity of PT was also reported against a number of RNA viruses. In this paper, we showed that PT could effectively inhibit herpes simplex virus types 1 and 2 (HSV-1 and HSV-2). PT inhibited HSV late gene (Glycoprotein D, gD) expression and the production of viral progeny, and this action was dependent on Zn(2+). Further studies showed that PT suppressed the expression of HSV immediate early (IE) gene, the infected cell polypeptide 4 (ICP4), but had less effect on another regulatory IE protein, ICP0. It was found that PT treatment could interfere with cellular ubiquitin-proteasome system (UPS), leading to the inhibition of HSV-2-induced IκB-α degradation to inhibit NF-κB activation and enhanced promyelocytic leukemia protein (PML) stability in nucleus. However, PT did not show direct inhibition of 26S proteasome activity. Instead, it induced Zn(2+) influx, which facilitated the dysregulation of UPS and the accumulation of intracellular ubiquitin-conjugates. UPS inhibition by PT caused disruption of IκB-α degradation and NF-κB activation thus leading to marked reduction of viral titer.

  7. The PUB domain: a putative protein-protein interaction domain implicated in the ubiquitin-proteasome pathway.

    PubMed

    Suzuki, T; Park, H; Till, E A; Lennarz, W J

    2001-10-12

    Cytoplasmic peptide:N-glycanase (PNGase) is a de-N-glycosylating enzyme which may be involved in the proteasome-dependent pathway for degradation of misfolded glycoproteins formed in the endoplasmic reticulum (ER) that are exported into the cytoplasm. A cytoplasmic PNGase found in Saccharomyces cerevisiae, Png1p, is widely distributed in higher eukaryotes as well as in yeast (Suzuki, T., et al. J. Cell Biol. 149, 1039-1051, 2000). The recently uncovered complete genome sequence of Arabidopsis thaliana prompted us to search for the protein homologue of Png1p in this organism. Interestingly, when the mouse Png1p homologue sequence was used as a query, not only a Png1p homologue containing a transglutaminase-like domain that is believed to contain a catalytic triad for PNGase activity, but also four proteins which had a domain of 46 amino acids in length that exhibited significant similarity to the N-terminus of mouse Png1p were identified. Moreover, three of these homologous proteins were also found to possess a UBA or UBX domain, which are found in various proteins involved in the ubiquitin-related pathway. We name this newly found homologous region the PUB (Peptide:N-glycanase/UBA or UBX-containing proteins) domain and propose that this domain may mediate protein-protein interactions.

  8. Foxp3 enhances HIF-1α target gene expression in human bladder cancer through decreasing its ubiquitin-proteasomal degradation

    PubMed Central

    Lin, Chang-Te; Tung, Chun-Liang; Shen, Cheng-Huang; Tsai, Hsin-Tzu; Yang, Wen-Horng; Chang, Hung-I; Chen, Syue-Yi; Tzai, Tzong-Shin

    2016-01-01

    Hypoxia-inducible factor-1α (HIF-1α) can control a transcriptional factor forkhead box P3 (Foxp3) protein expression in T lymphocyte differentiation through proteasome-mediated degradation. In this study, we unveil a reverse regulatory mechanism contributing to bladder cancer progression; Foxp3 expression attenuates HIF-1α degradation. We first demonstrated that Foxp3 expression positively correlates with the metastatic potential in T24 cells and can increase the expression of HIF-1α-target genes, such as vascular endothelial growth factor (VEGF) and glucose transporter (GLUT). Foxp3 protein can bind with HIF-1α, particularly under hypoxia. In vivo ubiquination assay demonstrated that Foxp3 can decrease HIF-1α degradation in a dose-dependent manner. Knocking-down of Foxp3 expression blocks in vivo tumor growth in mice and prolongs mice's survival, which is associated with von Willebrand factor expression. Thirty-three of 145 (22.8 %) bladder tumors exhibit Foxp3 expression. Foxp3 expression is an independent predictor for disease progression in superficial bladder cancer patients (p = 0.032), associated with less number of intratumoral CD8+ lymphocyte. The metaanalysis from 2 published datasets showed Foxp3 expression is positively associated with GLUT−4, −9, and VEGF-A, B-, D expression. This reverse post-translational regulation of HIF-1α protein by Foxp3 provides a new potential target for developing new therapeutic strategy for bladder cancer. PMID:27557492

  9. APC/C and retinoblastoma interaction: cross-talk of retinoblastoma protein with the ubiquitin proteasome pathway

    PubMed Central

    Ramanujan, Ajeena; Tiwari, Swati

    2016-01-01

    The ubiquitin (Ub) ligase anaphase promoting complex/cyclosome (APC/C) and the tumour suppressor retinoblastoma protein (pRB) play key roles in cell cycle regulation. APC/C is a critical regulator of mitosis and G1-phase of the cell cycle whereas pRB keeps a check on proliferation by inhibiting transition to the S-phase. APC/C and pRB interact with each other via the co-activator of APC/C, FZR1, providing an alternative pathway of regulation of G1 to S transition by pRB using a post-translational mechanism. Both pRB and FZR1 have complex roles and are implicated not only in regulation of cell proliferation but also in differentiation, quiescence, apoptosis, maintenance of chromosomal integrity and metabolism. Both are also targeted by transforming viruses. We discuss recent advances in our understanding of the involvement of APC/C and pRB in cell cycle based decisions and how these insights will be useful for development of anti-cancer and anti-viral drugs. PMID:27402801

  10. Cereblon inhibits proteasome activity by binding to the 20S core proteasome subunit beta type 4.

    PubMed

    Lee, Kwang Min; Lee, Jongwon; Park, Chul-Seung

    2012-10-26

    In humans, mutations in the gene encoding cereblon (CRBN) are associated with mental retardation. Although CRBN has been investigated in several cellular contexts, its function remains unclear. Here, we demonstrate that CRBN plays a role in regulating the ubiquitin-proteasome system (UPS). Heterologous expression of CRBN inhibited proteasome activity in a human neuroblastoma cell line. Furthermore, proteasome subunit beta type 4 (PSMB4), the β7 subunit of the 20S core complex, was identified as a direct binding partner of CRBN. These findings suggest that CRBN may modulate proteasome activity by directly interacting with the β7 subunit.

  11. Small molecule therapeutics targeting F-Box proteins in cancer

    PubMed Central

    Liu, Yuan; Mallampalli, Rama K.

    2015-01-01

    The ubiquitin proteasome system (UPS) plays vital roles in maintaining protein equilibrium mainly through proteolytic degradation of targeted substrates. The archetypical SCF ubiquitin E3 ligase complex contains a substrate recognition subunit F-box protein that recruits substrates to the catalytic ligase core for its polyubiquitylation and subsequent proteasomal degradation. Several well characterized F-box proteins have been demonstrated that are tightly linked to neoplasia. There is mounting information characterizing F-box protein-substrate interactions with the rationale to develop unique therapeutics for cancer treatment. Here we review that how F-box proteins function in cancer and summarize potential small molecule inhibitors for cancer therapy. PMID:26427329

  12. Small molecule therapeutics targeting F-box proteins in cancer.

    PubMed

    Liu, Yuan; Mallampalli, Rama K

    2016-02-01

    The ubiquitin proteasome system (UPS) plays vital roles in maintaining protein equilibrium mainly through proteolytic degradation of targeted substrates. The archetypical SCF ubiquitin E3 ligase complex contains a substrate recognition subunit F-box protein that recruits substrates to the catalytic ligase core for its polyubiquitylation and subsequent proteasomal degradation. Several well-characterized F-box proteins have been demonstrated that are tightly linked to neoplasia. There is mounting information characterizing F-box protein-substrate interactions with the rationale to develop unique therapeutics for cancer treatment. Here we review that how F-box proteins function in cancer and summarize potential small molecule inhibitors for cancer therapy.

  13. Electrostatic camera system functional design study

    NASA Technical Reports Server (NTRS)

    Botticelli, R. A.; Cook, F. J.; Moore, R. F.

    1972-01-01

    A functional design study for an electrostatic camera system for application to planetary missions is presented. The electrostatic camera can produce and store a large number of pictures and provide for transmission of the stored information at arbitrary times after exposure. Preliminary configuration drawings and circuit diagrams for the system are illustrated. The camera system's size, weight, power consumption, and performance are characterized. Tradeoffs between system weight, power, and storage capacity are identified.

  14. Design of membrane proteins: toward functional systems.

    PubMed

    Ghirlanda, Giovanna

    2009-12-01

    Over the years, membrane-soluble peptides have provided a convenient model system to investigate the folding and assembly of integral membrane proteins. Recent advances in experimental and computational methods are now being translated into the design of functional membrane proteins. Applications include artificial modulators of membrane protein function, inhibitors of protein-protein interactions, and redox membrane proteins.

  15. Human Systems Integration: Requirements and Functional Decomposition

    NASA Technical Reports Server (NTRS)

    Berson, Barry; Gershzohn, Gary; Boltz, Laura; Wolf, Russ; Schultz, Mike

    2005-01-01

    This deliverable was intended as an input to the Access 5 Policy and Simulation Integrated Product Teams. This document contains high-level pilot functionality for operations in the National Airspace System above FL430. Based on the derived pilot functions the associated pilot information and control requirements are given.

  16. Functional Translational Readthrough: A Systems Biology Perspective

    PubMed Central

    Schueren, Fabian

    2016-01-01

    Translational readthrough (TR) has come into renewed focus because systems biology approaches have identified the first human genes undergoing functional translational readthrough (FTR). FTR creates functional extensions to proteins by continuing translation of the mRNA downstream of the stop codon. Here we review recent developments in TR research with a focus on the identification of FTR in humans and the systems biology methods that have spurred these discoveries. PMID:27490485

  17. An Introduction to Systemic Functional Linguistics.

    ERIC Educational Resources Information Center

    Eggins, Suzanne

    The introduction to systemic functional linguistics explores the social semiotic approach to language most closely associated with the work of Michael Halliday and his colleagues. An approach that views language as a strategic, meaning-making resource, systemic linguistics focuses on the analysis of authentic, everyday texts and asks both how…

  18. Functional stability of cerebral circulatory system

    NASA Technical Reports Server (NTRS)

    Moskalenko, Y. Y.

    1980-01-01

    The functional stability of the cerebral circulation system seems to be based on the active mechanisms and on those stemming from specific of the biophysical structure of the system under study. This latter parameter has some relevant criteria for its quantitative estimation. The data obtained suggest that the essential part of the mechanism for active responses of cerebral vessels which maintains the functional stability of this portion of the vascular system, consists of a neurogenic component involving central nervous structures localized, for instance, in the medulla oblongata.

  19. Relations among Functional Systems in Behavior Analysis

    PubMed Central

    Thompson, Travis

    2007-01-01

    This paper proposes that an organism's integrated repertoire of operant behavior has the status of a biological system, similar to other biological systems, like the nervous, cardiovascular, or immune systems. Evidence from a number of sources indicates that the distinctions between biological and behavioral events is often misleading, engendering counterproductive explanatory controversy. A good deal of what is viewed as biological (often thought to be inaccessible or hypothetical) can become publicly measurable variables using currently available and developing technologies. Moreover, such endogenous variables can serve as establishing operations, discriminative stimuli, conjoint mediating events, and maintaining consequences within a functional analysis of behavior and need not lead to reductionistic explanation. I suggest that explanatory misunderstandings often arise from conflating different levels of analysis and that behavior analysis can extend its reach by identifying variables operating within a functional analysis that also serve functions in other biological systems. PMID:17575907

  20. Disassembly of Lys11 and Mixed Linkage Polyubiquitin Conjugates Provides Insights into Function of Proteasomal Deubiquitinases Rpn11 and Ubp6*

    PubMed Central

    Mansour, Wissam; Nakasone, Mark A.; von Delbrück, Maximilian; Yu, Zanlin; Krutauz, Daria; Reis, Noa; Kleifeld, Oded; Sommer, Thomas; Fushman, David; Glickman, Michael H.

    2015-01-01

    Protein homeostasis is largely dependent on proteolysis by the ubiquitin-proteasome system. Diverse polyubiquitin modifications are reported to target cellular proteins to the proteasome. At the proteasome, deubiquitination is an essential preprocessing event that contributes to degradation efficiency. We characterized the specificities of two proteasome-associated deubiquitinases (DUBs), Rpn11 and Ubp6, and explored their impact on overall proteasome DUB activity. This was accomplished by constructing a panel of well defined ubiquitin (Ub) conjugates, including homogeneous linkages of varying lengths as well as a heterogeneously modified target. Rpn11 and Ubp6 processed Lys11 and Lys63 linkages with comparable efficiencies that increased with chain length. In contrast, processing of Lys48 linkages by proteasome was inversely correlated to chain length. Fluorescently labeled tetra-Ub chains revealed endo-chain preference for Ubp6 acting on Lys48 and random action for Rpn11. Proteasomes were more efficient at deconjugating identical substrates than their constituent DUBs by roughly 2 orders of magnitude. Incorporation into proteasomes significantly enhanced enzymatic efficiency of Rpn11, due in part to alleviation of the autoinhibitory role of its C terminus. The broad specificity of Rpn11 could explain how proteasomes were more effective at disassembling a heterogeneously modified conjugate compared with homogeneous Lys48-linked chains. The reduced ability to disassemble homogeneous Lys48-linked chains longer than 4 Ub units may prolong residency time on the proteasome. PMID:25389291

  1. c.A2456C-substitution in Pck1 changes the enzyme kinetic and functional properties modifying fat distribution in pigs

    PubMed Central

    Latorre, Pedro; Burgos, Carmen; Hidalgo, Jorge; Varona, Luis; Carrodeguas, José Alberto; López-Buesa, Pascual

    2016-01-01

    Cytosolic phosphoenolpyruvate carboxykinase, PCK1, is one of the main regulatory enzymes of gluconeogenesis and glyceroneogenesis. The substitution of a single amino acid (Met139Leu) in PCK1 as a consequence of a single nucleotide polymorphism (SNP), c.A2456C, is associated in the pig to a negative phenotype characterized by reduced intramuscular fat content, enhanced backfat thickness and lower meat quality. The p.139L enzyme shows reduced kcat values in the glyceroneogenic direction and enhanced ones in the anaplerotic direction. Accordingly, the expression of the p.139L isoform results in about 30% lower glucose and 9% lower lipid production in cell cultures. Moreover, the ability of this isoform to be acetylated is also compromised, what would increase its susceptibility to be degraded in vivo by the ubiquitin-proteasome system. The high frequency of the c.2456C allele in modern pig breeds implies that the benefits of including c.A2456C SNP in selection programs could be considerable. PMID:26792594

  2. An siRNA-based functional genomics screen for the identification of regulators of ciliogenesis and ciliopathy genes.

    PubMed

    Wheway, Gabrielle; Schmidts, Miriam; Mans, Dorus A; Szymanska, Katarzyna; Nguyen, Thanh-Minh T; Racher, Hilary; Phelps, Ian G; Toedt, Grischa; Kennedy, Julie; Wunderlich, Kirsten A; Sorusch, Nasrin; Abdelhamed, Zakia A; Natarajan, Subaashini; Herridge, Warren; van Reeuwijk, Jeroen; Horn, Nicola; Boldt, Karsten; Parry, David A; Letteboer, Stef J F; Roosing, Susanne; Adams, Matthew; Bell, Sandra M; Bond, Jacquelyn; Higgins, Julie; Morrison, Ewan E; Tomlinson, Darren C; Slaats, Gisela G; van Dam, Teunis J P; Huang, Lijia; Kessler, Kristin; Giessl, Andreas; Logan, Clare V; Boyle, Evan A; Shendure, Jay; Anazi, Shamsa; Aldahmesh, Mohammed; Al Hazzaa, Selwa; Hegele, Robert A; Ober, Carole; Frosk, Patrick; Mhanni, Aizeddin A; Chodirker, Bernard N; Chudley, Albert E; Lamont, Ryan; Bernier, Francois P; Beaulieu, Chandree L; Gordon, Paul; Pon, Richard T; Donahue, Clem; Barkovich, A James; Wolf, Louis; Toomes, Carmel; Thiel, Christian T; Boycott, Kym M; McKibbin, Martin; Inglehearn, Chris F; Stewart, Fiona; Omran, Heymut; Huynen, Martijn A; Sergouniotis, Panagiotis I; Alkuraya, Fowzan S; Parboosingh, Jillian S; Innes, A Micheil; Willoughby, Colin E; Giles, Rachel H; Webster, Andrew R; Ueffing, Marius; Blacque, Oliver; Gleeson, Joseph G; Wolfrum, Uwe; Beales, Philip L; Gibson, Toby; Doherty, Dan; Mitchison, Hannah M; Roepman, Ronald; Johnson, Colin A

    2015-08-01

    Defects in primary cilium biogenesis underlie the ciliopathies, a growing group of genetic disorders. We describe a whole-genome siRNA-based reverse genetics screen for defects in biogenesis and/or maintenance of the primary cilium, obtaining a global resource. We identify 112 candidate ciliogenesis and ciliopathy genes, including 44 components of the ubiquitin-proteasome system, 12 G-protein-coupled receptors, and 3 pre-mRNA processing factors (PRPF6, PRPF8 and PRPF31) mutated in autosomal dominant retinitis pigmentosa. The PRPFs localize to the connecting cilium, and PRPF8- and PRPF31-mutated cells have ciliary defects. Combining the screen with exome sequencing data identified recessive mutations in PIBF1, also known as CEP90, and C21orf2, also known as LRRC76, as causes of the ciliopathies Joubert and Jeune syndromes. Biochemical approaches place C21orf2 within key ciliopathy-associated protein modules, offering an explanation for the skeletal and retinal involvement observed in individuals with C21orf2 variants. Our global, unbiased approaches provide insights into ciliogenesis complexity and identify roles for unanticipated pathways in human genetic disease.

  3. Influence of exposure to pesticides on telomere length in tobacco farmers: A biology system approach.

    PubMed

    Kahl, Vivian Francília Silva; da Silva, Juliana; da Silva, Fernanda Rabaioli

    Various pesticides in the form of mixtures must be used to keep tobacco crops pest-free. Recent studies have shown a link between occupational exposure to pesticides in tobacco crops and increased damage to the DNA, mononuclei, nuclear buds and binucleated cells in buccal cells as well as micronuclei in lymphocytes. Furthermore, pesticides used specifically for tobacco crops shorten telomere length (TL) significantly. However, the molecular mechanism of pesticide action on telomere length is not fully understood. Our study evaluated the interaction between a complex mixture of chemical compounds (tobacco cultivation pesticides plus nicotine) and proteins associated with maintaining TL, as well as the biological processes involved in this exposure by System Biology tools to provide insight regarding the influence of pesticide exposure on TL maintenance in tobacco farmers. Our analysis showed that one cluster was associated with TL proteins that act in bioprocesses such as (i) telomere maintenance via telomere lengthening; (ii) senescence; (iii) age-dependent telomere shortening; (iv) DNA repair (v) cellular response to stress and (vi) regulation of proteasome ubiquitin-dependent protein catabolic process. We also describe how pesticides and nicotine regulate telomere length. In addition, pesticides inhibit the ubiquitin proteasome system (UPS) and consequently increase proteins of the shelterin complex, avoiding the access of telomerase in telomere and, nicotine activates UPS mechanisms and promotes the degradation of human telomerase reverse transcriptase (hTERT), decreasing telomerase activity.

  4. Thermal enclosure system functional simulation user's manual

    NASA Technical Reports Server (NTRS)

    Morris, A. Terry

    1994-01-01

    A form and function simulation of the thermal enclosure system (TES) for a microgravity protein crystal growth experiment has been developed as part of an investigation of the benefits and limitations of intravehicular telerobotics to aid in microgravity science and production. A user can specify the time, temperature, and sample rate profile for a given experiment, and menu options and status are presented on an LCD display. This report describes the features and operational procedures for the functional simulation.

  5. Transfer Function Control for Biometric Monitoring System

    NASA Technical Reports Server (NTRS)

    Chmiel, Alan J. (Inventor); Humphreys, Bradley T. (Inventor); Grodinsky, Carlos M. (Inventor)

    2015-01-01

    A modular apparatus for acquiring biometric data may include circuitry operative to receive an input signal indicative of a biometric condition, the circuitry being configured to process the input signal according to a transfer function thereof and to provide a corresponding processed input signal. A controller is configured to provide at least one control signal to the circuitry to programmatically modify the transfer function of the modular system to facilitate acquisition of the biometric data.

  6. In-vehicle information system functions

    SciTech Connect

    Tufano, D.R.; Spelt, P.F.; Knee, H.E.

    1997-04-01

    This paper describes the functional requirement for an In-Vehicle Information System (IVIS), which will manage and display all driving-related information from many sources. There are numerous information systems currently being fielded or developed (e.g., routing and navigation, collision avoidance). However, without a logical integration of all of the possible on-board information, there is a potential for overwhelming the driver. The system described in this paper will filter and prioritize information across all sources, and present it to the driver in a timely manner, within a unified interface. To do this, IVIS will perform three general functions: (1) interact with other, on-board information subsystems and the vehicle; (2) manage the information by filtering, prioritizing, and integrating it; and (3) interact with the driver, both in terms of displaying information to the driver and allowing the driver to input requests, goals and preferences. The functional requirements described in this paper have either been derived from these three high-level functions or are directly mandated by the overriding requirements for modularity and flexibility. IVIS will have to be able to accommodate different types of information subsystems, of varying level of sophistication. The system will also have to meet the diverse needs of different types of drivers (private, commercial, transit), who may have very different levels of expertise in using information systems.

  7. Energy landscapes and functions of supramolecular systems

    NASA Astrophysics Data System (ADS)

    Tantakitti, Faifan; Boekhoven, Job; Wang, Xin; Kazantsev, Roman V.; Yu, Tao; Li, Jiahe; Zhuang, Ellen; Zandi, Roya; Ortony, Julia H.; Newcomb, Christina J.; Palmer, Liam C.; Shekhawat, Gajendra S.; de La Cruz, Monica Olvera; Schatz, George C.; Stupp, Samuel I.

    2016-04-01

    By means of two supramolecular systems--peptide amphiphiles engaged in hydrogen-bonded β-sheets, and chromophore amphiphiles driven to assemble by π-orbital overlaps--we show that the minima in the energy landscapes of supramolecular systems are defined by electrostatic repulsion and the ability of the dominant attractive forces to trap molecules in thermodynamically unfavourable configurations. These competing interactions can be selectively switched on and off, with the order of doing so determining the position of the final product in the energy landscape. Within the same energy landscape, the peptide-amphiphile system forms a thermodynamically favoured product characterized by long bundled fibres that promote biological cell adhesion and survival, and a metastable product characterized by short monodisperse fibres that interfere with adhesion and can lead to cell death. Our findings suggest that, in supramolecular systems, functions and energy landscapes are linked, superseding the more traditional connection between molecular design and function.

  8. Demonstration Advanced Avionics System (DAAS) function description

    NASA Technical Reports Server (NTRS)

    Bailey, A. J.; Bailey, D. G.; Gaabo, R. J.; Lahn, T. G.; Larson, J. C.; Peterson, E. M.; Schuck, J. W.; Rodgers, D. L.; Wroblewski, K. A.

    1982-01-01

    The Demonstration Advanced Avionics System, DAAS, is an integrated avionics system utilizing microprocessor technologies, data busing, and shared displays for demonstrating the potential of these technologies in improving the safety and utility of general aviation operations in the late 1980's and beyond. Major hardware elements of the DAAS include a functionally distributed microcomputer complex, an integrated data control center, an electronic horizontal situation indicator, and a radio adaptor unit. All processing and display resources are interconnected by an IEEE-488 bus in order to enhance the overall system effectiveness, reliability, modularity and maintainability. A detail description of the DAAS architecture, the DAAS hardware, and the DAAS functions is presented. The system is designed for installation and flight test in a NASA Cessna 402-B aircraft.

  9. Quality Function Deployment for Large Systems

    NASA Technical Reports Server (NTRS)

    Dean, Edwin B.

    1992-01-01

    Quality Function Deployment (QFD) is typically applied to small subsystems. This paper describes efforts to extend QFD to large scale systems. It links QFD to the system engineering process, the concurrent engineering process, the robust design process, and the costing process. The effect is to generate a tightly linked project management process of high dimensionality which flushes out issues early to provide a high quality, low cost, and, hence, competitive product. A pre-QFD matrix linking customers to customer desires is described.

  10. About orthogonality one system of functions

    NASA Astrophysics Data System (ADS)

    Barmenkov, A. N.

    2017-01-01

    For the modeling of physical processes is proposed to use representation of functions by a special trigonometric system. We present a method for constructing full orthogonal sequences of this type depending on the parameter. This parameter can be selected optimally based on specification of modeling task.

  11. Function representation with circle inversion map systems

    NASA Astrophysics Data System (ADS)

    Boreland, Bryson; Kunze, Herb

    2017-01-01

    The fractals literature develops the now well-known concept of local iterated function systems (using affine maps) with grey-level maps (LIFSM) as an approach to function representation in terms of the associated fixed point of the so-called fractal transform. While originally explored as a method to achieve signal (and 2-D image) compression, more recent work has explored various aspects of signal and image processing using this machinery. In this paper, we develop a similar framework for function representation using circle inversion map systems. Given a circle C with centre õ and radius r, inversion with respect to C transforms the point p˜ to the point p˜', such that p˜ and p˜' lie on the same radial half-line from õ and d(õ, p˜)d(õ, p˜') = r2, where d is Euclidean distance. We demonstrate the results with an example.

  12. On the entropy function in sociotechnical systems

    PubMed Central

    Montroll, Elliott W.

    1981-01-01

    The entropy function H = -Σpj log pj (pj being the probability of a system being in state j) and its continuum analogue H = ∫p(x) log p(x) dx are fundamental in Shannon's theory of information transfer in communication systems. It is here shown that the discrete form of H also appears naturally in single-lane traffic flow theory. In merchandising, goods flow from a whole-saler through a retailer to a customer. Certain features of the process may be deduced from price distribution functions derived from Sears Roebuck and Company catalogues. It is found that the dispersion in logarithm of catalogue prices of a given year has remained about constant, independently of the year, for over 75 years. From this it may be inferred that the continuum entropy function for the variable logarithm of price had inadvertently, through Sears Roebuck policies, been maximized for that firm subject to the observed dispersion. PMID:16593136

  13. On the entropy function in sociotechnical systems.

    PubMed

    Montroll, E W

    1981-12-01

    The entropy function H = -Sigmap(j) log p(j) (p(j) being the probability of a system being in state j) and its continuum analogue H = integralp(x) log p(x) dx are fundamental in Shannon's theory of information transfer in communication systems. It is here shown that the discrete form of H also appears naturally in single-lane traffic flow theory. In merchandising, goods flow from a whole-saler through a retailer to a customer. Certain features of the process may be deduced from price distribution functions derived from Sears Roebuck and Company catalogues. It is found that the dispersion in logarithm of catalogue prices of a given year has remained about constant, independently of the year, for over 75 years. From this it may be inferred that the continuum entropy function for the variable logarithm of price had inadvertently, through Sears Roebuck policies, been maximized for that firm subject to the observed dispersion.

  14. A Functional Cartography of Cognitive Systems.

    PubMed

    Mattar, Marcelo G; Cole, Michael W; Thompson-Schill, Sharon L; Bassett, Danielle S

    2015-12-01

    One of the most remarkable features of the human brain is its ability to adapt rapidly and efficiently to external task demands. Novel and non-routine tasks, for example, are implemented faster than structural connections can be formed. The neural underpinnings of these dynamics are far from understood. Here we develop and apply novel methods in network science to quantify how patterns of functional connectivity between brain regions reconfigure as human subjects perform 64 different tasks. By applying dynamic community detection algorithms, we identify groups of brain regions that form putative functional communities, and we uncover changes in these groups across the 64-task battery. We summarize these reconfiguration patterns by quantifying the probability that two brain regions engage in the same network community (or putative functional module) across tasks. These tools enable us to demonstrate that classically defined cognitive systems-including visual, sensorimotor, auditory, default mode, fronto-parietal, cingulo-opercular and salience systems-engage dynamically in cohesive network communities across tasks. We define the network role that a cognitive system plays in these dynamics along the following two dimensions: (i) stability vs. flexibility and (ii) connected vs. isolated. The role of each system is therefore summarized by how stably that system is recruited over the 64 tasks, and how consistently that system interacts with other systems. Using this cartography, classically defined cognitive systems can be categorized as ephemeral integrators, stable loners, and anything in between. Our results provide a new conceptual framework for understanding the dynamic integration and recruitment of cognitive systems in enabling behavioral adaptability across both task and rest conditions. This work has important implications for understanding cognitive network reconfiguration during different task sets and its relationship to cognitive effort, individual

  15. The Teleost Octavolateralis System: Structure and Function

    NASA Technical Reports Server (NTRS)

    Popper, Arthur N.

    1996-01-01

    This paper considers the detection of vibrational signals (including sound) by the two components of the octavolateralis system, the ear and mechanosensory lateral line. Together, these systems provide fishes with a good deal of information about their surrounding environment, and enable fishes to detect both predators and prey. While the mechanisms by which fishes and zooplankton produce and detect signals may differ, it is clear that the physical principles underlying the signals themselves are identical, no matter whether we are dealing with fish or zooplankton. Thus, an understanding of signal production and detection mechanisms by fishes can be of significant help in understanding how similar systems would function in zooplankton.

  16. Functional Network Dynamics of the Language System

    PubMed Central

    Chai, Lucy R.; Mattar, Marcelo G.; Blank, Idan Asher; Fedorenko, Evelina; Bassett, Danielle S.

    2016-01-01

    During linguistic processing, a set of brain regions on the lateral surfaces of the left frontal, temporal, and parietal cortices exhibit robust responses. These areas display highly correlated activity while a subject rests or performs a naturalistic language comprehension task, suggesting that they form an integrated functional system. Evidence suggests that this system is spatially and functionally distinct from other systems that support high-level cognition in humans. Yet, how different regions within this system might be recruited dynamically during task performance is not well understood. Here we use network methods, applied to fMRI data collected from 22 human subjects performing a language comprehension task, to reveal the dynamic nature of the language system. We observe the presence of a stable core of brain regions, predominantly located in the left hemisphere, that consistently coactivate with one another. We also observe the presence of a more flexible periphery of brain regions, predominantly located in the right hemisphere, that coactivate with different regions at different times. However, the language functional ROIs in the angular gyrus and the anterior temporal lobe were notable exceptions to this trend. By highlighting the temporal dimension of language processing, these results suggest a trade-off between a region's specialization and its capacity for flexible network reconfiguration. PMID:27550868

  17. Variational functions in driven open quantum systems

    NASA Astrophysics Data System (ADS)

    Jakob, Matthias; Stenholm, Stig

    2003-03-01

    We consider the Lindblad-type master equation of an open system. We address the question how to construct a functional of the quantum state which displays a monotonic behavior in time. This thus defines uniquely the direction of time in the system. As the generator of time evolution is not a Hermitian operator, the theory requires the considerations of right and left eigenstates. In this paper we assume them to form two complete bases, which allows us to construct the desired quantity. This can be interpreted as a generalized entropy functional. We show how the construction is carried out in the general case, and we illustrate the theory by solving the case of an externally driven and damped two-level system. The treatment is related to earlier work in the field, and its possible relation to time inversion is discussed.

  18. Adaptive functional systems: learning with chaos.

    PubMed

    Komarov, M A; Osipov, G V; Burtsev, M S

    2010-12-01

    We propose a new model of adaptive behavior that combines a winnerless competition principle and chaos to learn new functional systems. The model consists of a complex network of nonlinear dynamical elements producing sequences of goal-directed actions. Each element describes dynamics and activity of the functional system which is supposed to be a distributed set of interacting physiological elements such as nerve or muscle that cooperates to obtain certain goal at the level of the whole organism. During "normal" behavior, the dynamics of the system follows heteroclinic channels, but in the novel situation chaotic search is activated and a new channel leading to the target state is gradually created simulating the process of learning. The model was tested in single and multigoal environments and had demonstrated a good potential for generation of new adaptations.

  19. Distinct types of protease systems are involved in homeostasis regulation of mitochondrial morphology via balanced fusion and fission.

    PubMed

    Saita, Shotaro; Ishihara, Takaya; Maeda, Maki; Iemura, Shun-Ichiro; Natsume, Tohru; Mihara, Katsuyoshi; Ishihara, Naotada

    2016-05-01

    Mitochondrial morphology is dynamically regulated by fusion and fission. Several GTPase proteins control fusion and fission, and posttranslational modifications of these proteins are important for the regulation. However, it has not been clarified how the fusion and fission is balanced. Here, we report the molecular mechanism to regulate mitochondrial morphology in mammalian cells. Ablation of the mitochondrial fission, by repression of Drp1 or Mff, or by over-expression of MiD49 or MiD51, results in a reduction in the fusion GTPase mitofusins (Mfn1 and Mfn2) in outer membrane and long form of OPA1 (L-OPA1) in inner membrane. RNAi- or CRISPR-induced ablation of Drp1 in HeLa cells enhanced the degradation of Mfns via the ubiquitin-proteasome system (UPS). We further found that UPS-related protein BAT3/BAG6, here we identified as Mfn2-interacting protein, was implicated in the turnover of Mfns in the absence of mitochondrial fission. Ablation of the mitochondrial fission also enhanced the proteolytic cleavage of L-OPA1 to soluble S-OPA1, and the OPA1 processing was reversed by inhibition of the inner membrane protease OMA1 independent on the mitochondrial membrane potential. Our findings showed that the distinct degradation systems of the mitochondrial fusion proteins in different locations are enhanced in response to the mitochondrial morphology.

  20. Sialyltransferase regulates nervous system function in Drosophila

    PubMed Central

    Repnikova, Elena; Koles, Kate; Nakamura, Michiko; Pitts, Jared; Li, Haiwen; Ambavane, Apoorva; Zoran, Mark J.; Panin, Vladislav M.

    2012-01-01

    In vertebrates, sialylated glycans participate in a wide range of biological processes and affect nervous system’s development and function. While the complexity of glycosylation and the functional redundancy among sialyltransferases provide obstacles for revealing biological roles of sialylation in mammals, Drosophila possesses a sole vertebrate-type sialyltransferase, DSiaT, with significant homology to its mammalian counterparts, suggesting that Drosophila could be a suitable model to investigate the function of sialylation. To explore this possibility and investigate the role of sialylation in Drosophila, we inactivated DSiaT in vivo by gene targeting and analyzed phenotypes of DSiaT mutants using a combination of behavioural, immunolabeling, electrophysiological and pharmacological approaches. Our experiments demonstrated that DSiaT expression is restricted to a subset of CNS neurons throughout development. We found that DSiaT mutations result in significantly decreased life span, locomotor abnormalities, temperature-sensitive paralysis and defects of neuromuscular junctions. Our results indicate that DSiaT regulates neuronal excitability and affects the function of a voltage-gated sodium channel. Finally, we showed that sialyltransferase activity is required for DSiaT function in vivo, which suggests that DSiaT mutant phenotypes result from a defect in sialylation of N-glycans. This work provided the first evidence that sialylation has an important biological function in protostomes, while also revealing a novel, nervous system-specific function of α2,6 sialylation. Thus, our data shed light on one of the most ancient functions of sialic acids in metazoan organisms and suggest a possibility that this function is evolutionarily conserved between flies and mammals. PMID:20445073

  1. A Functional Cartography of Cognitive Systems

    PubMed Central

    Mattar, Marcelo G.; Cole, Michael W.; Thompson-Schill, Sharon L.; Bassett, Danielle S.

    2015-01-01

    One of the most remarkable features of the human brain is its ability to adapt rapidly and efficiently to external task demands. Novel and non-routine tasks, for example, are implemented faster than structural connections can be formed. The neural underpinnings of these dynamics are far from understood. Here we develop and apply novel methods in network science to quantify how patterns of functional connectivity between brain regions reconfigure as human subjects perform 64 different tasks. By applying dynamic community detection algorithms, we identify groups of brain regions that form putative functional communities, and we uncover changes in these groups across the 64-task battery. We summarize these reconfiguration patterns by quantifying the probability that two brain regions engage in the same network community (or putative functional module) across tasks. These tools enable us to demonstrate that classically defined cognitive systems—including visual, sensorimotor, auditory, default mode, fronto-parietal, cingulo-opercular and salience systems—engage dynamically in cohesive network communities across tasks. We define the network role that a cognitive system plays in these dynamics along the following two dimensions: (i) stability vs. flexibility and (ii) connected vs. isolated. The role of each system is therefore summarized by how stably that system is recruited over the 64 tasks, and how consistently that system interacts with other systems. Using this cartography, classically defined cognitive systems can be categorized as ephemeral integrators, stable loners, and anything in between. Our results provide a new conceptual framework for understanding the dynamic integration and recruitment of cognitive systems in enabling behavioral adaptability across both task and rest conditions. This work has important implications for understanding cognitive network reconfiguration during different task sets and its relationship to cognitive effort, individual

  2. General Green's function formalism for layered systems: Wave function approach

    NASA Astrophysics Data System (ADS)

    Zhang, Shu-Hui; Yang, Wen; Chang, Kai

    2017-02-01

    The single-particle Green's function (GF) of mesoscopic structures plays a central role in mesoscopic quantum transport. The recursive GF technique is a standard tool to compute this quantity numerically, but it lacks physical transparency and is limited to relatively small systems. Here we present a numerically efficient and physically transparent GF formalism for a general layered structure. In contrast to the recursive GF that directly calculates the GF through the Dyson equations, our approach converts the calculation of the GF to the generation and subsequent propagation of a scattering wave function emanating from a local excitation. This viewpoint not only allows us to reproduce existing results in a concise and physically intuitive manner, but also provides analytical expressions of the GF in terms of a generalized scattering matrix. This identifies the contributions from each individual scattering channel to the GF and hence allows this information to be extracted quantitatively from dual-probe STM experiments. The simplicity and physical transparency of the formalism further allows us to treat the multiple reflection analytically and derive an analytical rule to construct the GF of a general layered system. This could significantly reduce the computational time and enable quantum transport calculations for large samples. We apply this formalism to perform both analytical analysis and numerical simulation for the two-dimensional conductance map of a realistic graphene p -n junction. The results demonstrate the possibility of observing the spatially resolved interference pattern caused by negative refraction and further reveal a few interesting features, such as the distance-independent conductance and its quadratic dependence on the carrier concentration, as opposed to the linear dependence in uniform graphene.

  3. Functional integral for non-Lagrangian systems

    SciTech Connect

    Kochan, Denis

    2010-02-15

    A functional integral formulation of quantum mechanics for non-Lagrangian systems is presented. The approach, which we call ''stringy quantization,'' is based solely on classical equations of motion and is free of any ambiguity arising from Lagrangian and/or Hamiltonian formulation of the theory. The functionality of the proposed method is demonstrated on several examples. Special attention is paid to the stringy quantization of systems with a general A-power friction force -{kappa}q{sup A}. Results for A=1 are compared with those obtained in the approaches by Caldirola-Kanai, Bateman, and Kostin. Relations to the Caldeira-Leggett model and to the Feynman-Vernon approach are discussed as well.

  4. Chaos automata: iterated function systems with memory

    NASA Astrophysics Data System (ADS)

    Ashlock, Dan; Golden, Jim

    2003-07-01

    Transforming biological sequences into fractals in order to visualize them is a long standing technique, in the form of the traditional four-cornered chaos game. In this paper we give a generalization of the standard chaos game visualization for DNA sequences. It incorporates iterated function systems that are called under the control of a finite state automaton, yielding a DNA to fractal transformation system with memory. We term these fractal visualizers chaos automata. The use of memory enables association of widely separated sequence events in the drawing of the fractal, finessing the “forgetfulness” of other fractal visualization methods. We use a genetic algorithm to train chaos automata to distinguish introns and exons in Zea mays (corn). A substantial issue treated here is the creation of a fitness function that leads to good visual separation of distinct data types.

  5. Internal density functional theory of molecular systems

    NASA Astrophysics Data System (ADS)

    Nalewajski, Roman F.

    1984-08-01

    A thermodynamiclike theory of internal equilibrium and constrained equilibrium states of individual molecular systems is formulated, based on the Legendre transformed density functional theory (LT DFT). The molecular system (nonrelativistic, field free, Born-Oppenheimer or non-Born-Oppenheimer) is treated as the closed composite thermodynamic system, consisting of very small, rigid (open) subsystems (simple systems) containing a multi-(m)-component charged fluid in the presence of an external field. The generalized Levy constrained search construction of various ``thermodynamic'' potentials of LT DFT is given and the local Maxwell relations are derived. The reduction of various second-order partial functional derivatives (system sensitivities) in terms of few independent, basic kernels is described, using the Jacobian determinants technique. The qualitative implications for the basic kernels of the theory, from the Maxwell relations and stability criteria (generalized Le Châtelier and Le Châtelier-Braun principles) are systematically examined. Finally, possible applications of the general formalism in the thermodynamic analysis of the chemical bond, molecular stability, and chemical reactivity are identified.

  6. The serotonergic system and cognitive function

    PubMed Central

    Pivac, Nela; Mück-Šeler, Dorotea

    2016-01-01

    Abstract Symptoms of cognitive dysfunction like memory loss, poor concentration, impaired learning and executive functions are characteristic features of both schizophrenia and Alzheimer’s disease (AD). The neurobiological mechanisms underlying cognition in healthy subjects and neuropsychiatric patients are not completely understood. Studies have focused on serotonin (5-hydroxytryptamine, 5-HT) as one of the possible cognitionrelated biomarkers. The aim of this review is to provide a summary of the current literature on the role of the serotonergic (5-HTergic) system in cognitive function, particularly in AD and schizophrenia. The role of the 5-HTergic system in cognition is modulated by the activity and function of 5-HT receptors (5-HTR) classified into seven groups, which differ in structure, action, and localization. Many 5-HTR are located in the regions linked to various cognitive processes. Preclinical studies using animal models of learning and memory, as well as clinical in vivo (neuroimaging) and in vitro (post-mortem) studies in humans have shown that alterations in 5-HTR activity influence cognitive performance. The current evidence implies that reduced 5-HT neurotransmission negatively influences cognitive functions and that normalization of 5-HT activity may have beneficial effects, suggesting that 5-HT and 5-HTR represent important pharmacological targets for cognition enhancement and restoration of impaired cognitive performance in neuropsychiatric disorders. PMID:28123820

  7. Neurochemistry changes associated with mutations in familial Parkinson's disease.

    PubMed

    Siddique, M M; Tan, E K

    2010-01-01

    Parkinson's disease (PD), a common neurodegenerative disease, is characterized by the progressive loss of dopamine neurons and the accumulation of Lewy bodies and neurites. The exact role of genetic and environmental factors in the pathogenesis of PD has frequently been debated. The association of MPTP (methyl-4-phenyl-1, 2, 3, 6- tetrahydropyridine) and toxins (such as rotenone) with parkinsonism highlights the potential etiologic role of environmental toxins in disease causation. The recent discoveries of monogenic (such as α-synuclein, Parkin, UCHL1, PINK1, DJ-1, LRRK2) forms of PD have provided considerable insights into its pathophysiology. Parkin, an ubiquitin protein ligase assists in the degradation of toxic substrates via the ubiquitin proteasome system. It can also mediate a nondegradative form of ubiquitination. PINK1 and LRRK2 are possibly involved in the phosphorylation of substrates important for various cellular functions. Some toxins could interact with α-synuclein, an endogenous protein that is implicated in pathology of PD. Increasing in vitro and in vivo studies suggest that deficits in mitochondrial function, oxidative and nitrosative stress, the accumulation of aberrant or misfolded proteins, and ubiquitin-proteasome system dysfunction underpin the pathogenesis of sporadic and familial forms of PD. Elucidation of the functions of the proteins encoded by the diseasecausing genes will provide an opportunity for identification of specific pathways that could be targeted in neurotherapeutics.

  8. Emerging Mechanistic Insights into AAA Complexes Regulating Proteasomal Degradation

    PubMed Central

    Förster, Friedrich; Schuller, Jan M.; Unverdorben, Pia; Aufderheide, Antje

    2014-01-01

    The 26S proteasome is an integral element of the ubiquitin-proteasome system (UPS) and, as such, responsible for regulated degradation of proteins in eukaryotic cells. It consists of the core particle, which catalyzes the proteolysis of substrates into small peptides, and the regulatory particle, which ensures specificity for a broad range of substrates. The heart of the regulatory particle is an AAA-ATPase unfoldase, which is surrounded by non-ATPase subunits enabling substrate recognition and processing. Cryo-EM-based studies revealed the molecular architecture of the 26S proteasome and its conformational rearrangements, providing insights into substrate recognition, commitment, deubiquitylation and unfolding. The cytosol proteasomal degradation of polyubiquitylated substrates is tuned by various associating cofactors, including deubiquitylating enzymes, ubiquitin ligases, shuttling ubiquitin receptors and the AAA-ATPase Cdc48/p97. Cdc48/p97 and its cofactors function upstream of the 26S proteasome, and their modular organization exhibits some striking analogies to the regulatory particle. In archaea PAN, the closest regulatory particle homolog and Cdc48 even have overlapping functions, underscoring their intricate relationship. Here, we review recent insights into the structure and dynamics of the 26S proteasome and its associated machinery, as well as our current structural knowledge on the Cdc48/p97 and its cofactors that function in the ubiquitin-proteasome system (UPS). PMID:25102382

  9. Functional relationship-based alarm processing system

    DOEpatents

    Corsberg, Daniel R.

    1989-01-01

    A functional relationship-based alarm processing system and method analyzes each alarm as it is activated and determines its relative importance with other currently activated alarms and signals in accordance with the functional relationships that the newly activated alarm has with other currently activated alarms. Once the initial level of importance of the alarm has been determined, that alarm is again evaluated if another related alarm is activated or deactivated. Thus, each alarm's importance is continuously updated as the state of the process changes during a scenario. Four hierarchical relationships are defined by this alarm filtering methodology: (1) level precursor (usually occurs when there are two alarm settings on the same parameter); (2) direct precursor (based on causal factors between two alarms); (3) required action (system response or action expected within a specified time following activation of an alarm or combination of alarms and process signals); and (4) blocking condition (alarms that are normally expected and are not considered important). The alarm processing system and method is sensitive to the dynamic nature of the process being monitored and is capable of changing the relative importance of each alarm as necessary.

  10. Functional relationship-based alarm processing system

    DOEpatents

    Corsberg, D.R.

    1988-04-22

    A functional relationship-based alarm processing system and method analyzes each alarm as it is activated and determines its relative importance with other currently activated alarms and signals in accordance with the functional relationships that the newly activated alarm has with other currently activated alarms. Once the initial level of importance of the alarm has been determined, that alarm is again evaluated if another related alarm is activated or deactivated. Thus, each alarm's importance is continuously updated as the state of the process changes during a scenario. Four hierarchical relationships are defined by this alarm filtering methodology: (1) level precursor (usually occurs when there are two alarm settings on the same parameter); (2) direct precursor (based on causal factors between two alarms); (3) required action (system response or action expected within a specified time following activation of an alarm or combination of alarms and process signals); and (4) blocking condition (alarms that are normally expected and are not considered important). The alarm processing system and method is sensitive to the dynamic nature of the process being monitored and is capable of changing the relative importance of each alarm as necessary. 12 figs.

  11. N-Myristoylation of the Rpt2 subunit of the yeast 26S proteasome is implicated in the subcellular compartment-specific protein quality control system.

    PubMed

    Kimura, Ayuko; Kurata, Yoichi; Nakabayashi, Jun; Kagawa, Hiroyuki; Hirano, Hisashi

    2016-01-01

    Ubiquitination is the posttranslational modification of a protein by covalent attachment of ubiquitin. Controlled proteolysis via the ubiquitin-proteasome system (\\UPS) alleviates cellular stress by clearing misfolded proteins. In budding yeast, UPS within the nucleus degrades the nuclear proteins as well as proteins imported from the cytoplasm. While the predominantly nuclear localization of the yeast proteasome is maintained by the importin-mediated transport, N-myristoylation of the proteasome subunit Rpt2 was indicated to cause dynamic nucleo-cytoplasmic localization of proteasomes. Here, we quantitatively analyzed the ubiquitinated peptides using anti-K-ε-GG antibody in yeast cell lines with or without a mutation in the N-myristoylation site of Rpt2 and detected upregulated ubiquitination of proteins with nucleo-cytoplasmic localizations in the mutant strains. Moreover, both the protein and ubiquitinated peptide levels of two Hsp70 family chaperones involved in the nuclear import of misfolded proteins, Ssa and Sse1, were elevated in the mutant strains, whereas levels of an Hsp70 family chaperone involved in the nuclear export, Ssb, were reduced. Taken together, our results indicate that N-myristoylation of Rpt2 is involved in controlled proteolysis via regulation of the nucleo-cytoplasmic localization of the yeast proteasome.

  12. New suggestive genetic loci and biological pathways for attention function in adult attention-deficit/hyperactivity disorder.

    PubMed

    Alemany, Silvia; Ribasés, Marta; Vilor-Tejedor, Natàlia; Bustamante, Mariona; Sánchez-Mora, Cristina; Bosch, Rosa; Richarte, Vanesa; Cormand, Bru; Casas, Miguel; Ramos-Quiroga, Josep A; Sunyer, Jordi

    2015-09-01

    Attention deficit is one of the core symptoms of the attention-deficit/hyperactivity disorder (ADHD). However, the specific genetic variants that may be associated with attention function in adult ADHD remain largely unknown. The present study aimed to identifying SNPs associated with attention function in adult ADHD and tested whether these associations were enriched for specific biological pathways. Commissions, hit-reaction time (HRT), the standard error of HRT (HRTSE), and intraindividual coefficient variability (ICV) of the Conners Continuous Performance Test (CPT-II) were assessed in 479 unmedicated adult ADHD individuals. A Genome-Wide Association Study (GWAS) was conducted for each outcome and, subsequently, gene set enrichment analyses were performed. Although no SNPs reached genome-wide significance (P < 5E-08), 27 loci showed suggestive evidence of association with the CPT outcomes (P < E-05). The most relevant associated SNP was located in the SORCS2 gene (P = 3.65E-07), previously associated with bipolar disorder (BP), Alzheimer disease (AD), and brain structure in elderly individuals. We detected other genes suggested to be involved in synaptic plasticity, cognitive function, neurological and neuropsychiatric disorders, and smoking behavior such as NUAK1, FGF20, NETO1, BTBD9, DLG2, TOP3B, and CHRNB4. Also, several of the pathways nominally associated with the CPT outcomes are relevant for ADHD such as the ubiquitin proteasome, neurodegenerative disorders, axon guidance, and AD amyloid secretase pathways. To our knowledge, this is the first GWAS and pathway analysis of attention function in patients with persistent ADHD. Overall, our findings reinforce the conceptualization of attention function as a potential endophenotype for studying the molecular basis of adult ADHD. © 2015 Wiley Periodicals, Inc.

  13. Ubiquitination and proteolysis in limb and respiratory muscles of patients with chronic obstructive pulmonary disease.

    PubMed

    Debigaré, Richard; Côté, Claude H; Maltais, François

    2010-02-01

    Peripheral muscle dysfunction associated with chronic diseases is undeniably a growing problem as one of its main causes, chronic obstructive pulmonary disease (COPD), progresses. Among others, muscle atrophy is one component building the concept of muscle dysfunction. Muscle atrophy has a significant impact on patient clinical status, independent of the impairment in lung function. A lot of effort has been devoted lately to increasing our understanding of the relationship between COPD and the initiation and the development of muscle atrophy. A growing body of evidence is showing that the ubiquitin-proteasome system, an ATP-dependent proteolytic pathway, is playing a crucial role in the cascade leading to degradation of contractile proteins, thus promoting the development of muscle atrophy. Interestingly, this system is also involved in essential cellular processes such as response to hypoxemia and muscle tissue regeneration. In this review, existing evidence linking the activity of the ubiquitin-proteasome system and the cellular events taking place in respiratory and peripheral muscles of patients with COPD are reported. Based on this information, the reader should be able to understand the essential role of this pathway in the context of muscle homeostasis and to picture the coming research in this area.

  14. Infrared Imaging System for Studying Brain Function

    NASA Technical Reports Server (NTRS)

    Mintz, Frederick; Mintz, Frederick; Gunapala, Sarath

    2007-01-01

    A proposed special-purpose infrared imaging system would be a compact, portable, less-expensive alternative to functional magnetic resonance imaging (fMRI) systems heretofore used to study brain function. Whereas a typical fMRI system fills a large room, and must be magnetically isolated, this system would fit into a bicycle helmet. The system would include an assembly that would be mounted inside the padding in a modified bicycle helmet or other suitable headgear. The assembly would include newly designed infrared photodetectors and data-acquisition circuits on integrated-circuit chips on low-thermal-conductivity supports in evacuated housings (see figure) arranged in multiple rows and columns that would define image coordinates. Each housing would be spring-loaded against the wearer s head. The chips would be cooled by a small Stirling Engine mounted contiguous to, but thermally isolated from, the portions of the assembly in thermal contact with the wearer s head. Flexible wires or cables for transmitting data from the aforementioned chips would be routed to an integrated, multichannel transmitter and thence through the top of the assembly to a patch antenna on the outside of the helmet. The multiple streams of data from the infrared-detector chips would be sent to a remote site, where they would be processed, by software, into a three-dimensional display of evoked potentials that would represent firing neuronal bundles and thereby indicate locations of neuronal activity associated with mental or physical activity. The 3D images will be analogous to current fMRI images. The data would also be made available, in real-time, for comparison with data in local or internationally accessible relational databases that already exist in universities and research centers. Hence, this system could be used in research on, and for the diagnosis of response from the wearer s brain to physiological, psychological, and environmental changes in real time. The images would also be

  15. The Evolutionarily Conserved C-terminal Domains in the Mammalian Retinoblastoma Tumor Suppressor Family Serve as Dual Regulators of Protein Stability and Transcriptional Potency*

    PubMed Central

    Sengupta, Satyaki; Lingnurkar, Raj; Carey, Timothy S.; Pomaville, Monica; Kar, Parimal; Feig, Michael; Wilson, Catherine A.; Knott, Jason G.; Arnosti, David N.; Henry, R. William

    2015-01-01

    The retinoblastoma (RB) tumor suppressor and related family of proteins play critical roles in development through their regulation of genes involved in cell fate. Multiple regulatory pathways impact RB function, including the ubiquitin-proteasome system with deregulated RB destruction frequently associated with pathogenesis. With the current study we explored the mechanisms connecting proteasome-mediated turnover of the RB family to the regulation of repressor activity. We find that steady state levels of all RB family members, RB, p107, and p130, were diminished during embryonic stem cell differentiation concomitant with their target gene acquisition. Proteasome-dependent turnover of the RB family is mediated by distinct and autonomously acting instability elements (IE) located in their C-terminal regulatory domains in a process that is sensitive to cyclin-dependent kinase (CDK4) perturbation. The IE regions include motifs that contribute to E2F-DP transcription factor interaction, and consistently, p107 and p130 repressor potency was reduced by IE deletion. The juxtaposition of degron sequences and E2F interaction motifs appears to be a conserved feature across the RB family, suggesting the potential for repressor ubiquitination and specific target gene regulation. These findings establish a mechanistic link between regulation of RB family repressor potency and the ubiquitin-proteasome system. PMID:25903125

  16. Aerobic Exercise Recovers Disuse-induced Atrophy Through the Stimulus of the LRP130/PGC-1α Complex in Aged Rats.

    PubMed

    Vechetti-Junior, Ivan J; Bertaglia, Raquel S; Fernandez, Geysson J; de Paula, Tassiana G; de Souza, Rodrigo W A; Moraes, Leonardo N; Mareco, Edson A; de Freitas, Carlos E A; Aguiar, Andreo F; Carvalho, Robson F; Dal-Pai-Silva, Maeli

    2016-05-01

    Physical training has been shown to be important to the control of muscle mass during aging, through the activation of several pathways including, IGF1-AKT and PGC-1α. Also, it was demonstrated that LRP130, a component of the PGC-1α complex, is important for the PGC-1α-dependent transcription of several mitochondrial genes in vivo. To explore the role of physical training during aging, we investigated the effects on muscle recovery after short-term immobilization followed by 3 or 7 days with aerobic or resistance training. Using morphological (myofibrillar adenosine triphosphatase activity, to assess the total muscle fiber cross-sectional area (CSA) and the frequency of specific fiber types), biochemical (myosin heavy chain), and molecular analyses (quantitative real-time PCR, functional pathways analyses, and Western blot), our results indicated that after an atrophic stimulus, only animals subjected to aerobic training showed entire recovery of cross-sectional area; aerobic training reduced the ubiquitin-proteasome system components involved in muscle atrophy after 3 days of recovery, and the upregulation in PGC-1α expression enhanced the process of muscle recovery by inhibiting the FoxO pathway, with the possible involvement of LRP130. These results suggest that aerobic training enhanced the muscle regeneration process after disuse-induced atrophy in aged rats possibly through of the LRP130/PGC-1α complex by inhibiting the ubiquitin-proteasome system.

  17. Function analysis for waste information systems

    SciTech Connect

    Sexton, J.L.; Neal, C.T.; Heath, T.C.; Starling, C.D.

    1996-04-01

    This study has a two-fold purpose. It seeks to identify the functional requirements of a waste tracking information system and to find feasible alternatives for meeting those requirements on the Oak Ridge Reservation (ORR) and the Portsmouth (PORTS) and Paducah (PGDP) facilities; identify options that offer potential cost savings to the US government and also show opportunities for improved efficiency and effectiveness in managing waste information; and, finally, to recommend a practical course of action that can be immediately initiated. In addition to identifying relevant requirements, it also identifies any existing requirements that are currently not being completely met. Another aim of this study is to carry out preliminary benchmarking by contacting representative companies about their strategic directions in waste information. The information obtained from representatives of these organizations is contained in an appendix to the document; a full benchmarking effort, however, is beyond the intended scope of this study.

  18. From Systemic-Functional Grammar to Systemic-Functional Text Generation: Escalating the Exchange

    DTIC Science & Technology

    1990-04-01

    if necessary and identify by block number) FIELD I GROUP SUB-GROUP t 09 02 ’Ncomputational systemic linguistics , text generation, text planning...unclear where the borders are best drawn. This report shows that systemic-functional linguis- tics (SFL) offers a rich body of linguistic work...unclear where the borders are best to be drawn. My concern here will be to show that there is an existing rich body of linguistic work that has been

  19. Cancer stem-like cell related protein CD166 degrades through E3 ubiquitin ligase CHIP in head and neck cancer.

    PubMed

    Xiao, Meng; Yan, Ming; Zhang, Jianjun; Xu, Qin; Qi, Shengcai; Wang, Xu; Chen, Wantao

    2017-04-01

    Our previous studies have identified that CD166 works as a cancer stem-like cell (CSC) marker in epithelial cancers with a large repertoire of cellular functions. However, the post-translational regulatory mechanisms underlying CD166 turnover remain elusive. Several independent studies have reported that E3 ubiquitin ligase CHIP revealed significant biological effects through ubiquitin proteasome pathway on some kinds of malignant tumors. With analyzing the effects of CHIP expressions on stem-like cell populations, we found that CHIP represses CSC characteristics mainly targeting the CSC related protein CD166 in head and neck cancer (HNC). To investigate the role and relationship between CD166 and CHIP, HNC tissues and cell lines were used in this study. A significant negative correlation was observed between the expression levels of CHIP and CD166 in HNC patient samples. We also found that CHIP directly regulates the stability of CD166 protein through the ubiquitin proteasome system, which was also identified participating in the regulation of CSC behaviors in HNCs. Our findings demonstrate that CHIP-CD166-proteasome axis participates in regulating CSC properties in HNCs, suggesting that the regulation of CD166 by CHIP could provide new options for diagnosing and treating in the patients with HNCs.

  20. The role of histone ubiquitination during spermatogenesis.

    PubMed

    Sheng, Kai; Liang, Xiaotong; Huang, Sizhou; Xu, Wenming

    2014-01-01

    Protein ubiquitin-proteasome (ubiquitin-proteasome) system is the major mechanism responsible for protein degradation in eukaryotic cell. During spermatogenesis, the replacement of histone by protamine is vital for normal sperm formation, which is involved in ubiquitination enzymes expressed in testis. Recently, histone ubiquitin ligases have been shown to play critical roles in several aspects of spermatogenesis, such as meiotic sex chromosome inactivation (MSCI), DNA damage response, and spermiogenesis. In this review, we highlight recent progress in the discovery of several histone ubiquitin ligases and elaborate mechanisms of how these enzymes are involved in these processes through knockout mouse model. Using Huwe1, UBR2, and RNF8 as examples, we emphasized the diverse functions for each enzyme and the broad involvement of these enzymes in every stage, from spermatogonia differentiation and meiotic division to spermiogenesis; thus histone ubiquitin ligases represent a class of enzymes, which play important roles in spermatogenesis through targeting histone for ubiquitination and therefore are involved in transcription regulation, epigenetic modification, and other processes essential for normal gametes formation.

  1. Regulation of proteolysis by cytokines in the human intestinal epithelial cell line HCT-8: role of IFNgamma.

    PubMed

    Leblond, Jonathan; Hubert-Buron, Aurélie; Bole-Feysot, Christine; Ducrotté, Philippe; Déchelotte, Pierre; Coëffier, Moïse

    2006-07-01

    Protein metabolism contributes in the regulation of gut barrier function, which may be altered during inflammatory states. There are three major proteolytic pathways in mammalian cells: lysosomal, Ca(2+)-activated and ubiquitin-proteasome. The regulation of proteolytic activities during inflammation remains unknown in intestine. Intestinal epithelial cells, HCT-8, were stimulated by IL-1beta, IFNgamma and TNFalpha each alone or in combination (Cytomix). Proteolytic activities were assessed using fluorogenic substrates and specific inhibitors, protein expressions by Western blot. Lysosomal and Ca(2+)-activated pathways were not significantly altered by any treatment. In contrast, the activity of ubiquitin-proteasome system was stimulated by IFNgamma and Cytomix (155, 160 versus 100, P<0.05, respectively) but remained unaffected by IL-1beta and TNFalpha. Free ubiquitin expression, but not ubiquitinated proteins, was enhanced by IFNgamma and Cytomix. The expression of proteasome 20S alpha1 subunit, a constitutive proteasome 20S subunit, was not altered, beta5 subunit expression was weakly decreased by Cytomix and inducible beta5i subunit expression was markedly increased in response to IFNgamma and to Cytomix (202, 206 versus 100, P<0.05, respectively). In conclusion, lysosomal, Ca(2+)-activated and constitutive proteasome activities were not affected by IL-1beta, IFNgamma and TNFalpha alone or in combination, in HCT-8 cells. These results suggest that IFNgamma, but not IL-1beta and TNFalpha, increases immunoproteasome, which might contribute to enhanced antigen presentation during inflammatory bowel diseases.

  2. The Role of the Protein Quality Control System in SBMA.

    PubMed

    Rusmini, Paola; Crippa, Valeria; Cristofani, Riccardo; Rinaldi, Carlo; Cicardi, Maria Elena; Galbiati, Mariarita; Carra, Serena; Malik, Bilal; Greensmith, Linda; Poletti, Angelo

    2016-03-01

    Spinal and bulbar muscular atrophy (SBMA) or Kennedy's disease is an X-linked disease associated with the expansion of the CAG triplet repeat present in exon 1 of the androgen receptor (AR) gene. This results in the production of a mutant AR containing an elongated polyglutamine tract (polyQ) in its N-terminus. Interestingly, the ARpolyQ becomes toxic only after its activation by the natural androgenic ligands, possibly because of aberrant androgen-induced conformational changes of the ARpolyQ, which generate misfolded species. These misfolded ARpolyQ species must be cleared from motoneurons and muscle cells, and this process is mediated by the protein quality control (PQC) system. Experimental evidence suggested that failure of the PQC pathways occurs in disease, leading to ARpolyQ accumulation and toxicity in the target cells. In this review, we summarized the overall impact of mutant and misfolded ARpolyQ on the PQC system and described how molecular chaperones and the degradative pathways (ubiquitin-proteasome system (UPS), the autophagy-lysosome pathway (ALP), and the unfolded protein response (UPR), which activates the endoplasmic reticulum-associated degradation (ERAD)) are differentially affected in SBMA. We also extensively and critically reviewed several molecular and pharmacological approaches proposed to restore a global intracellular activity of the PQC system. Collectively, these data suggest that the fine and delicate equilibrium existing among the different players of the PQC system could be restored in a therapeutic perspective by the synergic/additive activities of compounds designed to tackle sequential or alternative steps of the intracellular defense mechanisms triggered against proteotoxic misfolded species.

  3. [Mechanisms underlying physiological functions of food factors via non-specific interactions with biological proteins].

    PubMed

    Murakami, Akira

    2015-01-01

      We previously reported that zerumbone, a sesquiterpene found in Zingiber zerumbet SMITH, showed notable cancer preventive effects in various organs of experimental rodents. This agent up-regulated nuclear factor-E2-related factor (Nrf2)-dependent expressions of anti-oxidative and xenobiotics-metabolizing enzymes, leading to an increased self-defense capacity. On the other hand, zerumbone markedly suppressed the expression of cyclooxygenase-2, an inducible pro-inflammatory enzyme, by disrupting mRNA stabilizing processes. Binding experiments using a biotin derivative of zerumbone demonstrated that Keap1, an Nrf2 repressive protein, is one of its major binding proteins that promotes their dissociation for inducing Nrf2 transactivation. We then generated a specific antibody against zerumbone-modified proteins and found that zerumbone modified numerous cellular proteins in a non-specific manner, with global distribution of the modified proteins seen not only in cytoplasm but also the nucleus. Based on those observations, zerumbone was speculated to cause proteo-stress, a notion supported by previous findings that it increased the C-terminus of Hsc70 interacting protein-dependent protein ubiquitination and also promoted aggresome formation. Interestingly, zerumbone counteracted proteo-stress and heat stress via up-regulation of the protein quality control systems (PQCs), e.g., heat shock proteins (HSPs), ubiquitin-proteasome, and autophagy. Meanwhile, several phytochemicals, including ursolic acid and curcumin, were identified as marked HSP70 inducers, whereas most nutrients tested were scarcely active. Recent studies have revealed that PQCs play important roles in the prevention of many lifestyle related diseases, such as cancer, thus non-specific binding of phytochemicals to cellular proteins may be a novel and unique mechanism underlying their physiological activities.

  4. Functional Nanomaterials Useful for Magnetic Refrigeration Systems

    NASA Astrophysics Data System (ADS)

    Aslani, Amir

    Magnetic refrigeration is an emerging energy efficient and environmentally friendly refrigeration technology. The principle of magnetic refrigeration is based on the effect of varying a magnetic field on the temperature change of a magnetocaloric material (refrigerant). By applying a magnetic field, the magnetic moments of a magnetic material tend to align parallel to it, and the thermal energy released in this process heats the material. Reversibly, the magnetic moments become randomly oriented when the magnetic field is removed, and the material cools down. The heating and the cooling of a refrigerant in response to a changing magnetic field is similar to the heating and the cooling of a gaseous medium in response to an adiabatic compression and expansion in a conventional refrigeration system. One requirement to make a practical magnetic refrigerator is to have a large temperature change per unit of applied magnetic field, with sufficiently wide operating temperature. So far, no commercially viable magnetic refrigerator has been built primarily due to the low temperature change of bulk refrigerants, the added burden of hysteresis, and the system's low cooling capacity. The purpose of this dissertation is to explore magnetic refrigeration system. First, the Active Magnetic Regenerator (AMR) system built by Shir et al at the GWU's Institute for Magnetics Research (IMR) is optimized by tuning the heat transfer medium parameters and system's operating conditions. Next, by reviewing literature and works done so far on refrigerants, a number of materials that may be suitable to be used in magnetic refrigeration technology were identified. Theoretical work by Bennett et al showed an enhancement in magnetocaloric effect of magnetic nanoparticles. Research was performed on functional magnetic nanoparticles and their use in magnetic refrigeration technology. Different aspects such as the size, shape, chemical composition, structure and interaction of the nanoparticle with

  5. A system decomposition approach to the design of functional observers

    NASA Astrophysics Data System (ADS)

    Fernando, Tyrone; Trinh, Hieu

    2014-09-01

    This paper reports a system decomposition that allows the construction of a minimum-order functional observer using a state observer design approach. The system decomposition translates the functional observer design problem to that of a state observer for a smaller decomposed subsystem. Functional observability indices are introduced, and a closed-form expression for the minimum order required for a functional observer is derived in terms of those functional observability indices.

  6. Functional self-organization in complex systems

    SciTech Connect

    Fontana, W. Santa Fe Inst., NM )

    1990-01-01

    A novel approach to functional self-organization is presented. It consists of a universe generated by a formal language that defines objects (=programs), their meaning (=functions), and their interactions (=composition). Results obtained so far are briefly discussed. 17 refs., 5 figs.

  7. New Mathematical Functions for Vacuum System Analysis

    NASA Technical Reports Server (NTRS)

    Woronowicz, Michael S.

    2017-01-01

    A new bivariate function has been found that provides solutions of integrals having the form u (sup minus eta) e (sup u) du which arise when developing predictions for the behavior of pressure within a rigid volume under high vacuum conditions in the presence of venting as well as sources characterized by power law transient decay over the range [0,1] for eta and for u greater than or equal to 0. A few properties of the new function are explored in this work. For instance the eta equals 1/2 case reproduces the Dawson function. In addition, a slight variation of the solution technique reproduces the exponential integral for eta equals 1. The technique used to generate these functions leads to an approach for solving a more general class of nonlinear ordinary differential equations, with the potential for identifying other new functions that solve other integrals.

  8. Targeting apoptosis in solid tumors: the role of bortezomib from preclinical to clinical evidence.

    PubMed

    Russo, Antonio; Fratto, Maria E; Bazan, Viviana; Schiró, Valentina; Agnese, Valentina; Cicero, Giuseppe; Vincenzi, Bruno; Tonini, Giuseppe; Santini, Daniele

    2007-12-01

    The ubiquitin-proteasome pathway is the main proteolytic system present in the nucleus and cytoplasm of all eukaryotic cells. Apoptosis activation induced by ubiquitin-proteasome pathway inhibition makes the proteasome a new target of anticancer therapy. Bortezomib is the first proteasome inhibitor to be approved by the US FDA; in 2003 as a third line and in 2005 as a second line therapy for the treatment of multiple myeloma only. This review focuses on the use of bortezomib, not only in its therapeutic role but also, more specifically, in its biologic role and discusses the most recent applications of the drug in solid tumors, both at a preclinical and clinical level.

  9. Continuous and discrete describing function analysis of the LST system

    NASA Technical Reports Server (NTRS)

    Kuo, B. C.; Singh, G.; Yackel, R. A.

    1973-01-01

    A describing function of the control moment gyros (CMG) frictional nonlinearity is derived using the analytic torque equation. Computer simulation of the simplified Large Space Telescope (LST) system with the analytic torque expression is discussed along with the transfer functions of the sampled-data LST system, and the discrete describing function of the GMC frictionality.

  10. 18 CFR 301.7 - Average System Cost methodology functionalization.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... methodology functionalization. 301.7 Section 301.7 Conservation of Power and Water Resources FEDERAL ENERGY... SYSTEM COST METHODOLOGY FOR SALES FROM UTILITIES TO BONNEVILLE POWER ADMINISTRATION UNDER NORTHWEST POWER ACT § 301.7 Average System Cost methodology functionalization. (a) Functionalization of each...

  11. Relations among Functional Systems in Behavior Analysis

    ERIC Educational Resources Information Center

    Thompson, Travis

    2007-01-01

    This paper proposes that an organism's integrated repertoire of operant behavior has the status of a biological system, similar to other biological systems, like the nervous, cardiovascular, or immune systems. Evidence from a number of sources indicates that the distinctions between biological and behavioral events is often misleading, engendering…

  12. Rotorcraft digital advanced avionics system (RODAAS) functional description

    NASA Technical Reports Server (NTRS)

    Peterson, E. M.; Bailey, J.; Mcmanus, T. J.

    1985-01-01

    A functional design of a rotorcraft digital advanced avionics system (RODAAS) to transfer the technology developed for general aviation in the Demonstration Advanced Avionics System (DAAS) program to rotorcraft operation was undertaken. The objective was to develop an integrated avionics system design that enhances rotorcraft single pilot IFR operations without increasing the required pilot training/experience by exploiting advanced technology in computers, busing, displays and integrated systems design. A key element of the avionics system is the functionally distributed architecture that has the potential for high reliability with low weight, power and cost. A functional description of the RODAAS hardware and software functions is presented.

  13. The Delis-Kaplan Executive Function System: A Review

    ERIC Educational Resources Information Center

    Swanson, Jewel

    2005-01-01

    The Delis-Kaplan Executive Function System (D-KEFS; Delis, Kaplan, & Kramer, 2001a) is a set of standardized tests for comprehensively assessing higher-level cognitive functions, referred to as "executive functions," in both children and adults (aged 8 to 89). Executive functions draw on the individual's more fundamental or primary cognitive…

  14. Modifying bitterness in functional food systems.

    PubMed

    Gaudette, Nicole J; Pickering, Gary J

    2013-01-01

    The functional foods sector represents a significant and growing portion of the food industry, yet formulation of these products often involves the use of ingredients that elicit less than desirable oral sensations, including bitterness. Promising new functional ingredients, including polyphenolics, may be more widely and readily employed in the creation of novel functional foods if their aversive bitter taste can be significantly reduced. A number of approaches are used by the industry to improve the taste properties and thus the acceptance of conventional foods that elicit excessive bitterness. This article reviews the most commonly employed techniques, including the use of bitter-modifying additives, which may prove useful for successfully introducing new functional ingredients into this rapidly growing sector.

  15. 14 CFR 25.1705 - Systems and functions: EWIS.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Systems and functions: EWIS. 25.1705 Section 25.1705 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF TRANSPORTATION... (EWIS) § 25.1705 Systems and functions: EWIS. (a) EWIS associated with any system required for...

  16. Robustness, canalyzing functions and systems design.

    PubMed

    Rauh, Johannes; Ay, Nihat

    2014-06-01

    We study a notion of knockout robustness of a stochastic map (Markov kernel) that describes a system of several input random variables and one output random variable. Robustness requires that the behaviour of the system does not change if one or several of the input variables are knocked out. Gibbs potentials are used to give a mechanistic description of the behaviour of the system after knockouts. Robustness imposes structural constraints on these potentials. We show that robust systems can be described in terms of suitable interaction families of Gibbs potentials, which allows us to address the problem of systems design. Robustness is also characterized by conditional independence constraints on the joint distribution of input and output. The set of all probability distributions corresponding to robust systems can be decomposed into a finite union of components, and we find parametrizations of the components.

  17. Functional mapping of the primate auditory system.

    PubMed

    Poremba, Amy; Saunders, Richard C; Crane, Alison M; Cook, Michelle; Sokoloff, Louis; Mishkin, Mortimer

    2003-01-24

    Cerebral auditory areas were delineated in the awake, passively listening, rhesus monkey by comparing the rates of glucose utilization in an intact hemisphere and in an acoustically isolated contralateral hemisphere of the same animal. The auditory system defined in this way occupied large portions of cerebral tissue, an extent probably second only to that of the visual system. Cortically, the activated areas included the entire superior temporal gyrus and large portions of the parietal, prefrontal, and limbic lobes. Several auditory areas overlapped with previously identified visual areas, suggesting that the auditory system, like the visual system, contains separate pathways for processing stimulus quality, location, and motion.

  18. System support documentation: IDIMS FUNCTION AMOEBA

    NASA Technical Reports Server (NTRS)

    Bryant, J.

    1982-01-01

    A listing is provided for AMOEBA, a clustering program based on a spatial-spectral model for image data. The program is fast and automatic (in the sense that no parameters are required), and classifies each picture element into classes which are determined internally. As an IDIMS function, no limit on the size of the image is imposed.

  19. Manufacturing Technology Program Information System: Functional Description.

    DTIC Science & Technology

    1983-02-01

    D-A27 293 MANUACTURING TECNOLOGY PROGRAM INFORMATIONSSEM: /; FUNCTIONAL DESCRIPTIONU ALOGSTS CsMANAGEMENT NST WASHINGTON DC K WRIGHT ET AL FEB 83...TSARCOM ness Command - U.S. Army Mobility Equipment R&D Command MERADCOM - U.S. Army Natick R&D Command NARADCOM 1-3 TABLE 1-1. (cont.) POTENTIAL MTPIS

  20. The Microbiome, Systemic Immune Function, and Allotransplantation.

    PubMed

    Nellore, Anoma; Fishman, Jay A

    2016-01-01

    Diverse effects of the microbiome on solid organ transplantation are beginning to be recognized. In allograft recipients, microbial networks are disrupted by immunosuppression, nosocomial and community-based infectious exposures, antimicrobial therapies, surgery, and immune processes. Shifting microbial patterns, including acute infectious exposures, have dynamic and reciprocal interactions with local and systemic immune systems. Both individual microbial species and microbial networks have central roles in the induction and control of innate and adaptive immune responses, in graft rejection, and in ischemia-reperfusion injury. Understanding the diverse interactions between the microbiome and the immune system of allograft recipients may facilitate clinical management in the future.

  1. The Microbiome, Systemic Immune Function, and Allotransplantation

    PubMed Central

    Nellore, Anoma

    2015-01-01

    SUMMARY Diverse effects of the microbiome on solid organ transplantation are beginning to be recognized. In allograft recipients, microbial networks are disrupted by immunosuppression, nosocomial and community-based infectious exposures, antimicrobial therapies, surgery, and immune processes. Shifting microbial patterns, including acute infectious exposures, have dynamic and reciprocal interactions with local and systemic immune systems. Both individual microbial species and microbial networks have central roles in the induction and control of innate and adaptive immune responses, in graft rejection, and in ischemia-reperfusion injury. Understanding the diverse interactions between the microbiome and the immune system of allograft recipients may facilitate clinical management in the future. PMID:26656674

  2. OFMTutor: An operator function model intelligent tutoring system

    NASA Technical Reports Server (NTRS)

    Jones, Patricia M.

    1989-01-01

    The design, implementation, and evaluation of an Operator Function Model intelligent tutoring system (OFMTutor) is presented. OFMTutor is intended to provide intelligent tutoring in the context of complex dynamic systems for which an operator function model (OFM) can be constructed. The human operator's role in such complex, dynamic, and highly automated systems is that of a supervisory controller whose primary responsibilities are routine monitoring and fine-tuning of system parameters and occasional compensation for system abnormalities. The automated systems must support the human operator. One potentially useful form of support is the use of intelligent tutoring systems to teach the operator about the system and how to function within that system. Previous research on intelligent tutoring systems (ITS) is considered. The proposed design for OFMTutor is presented, and an experimental evaluation is described.

  3. An automated system for pulmonary function testing

    NASA Technical Reports Server (NTRS)

    Mauldin, D. G.

    1974-01-01

    An experiment to quantitate pulmonary function was accepted for the space shuttle concept verification test. The single breath maneuver and the nitrogen washout are combined to reduce the test time. Parameters are defined from the forced vital capacity maneuvers. A spirometer measures the breath volume and a magnetic section mass spectrometer provides definition of gas composition. Mass spectrometer and spirometer data are analyzed by a PDP-81 digital computer.

  4. Functional neuroanatomy of the central noradrenergic system.

    PubMed

    Szabadi, Elemer

    2013-08-01

    The central noradrenergic neurone, like the peripheral sympathetic neurone, is characterized by a diffusely arborizing terminal axonal network. The central neurones aggregate in distinct brainstem nuclei, of which the locus coeruleus (LC) is the most prominent. LC neurones project widely to most areas of the neuraxis, where they mediate dual effects: neuronal excitation by α₁-adrenoceptors and inhibition by α₂-adrenoceptors. The LC plays an important role in physiological regulatory networks. In the sleep/arousal network the LC promotes wakefulness, via excitatory projections to the cerebral cortex and other wakefulness-promoting nuclei, and inhibitory projections to sleep-promoting nuclei. The LC, together with other pontine noradrenergic nuclei, modulates autonomic functions by excitatory projections to preganglionic sympathetic, and inhibitory projections to preganglionic parasympathetic neurones. The LC also modulates the acute effects of light on physiological functions ('photomodulation'): stimulation of arousal and sympathetic activity by light via the LC opposes the inhibitory effects of light mediated by the ventrolateral preoptic nucleus on arousal and by the paraventricular nucleus on sympathetic activity. Photostimulation of arousal by light via the LC may enable diurnal animals to function during daytime. LC neurones degenerate early and progressively in Parkinson's disease and Alzheimer's disease, leading to cognitive impairment, depression and sleep disturbance.

  5. Improving Function Allocation for Integrated Systems Design

    DTIC Science & Technology

    1996-06-01

    seeks to do, but perhaps with some better appreciation of the humanistic character of the worker or operator. Another theory, attributed to A. Maslow ...that can be implemented to satisfy overall system-level requirements. At the bottom of the acquisition pyramid , the human factors engineers

  6. Functional Systems and Culturally-Determined Cognitive Differences.

    ERIC Educational Resources Information Center

    Wiseman, Richard L.

    Noting that one means of better understanding the nature of cultural differences is to elucidate the cognitive differences between members of differing cultures, this paper examines Alexander Luria's sociohistorical theory of functional cognitive systems. The paper first describes Luria's notion of functional systems, the crux of which postulates…

  7. Genetically engineered mouse models for functional studies of SKP1-CUL1-F-box-protein (SCF) E3 ubiquitin ligases

    PubMed Central

    Zhou, Weihua; Wei, Wenyi; Sun, Yi

    2013-01-01

    The SCF (SKP1 (S-phase-kinase-associated protein 1), Cullin-1, F-box protein) E3 ubiquitin ligases, the founding member of Cullin-RING ligases (CRLs), are the largest family of E3 ubiquitin ligases in mammals. Each individual SCF E3 ligase consists of one adaptor protein SKP1, one scaffold protein cullin-1 (the first family member of the eight cullins), one F-box protein out of 69 family members, and one out of two RING (Really Interesting New Gene) family proteins RBX1/ROC1 or RBX2/ROC2/SAG/RNF7. Various combinations of these four components construct a large number of SCF E3s that promote the degradation of many key regulatory proteins in cell-context, temporally, and spatially dependent manners, thus controlling precisely numerous important cellular processes, including cell cycle progression, apoptosis, gene transcription, signal transduction, DNA replication, maintenance of genome integrity, and tumorigenesis. To understand how the SCF E3 ligases regulate these cellular processes and embryonic development under in vivo physiological conditions, a number of mouse models with transgenic (Tg) expression or targeted deletion of components of SCF have been established and characterized. In this review, we will provide a brief introduction to the ubiquitin-proteasome system (UPS) and the SCF E3 ubiquitin ligases, followed by a comprehensive overview on the existing Tg and knockout (KO) mouse models of the SCF E3s, and discuss the role of each component in mouse embryogenesis, cell proliferation, apoptosis, carcinogenesis, as well as other pathogenic processes associated with human diseases. We will end with a brief discussion on the future directions of this research area and the potential applications of the knowledge gained to more effective therapeutic interventions of human diseases. PMID:23528706

  8. Tank waste remediation system functions and requirements document

    SciTech Connect

    Carpenter, K.E

    1996-10-03

    This is the Tank Waste Remediation System (TWRS) Functions and Requirements Document derived from the TWRS Technical Baseline. The document consists of several text sections that provide the purpose, scope, background information, and an explanation of how this document assists the application of Systems Engineering to the TWRS. The primary functions identified in the TWRS Functions and Requirements Document are identified in Figure 4.1 (Section 4.0) Currently, this document is part of the overall effort to develop the TWRS Functional Requirements Baseline, and contains the functions and requirements needed to properly define the top three TWRS function levels. TWRS Technical Baseline information (RDD-100 database) included in the appendices of the attached document contain the TWRS functions, requirements, and architecture necessary to define the TWRS Functional Requirements Baseline. Document organization and user directions are provided in the introductory text. This document will continue to be modified during the TWRS life-cycle.

  9. Autophagy and ubiquitin–proteasome system contribute to sperm mitophagy after mammalian fertilization

    PubMed Central

    Song, Won-Hee; Yi, Young-Joo; Sutovsky, Miriam; Meyers, Stuart; Sutovsky, Peter

    2016-01-01

    Maternal inheritance of mitochondria and mtDNA is a universal principle in human and animal development, guided by selective ubiquitin-dependent degradation of the sperm-borne mitochondria after fertilization. However, it is not clear how the 26S proteasome, the ubiquitin-dependent protease that is only capable of degrading one protein molecule at a time, can dispose of a whole sperm mitochondrial sheath. We hypothesized that the canonical ubiquitin-like autophagy receptors [sequestosome 1 (SQSTM1), microtubule-associated protein 1 light chain 3 (LC3), gamma-aminobutyric acid receptor-associated protein (GABARAP)] and the nontraditional mitophagy pathways involving ubiquitin-proteasome system and the ubiquitin-binding protein dislocase, valosin-containing protein (VCP), may act in concert during mammalian sperm mitophagy. We found that the SQSTM1, but not GABARAP or LC3, associated with sperm mitochondria after fertilization in pig and rhesus monkey zygotes. Three sperm mitochondrial proteins copurified with the recombinant, ubiquitin-associated domain of SQSTM1. The accumulation of GABARAP-containing protein aggregates was observed in the vicinity of sperm mitochondrial sheaths in the zygotes and increased in the embryos treated with proteasomal inhibitor MG132, in which intact sperm mitochondrial sheaths were observed. Pharmacological inhibition of VCP significantly delayed the process of sperm mitophagy and completely prevented it when combined with microinjection of autophagy-targeting antibodies specific to SQSTM1 and/or GABARAP. Sperm mitophagy in higher mammals thus relies on a combined action of SQSTM1-dependent autophagy and VCP-mediated dislocation and presentation of ubiquitinated sperm mitochondrial proteins to the 26S proteasome, explaining how the whole sperm mitochondria are degraded inside the fertilized mammalian oocytes by a protein recycling system involved in degradation of single protein molecules. PMID:27551072

  10. A systems-wide screen identifies substrates of the SCFβTrCP ubiquitin ligase.

    PubMed

    Low, Teck Yew; Peng, Mao; Magliozzi, Roberto; Mohammed, Shabaz; Guardavaccaro, Daniele; Heck, Albert J R

    2014-12-16

    Cellular proteins are degraded by the ubiquitin-proteasome system (UPS) in a precise and timely fashion. Such precision is conferred by the high substrate specificity of ubiquitin ligases. Identification of substrates of ubiquitin ligases is crucial not only to unravel the molecular mechanisms by which the UPS controls protein degradation but also for drug discovery purposes because many established UPS substrates are implicated in disease. We developed a combined bioinformatics and affinity purification-mass spectrometry (AP-MS) workflow for the system-wide identification of substrates of SCF(βTrCP), a member of the SCF family of ubiquitin ligases. These ubiquitin ligases are characterized by a multisubunit architecture typically consisting of the invariable subunits Rbx1, Cul1, and Skp1 and one of 69 F-box proteins. The F-box protein of this member of the family is βTrCP. SCF(βTrCP) binds, through the WD40 repeats of βTrCP, to the DpSGXX(X)pS diphosphorylated motif in its substrates. We recovered 27 previously reported SCF(βTrCP) substrates, of which 22 were verified by two independent statistical protocols, thereby confirming the reliability of this approach. In addition to known substrates, we identified 221 proteins that contained the DpSGXX(X)pS motif and also interacted specifically with the WD40 repeats of βTrCP. Thus, with SCF(βTrCP), as the example, we showed that integration of structural information, AP-MS, and degron motif mining constitutes an effective method to screen for substrates of ubiquitin ligases.

  11. Functional description of the ISIS system

    NASA Technical Reports Server (NTRS)

    Berman, W. J.

    1979-01-01

    Development of software for avionic and aerospace applications (flight software) is influenced by a unique combination of factors which includes: (1) length of the life cycle of each project; (2) necessity for cooperation between the aerospace industry and NASA; (3) the need for flight software that is highly reliable; (4) the increasing complexity and size of flight software; and (5) the high quality of the programmers and the tightening of project budgets. The interactive software invocation system (ISIS) which is described is designed to overcome the problems created by this combination of factors.

  12. Introduction to the Subjective Transfer Function Approach to Analyzing Systems.

    DTIC Science & Technology

    1984-07-01

    STANDARtDS- 1963-A R-3021-AF Intoduction to the Subjective Transfer Function Approach to Analyzing Systems 00 • CO Lf. Clairice T. Veit, Monti Callero ...34Prepared for the United States Air Force." Bibliography: p. • "R-3021-AF." 1. Subjective transfer function method. 2. System analysis. I. Callero , Monti...to Analyzing Systems T, Clairice T. Veit, Monti Callero , Barbara J. Rose July 1984 A Project AIR FORCE report prepared for the - United States Air

  13. With the Help of MOM: Mitochondrial Contributions to Cellular Quality Control.

    PubMed

    Braun, Ralf J; Westermann, Benedikt

    2017-03-10

    Mitochondria are essential organelles because they have key roles in cellular energy metabolism and many other metabolic pathways. Several quality control systems have evolved to ensure that dysfunctional mitochondria are either repaired or eliminated. The activities of these pathways are crucial for cellular health because they maintain functional mitochondria. In addition, the cytosolic ubiquitin-proteasome system (UPS) and the mitochondria-associated degradation pathway (MAD) share some of their core components, are functionally tightly interconnected, and mutually modulate their activities. Thus, the mitochondrial outer membrane (MOM) actively supports quality control systems in extramitochondrial compartments. Furthermore, mitochondrial quality surveillance systems also act on cytosolic or endoplasmic reticulum (ER) substrates and modulate immune responses. Therefore, mitochondria contribute to cellular quality control and homeostasis on several levels.

  14. A design principle underlying the paradoxical roles of E3 ubiquitin ligases

    PubMed Central

    Lee, Daewon; Kim, Minjin; Cho, Kwang-Hyun

    2014-01-01

    E3 ubiquitin ligases are important cellular components that determine the specificity of proteolysis in the ubiquitin-proteasome system. However, an increasing number of studies have indicated that E3 ubiquitin ligases also participate in transcription. Intrigued by the apparently paradoxical functions of E3 ubiquitin ligases in both proteolysis and transcriptional activation, we investigated the underlying design principles using mathematical modeling. We found that the antagonistic functions integrated in E3 ubiquitin ligases can prevent any undesirable sustained activation of downstream genes when E3 ubiquitin ligases are destabilized by unexpected perturbations. Interestingly, this design principle of the system is similar to the operational principle of a safety interlock device in engineering systems, which prevents a system from abnormal operation unless stability is guaranteed. PMID:24994517

  15. A design principle underlying the paradoxical roles of E3 ubiquitin ligases

    NASA Astrophysics Data System (ADS)

    Lee, Daewon; Kim, Minjin; Cho, Kwang-Hyun

    2014-07-01

    E3 ubiquitin ligases are important cellular components that determine the specificity of proteolysis in the ubiquitin-proteasome system. However, an increasing number of studies have indicated that E3 ubiquitin ligases also participate in transcription. Intrigued by the apparently paradoxical functions of E3 ubiquitin ligases in both proteolysis and transcriptional activation, we investigated the underlying design principles using mathematical modeling. We found that the antagonistic functions integrated in E3 ubiquitin ligases can prevent any undesirable sustained activation of downstream genes when E3 ubiquitin ligases are destabilized by unexpected perturbations. Interestingly, this design principle of the system is similar to the operational principle of a safety interlock device in engineering systems, which prevents a system from abnormal operation unless stability is guaranteed.

  16. Gross functional anatomy: Integumentary system: Chapter 5

    USGS Publications Warehouse

    Elliott, Diane G.; Ostrander, Gary K.

    2000-01-01

    The integument or skin of a fish is the envelope for the body that separates and protects the animal from its environment, but it also provides the means through which most of the contacts with the outer world are made. The integument is continuous with the lining of all the body openings, and also covers the fins. The skin of a fish is a multifunctional organ, and may serve important roles in protection, communication, sensory perception, locomotion, respiration, ion regulation, excretion, and thermal regulation. The most obvious functions of fish integument are protective. For example, mucous secretions help to keep the skin surface free of pathogens by means of constant sloughing and renewal and the presence of antimicrobial substances. Integumentary features can assist a fish during locomotion. The slippery mucus of some fishes has marked friction-reducing properties that enable a fish to move at greater speed with less expenditure of energy. The integument is an important adjunct to the breathing equipment of some fish species. Gas exchange across the skin is known to play a significant role in the respiration of larval fish.

  17. On a useful functional representation of control system structure

    NASA Technical Reports Server (NTRS)

    Malchow, Harvey L.

    1988-01-01

    An alternative structure for control systems is proposed. The structure is represented by a three-element block diagram and three functional definitions. It is argued that the three functional elements form a canonical set. The set includes the functions description, estimation and control. General overlay of the structure on parallel state and nested-state control systems is discussed. Breakdown of two real nested-state control systems into the proposed functional format is displayed. Application of the process to the mapping of complex control systems R and D efforts is explained with the Mars Rover Sample and Return mission as an example. A previous application of this basic functional structure to Space Station performance requirements organization is discussed.

  18. Theory of functional systems and human general pathology.

    PubMed

    Khitrov, N K; Saltykov, A B

    2003-07-01

    We analyze the role of the theory of functional systems for human general pathology and the necessity of integration of this theory with the concepts of pathological and ambivalent systems. Multiple (qualitatively heterogeneous) nature of system-forming factors and principle possibility of the formation of physiological, pathological, and ambivalent systems by the same factors are discussed. These theses broaden the application of the theory of functional systems as the fundamental basis for studies of informational mechanisms of vital activity under normal and pathological conditions.

  19. [Ubiquitous Ribonucleic Acid:miRNA is the Ubiquitin of RNA].

    PubMed

    Zheng, Xiao-fei

    2015-10-01

    Small RNAs, especially microRNAs (miRNAs),widely exist in eukaryotic cells, with their main functions being regulating gene expression and function of target molecules through the degradation of cellular target RNAs by the ribonuclease-based system. Ubiquitins and ubiquitin-like proteins are polypeptides that exist in most eukaryotic cells, and their main function is almost to regulate protein level through the degradation of cellular proteins by ubiquitin proteasome system. Small RNAs, including miRNAs,and ubiquitins or ubiquitin-like proteins have similarities in many aspects although small RNAs and ubiquitin or ubiquitin-like proteins interact different substrates respectively. Therefore, miRNAs can be defined as ubiquitra (ubiquitous ribonucleic acid, ubiquitra or uRNA), and the other small RNAs can be defined as ubiquitra-like RNA or uRNA-like RNA. The concept of ubiquitra may be applied for explaining the biological essence of small RNAs diversity.

  20. Selective multifaceted E3 ubiquitin ligases barricade extreme defense: Potential therapeutic targets for neurodegeneration and ageing.

    PubMed

    Upadhyay, Arun; Amanullah, Ayeman; Chhangani, Deepak; Mishra, Ribhav; Mishra, Amit

    2015-11-01

    Efficient and regular performance of Ubiquitin Proteasome System and Autophagy continuously eliminate deleterious accumulation of nonnative protiens. In cellular quality control system, E3 ubiquitin ligases are significant employees for defense mechanism against abnormal toxic proteins. Few findings indicate that lack of functions of E3 ubiquitin ligases can be a causative factor of neurodevelopmental disorders, neurodegeneration, cancer and ageing. However, the detailed molecular pathomechanism implying E3 ubiquitin ligases in cellular functions in multifactorial disease conditions are not well understood. This article systematically represents the unique characteristics, molecular nature, and recent developments in the knowledge of neurobiological functions of few crucial E3 ubiquitin ligases. Here, we review recent literature on the roles of E6-AP, HRD1 and ITCH E3 ubiquitin ligases in the neuro-pathobiological mechanisms, with precise focus on the processes of neurodegeneration, and thereby propose new lines of potential targets for therapeutic interventions.

  1. Functional system design document for the Intelligent Inspection System (IIS)

    NASA Astrophysics Data System (ADS)

    1992-01-01

    IIS (Intelligent Inspection System) is a Martin Marietta Energy Systems Quality Services division project to design and implement a new generation inspection workstation/machine system to be used on all new and upgraded inspection machines for the next several years. The initial implementation will be on upgraded YZ inspection machines. These machines now utilize the dual processor (PDP-ll/Allen Bradley combination) hardware and software. Portions of the hardware for these current systems are no longer available. Future implementations will include dual YZ, CMM and OMM systems, both upgrades and new. IIS project scope includes all of the inspection machine control hardware and software, all software to receive a part program, collect inspection data, analyze the data, output results, and the operator interface. Also included in the IIS scope are the operator interface and electronic data handling for the part programming interface and the shop floor interface.

  2. Performance monitor system functional simulator, environmental data, orbiter 101(HFT)

    NASA Technical Reports Server (NTRS)

    Parker, F. W.

    1974-01-01

    Information concerning the environment component of the space shuttle performance monitor system simulator (PMSS) and those subsystems operational on the shuttle orbiter 101 used for horizontal flight test (HFT) is provided, along with detailed data for the shuttle performance monitor system (PMS) whose software requirements evolve from three basic PMS functions: (1) fault detection and annunciation; (2) subsystem measurement management; and (3) subsystem configuration management. Information relative to the design and operation of Orbiter systems for HFT is also presented, and the functional paths are identified to the lowest level at which the crew can control the system functions. Measurement requirements are given which are necessary to adequately monitor the health status of the system. PMS process requirements, relative to the measurements which are necessary for fault detection and annunciation of a failed functional path, consist of measurement characteristics, tolerance limits, precondition tests, and correlation measurements.

  3. Development of the Gross Motor Function Classification System (1997)

    ERIC Educational Resources Information Center

    Morris, Christopher

    2008-01-01

    To address the need for a standardized system to classify the gross motor function of children with cerebral palsy, the authors developed a five-level classification system analogous to the staging and grading systems used in medicine. Nominal group process and Delphi survey consensus methods were used to examine content validity and revise the…

  4. On-line mass storage system functional design document

    NASA Technical Reports Server (NTRS)

    Earnest, D.

    1975-01-01

    A functional system definition for an on-line high density magnetic tape data storage system is provided. This system can be implemented in a multi-purpose, multi-host environment, and satisfy the requirements of economical data storage in the range of 2 to 50 billion bytes.

  5. Engineering study for the functional design of a multiprocessor system

    NASA Technical Reports Server (NTRS)

    Miller, J. S.; Vandever, W. H.; Stanten, S. F.; Avakian, A. E.; Kosmala, A. L.

    1972-01-01

    The results are presented of a study to generate a functional system design of a multiprocessing computer system capable of satisfying the computational requirements of a space station. These data management system requirements were specified to include: (1) real time control, (2) data processing and storage, (3) data retrieval, and (4) remote terminal servicing.

  6. Methodology for the systems engineering process. Volume 1: System functional activities

    NASA Technical Reports Server (NTRS)

    Nelson, J. H.

    1972-01-01

    Systems engineering is examined in terms of functional activities that are performed in the conduct of a system definition/design, and system development is described in a parametric analysis that combines functions, performance, and design variables. Emphasis is placed on identification of activities performed by design organizations, design specialty groups, as well as a central systems engineering organizational element. Identification of specific roles and responsibilities for doing functions, and monitoring and controlling activities within the system development operation are also emphasized.

  7. Modified function projective combination synchronization of hyperchaotic systems

    NASA Astrophysics Data System (ADS)

    Sudheer, K. Sebastian; Sabir, M.

    2017-03-01

    In this work, a novel combination synchronization scheme in which synchronization of a new combination hyperchaotic drive system formed by combining state variables of the original drive system with appropriate scaling factors with a response hyperchaotic system is considered. A self-combination system is constructed from hyperchaotic Lorenz system by combining state variables of the Lorenz system with appropriate scaling factors. Modified function projective synchronization between the newly constructed combination hyperchaotic Lorenz system and hyperchaotic Lu system is investigated using adaptive method. By Lyapunov stability theory, the adaptive control law and the parameter update law are derived to make the state of two systems as modified function projective synchronized. Numerical simulations are done to show the validity and effectiveness of the proposed synchronization scheme.

  8. Neuroscience in the era of functional genomics and systems biology.

    PubMed

    Geschwind, Daniel H; Konopka, Genevieve

    2009-10-15

    Advances in genetics and genomics have fuelled a revolution in discovery-based, or hypothesis-generating, research that provides a powerful complement to the more directly hypothesis-driven molecular, cellular and systems neuroscience. Genetic and functional genomic studies have already yielded important insights into neuronal diversity and function, as well as disease. One of the most exciting and challenging frontiers in neuroscience involves harnessing the power of large-scale genetic, genomic and phenotypic data sets, and the development of tools for data integration and mining. Methods for network analysis and systems biology offer the promise of integrating these multiple levels of data, connecting molecular pathways to nervous system function.

  9. Structure and function of large-scale brain systems.

    PubMed

    Koziol, Leonard F; Barker, Lauren A; Joyce, Arthur W; Hrin, Skip

    2014-01-01

    This article introduces the functional neuroanatomy of large-scale brain systems. Both the structure and functions of these brain networks are presented. All human behavior is the result of interactions within and between these brain systems. This system of brain function completely changes our understanding of how cognition and behavior are organized within the brain, replacing the traditional lesion model. Understanding behavior within the context of brain network interactions has profound implications for modifying abstract constructs such as attention, learning, and memory. These constructs also must be understood within the framework of a paradigm shift, which emphasizes ongoing interactions within a dynamically changing environment.

  10. The wave function and minimum uncertainty function of the bound quadratic Hamiltonian system

    NASA Technical Reports Server (NTRS)

    Yeon, Kyu Hwang; Um, Chung IN; George, T. F.

    1994-01-01

    The bound quadratic Hamiltonian system is analyzed explicitly on the basis of quantum mechanics. We have derived the invariant quantity with an auxiliary equation as the classical equation of motion. With the use of this invariant it can be determined whether or not the system is bound. In bound system we have evaluated the exact eigenfunction and minimum uncertainty function through unitary transformation.

  11. Functional and numerical response in prey-predator system

    NASA Astrophysics Data System (ADS)

    Hasan, Y. Abu; Alebraheem, J.

    2015-03-01

    Two of the important terms describing the relationship in a prey-predator system of equations are the functional and numerical responses. The standard functional response used by theoretical and field ecologists is the Holling type-2 functional response. This function was later modified to take into account predator interference as a result of an increase in predator density. In this paper, we introduce a model that can take into account the predator interactions through the numerical response, without modifying the Holling functional response. The correctness of the model and its dynamical behaviour is discussed. Comparisons are made with model with a standard response.

  12. [Portable lung function parameters testing system based on DSP].

    PubMed

    Guo, Zhanshe; Yuan, Minzhong; Zhou, Hui

    2012-11-01

    Lung function monitoring is a critical technique for clinical medicine. Currently, the lung function testing devices used in our domestic hospitals are both expensive and bulky. A portable and accurate lung function parameters testing system is highly desired and is proposed in this paper. The hardware of the system is based on DSP technology. The breathing passage is designed with an aim suitable for the breathe and signal detection. We use the direct detection method to detect the gas flow, the breathing passage pressure and the breathing time. Thanks to the powerful data processing ability and the high operation speed of the DSP, breathing signals can be easily analyzed. Thus, several lung function parameters of clinical significance can be obtained. Experiments show that the accuracy of the system is better than 3%, and could meet the demand of the lung function testing.

  13. Screening for E3-Ubiquitin ligase inhibitors: challenges and opportunities

    PubMed Central

    Landré, Vivien; Rotblat, Barak; Melino, Sonia; Bernassola, Francesca; Melino, Gerry

    2014-01-01

    The ubiquitin proteasome system (UPS) plays a role in the regulation of most cellular pathways, and its deregulation has been implicated in a wide range of human pathologies that include cancer, neurodegenerative and immunological disorders and viral infections. Targeting the UPS by small molecular regulators thus provides an opportunity for the development of therapeutics for the treatment of several diseases. The proteasome inhibitor Bortezomib was approved for treatment of hematologic malignancies by the FDA in 2003, becoming the first drug targeting the ubiquitin proteasome system in the clinic. Development of drugs targeting specific components of the ubiquitin proteasome system, however, has lagged behind, mainly due to the complexity of the ubiquitination reaction and its outcomes. However, significant advances have been made in recent years in understanding the molecular nature of the ubiquitination system and the vast variety of cellular signals that it produces. Additionally, improvement of screening methods, both in vitro and in silico, have led to the discovery of a number of compounds targeting components of the ubiquitin proteasome system, and some of these have now entered clinical trials. Here, we discuss the current state of drug discovery targeting E3 ligases and the opportunities and challenges that it provides. PMID:25237759

  14. A System for Performing High Throughput Assays of Synaptic Function

    PubMed Central

    Hempel, Chris M.; Sivula, Michael; Levenson, Jonathan M.; Rose, David M.; Li, Bing; Sirianni, Ana C.; Xia, Eva; Ryan, Timothy A.; Gerber, David J.; Cottrell, Jeffrey R.

    2011-01-01

    Unbiased, high-throughput screening has proven invaluable for dissecting complex biological processes. Application of this general approach to synaptic function would have a major impact on neuroscience research and drug discovery. However, existing techniques for studying synaptic physiology are labor intensive and low-throughput. Here, we describe a new high-throughput technology for performing assays of synaptic function in primary neurons cultured in microtiter plates. We show that this system can perform 96 synaptic vesicle cycling assays in parallel with high sensitivity, precision, uniformity, and reproducibility and can detect modulators of presynaptic function. By screening libraries of pharmacologically defined compounds on rat forebrain cultures, we have used this system to identify novel effects of compounds on specific aspects of presynaptic function. As a system for unbiased compound as well as genomic screening, this technology has significant applications for basic neuroscience research and for the discovery of novel, mechanism-based treatments for central nervous system disorders. PMID:21998743

  15. Ubiquitin/proteasome-rich particulate cytoplasmic structures (PaCSs) in the platelets and megakaryocytes of ANKRD26-related thrombo-cytopenia.

    PubMed

    Necchi, Vittorio; Balduini, Alessandra; Noris, Patrizia; Barozzi, Serena; Sommi, Patrizia; di Buduo, Christian; Balduini, Carlo L; Solcia, Enrico; Pecci, Alessandro

    2013-02-01

    ANKRD26-related thrombocytopenia (ANKRD26-RT) is an autosomal-dominant thrombocytopenia caused by mutations in the 5'UTR of the ANKRD26 gene. ANKRD26-RT is characterised by dysmegakaryopoiesis and an increased risk of leukaemia. PaCSs are novel particulate cytoplasmic structures with selective immunoreactivity for polyubiquitinated proteins and proteasome that have been detected in a number of solid cancers, in the epithelia of Helicobacter pylori gastritis and related preneoplastic lesions, and in the neutrophils of Schwachman-Diamond syndrome, a genetic disease with neutropenia and increased leukaemia risk. We searched for PaCSs in blood cells from 14 consecutive patients with ANKRD26-RT. Electron microscopy combined with immunogold staining for polyubiquitinated proteins, 20S and 19S proteasome showed PaCSs in most ANKRD26-RT platelets, as in a restricted minority of platelets from healthy controls and from subjects with other inherited or immune thrombocytopenias. In ANKRD26-RT platelets, the PaCS amount exceeded that of control platelets by a factor of 5 (p<0.0001). Immunoblotting showed that the higher PaCS number was associated with increased amounts of polyubiquitinated proteins and proteasome in ANKRD26-RT platelets. PaCSs were also extensively represented in ANKRD26-RT megakaryocytes, but not in healthy control megakaryocytes, and were absent in other ANKRD26-RT and control blood cells. Therefore, large amounts of PaCSs are a characteristic feature of ANKRD26-RT platelets and megakaryocytes, although these novel cell components are also present in a small subpopulation of normal platelets. The widespread presence of PaCSs in inherited diseases with increased leukaemia risk, as well as in solid neoplasms and their preneoplastic lesions, suggests a link of these structures with oncogenesis.

  16. Arabidopsis ABA-Activated Kinase MAPKKK18 is Regulated by Protein Phosphatase 2C ABI1 and the Ubiquitin-Proteasome Pathway.

    PubMed

    Mitula, Filip; Tajdel, Malgorzata; Cieśla, Agata; Kasprowicz-Maluśki, Anna; Kulik, Anna; Babula-Skowrońska, Danuta; Michalak, Michal; Dobrowolska, Grazyna; Sadowski, Jan; Ludwików, Agnieszka

    2015-12-01

    Phosphorylation and dephosphorylation events play an important role in the transmission of the ABA signal. Although SnRK2 [sucrose non-fermenting1-related kinase2] protein kinases and group A protein phosphatase type 2C (PP2C)-type phosphatases constitute the core ABA pathway, mitogen-activated protein kinase (MAPK) pathways are also involved in plant response to ABA. However, little is known about the interplay between MAPKs and PP2Cs or SnRK2 in the regulation of ABA pathways. In this study, an effort was made to elucidate the role of MAP kinase kinase kinase18 (MKKK18) in relation to ABA signaling and response. The MKKK18 knockout lines showed more vigorous root growth, decreased abaxial stomatal index and increased stomatal aperture under normal growth conditions, compared with the control wild-type Columbia line. In addition to transcriptional regulation of the MKKK18 promoter by ABA, we demonstrated using in vitro and in vivo kinase assays that the kinase activity of MKKK18 was regulated by ABA. Analysis of the cellular localization of MKKK18 showed that the active kinase was targeted specifically to the nucleus. Notably, we identified abscisic acid insensitive 1 (ABI1) PP2C as a MKKK18-interacting protein, and demonstrated that ABI1 inhibited its activity. Using a cell-free degradation assay, we also established that MKKK18 was unstable and was degraded by the proteasome pathway. The rate of MKKK18 degradation was delayed in the ABI1 knockout line. Overall, we provide evidence that ABI1 regulates the activity and promotes proteasomal degradation of MKKK18.

  17. Regulation of Akt-mTOR, ubiquitin-proteasome and autophagy-lysosome pathways in response to formoterol administration in rat skeletal muscle.

    PubMed

    Joassard, Olivier Roger; Amirouche, Adel; Gallot, Yann Simon; Desgeorges, Marine Maud; Castells, Josiane; Durieux, Anne-Cécile; Berthon, Phanélie; Freyssenet, Damien Gilles

    2013-11-01

    Administration of β2-agonists triggers skeletal muscle anabolism and hypertrophy. We investigated the time course of the molecular events responsible for rat skeletal muscle hypertrophy in response to 1, 3 and 10 days of formoterol administration (i.p. 2000μg/kg/day). A marked hypertrophy of rat tibialis anterior muscle culminated at day 10. Phosphorylation of Akt, ribosomal protein S6, 4E-BP1 and ERK1/2 was increased at day 3, but returned to control level at day 10. This could lead to a transient increase in protein translation and could explain previous studies that reported increase in protein synthesis following β2-agonist administration. Formoterol administration was also associated with a significant reduction in MAFbx/atrogin-1 mRNA level (day 3), suggesting that formoterol can also affect protein degradation of MAFbx/atrogin1 targeted substrates, including MyoD and eukaryotic initiation factor-3f (eIF3-f). Surprisingly, mRNA level of autophagy-related genes, light chain 3 beta (LC3b) and gamma-aminobutyric acid receptor-associated protein-like 1 (Gabarapl1), as well as lysosomal hydrolases, cathepsin B and cathepsin L, was significantly and transiently increased after 1 and/or 3 days, suggesting that autophagosome formation would be increased in response to formoterol administration. However, this has to be relativized since the mRNA level of Unc-51-like kinase1 (Ulk1), BCL2/adenovirus E1B interacting protein3 (Bnip3), and transcription factor EB (TFEB), as well as the protein content of Ulk1, Atg13, Atg5-Atg12 complex and p62/Sqstm1 remained unchanged or was even decreased in response to formoterol administration. These results demonstrate that the effects of formoterol are mediated, in part, through the activation of Akt-mTOR pathway and that other signaling pathways become more important in the regulation of skeletal muscle mass with chronic administration of β2-agonists.

  18. Roles for the ubiquitin-proteasome pathway in protein quality control and signaling in the retina: implications in the pathogenesis of age-related macular degeneration

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The accumulation of damaged or postsynthetically modified proteins and dysregulation of inflammatory responses and angiogenesis in the retina/RPE are thought be etiologically related to formation of drusen and choroidal neovascularization (CNV), hallmarks of age-related macular degeneration (AMD). T...

  19. The Training Information Management System. Volume 3. Functional Specifications

    DTIC Science & Technology

    1986-07-01

    ARI Research Note 86-79 Q THE TRAINING INFORMATION MANAGEMENT SYSTEM : (1% Phase II Functional Specifications Perceptronics for ARI Field Unit at...Subtitle) S. TYPE OF REPORT & PERIOD COVERED THE TRAINING INFORMATION MANAGEMENT SYSTEM : Final Report, Vol. 3 Phase II Functional Specifications April...CMinMM us rG~mr i14m I ne eat Md IdeLlIf’ bY block numsber) NThe Training Information Management System (TIMS) is a computer-based system which can be

  20. HAL/S-FC compiler system functional specification

    NASA Technical Reports Server (NTRS)

    1974-01-01

    The functional requirements to be met by the HAL/S-FC compiler, and the hardware and software compatibilities between the compiler system and the environment in which it operates are defined. Associated runtime facilities and the interface with the Software Development Laboratory are specified. The construction of the HAL/S-FC system as functionally separate units and the interfaces between those units is described. An overview of the system's capabilities is presented and the hardware/operating system requirements are specified. The computer-dependent aspects of the HAL/S-FC are also specified. Compiler directives are included.

  1. LRRK2, a puzzling protein: insights into Parkinson’s disease pathogenesis

    PubMed Central

    Esteves, A Raquel; Swerdlow, Russell H; Cardoso, Sandra M

    2014-01-01

    Leucine-rich repeat kinase 2 (LRRK2) is a large, ubiquitous protein of unknown function. Mutations in the gene encoding LRRK2 have been linked to familial and sporadic Parkinson disease (PD) cases. The LRRK2 protein is a single polypeptide that displays GTPase and kinase activity. Kinase and GTPase domains are involved in different cellular signalling pathways. Despite several experimental studies associating LRRK2 protein with various intracellular membranes and vesicular structures such as endosomal/lysosomal compartments, the mitochondrial outer membrane, lipid rafts, microtubule-associated vesicles, the golgi complex, and the endoplasmic reticulum its broader physiologic function(s) remain unidentified. Additionally, the cellular distribution of LRRK2 may indicate its role in several different pathways, such as the ubiquitin-proteasome system, the autophagic-lysosomal pathway, intracellular trafficking, and mitochondrial dysfunction. This review discusses potential mechanisms through which LRRK2 may mediate neurodegeneration and cause PD. PMID:24907399

  2. RING-type E3 ligases: Master manipulators of E2 ubiquitin-conjugating enzymes and ubiquitination

    PubMed Central

    Metzger, Meredith B.; Pruneda, Jonathan N.; Klevit, Rachel E.; Weissman, Allan M.

    2013-01-01

    RING finger domain and RING finger-like ubiquitin ligases (E3s), such as U-box proteins, constitute the vast majority of known E3s. RING-type E3s function together with ubiquitin-conjugating enzymes (E2s) to mediate ubiquitination and are implicated in numerous cellular processes. In part because of their importance in human physiology and disease, these proteins and their cellular functions represent an intense area of study. Here we review recent advances in RING-type E3 recognition of substrates, their cellular regulation, and their varied architecture. Additionally, recent structural insights into RING-type E3 function, with a focus on important interactions with E2s and ubiquitin, are reviewed. This article is part of a Special Issue entitled: Ubiquitin-Proteasome System. PMID:23747565

  3. Systemic vascular function is associated with muscular power in adults

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Age-associated loss of muscular strength and muscular power are critical determinants of loss of physical function and progression to disability in older adults. In this study, we examined the association of systemic vascular function and measures of muscle strength and power in older adults. Measu...

  4. Occlusion and functional disorders of the masticatory system.

    PubMed

    Okeson, J P

    1995-04-01

    Understanding the relationship between occlusion and functional disorders of the masticatory system is no easy task. This article explores the static, functional, and dynamic relationships of the occlusal condition to the signs and symptoms of masticatory dysfunction. Some possible relationships are discussed.

  5. Efficient methods for finding transfer function zeros of power systems

    SciTech Connect

    Martins, N.; Pinto, H.J.C.P. ); Lima, L.T.G. )

    1992-08-01

    This paper is probably the first to describe algorithms suited to the efficient calculation of both proper and non-proper transfer function zeros of linearized dynamic models for large interconnected power systems. The paper also describes an improvement to the well known AESOPS algorithm, formulating it as an exact transfer function zero finding problem which is efficiently solved by a Newton-Raphson iterative scheme. Large power system results are presented in this paper.

  6. Transfer Functions for Nonlinear Systems via Fourier-Borel Transforms.

    DTIC Science & Technology

    Fourier series or integral expansions of response functions of linear systems. The shuffle product which is the characteristic of the noncommutative ... noncommutative algebra on a computer in any of the currently available symbolic programming languages such as Macsyma, Reduce, PL1, and Lisp...gives the transform of the response of the nonlinear system as a Cauchy product of its transfer function which is introduced for the first time here

  7. Gutzwiller density functional theory for correlated electron systems

    SciTech Connect

    Ho, K. M.; Schmalian, J.; Wang, C. Z.

    2008-02-04

    We develop a density functional theory (DFT) and formalism for correlated electron systems by taking as reference an interacting electron system that has a ground state wave function which exactly obeys the Gutzwiller approximation for all one-particle operators. The solution of the many-electron problem is mapped onto the self-consistent solution of a set of single-particle Schroedinger equations, analogously to standard DFT-local density approximation calculations.

  8. Energy Management and Control System: Desired Capabilities and Functionality

    SciTech Connect

    Hatley, Darrel D.; Meador, Richard J.; Katipamula, Srinivas; Brambley, Michael R.; Wouden, Carl

    2005-04-29

    This document discusses functions and capabilities of a typical building/facility energy management and control systems (EMCS). The overall intent is to provide a building operator, manager or engineer with basic background information and recommended functions, capabilities, and good/best practices that will enable the control systems to be fully utilized/optimized, resulting in improved building occupant quality of life and more reliable, energy efficient facilities.

  9. A functional system architecture for fully autonomous robot

    NASA Astrophysics Data System (ADS)

    Kalaycioglu, S.

    The Mobile Servicing System (MSS) Autonomous Robotics Program intends to define and plan the development of technologies required to provide a supervised autonomous operation capability for the Special Purpose Dexterous Manipulator (SPDM) on the MSS. The operational functions for the SPDM to perform the required tasks, both in fully autonomous or supervised modes, are identified. Functional decomposition is performed using a graphics oriented methodology called Structural Analysis Design Technique. This process defines the functional architecture of the system, the types of data required to support its functionality, and the control processes that need to be emplaced. On the basis of the functional decomposition, a technology breakdown structure is also developed. A preliminary estimate of the status and maturity of each relevant technology is made, based on this technology breakdown. The developed functional hierarchy is found to be very effective for a robotic system with any level of autonomy. Moreover, this hierarchy can easily be applied to an existing very low level autonomous system and can provide a smooth transition towards a higher degree of autonomy. The effectiveness of the developed functional hierarchy will also play a very significant role both in the system design as well as in the development of the control hierarchy.

  10. Cronus, A Distributed Operating System: Functional Definition and System Concept.

    DTIC Science & Technology

    1984-02-01

    Digital Equipment Corporation VAX computer running the VMS operating system) which are enhanced and or modified to integrate the host in’o the DOS Thus...Interprocessor communicatio f data. - Multi-level data security With the exception of multi-level the scope of this project, our sy areas. The first two

  11. Efficient Evaluation Functions for Multi-Rover Systems

    NASA Technical Reports Server (NTRS)

    Agogino, Adrian; Tumer, Kagan

    2004-01-01

    Evolutionary computation can be a powerful tool in cresting a control policy for a single agent receiving local continuous input. This paper extends single-agent evolutionary computation to multi-agent systems, where a collection of agents strives to maximize a global fitness evaluation function that rates the performance of the entire system. This problem is solved in a distributed manner, where each agent evolves its own population of neural networks that are used as the control policies for the agent. Each agent evolves its population using its own agent-specific fitness evaluation function. We propose to create these agent-specific evaluation functions using the theory of collectives to avoid the coordination problem where each agent evolves a population that maximizes its own fitness function, yet the system has a whole achieves low values of the global fitness function. Instead we will ensure that each fitness evaluation function is both "aligned" with the global evaluation function and is "learnable," i.e., the agents can readily see how their behavior affects their evaluation function. We then show how these agent-specific evaluation functions outperform global evaluation methods by up to 600% in a domain where a set of rovers attempt to maximize the amount of information observed while navigating through a simulated environment.

  12. Activities of proteasome and m-calpain are essential for Chikungunya virus replication.

    PubMed

    Karpe, Yogesh A; Pingale, Kunal D; Kanade, Gayatri D

    2016-10-01

    Replication of many viruses is dependent on the ubiquitin proteasome system. The present study demonstrates that Chikungunya virus replication increases proteasome activity and induces unfolded protein response (UPR) in cultured cells. Further, it was seen that the virus replication was dependent on the activities of proteasomes and m-calpain. Proteasome inhibition induced accumulation of polyubiquitinated proteins and earlier visualization of UPR.

  13. Amino acids, independent of insulin, attenuate skeletal muscle autophagy in neonatal pigs during endotoxemia

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Sepsis induces loss of skeletal muscle mass by activating the ubiquitin proteasome (UPS) and autophagy systems. Although muscle protein synthesis in healthy neonatal piglets is responsive to amino acids (AA) stimulation, it is not known if AA can prevent the activation of muscle protein degradation ...

  14. Autonomic nervous system function in young children with functional abdominal pain or irritable bowel syndrome

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Adults with irritable bowel syndrome (IBS) have been reported to have alterations in autonomic nervous system function as measured by vagal activity via heart rate variability. Whether the same is true for children is unknown. We compared young children 7 to 10 years of age with functional abdominal...

  15. Data-Driven Assistance Functions for Industrial Automation Systems

    NASA Astrophysics Data System (ADS)

    Windmann, Stefan; Niggemann, Oliver

    2015-11-01

    The increasing amount of data in industrial automation systems overburdens the user in process control and diagnosis tasks. One possibility to cope with these challenges consists of using smart assistance systems that automatically monitor and optimize processes. This article deals with aspects of data-driven assistance systems such as assistance functions, process models and data acquisition. The paper describes novel approaches for self-diagnosis and self-optimization, and shows how these assistance functions can be integrated in different industrial environments. The considered assistance functions are based on process models that are automatically learned from process data. Fault detection and isolation is based on the comparison of observations of the real system with predictions obtained by application of the process models. The process models are further employed for energy efficiency optimization of industrial processes. Experimental results are presented for fault detection and energy efficiency optimization of a drive system.

  16. Functional implications of component commonality in operational systems

    NASA Technical Reports Server (NTRS)

    Thomas, Lawrence D.

    1992-01-01

    The application of commonality in a system represents an attempt to reduce costs by reducing the number of unique components. Research in this area has primarily addressed a significant benefit of commonality, the reduction of parts inventories in assemble-to-order manufacturing systems. Likewise, in an operational system subject to component failures, spares inventories are reduced through the increased commonality of components. However, commonality tends to degrade system performance parameters, a degradation that can preclude commonality in resource-constrained systems such as spacecraft. The functional impacts of component commonality on a system is addressed in a manner that allows inclusion in a commonality analysis.

  17. Functional classifications for cerebral palsy: correlations between the gross motor function classification system (GMFCS), the manual ability classification system (MACS) and the communication function classification system (CFCS).

    PubMed

    Compagnone, Eliana; Maniglio, Jlenia; Camposeo, Serena; Vespino, Teresa; Losito, Luciana; De Rinaldis, Marta; Gennaro, Leonarda; Trabacca, Antonio

    2014-11-01

    This study aimed to investigate a possible correlation between the gross motor function classification system-expanded and revised (GMFCS-E&R), the manual abilities classification system (MACS) and the communication function classification system (CFCS) functional levels in children with cerebral palsy (CP) by CP subtype. It was also geared to verify whether there is a correlation between these classification systems and intellectual functioning (IF) and parental socio-economic status (SES). A total of 87 children (47 males and 40 females, age range 4-18 years, mean age 8.9±4.2) were included in the study. A strong correlation was found between the three classifications: Level V of the GMFCS-E&R corresponds to Level V of the MACS (rs=0.67, p=0.001); the same relationship was found for the CFCS and the MACS (rs=0.73, p<0.001) and for the GMFCS-E&R and the CFCS (rs=0.61, p=0.001). The correlations between the IQ and the global functional disability profile were strong or moderate (GMFCS and IQ: rs=0.66, p=0.001; MACS and IQ: rs=0.58, p=0.001; CFCS and MACS: rs=0.65, p=0.001). The Kruskal-Wallis test was used to determine if there were differences between the GMFCS-E&R, the CFCS and the MACS by CP type. CP types showed different scores for the IQ level (Chi-square=8.59, df=2, p=0.014), the GMFCS-E&R (Chi-square=36.46, df=2, p<0.001), the CFCS (Chi-square=12.87, df=2, p=0.002), and the MACS Level (Chi-square=13.96, df=2, p<0.001) but no significant differences emerged for the SES (Chi-square=1.19, df=2, p=0.554). This study shows how the three functional classifications (GMFCS-E&R, CFCS and MACS) complement each other to provide a better description of the functional profile of CP. The systematic evaluation of the IQ can provide useful information about a possible future outcome for every functional level. The SES does not appear to affect functional profiles.

  18. Novel RNA modifications in the nervous system: form and function.

    PubMed

    Satterlee, John S; Basanta-Sanchez, Maria; Blanco, Sandra; Li, Jin Billy; Meyer, Kate; Pollock, Jonathan; Sadri-Vakili, Ghazaleh; Rybak-Wolf, Agnieszka

    2014-11-12

    Modified RNA molecules have recently been shown to regulate nervous system functions. This mini-review and associated mini-symposium provide an overview of the types and known functions of novel modified RNAs in the nervous system, including covalently modified RNAs, edited RNAs, and circular RNAs. We discuss basic molecular mechanisms involving RNA modifications as well as the impact of modified RNAs and their regulation on neuronal processes and disorders, including neural fate specification, intellectual disability, neurodegeneration, dopamine neuron function, and substance use disorders.

  19. Does autophagy work in synaptic plasticity and memory?

    PubMed

    Shehata, Mohammad; Inokuchi, Kaoru

    2014-01-01

    Many studies have reported the roles played by regulated proteolysis in neural plasticity and memory. Within this context, most of the research focused on the ubiquitin-proteasome system and the endosome-lysosome system while giving lesser consideration to another major protein degradation system, namely, autophagy. Although autophagy intersects with many of the pathways known to underlie synaptic plasticity and memory, only few reports related autophagy to synaptic remodeling. These pathways include PI3K-mTOR pathway and endosome-dependent proteolysis. In this review, we will discuss several lines of evidence supporting a physiological role of autophagy in memory processes, and the possible mechanistic scenarios for how autophagy could fulfill this function.

  20. Modular functional organisation of the axial locomotor system in salamanders.

    PubMed

    Cabelguen, Jean-Marie; Charrier, Vanessa; Mathou, Alexia

    2014-02-01

    Most investigations on tetrapod locomotion have been concerned with limb movements. However, there is compelling evidence that the axial musculoskeletal system contributes to important functions during locomotion. Adult salamanders offer a remarkable opportunity to examine these functions because these amphibians use axial undulations to propel themselves in both aquatic and terrestrial environments. In this article, we review the currently available biological data on axial functions during various locomotor modes in salamanders. We also present data showing the modular organisation of the neural networks that generate axial synergies during locomotion. The functional implication of this modular organisation is discussed.

  1. Opioid System Modulates the Immune Function: A Review

    PubMed Central

    Liang, Xuan; Liu, Renyu; Chen, Chunhua; Ji, Fang; Li, Tianzuo

    2016-01-01

    Opioid receptors and their ligands produce powerful analgesia that is effective in perioperative period and chronic pain managements accompanied with various side effects including respiratory depression, constipation and addiction etc. Opioids can also interfere with the immune system, not only participating in the function of the immune cells, but also modulating innate and acquired immune responses. The traditional notion of opioids is immunosuppressive. Recent studies indicate that the role of opioid receptors on immune function is complicated, working through various different mechanisms. Different opioids or opioids administrations show various effects on the immune system: immunosuppressive, immunostimulatory, or dual effect. It is important to elucidate the relationship between opioids and immune function, since immune system plays critical role in various physiological and pathophysiological processes, including the inflammation, tumor growth and metastasis, drug abuse, and so on. This review article tends to have an overview of the recent work and perspectives on opioids and the immune function. PMID:26985446

  2. Opioid System Modulates the Immune Function: A Review.

    PubMed

    Liang, Xuan; Liu, Renyu; Chen, Chunhua; Ji, Fang; Li, Tianzuo

    Opioid receptors and their ligands produce powerful analgesia that is effective in perioperative period and chronic pain managements accompanied with various side effects including respiratory depression, constipation and addiction etc. Opioids can also interfere with the immune system, not only participating in the function of the immune cells, but also modulating innate and acquired immune responses. The traditional notion of opioids is immunosuppressive. Recent studies indicate that the role of opioid receptors on immune function is complicated, working through various different mechanisms. Different opioids or opioids administrations show various effects on the immune system: immunosuppressive, immunostimulatory, or dual effect. It is important to elucidate the relationship between opioids and immune function, since immune system plays critical role in various physiological and pathophysiological processes, including the inflammation, tumor growth and metastasis, drug abuse, and so on. This review article tends to have an overview of the recent work and perspectives on opioids and the immune function.

  3. Multigenic control of thyroid hormone functions in the nervous system

    PubMed Central

    Nunez, Jacques; Celi, Francesco S.; Ng, Lily; Forrest, Douglas

    2008-01-01

    Summary Thyroid hormone (TH) has a remarkable range of actions in the development and function of the nervous system. A multigenic picture is emerging of the mechanisms that specify these diverse functions in target tissues. Distinct responses are mediated by α and β isoforms of TH receptor which act as ligand-regulated transcription factors. Receptor activity can be regulated at several levels including that of uptake of TH ligand and the activation or inactivation of ligand by deiodinase enzymes in target tissues. Processes under the control of TH range from learning and anxiety-like behaviour to sensory function. At the cellular level, TH controls events as diverse as axonal outgrowth, hippocampal synaptic activity and the patterning of opsin photopigments necessary for colour vision. Overall, TH coordinates this variety of events in both central and sensory systems to promote the function of the nervous system as a complete entity. PMID:18448240

  4. The lumbrical muscle: a novel in situ system to evaluate adult skeletal muscle proteolysis and anticatabolic drugs for therapeutic purposes.

    PubMed

    Bergantin, Leandro Bueno; Figueiredo, Leonardo Bruno; Godinho, Rosely Oliveira

    2011-12-01

    The molecular regulation of skeletal muscle proteolysis and the pharmacological screening of anticatabolic drugs have been addressed by measuring tyrosine release from prepubertal rat skeletal muscles, which are thin enough to allow adequate in vitro diffusion of oxygen and substrates. However, the use of muscle at accelerated prepubertal growth has limited the analysis of adult muscle proteolysis or that associated with aging and neurodegenerative diseases. Here we established the adult rat lumbrical muscle (4/hindpaw; 8/rat) as a new in situ experimental model for dynamic measurement of skeletal muscle proteolysis. By incubating lumbrical muscles attached to their individual metatarsal bones in Tyrode solution, we showed that the muscle proteolysis rate of adult and aged rats (3-4 to 24 mo old) is 45-25% of that in prepubertal animals (1 mo old), which makes questionable the usual extrapolation of proteolysis from prepubertal to adult/senile muscles. While acute mechanical injury or 1- to 7-day denervation increased tyrosine release from adult lumbrical muscle by up to 60%, it was reduced by 20-28% after 2-h incubation with β-adrenoceptor agonists, forskolin or phosphodiesterase inhibitor IBMX. Using inhibitors of 26S-proteasome (MG132), lysosome (methylamine), or calpain (E64/leupeptin) systems, we showed that ubiquitin-proteasome is accountable for 40-50% of total lumbrical proteolysis of adult, middle-aged, and aged rats. In conclusion, the lumbrical model allows the analysis of muscle proteolysis rate from prepubertal to senile rats. By permitting eight simultaneous matched measurements per rat, the new model improves similar protocols performed in paired extensor digitorum longus (EDL) muscles from prepubertal rats, optimizing the pharmacological screening of drugs for anticatabolic purposes.

  5. Dialogic Space: Intersections between Dialogic Teaching and Systemic Functional Linguistics

    ERIC Educational Resources Information Center

    Hammond, Jennifer

    2016-01-01

    The aim of this article is to foster dialogue between proponents of Alexander's notion of dialogic teaching and those working with educational linguistics--in particular those working with systemic functional theory. To this end, the article begins by highlighting important points of alignment between dialogic teaching and systemic theory: their…

  6. Materials for programmed, functional transformation in transient electronic systems.

    PubMed

    Hwang, Suk-Won; Kang, Seung-Kyun; Huang, Xian; Brenckle, Mark A; Omenetto, Fiorenzo G; Rogers, John A

    2015-01-07

    Materials and device designs are presented for electronic systems that undergo functional transformation by a controlled time sequence in the dissolution of active materials and/or encapsulation layers. Demonstration examples include various biocompatible, multifunctional systems with autonomous behavior defined by materials selection and layout.

  7. Evolution of wave function in a dissipative system

    NASA Technical Reports Server (NTRS)

    Yu, Li-Hua; Sun, Chang-Pu

    1994-01-01

    For a dissipative system with Ohmic friction, we obtain a simple and exact solution for the wave function of the system plus the bath. It is described by the direct product in two independent Hilbert space. One of them is described by an effective Hamiltonian, the other represents the effect of the bath, i.e., the Brownian motion, thus clarifying the structure of the wave function of the system whose energy is dissipated by its interaction with the bath. No path integral technology is needed in this treatment. The derivation of the Weisskopf-Wigner line width theory follows easily.

  8. Hormone signaling through protein destruction: a lesson from plants.

    PubMed

    Tan, Xu; Zheng, Ning

    2009-02-01

    Ubiquitin-dependent protein degradation has emerged as a major pathway regulating eukaryotic biology. By employing a variety of ubiquitin ligases to target specific cellular proteins, the ubiquitin-proteasome system controls physiological processes in a highly regulated fashion. Recent studies on a plant hormone auxin have unveiled a novel paradigm of signal transduction in which ubiquitin ligases function as hormone receptors. Perceived by the F-box protein subunit of the SCF(TIR1) ubiquitin ligase, auxin directly promotes the recruitment of a family of transcriptional repressors for ubiquitination, thereby activating extensive transcriptional programs. Structural studies have revealed that auxin functions through a "molecular glue" mechanism to enhance protein-protein interactions with the assistance of another small molecule cofactor, inositol hexakisphosphate. Given the extensive repertoire of similar ubiquitin ligases in eukaryotic cells, this novel and widely adopted hormone-signaling mechanism in plants may also exist in other organisms.

  9. Targeting p97 to Disrupt Protein Homeostasis in Cancer

    PubMed Central

    Vekaria, Pratikkumar Harsukhbhai; Home, Trisha; Weir, Scott; Schoenen, Frank J.; Rao, Rekha

    2016-01-01

    Cancer cells are addicted to numerous non-oncogenic traits that enable them to thrive. Proteotoxic stress is one such non-oncogenic trait that is experienced by all tumor cells owing to increased genomic abnormalities and the resulting synthesis and accumulation of non-stoichiometric amounts of cellular proteins. This imbalance in the amounts of proteins ultimately culminates in proteotoxic stress. p97, or valosin-containing protein (VCP), is an ATPase whose function is essential to restore protein homeostasis in the cells. Working in concert with the ubiquitin proteasome system, p97 promotes the retrotranslocation from cellular organelles and/or degradation of misfolded proteins. Consequently, p97 inhibition has emerged as a novel therapeutic target in cancer cells, especially those that have a highly secretory phenotype. This review summarizes our current understanding of the function of p97 in maintaining protein homeostasis and its inhibition with small molecule inhibitors as an emerging strategy to target cancer cells. PMID:27536557

  10. Regulation of Posttranscriptional Modification as a Possible Therapeutic Approach for Retinal Neuroprotection

    PubMed Central

    Ozawa, Yoko; Kurihara, Toshihide; Tsubota, Kazuo; Okano, Hideyuki

    2011-01-01

    Understanding pathogenesis at the molecular level is the first step toward developing new therapeutic approaches. Here, we review the molecular mechanisms of visual dysfunction in two common diseases, innate chorioretinal inflammation and diabetic retinopathy, and the role of the ubiquitin-proteasome system (UPS) in both processes. In innate chorioretinal inflammation, interleukin-6 family ligands induce STAT3 activation in photoreceptors, which causes UPS-mediated excessive degradation of the visual substance, rhodopsin. In diabetic retinopathy, angiotensin II type 1 receptor (AT1R) signaling activates ERK in the inner layers of the retina, causing UPS-mediated excessive degradation of the synaptic vesicle protein, synaptophysin. This latter effect may decrease synaptic activity, in turn adversely affecting neuronal survival. Both mechanisms involve increased UPS activity and the subsequent excessive degradation of a protein required for visual function. Finally, we review the therapeutic potential of regulating the UPS to protect tissue function, citing examples from clinical applications in other medical fields. PMID:21076532

  11. A Spectral Lyapunov Function for Exponentially Stable LTV Systems

    NASA Technical Reports Server (NTRS)

    Zhu, J. Jim; Liu, Yong; Hang, Rui

    2010-01-01

    This paper presents the formulation of a Lyapunov function for an exponentially stable linear timevarying (LTV) system using a well-defined PD-spectrum and the associated PD-eigenvectors. It provides a bridge between the first and second methods of Lyapunov for stability assessment, and will find significant applications in the analysis and control law design for LTV systems and linearizable nonlinear time-varying systems.

  12. Speech recognition in dental software systems: features and functionality.

    PubMed

    Yuhaniak Irwin, Jeannie; Fernando, Shawn; Schleyer, Titus; Spallek, Heiko

    2007-01-01

    Speech recognition allows clinicians a hands-free option for interacting with computers, which is important for dentists who have difficulty using a keyboard and a mouse when working with patients. While roughly 13% of all general dentists with computers at chairside use speech recognition for data entry, 16% have tried and discontinued using this technology. In this study, researches explored the speech recognition features and functionality of four dental software applications. For each system, the documentation as well as the working program was evaluated to determine speech recognition capabilities. A comparison checklist was created to highlight each program's speech functionality. Next, after the development of charting scripts, feasibility user tests were conducted to determine if performance comparisons could be made across systems. While four systems were evaluated in the feature comparison, only two of the systems were reviewed during the feasibility user tests. Results show that current speech functionality, instead of being intuitive, is directly comparable to using a mouse. Further, systems require memorizing an enormous amount of specific terminology opposed to using natural language. User testing is a feasible way to measure the performance of speech recognition across systems and will be conducted in the near future. Overall, limited speech functionality reduces the ability of clinicians to interact directly with the computer during clinical care. This can hinder the benefits of electronic patient records and clinical decision support systems.

  13. The function of the earth observing system - Data information system Distributed Active Archive Centers

    NASA Technical Reports Server (NTRS)

    Lapenta, C. C.

    1992-01-01

    The functionality of the Distributed Active Archive Centers (DAACs) which are significant elements of the Earth Observing System Data and Information System (EOSDIS) is discussed. Each DAAC encompasses the information management system, the data archival and distribution system, and the product generation system. The EOSDIS DAACs are expected to improve the access to earth science data set needed for global change research.

  14. Customizing Laboratory Information Systems: Closing the Functionality Gap.

    PubMed

    Gershkovich, Peter; Sinard, John H

    2015-09-01

    Highly customizable laboratory information systems help to address great variations in laboratory workflows, typical in Pathology. Often, however, built-in customization tools are not sufficient to add all of the desired functionality and improve systems interoperability. Emerging technologies and advances in medicine often create a void in functionality that we call a functionality gap. These gaps have distinct characteristics—a persuasive need to change the way a pathology group operates, the general availability of technology to address the missing functionality, the absence of this technology from your laboratory information system, and inability of built-in customization tools to address it. We emphasize the pervasive nature of these gaps, the role of pathology informatics in closing them, and suggest methods on how to achieve that. We found that a large number of the papers in the Journal of Pathology Informatics are concerned with these functionality gaps, and an even larger proportion of electronic posters and abstracts presented at the Pathology Informatics Summit conference each year deal directly with these unmet needs in pathology practice. A rapid, continuous, and sustainable approach to closing these gaps is critical for Pathology to provide the highest quality of care, adopt new technologies, and meet regulatory and financial challenges. The key element of successfully addressing functionality gaps is gap ownership—the ability to control the entire pathology information infrastructure with access to complementary systems and components. In addition, software developers with detailed domain expertise, equipped with right tools and methodology can effectively address these needs as they emerge.

  15. Systemic inflammation and lung function: A longitudinal analysis

    PubMed Central

    Hancox, Robert J.; Gray, Andrew R.; Sears, Malcolm R.; Poulton, Richie

    2016-01-01

    Background Systemic inflammation is associated with impaired lung function in healthy adults as well as in patients with lung disease. The mechanism for this association is unknown and it is unclear if systemic inflammation leads to impaired lung function or if poor lung function leads to inflammation. We explored the temporal associations between blood C-reactive protein (CRP), fibrinogen, and white blood cells, and lung function in young adults. Methods Spirometry, plethysmography, and diffusion capacity were measured in a population-based cohort at ages 32 and 38 years. High-sensitivity CRP, fibrinogen, and white blood cells were measured at the same ages. Results Higher levels of CRP and, to a lesser extent, fibrinogen were associated with lower lung volumes in cross-sectional analyses at both ages 32 and 38 years. Higher CRP and fibrinogen at age 32 were associated with higher FEV1 and FEV1/FVC at age 38, but not other measures of lung function. Lower lung volumes (total lung capacity, functional residual capacity, and residual volume) but not airflow obstruction (FEV1/FVC) at age 32 were associated with higher CRP at age 38. Associations between age 32 lung function and fibrinogen at follow-up were weaker, but consistent. There were no longitudinal associations between white blood cells and lung function. Conclusions We found no evidence that systemic inflammation causes a decline in lung function. However, lower lung volumes were associated with higher CRP and fibrinogen at follow-up indicating that pulmonary restriction may be a risk factor for systemic inflammation. The mechanism for this association remains unclear. PMID:26733230

  16. Ubiquitination of newly synthesized proteins at the ribosome.

    PubMed

    Wang, Feng; Canadeo, Larissa A; Huibregtse, Jon M

    2015-07-01

    Newly synthesized proteins can be misfolded or damaged because of errors during synthesis or environmental insults (e.g., heat shock), placing a significant burden on protein quality control systems. In addition, numerous human diseases are associated with a deficiency in eliminating aberrant proteins or accumulation of aggregated proteins. Understanding the mechanisms of protein quality control and disposal pathways for misfolded proteins is therefore crucial for therapeutic intervention in these diseases. Quality control processes function at many points in the life cycle of proteins, and a subset act at the actual site of protein synthesis, the ribosome. Here we summarize recent advances in the role of the ubiquitin proteasome system in protein quality control during the process of translation.

  17. Ubiquitination of Newly Synthesized Proteins at the Ribosome

    PubMed Central

    Wang, Feng; Canadeo, Larissa A.; Huibregtse, Jon M.

    2015-01-01

    Newly synthesized proteins can be misfolded or damaged because of errors during synthesis or environmental insults (e.g., heat shock), placing a significant burden on protein quality control systems. In addition, numerous human diseases are associated with a deficiency in eliminating aberrant proteins or accumulation of aggregated proteins. Understanding the mechanisms of protein quality control and disposal pathways for misfolded proteins is therefore crucial for therapeutic intervention in these diseases. Quality control processes function at many points in the life cycle of proteins, and a subset act at the actual site of protein synthesis, the ribosome. Here we summarize recent advances in the role of the ubiquitin proteasome system in protein quality control during the process of translation. PMID:25701549

  18. ROS and ROS-Mediated Cellular Signaling

    PubMed Central

    Zhang, Jixiang; Wang, Xiaoli; Vikash, Vikash; Ye, Qing; Wu, Dandan; Liu, Yulan; Dong, Weiguo

    2016-01-01

    It has long been recognized that an increase of reactive oxygen species (ROS) can modify the cell-signaling proteins and have functional consequences, which successively mediate pathological processes such as atherosclerosis, diabetes, unchecked growth, neurodegeneration, inflammation, and aging. While numerous articles have demonstrated the impacts of ROS on various signaling pathways and clarify the mechanism of action of cell-signaling proteins, their influence on the level of intracellular ROS, and their complex interactions among multiple ROS associated signaling pathways, the systemic summary is necessary. In this review paper, we particularly focus on the pattern of the generation and homeostasis of intracellular ROS, the mechanisms and targets of ROS impacting on cell-signaling proteins (NF-κB, MAPKs, Keap1-Nrf2-ARE, and PI3K-Akt), ion channels and transporters (Ca2+ and mPTP), and modifying protein kinase and Ubiquitination/Proteasome System. PMID:26998193

  19. Systematic approaches to identify E3 ligase substrates

    PubMed Central

    Iconomou, Mary; Saunders, Darren N.

    2016-01-01

    Protein ubiquitylation is a widespread post-translational modification, regulating cellular signalling with many outcomes, such as protein degradation, endocytosis, cell cycle progression, DNA repair and transcription. E3 ligases are a critical component of the ubiquitin proteasome system (UPS), determining the substrate specificity of the cascade by the covalent attachment of ubiquitin to substrate proteins. Currently, there are over 600 putative E3 ligases, but many are poorly characterized, particularly with respect to individual protein substrates. Here, we highlight systematic approaches to identify and validate UPS targets and discuss how they are underpinning rapid advances in our understanding of the biochemistry and biology of the UPS. The integration of novel tools, model systems and methods for target identification is driving significant interest in drug development, targeting various aspects of UPS function and advancing the understanding of a diverse range of disease processes. PMID:27834739

  20. Ubiquitin C-terminal hydrolase L1 deficiency decreases bone mineralization.

    PubMed

    Shim, Sehwan; Kwon, Young-Bae; Yoshikawa, Yasuhiro; Kwon, Jungkee

    2008-06-01

    Ubiquitin C-terminal hydrolase L1 is a component of the ubiquitin proteasome system, which evidences unique biological activities. In this study, we report the pattern of UCH-L1 expression, and show that it regulates bone mineralization in osteogenesis. UCH-L1 was expressed in osteoblasts, osteoclasts, and hematopoietic precursor cells of bone marrow in the metaphysis and diaphysis of the femora. To further assess the involvement of UCH-L1 in the regulation of bone mineralization, we evaluated the bone mineral density (BMD) rate of gad mice, using the Latheta computed tomography system. Male gad mice evidenced a significantly decreased BMD rate in the metaphysis and diaphysis of the femora. These findings of decreased BMD rate in the bones of gad mice may suggest that UCH-L1 function regulates bone mineralization during osteogenesis.

  1. On the role of general system theory for functional neuroimaging

    PubMed Central

    Stephan, Klaas Enno

    2004-01-01

    One of the most important goals of neuroscience is to establish precise structure–function relationships in the brain. Since the 19th century, a major scientific endeavour has been to associate structurally distinct cortical regions with specific cognitive functions. This was traditionally accomplished by correlating microstructurally defined areas with lesion sites found in patients with specific neuropsychological symptoms. Modern neuroimaging techniques with high spatial resolution have promised an alternative approach, enabling non-invasive measurements of regionally specific changes of brain activity that are correlated with certain components of a cognitive process. Reviewing classic approaches towards brain structure–function relationships that are based on correlational approaches, this article argues that these approaches are not sufficient to provide an understanding of the operational principles of a dynamic system such as the brain but must be complemented by models based on general system theory. These models reflect the connectional structure of the system under investigation and emphasize context-dependent couplings between the system elements in terms of effective connectivity. The usefulness of system models whose parameters are fitted to measured functional imaging data for testing hypotheses about structure–function relationships in the brain and their potential for clinical applications is demonstrated by several empirical examples. PMID:15610393

  2. The small light multi-function integrated remote sensing system

    NASA Astrophysics Data System (ADS)

    Zhang, Weiwei; Lin, Zhaorong; Yao, Yigang

    2015-08-01

    With the development of network information, the era of big data is coming, and this has high demand to the information quantity and the diversity of the remote sensing images. Currently the available remote sensing system focuses on the convenience and the celerity of the acquiring images, and lacking the remote sensing system which can acquire the image with the diversity and large amount of information. In this paper, a new small light multifunction integrated remote sensing and the remote sensing information network system of multi-sensor are proposed to meet the new developing requirements of the current network information. The small light multi-function integrated remote sensing system consists of a load platform, the integrated sensor system, the airborne control system, the stabilized platform, the transmission system and the ground processing system. The components, function and the principle of the system are introduced, and the key technologies of the integrated remote sensing system are analyzed, in the last the applications of the system are described in order to make a contribution to the industrialization of the big data remote sensing.

  3. [Human vital function monitoring as a system with hybrid intelligence].

    PubMed

    Popov, Iu B

    2005-01-01

    Monitoring system is considered in this work as a reanimatologist-monitor-patient-medium system. This work is an upgrade to the previous concept of monitoring systems as systems with hybrid intelligence acting under variable conditions of object and medium. Human cardiorespiratory system was considered within the framework of the P. K. Anokhin theory of functional systems. The problem of resuscitation was formulated for this system and volume of required information was determined. Environment characteristics in resuscitation and surgery departments were considered. The requirements for monitor were formulated on the basis of analysis of these systems. The law of mutual adaptation of reanimatologist and monitor was put forward and safety problems associated with human factor were considered. Implementation of these principles in the MITAR 01-R-D is described.

  4. Nonanalyticities of entropy functions of finite and infinite systems.

    PubMed

    Casetti, Lapo; Kastner, Michael

    2006-09-08

    In contrast to the canonical ensemble where thermodynamic functions are smooth for all finite system sizes, the microcanonical entropy can show nonanalytic points also for finite systems. The relation between finite and infinite system nonanalyticities is illustrated by means of a simple classical spinlike model which is exactly solvable for both finite and infinite system sizes, showing a phase transition in the latter case. The microcanonical entropy is found to have exactly one nonanalytic point in the interior of its domain. For all finite system sizes, this point is located at the same fixed energy value epsilon(c)(finite), jumping discontinuously to a different value epsilon(c)(infinite) in the thermodynamic limit. Remarkably, epsilon(c)(finite) equals the average potential energy of the infinite system at the phase transition point. The result indicates that care is required when trying to infer infinite system properties from finite system nonanalyticities.

  5. Next Generation Nuclear Plant Resilient Control System Functional Analysis

    SciTech Connect

    Lynne M. Stevens

    2010-07-01

    Control Systems and their associated instrumentation must meet reliability, availability, maintainability, and resiliency criteria in order for high temperature gas-cooled reactors (HTGRs) to be economically competitive. Research, perhaps requiring several years, may be needed to develop control systems to support plant availability and resiliency. This report functionally analyzes the gaps between traditional and resilient control systems as applicable to HTGRs, which includes the Next Generation Nuclear Plant; defines resilient controls; assesses the current state of both traditional and resilient control systems; and documents the functional gaps existing between these two controls approaches as applicable to HTGRs. This report supports the development of an overall strategy for applying resilient controls to HTGRs by showing that control systems with adequate levels of resilience perform at higher levels, respond more quickly to disturbances, increase operational efficiency, and increase public protection.

  6. An automated system for assessing cognitive function in any environment

    NASA Astrophysics Data System (ADS)

    Wesnes, Keith A.

    2005-05-01

    The Cognitive Drug Research (CDR) computerized assessment system has been in use in worldwide clinical trials for over 20 years. It is a computer based system which assesses core aspects of human cognitive function including attention, information, working memory and long-term memory. It has been extensively validated and can be performed by a wide range of clinical populations including patients with various types of dementia. It is currently in worldwide use in clinical trials to evaluate new medicines, as well as a variety of programs involving the effects of age, stressors illnesses and trauma upon human cognitive function. Besides being highly sensitive to drugs which will impair or improve function, its utility has been maintained over the last two decades by constantly increasing the number of platforms upon which it can operate. Besides notebook versions, the system can be used on a wrist worn device, PDA, via tht telephone and over the internet. It is the most widely used automated cognitive function assessment system in worldwide clinical research. It has dozens of parallel forms and requires little training to use or administer. The basic development of the system wil be identified, and the huge databases (normative, patient population, drug effects) which have been built up from hundreds of clinical trials will be described. The system is available for use in virtually any environment or type of trial.

  7. Dynamic Correlation Functions of Adsorption Stochastic Systems with Diffusional Relaxation

    NASA Astrophysics Data System (ADS)

    Grynberg, Marcelo D.; Stinchcombe, Robin B.

    1995-02-01

    We investigate the nonequilibrium behavior of dynamic correlation functions of random sequential adsorption processes with diffusional relaxation. Depending on the relative values of the transition probability rates, in one dimension these systems reduce to a soluble problem of many fermions. In contrast to the standard diffusive relaxation of the macroscopic density, the correlation functions exhibit a faster decay. Our results are supported and compared with Monte Carlo simulations.

  8. Evaluation of computing systems using functionals of a Stochastic process

    NASA Technical Reports Server (NTRS)

    Meyer, J. F.; Wu, L. T.

    1980-01-01

    An intermediate model was used to represent the probabilistic nature of a total system at a level which is higher than the base model and thus closer to the performance variable. A class of intermediate models, which are generally referred to as functionals of a Markov process, were considered. A closed form solution of performability for the case where performance is identified with the minimum value of a functional was developed.

  9. Modeling Functional Motions of Biological Systems by Customized Natural Moves.

    PubMed

    Demharter, Samuel; Knapp, Bernhard; Deane, Charlotte M; Minary, Peter

    2016-08-23

    Simulating the functional motions of biomolecular systems requires large computational resources. We introduce a computationally inexpensive protocol for the systematic testing of hypotheses regarding the dynamic behavior of proteins and nucleic acids. The protocol is based on natural move Monte Carlo, a highly efficient conformational sampling method with built-in customization capabilities that allows researchers to design and perform a large number of simulations to investigate functional motions in biological systems. We demonstrate the use of this protocol on both a protein and a DNA case study. Firstly, we investigate the plasticity of a class II major histocompatibility complex in the absence of a bound peptide. Secondly, we study the effects of the epigenetic mark 5-hydroxymethyl on cytosine on the structure of the Dickerson-Drew dodecamer. We show how our customized natural moves protocol can be used to investigate causal relationships of functional motions in biological systems.

  10. Nondivergent classical response functions from uncertainty principle: quasiperiodic systems.

    PubMed

    Kryvohuz, Maksym; Cao, Jianshu

    2005-01-08

    Time-divergence in linear and nonlinear classical response functions can be removed by taking a phase-space average within the quantized uncertainty volume O(hn) around the microcanonical energy surface. For a quasiperiodic system, the replacement of the microcanonical distribution density in the classical response function with the quantized uniform distribution density results in agreement of quantum and classical expressions through Heisenberg's correspondence principle: each matrix element (u/alpha(t)/v) corresponds to the (u-v)th Fourier component of alpha(t) evaluated along the classical trajectory with mean action (Ju+Jv)/2. Numerical calculations for one- and two-dimensional systems show good agreement between quantum and classical results. The generalization to the case of N degrees of freedom is made. Thus, phase-space averaging within the quantized uncertainty volume provides a useful way to establish the classical-quantum correspondence for the linear and nonlinear response functions of a quasiperiodic system.

  11. Pharmacological strategies in lung cancer-induced cachexia: effects on muscle proteolysis, autophagy, structure, and weakness.

    PubMed

    Chacon-Cabrera, Alba; Fermoselle, Clara; Urtreger, Alejandro J; Mateu-Jimenez, Mercè; Diament, Miriam J; de Kier Joffé, Elisa D Bal; Sandri, Marco; Barreiro, Esther

    2014-11-01

    Cachexia is a relevant comorbid condition of chronic diseases including cancer. Inflammation, oxidative stress, autophagy, ubiquitin-proteasome system, nuclear factor (NF)-κB, and mitogen-activated protein kinases (MAPK) are involved in the pathophysiology of cancer cachexia. Currently available treatment is limited and data demonstrating effectiveness in in vivo models are lacking. Our objectives were to explore in respiratory and limb muscles of lung cancer (LC) cachectic mice whether proteasome, NF-κB, and MAPK inhibitors improve muscle mass and function loss through several molecular mechanisms. Body and muscle weights, limb muscle force, protein degradation and the ubiquitin-proteasome system, signaling pathways, oxidative stress and inflammation, autophagy, contractile and functional proteins, myostatin and myogenin, and muscle structure were evaluated in the diaphragm and gastrocnemius of LC (LP07 adenocarcinoma) bearing cachectic mice (BALB/c), with and without concomitant treatment with NF-κB (sulfasalazine), MAPK (U0126), and proteasome (bortezomib) inhibitors. Compared to control animals, in both respiratory and limb muscles of LC cachectic mice: muscle proteolysis, ubiquitinated proteins, autophagy, myostatin, protein oxidation, FoxO-1, NF-κB and MAPK signaling pathways, and muscle abnormalities were increased, while myosin, creatine kinase, myogenin, and slow- and fast-twitch muscle fiber size were decreased. Pharmacological inhibition of NF-κB and MAPK, but not the proteasome system, induced in cancer cachectic animals, a substantial restoration of muscle mass and force through a decrease in muscle protein oxidation and catabolism, myostatin, and autophagy, together with a greater content of myogenin, and contractile and functional proteins. Attenuation of MAPK and NF-κB signaling pathway effects on muscles is beneficial in cancer-induced cachexia.

  12. Free energy functional for nonequilibrium systems: an exactly solvable case.

    PubMed

    Derrida, B; Lebowitz, J L; Speer, E R

    2001-10-08

    We consider the steady state of an open system in which there is a flux of matter between two reservoirs at different chemical potentials. For a large system of size N, the probability of any macroscopic density profile rho(x) is exp[-NF([rho])]; F thus generalizes to nonequilibrium systems the notion of free energy density for equilibrium systems. Our exact expression for F is a nonlocal functional of rho, which yields the macroscopically long range correlations in the nonequilibrium steady state previously predicted by fluctuating hydrodynamics and observed experimentally.

  13. Free Energy Functional for Nonequilibrium Systems: An Exactly Solvable Case

    NASA Astrophysics Data System (ADS)

    Derrida, B.; Lebowitz, J. L.; Speer, E. R.

    2001-10-01

    We consider the steady state of an open system in which there is a flux of matter between two reservoirs at different chemical potentials. For a large system of size N, the probability of any macroscopic density profile ρ(x) is exp[-NF(\\{ρ\\})] F thus generalizes to nonequilibrium systems the notion of free energy density for equilibrium systems. Our exact expression for F is a nonlocal functional of ρ, which yields the macroscopically long range correlations in the nonequilibrium steady state previously predicted by fluctuating hydrodynamics and observed experimentally.

  14. Functional self-assembled lipidic systems derived from renewable resources.

    PubMed

    Silverman, Julian R; Samateh, Malick; John, George

    2016-01-01

    Self-assembled lipidic amphiphile systems can create a variety of multi-functional soft materials with value-added properties. When employing natural reagents and following biocatalytic syntheses, self-assembling monomers may be inherently designed for degradation, making them potential alternatives to conventional and persistent polymers. By using non-covalent forces, self-assembled amphiphiles can form nanotubes, fibers, and other stimuli responsive architectures prime for further applied research and incorporation into commercial products. By viewing these lipid derivatives under a lens of green principles, there is the hope that in developing a structure-function relationship and functional smart materials that research may remain safe, economic, and efficient.

  15. Functional asymmetry of posture and body system regulation

    NASA Technical Reports Server (NTRS)

    Boloban, V. N.; Otsupok, A. P.

    1980-01-01

    The manifestation of functional asymmetry during the regulation of an athlete's posture and a system of bodies and its effect on the execution of individual and group acrobatic exercises were studied. Functional asymmetry of posture regulation was recorded in acrobats during the execution of individual and group exercises. It was shown that stability is maintained at the expense of bending and twisting motions. It is important to consider whether the functional asymmetry of posture regulation is left or right sided in making up pairs and groups of acrobats.

  16. SPECTRAL FUNCTIONS OF A CANONICAL SYSTEM OF ORDER 2n

    NASA Astrophysics Data System (ADS)

    Sakhnovich, A. L.

    1992-02-01

    The author describes a set of pseudospectral functions of the canonical system of differential equations \\displaystyle dW(x,\\,\\lambda)/dx = i\\lambda JH(x)W(x,\\lambda),\\qquad W(0,\\,\\lambda) = E_{2n},where \\displaystyle 0\\leq x\\leq l<\\infty,\\qquad H(x)=H^*(x)\\geq0,\\qquad J=\\begin{bmatrix}0 & E_n\\\\E_n & 0\\end{bmatrix}.In terms of the Hamiltonians H(x), conditions are given under which the pseudospectral functions are spectral functions.

  17. Diagonal dominance using function minimization algorithms. [multivariable control system design

    NASA Technical Reports Server (NTRS)

    Leininger, G. G.

    1977-01-01

    A new approach to the design of multivariable control systems using the inverse Nyquist array method is proposed. The technique utilizes a conjugate direction function minimization algorithm to achieve dominance over a specified frequency range by minimizing the ratio of the moduli of the off-diagonal terms to the moduli of the diagonal term of the inverse open loop transfer function matrix. The technique is easily implemented in either a batch or interactive computer mode and will yield diagonalization when previously suggested methods fail. The proposed method has been successfully applied to design a control system for a sixteenth order state model of the F-100 turbofan engine with three inputs.

  18. Representation Issues in Systemic Functional Grammar and Systemic Grammar and Functional Unification Grammar.

    DTIC Science & Technology

    1987-05-01

    can be represented in FUG notation, as a step toward creating a grammatical analysis program for English . Because FUG has been developed as a... English for text generation started at the Information Sciences Institute of the University of Southern California. It is called the Nigel grammar and...Fawcett is developing a computational systemic grammar of English , implementing his contributions to systemic grammar (cf. Fawcett (1980)). The present

  19. Characterization of the system functions of ultrasonic linear phased array inspection systems.

    PubMed

    Huang, Ruiju; Schmerr, Lester W

    2009-02-01

    This work characterizes the electrical and electromechanical aspects of an ultrasonic linear phased array inspection system, using a matrix of system functions that are obtained from the measured response of individual array elements in a simple reference experiment. It is shown that for the arrays tested all these system functions are essentially identical, allowing one to use a single system function to characterize the entire array, as done for an ordinary single element transducer. The variation of this single system function with the number of elements firing in the array or with changes of the delay law used is examined. It is also demonstrated that once such a single system function is obtained for an array, it can be used in a complete ultrasonic measurement model to accurately predict the array response measured from a reference reflector in an immersion setup.

  20. Digital controller design for absolute value function constrained nonlinear systems via scalar sign function approach.

    PubMed

    Wu, Jian; Singla, Mithun; Olmi, Claudio; Shieh, Leang S; Song, Gangbing

    2010-07-01

    In this paper, a scalar sign function-based digital design methodology is developed for modeling and control of a class of analog nonlinear systems that are restricted by the absolute value function constraints. As is found to be not uncommon, many real systems are subject to the constraints which are described by the non-smooth functions such as absolute value function. The non-smooth and nonlinear nature poses significant challenges to the modeling and control work. To overcome these difficulties, a novel idea proposed in this work is to use a scalar sign function approach to effectively transform the original nonlinear and non-smooth model into a smooth nonlinear rational function model. Upon the resulting smooth model, a systematic digital controller design procedure is established, in which an optimal linearization method, LQR design and digital implementation through an advanced digital redesign technique are sequentially applied. The example of tracking control of a piezoelectric actuator system is utilized throughout the paper for illustrating the proposed methodology.

  1. In-vehicle signing functions and systems concepts

    SciTech Connect

    Tufano, D.R.; Spelt, P.F.; Knee, H.E.

    1996-03-01

    This paper describes functional requirements and system concepts for an In-Vehicle Signing (IVS) system, which will bring information from roadway signs, signals, and pavement markings into the vehicle for presentation to the driver. Information filter functions will assure that the only messages displayed are those which are important to the driver and which apply. Display functions will optimize the presentation of the message to ambient conditions, driver preferences, the number of simultaneous messages, and the urgency of the message. Timing functions will display a sign as soon as it is needed, for the entire time that it applies, and only while it applies. IVS is one of the core components of an integrated In-Vehicle Information System, which will manage and fuse all driving-related information. Two different IVS system concepts have been investigated: one based on a map database, the other on beacon technology. This work is being conducted by the Oak Ridge National Laboratory for the US Federal Highway Administration as part of the Intelligent Transportation System Program.

  2. Functional Description for the Integrated Booking System (IBS)

    SciTech Connect

    Truett, L.F.; Wheeler, V.V.; Yow, T.G.; Stamm, S.E.; Valentine, D.E.

    1991-07-01

    The Military Traffic Management Command Directorate of International Traffic (MTIT) tasked the Oak Ridge National Laboratory to analyze the requirements for an Integrated Booking System (IBS), to design and build a prototype of the system, and to provide documentation that would be used in building the target system. This Functional Description (FD) follows the guidelines of DOD-STD-7935-A, Military Standard: DOD Automated Information Systems (AIS) Documentation Standards. It describes the current methodologies for accomplishing the booking mission and defines the functional requirements for IBS. The report also discusses general architectural requirements and issues such as security, data exchanges, and system impacts. The ultimate goal of IBS is to provide international cargo booking for both unit and nonunit movements during peacetime and wartime. This FD provides booking requirements for the continental United States only. The results of the analysis of requirements are that IBS is a feasible system for accomplishing MTIT's cargo management goals. IBS will replace aging systems and integrate automated and manual procedures. It will provide a single automated system during wartime for viewing both unit and nonunit international cargo requests. Good human-computer interface design will be incorporated into the system during its development. Because of IBS querying capabilities, visibility of the booking process by MTIT will be enhanced. 2 figs., 2 tabs.

  3. Posttranslational modification and quality control.

    PubMed

    Wang, Xuejun; Pattison, J Scott; Su, Huabo

    2013-01-18

    Protein quality control functions to minimize the level and toxicity of misfolded proteins in the cell. Protein quality control is performed by intricate collaboration among chaperones and target protein degradation. The latter is performed primarily by the ubiquitin-proteasome system and perhaps autophagy. Terminally misfolded proteins that are not timely removed tend to form aggregates. Their clearance requires macroautophagy. Macroautophagy serves in intracellular quality control also by selectively segregating defective organelles (eg, mitochondria) and targeting them for degradation by the lysosome. Inadequate protein quality control is observed in a large subset of failing human hearts with a variety of causes, and its pathogenic role has been experimentally demonstrated. Multiple posttranslational modifications can occur to substrate proteins and protein quality control machineries, promoting or hindering the removal of the misfolded proteins. This article highlights recent advances in posttranslational modification-mediated regulation of intracellular quality control mechanisms and its known involvement in cardiac pathology.

  4. Role of Ubiquitin Ligases and the Proteasome in Oncogenesis: Novel Targets for Anticancer Therapies

    PubMed Central

    Micel, Lindsey N.; Tentler, John J.; Smith, Peter G.; Eckhardt, Gail S.

    2013-01-01

    The ubiquitin proteasome system (UPS) regulates the ubiquitination, and thus degradation and turnover, of many proteins vital to cellular regulation and function. The UPS comprises a sequential series of enzymatic processes using four key enzyme families: E1 (ubiquitin-activating enzymes), E2 (ubiquitin-carrier proteins), E3 (ubiquitin-protein ligases), and E4 (ubiquitin chain assembly factors). Because the UPS is a crucial regulator of the cell cycle, and abnormal cell-cycle control can lead to oncogenesis, aberrancies within the UPS pathway can result in a malignant cellular phenotype and thus has become an attractive target for novel anticancer agents. This article will provide an overall review of the mechanics of the UPS, describe aberrancies leading to cancer, and give an overview of current drug therapies selectively targeting the UPS. PMID:23358974

  5. Post-Translational Regulation of miRNA Pathway Components, AGO1 and HYL1, in Plants

    PubMed Central

    Cho, Seok Keun; Ryu, Moon Young; Shah, Pratik; Poulsen, Christian Peter; Yang, Seong Wook

    2016-01-01

    Post-translational modifications (PTMs) of proteins are essential to increase the functional diversity of the proteome. By adding chemical groups to proteins, or degrading entire proteins by phosphorylation, glycosylation, ubiquitination, neddylation, acetylation, lipidation, and proteolysis, the complexity of the proteome increases, and this then influences most biological processes. Although small RNAs are crucial regulatory elements for gene expression in most eukaryotes, PTMs of small RNA microprocessor and RNA silencing components have not been extensively investigated in plants. To date, several studies have shown that the proteolytic regulation of AGOs is important for host-pathogen interactions. DRB4 is regulated by the ubiquitin-proteasome system, and the degradation of HYL1 is modulated by a de-etiolation repressor, COP1, and an unknown cytoplasmic protease. Here, we discuss current findings on the PTMs of microprocessor and RNA silencing components in plants. PMID:27440184

  6. Expression of expanded polyglutamine targets profilin for degradation and alters actin dynamics

    PubMed Central

    Burnett, Barrington G.; Andrews, Jaime; Ranganathan, Srikanth; Fischbeck, Kenneth H.; Di Prospero, Nicholas A.

    2008-01-01

    Huntington’s disease is caused by polyglutamine expansion in the huntingtin protein. Huntingtin directly interacts with profilin, a major actin monomer sequestering protein and a key integrator of signals leading to actin polymerization. We observed a progressive loss of profilin in the cerebral cortex of Huntington’s disease patients, and in cell culture and Drosophila models of polyglutamine disease. This loss of profilin is likely due to increased degradation through the ubiquitin-proteasome system. Profilin loss reduces the F/G actin ratio, indicating a shift in actin polymerization. Overexpression of profilin abolishes mutant huntingtin toxicity in cells and partially ameliorates the morphological and functional eye phenotype and extends lifespan in a transgenic polyglutamine Drosophila model. These results indicate a link between huntingtin and profilin and implicate profilin in Huntington’s disease pathogenesis. PMID:18417352

  7. Delineating role of ubiquitination on nuclear factor-kappa B pathway by a computational modeling approach

    SciTech Connect

    Lee, Jungsul; Choi, Kyungsun; Choi, Chulhee

    2010-01-01

    Mutant ubiquitin found in neurodegenerative diseases has been thought to hamper activation of transcription factor nuclear factor-kappa B (NF-{kappa}B) by inhibiting ubiquitin-proteasome system (UPS). It has been reported that ubiquitin also is involved in signal transduction in an UPS-independent manner. We used a modeling and simulation approach to delineate the roles of ubiquitin on NF-{kappa}B activation. Inhibition of proteasome complex increased maximal activation of IKK mainly by decreasing the UPS efficiency. On the contrary, mutant ubiquitin decreased maximal activity of IKK. Computational modeling showed that the inhibition effect of mutant ubiquitin is mainly attributed to decreased activity of UPS-independent function of ubiquitin. Collectively, our results suggest that mutant ubiquitin affects NF-{kappa}B activation in an UPS-independent manner.

  8. Cycle inhibiting factors (cifs): cyclomodulins that usurp the ubiquitin-dependent degradation pathway of host cells.

    PubMed

    Taieb, Frédéric; Nougayrède, Jean-Philippe; Oswald, Eric

    2011-04-01

    Cycle inhibiting factors (Cifs) are type III secreted effectors produced by diverse pathogenic bacteria. Cifs are "cyclomodulins" that inhibit the eukaryotic host cell cycle and also hijack other key cellular processes such as those controlling the actin network and apoptosis. This review summarizes current knowledge on Cif since its first characterization in enteropathogenic Escherichia coli, the identification of several xenologues in distant pathogenic bacteria, to its structure elucidation and the recent deciphering of its mode of action. Cif impairs the host ubiquitin proteasome system through deamidation of ubiquitin or the ubiquitin-like protein NEDD8 that regulates Cullin-Ring-ubiquitin Ligase (CRL) complexes. The hijacking of the ubiquitin-dependent degradation pathway of host cells results in the modulation of various cellular functions such as epithelium renewal, apoptosis and immune response. Cif is therefore a powerful weapon in the continuous arm race that characterizes host-bacteria interactions.

  9. Adaptive preconditioning in neurological diseases – therapeutic insights from proteostatic perturbations

    PubMed Central

    Mollereau, B.; Rzechorzek, N.M.; Roussel, B.D.; Sedru, M.; Van den Brink, D.M.; Bailly-Maitre, B.; Palladino, F.; Medinas, D.B.; Domingos, P.M.; Hunot, S.; Chandran, S.; Birman, S.; Baron, T.; Vivien, D.; Duarte, C.B.; Ryoo, H.D.; Steller, H.; Urano, F.; Chevet, E.; Kroemer, G.; Ciechanover, A.; Calabrese, E.J.; Kaufman, R.J.; Hetz, C.

    2016-01-01

    In neurological disorders, both acute and chronic neural stress can disrupt cellular proteostasis, resulting in the generation of pathological protein. However in most cases, neurons adapt to these proteostatic perturbations by activating a range of cellular protective and repair responses, thus maintaining cell function. These interconnected adaptive mechanisms comprise a ‘proteostasis network’ and include the unfolded protein response, the ubiquitin proteasome system and autophagy. Interestingly, several recent studies have shown that these adaptive responses can be stimulated by preconditioning treatments, which confer resistance to a subsequent toxic challenge – the phenomenon known as hormesis. In this review we discuss the impact of adaptive stress responses stimulated in diverse human neuropathologies including Parkinson’s disease, Wolfram syndrome, brain ischemia, and brain cancer. Further, we examine how these responses and the molecular pathways they recruit might be exploited for therapeutic gain. PMID:26923166

  10. Ubiquitin carboxyl hydrolase L1 significance for human diseases.

    PubMed

    Suong, Dang Ngoc Anh; Thao, Dang Thi Phuong; Masamitsu, Yamaguchi; Thuoc, Tran Linh

    2014-07-01

    Ubiquitin carboxyl hydrolase L1 (UCH-L1) is an abundant multifunctional neuron protein. It plays an important role in maintaining the ubiquitin proteasome system (UPS), vital for recognizing and degrading dysfunctional proteins in organisms. In recent decades, UCH-L1 has been implicated in the pathogenesis of many diseases, including neurodegenerative disorders, cancer and diabetes. However, the mechanisms of UCH-L1 involvement have yet to be revealed in detail. Since UCH-L1 contributes many different functions to cell metabolism, its role and regulation might be more complex than previously thought and it has become a research target in many laboratories. In this review, we summarize recent findings related to the actions of UCH-L1 in several human diseases.

  11. ERP (enterprise resource planning) systems can streamline healthcare business functions.

    PubMed

    Jenkins, E K; Christenson, E

    2001-05-01

    Enterprise resource planning (ERP) software applications are designed to facilitate the systemwide integration of complex processes and functions across a large enterprise consisting of many internal and external constituents. Although most currently available ERP applications generally are tailored to the needs of the manufacturing industry, many large healthcare systems are investigating these applications. Due to the significant differences between manufacturing and patient care, ERP-based systems do not easily translate to the healthcare setting. In particular, the lack of clinical standardization impedes the use of ERP systems for clinical integration. Nonetheless, an ERP-based system can help a healthcare organization integrate many functions, including patient scheduling, human resources management, workload forecasting, and management of workflow, that are not directly dependent on clinical decision making.

  12. The function and structure of the cerebrospinal fluid outflow system

    PubMed Central

    2010-01-01

    This review traces the development of our understanding of the anatomy and physiological properties of the two systems responsible for the drainage of cerebrospinal fluid (CSF) into the systemic circulation. The roles of the cranial and spinal arachnoid villi (AV) and the lymphatic outflow systems are evaluated as to the dominance of one over the other in various species and degree of animal maturation. The functional capabilities of the total CSF drainage system are presented, with evidence that the duality of the system is supported by the changes in fluid outflow dynamics in human and sub-human primates in hydrocephalus. The review also reconciles the relative importance and alterations of each of the outflow systems in a variety of clinical pathological conditions. PMID:20565964

  13. Functional integral approach to the kinetic theory of inhomogeneous systems

    NASA Astrophysics Data System (ADS)

    Fouvry, Jean-Baptiste; Chavanis, Pierre-Henri; Pichon, Christophe

    2016-10-01

    We present a derivation of the kinetic equation describing the secular evolution of spatially inhomogeneous systems with long-range interactions, the so-called inhomogeneous Landau equation, by relying on a functional integral formalism. We start from the BBGKY hierarchy derived from the Liouville equation. At the order 1 / N, where N is the number of particles, the evolution of the system is characterised by its 1-body distribution function and its 2-body correlation function. Introducing associated auxiliary fields, the evolution of these quantities may be rewritten as a traditional functional integral. By functionally integrating over the 2-body autocorrelation, one obtains a new constraint connecting the 1-body DF and the auxiliary fields. When inverted, this constraint allows us to obtain the closed non-linear kinetic equation satisfied by the 1-body distribution function. This derivation provides an alternative to previous methods, either based on the direct resolution of the truncated BBGKY hierarchy or on the Klimontovich equation. It may turn out to be fruitful to derive more accurate kinetic equations, e.g., accounting for collective effects, or higher order correlation terms.

  14. Memory Systems, Processing Modes, and Components: Functional Neuroimaging Evidence.

    PubMed

    Cabeza, Roberto; Moscovitch, Morris

    2013-01-01

    In the 1980s and 1990s, there was a major theoretical debate in the memory domain regarding the multiple memory systems and processing modes frameworks. The components of processing framework argued for a middle ground: Instead of neatly divided memory systems or processing modes, this framework proposed the existence of numerous processing components that are recruited in different combinations by memory tasks and yield complex patterns of associations and dissociations. Because behavioral evidence was not sufficient to decide among these three frameworks, the debate was largely abandoned. However, functional neuroimaging evidence accumulated during the last two decades resolves the stalemate, because this evidence is more consistent with the components framework than with the other two frameworks. For example, functional neuroimaging evidence shows that brain regions attributed to one memory system can contribute to tasks associated with other memory systems and that brain regions attributed to the same processing mode (perceptual or conceptual) can be dissociated from each other. Functional neuroimaging evidence suggests that memory processes are supported by transient interactions between a few regions called process-specific alliances. These conceptual developments are an example of how functional neuroimaging can contribute to theoretical debates in cognitive psychology.

  15. The nicotinic cholinergic system function in the human brain.

    PubMed

    Nees, Frauke

    2015-09-01

    Research on the nicotinic cholinergic system function in the brain was previously mainly derived from animal studies, yet, research in humans is growing. Up to date, findings allow significant advances on the understanding of nicotinic cholinergic effects on human cognition, emotion and behavior using a range of functional brain imaging approaches such as pharmacological functional magnetic resonance imaging or positron emission tomography. Studies provided insights across various mechanistic psychological domains using different tasks as well as at rest in both healthy individuals and patient populations, with so far partly mixed results reporting both enhancements and decrements of neural activity related to the nicotinic cholinergic system. Moreover, studies on the relation between brain structure and the nicotinic cholinergic system add important information in this context. The present review summarizes the current status of human brain imaging studies and presents the findings within a theoretical and clinical perspective as they may be useful not only for an advancement of the understanding of basic nicotinic cholinergic-related mechanisms, but also for the development and integration of psychological and pharmacological treatment approaches. Patterns of functional neuroanatomy and neural circuitry across various cognitive and emotional domains may be used as neuropsychological markers of mental disorders such as addiction, Alzheimer's disease, Parkinson disease or schizophrenia, where nicotinic cholinergic system changes are characteristic. This article is part of the Special Issue entitled 'The Nicotinic Acetylcholine Receptor: From Molecular Biology to Cognition'.

  16. Functional models of power electronic components for system studies

    NASA Technical Reports Server (NTRS)

    Tam, Kwa-Sur; Yang, Lifeng; Dravid, Narayan

    1991-01-01

    A novel approach to model power electronic circuits has been developed to facilitate simulation studies of system-level issues. The underlying concept for this approach is to develop an equivalent circuit, the functional model, that performs the same functions as the actual circuit but whose operation can be simulated by using larger time step size and the reduction in model complexity, the computation time required by a functional model is significantly shorter than that required by alternative approaches. The authors present this novel modeling approach and discuss the functional models of two major power electronic components, the DC/DC converter unit and the load converter, that are being considered by NASA for use in the Space Station Freedom electric power system. The validity of these models is established by comparing the simulation results with available experimental data and other simulation results obtained by using a more established modeling approach. The usefulness of this approach is demonstrated by incorporating these models into a power system model and simulating the system responses and interactions between components under various conditions.

  17. Academic Literacies and Systemic Functional Linguistics: How Do They Relate?

    ERIC Educational Resources Information Center

    Coffin, Caroline; Donohue, James P.

    2012-01-01

    Two approaches to English for Academic Purposes (EAP) research and teaching which have arisen in recent years are systemic functional linguistics (SFL) approaches in Australia and elsewhere (e.g. Hood, 2006; Lee, 2010; Woodward-Kron, 2009) and Academic Literacies approaches in the UK and elsewhere (e.g. Lillis & Scott, 2008; Thesen &…

  18. The Assessment of Neurological Systems with Functional Imaging

    ERIC Educational Resources Information Center

    Eidelberg, David

    2007-01-01

    In recent years a number of multivariate approaches have been introduced to map neural systems in health and disease. In this review, we focus on spatial covariance methods applied to functional imaging data to identify patterns of regional activity associated with behavior. In the rest state, this form of network analysis can be used to detect…

  19. On the Functions of a System of Vocational Qualifications

    ERIC Educational Resources Information Center

    Lum, Gerard

    2015-01-01

    While acknowledging that a system of vocational qualifications might be perceived as having any number of possible purposes, this paper identifies three primary functions that any vocational qualification must fulfil by dint of being a vocational qualification. It is argued that current arrangements are unable to fulfil these essential functions…

  20. Microprocessor systems for self-control of vital bodily functions.

    PubMed

    Yumatov, E A

    2000-01-01

    This article presents a fundamentally novel approach to an urgent medico-social problem of providing the timely medical care. To maintain people's health and life in their everyday activities, a new concept of the medical instrument-making industry was put forward. This concept was developed in terms of the theory of functional systems, which revealed the universal rules of self-regulation of bodily functions. The practical realization of the above-mentioned concept involved the construction, patenting, and production of a number of original devices capable of warning the patient about disorders in basic bodily functions. These devices included a Heart Protection System, a Stress Doser, a Physiological Clock, a Ration Controller, and a Mother-Fetus Controller. They can all be regarded as informational household microprocessor-based instruments of the 21st century.

  1. Regulation of sympathetic nervous system function after cardiovascular deconditioning

    NASA Technical Reports Server (NTRS)

    Hasser, E. M.; Moffitt, J. A.

    2001-01-01

    Humans subjected to prolonged periods of bed rest or microgravity undergo deconditioning of the cardiovascular system, characterized by resting tachycardia, reduced exercise capability, and a predisposition for orthostatic intolerance. These changes in cardiovascular function are likely due to a combination of factors, including changes in control of body fluid balance or cardiac alterations resulting in inadequate maintenance of stroke volume, altered arterial or venous vascular function, reduced activation of cardiovascular hormones, and diminished autonomic reflex function. There is evidence indicating a role for each of these mechanisms. Diminished reflex activation of the sympathetic nervous system and subsequent vasoconstriction appear to play an important role. Studies utilizing the hindlimb-unloaded (HU) rat, an animal model of deconditioning, evaluated the potential role of altered arterial baroreflex control of the sympathetic nervous system. These studies indicate that HU results in blunted baroreflex-mediated activation of both renal and lumbar sympathetic nerve activity in response to a hypotensive stimulus. HU rats are less able to maintain arterial pressure during hemorrhage, suggesting that diminished ability to increase sympathetic activity has functional consequences for the animal. Reflex control of vasopressin secretion appears to be enhanced following HU. Blunted baroreflex-mediated sympathoexcitation appears to involve altered central nervous system function. Baroreceptor afferent activity in response to changes in arterial pressure is unaltered in HU rats. However, increases in efferent sympathetic nerve activity for a given decrease in afferent input are blunted after HU. This altered central nervous system processing of baroreceptor inputs appears to involve an effect at the rostral ventrolateral medulla (RVLM). Specifically, it appears that tonic GABAA-mediated inhibition of the RVLM is enhanced after HU. Augmented inhibition apparently

  2. Functionally graded alumina-based thin film systems

    DOEpatents

    Moore, John J.; Zhong, Dalong

    2006-08-29

    The present invention provides coating systems that minimize thermal and residual stresses to create a fatigue- and soldering-resistant coating for aluminum die casting dies. The coating systems include at least three layers. The outer layer is an alumina- or boro-carbide-based outer layer that has superior non-wettability characteristics with molten aluminum coupled with oxidation and wear resistance. A functionally-graded intermediate layer or "interlayer" enhances the erosive wear, toughness, and corrosion resistance of the die. A thin adhesion layer of reactive metal is used between the die substrate and the interlayer to increase adhesion of the coating system to the die surface.

  3. Canonical Functional Quantization of Pseudo-Photons in Planar Systems

    SciTech Connect

    Ferreira, P. Castelo

    2008-06-25

    Extended U{sub e}(1)xU{sub g}(1) electromagnetism containing both a photon and a pseudo-photon is introduced at the variational level and is justified by the violation of the Bianchi identities in conceptual systems, either in the presence of magnetic monopoles or non-regular external fields, not being accounted for by the standard Maxwell Lagrangian. A dimensional reduction is carried out that yields a U{sub e}(1)xU{sub g}(1) Maxwell-BF type theory and a canonical functional quantization in planar systems is considered which may be relevant in Hall systems.

  4. Flight Experiment Demonstration System (FEDS) functional description and interface document

    NASA Technical Reports Server (NTRS)

    Belcher, R. C.; Shank, D. E.

    1984-01-01

    This document presents a functional description of the Flight Experiment Demonstration System (FEDS) and of interfaces between FEDS and external hardware and software. FEDS is a modification of the Automated Orbit Determination System (AODS). FEDS has been developed to support a ground demonstration of microprocessor-based onboard orbit determination. This document provides an overview of the structure and logic of FEDS and details the various operational procedures to build and execute FEDS. It also documents a microprocessor interface between FEDS and a TDRSS user transponder and describes a software simulator of the interface used in the development and system testing of FEDS.

  5. Laser system range calculations and the Lambert W function.

    PubMed

    Steinvall, Ove

    2009-02-01

    The knowledge of range performance versus atmospheric transmission, often given by the visibility, is critical for the design, use, and prediction of laser and passive electro-optic systems. I present a solution of the ladar-lidar equation based on Lambert's W function. This solution will reveal the dependence of the maximum range on the system and target parameters for different atmospheric attenuations and will also allow us to take the signal statistics into account by studying the influence on the threshold signal-to-noise ratio. The method is also applicable to many range calculations for passive systems where the atmospheric loss can be approximated by an exponential term.

  6. Design of multi-function Hanford tank corrosion monitoring system

    SciTech Connect

    EDGEMON, G.L.

    1999-04-01

    A multi-fiction corrosion monitoring system has been designed for installation into DST 241-AN-105 at the Hanford Site in fiscal year 1999. The 241-AN-105 system is the third-generation corrosion monitoring system described by TTP RLO-8-WT-21. Improvements and upgrades from the second-generation system (installed in 241-AN-102) that have been incorporated into the third-generation system include: Gasket seating surfaces utilize O-rings instead of a washer type gasket for improved seal; Probe design contains an equally spaced array of 22 thermocouples; Probe design contains an adjustable verification thermocouple; Probe design contains three ports for pressure/gas sampling; Probe design contains one set of strain gauges to monitor probe flexure if flexure occurs; Probe utilizes an adjustable collar to allow depth adjustment of probe during installation; System is capable of periodically conducting LPR scans; System is housed in a climate controlled enclosure adjacent to the riser containing the probe; System uses wireless Ethernet links to send data to Hanford Local Area Network; System uses commercial remote access software to allow remote command and control; and Above ground wiring uses driven shields to reduce external electrostatic noise in the data. These new design features have transformed what was primarily a second-generation corrosion monitoring system into a multi-function tank monitoring system that adds a great deal of functionality to the probe, provides for a better understanding of the relationship between corrosion and other tank operating parameters, and optimizes the use of the riser that houses the probe in the tank.

  7. Temperature Measurement and Control System for Transtibial Prostheses: Functional Evaluation.

    PubMed

    Ghoseiri, Kamiar; Zheng, Yong Ping; Leung, Aaron K L; Rahgozar, Mehdi; Aminian, Gholamreza; Lee, Tat Hing; Safari, Mohammad Reza

    2016-10-03

    The accumulation of heat inside the prosthetic socket increases skin temperature and fosters perspiration, which consequently leads to high tissue stress, friction blister, discomfort, unpleasant odor, and decreased prosthesis suspension and use. In the present study, the prototype of a temperature measurement and control (TM&C) system was designed, fabricated, and functionally evaluated in a phantom model of the transtibial prosthetic socket. The TM&C system was comprised of 12 thermistors divided equally into two groups that arranged internal and external to a prosthetic silicone liner. Its control system was programmed to select the required heating or cooling function of a thermal pump to provide thermal equilibrium based on the amount of temperature difference from a defined set temperature, or the amount of difference between the mean temperature recorded by inside and outside thermistors. A thin layer of aluminum was used for thermal conduction between the thermal pump and different sites around the silicone liner. The results showed functionality of the TM&C system for thermoregulation inside the prosthetic socket. However, enhancing the structure of this TM&C system, increasing its thermal power, and decreasing its weight and cost are main priorities before further development.

  8. Radial Basis Function Neural Network-based PID model for functional electrical stimulation system control.

    PubMed

    Cheng, Longlong; Zhang, Guangju; Wan, Baikun; Hao, Linlin; Qi, Hongzhi; Ming, Dong

    2009-01-01

    Functional electrical stimulation (FES) has been widely used in the area of neural engineering. It utilizes electrical current to activate nerves innervating extremities affected by paralysis. An effective combination of a traditional PID controller and a neural network, being capable of nonlinear expression and adaptive learning property, supply a more reliable approach to construct FES controller that help the paraplegia complete the action they want. A FES system tuned by Radial Basis Function (RBF) Neural Network-based Proportional-Integral-Derivative (PID) model was designed to control the knee joint according to the desired trajectory through stimulation of lower limbs muscles in this paper. Experiment result shows that the FES system with RBF Neural Network-based PID model get a better performance when tracking the preset trajectory of knee angle comparing with the system adjusted by Ziegler- Nichols tuning PID model.

  9. Imaging systems based on the encoding of optical coherence functions.

    PubMed

    James, J Christopher; Bennett, Gisele Welch; Rhodes, William T

    2005-09-01

    An imaging scheme is described that is based on the transmission of image-forming information encoded within optical coherence functions. The scheme makes use of dynamic random-valued encoding-decoding masks placed in the input-output planes of any linear optical system. The mask transmittance functions are complex conjugates of each other, as opposed to a similar coherence encoding scheme proposed earlier by two of this paper's authors that used identical masks. [Rhodes and Welch, in Euro-American Workshop on Optoelectronic Information Processing, SPIE Critical Review Series (SPIE, 1999), Vol. CR74, p. 1]. General analyses of the two coherence encoding schemes are performed by using the more general mutual coherence function as opposed to the mutual intensity function used in the earlier scheme. The capabilities and limitations of both encoding schemes are discussed by using simple examples that combine the encoding-decoding masks with free-space propagation, passage through a four-f system, and a single-lens imaging system.

  10. Protein Expression of Proteasome Subunits in Elderly Patients with Schizophrenia

    PubMed Central

    Scott, Madeline R; Rubio, Maria D; Haroutunian, Vahram; Meador-Woodruff, James H

    2016-01-01

    The ubiquitin proteasome system (UPS) is a major regulator of protein processing, trafficking, and degradation. While protein ubiquitination is utilized for many cellular processes, one major function of this system is to target proteins to the proteasome for degradation. In schizophrenia, studies have found UPS transcript abnormalities in both blood and brain, and we have previously reported decreased protein expression of ubiquitin-associated proteins in brain. To test whether the proteasome is similarly dysregulated, we measured the protein expression of proteasome catalytic subunits as well as essential subunits from proteasome regulatory complexes in 14 pair-matched schizophrenia and comparison subjects in superior temporal cortex. We found decreased expression of Rpt1, Rpt3, and Rpt6, subunits of the 19S regulatory particle essential for ubiquitin-dependent degradation by the proteasome. Additionally, the α subunit of the 11S αβ regulatory particle, which enhances proteasomal degradation of small peptides and unfolded proteins, was also decreased. Haloperidol-treated rats did not have altered expression of these subunits, suggesting the changes we observed in schizophrenia are likely not due to chronic antipsychotic treatment. Interestingly, expression of the catalytic subunits of both the standard and immunoproteasome were unchanged, suggesting the abnormalities we observed may be specific to the complexed state of the proteasome. Aging has significant effects on the proteasome, and several subunits (20S β2, Rpn10, Rpn13, 11Sβ, and 11Sγ) were significantly correlated with subject age. These data provide further evidence of dysfunction of the ubiquitin-proteasome system in schizophrenia, and suggest that altered proteasome activity may be associated with the pathophysiology of this illness. PMID:26202105

  11. Proteasome stress responses in Schistosoma mansoni.

    PubMed

    de Paula, Renato Graciano; de Magalhães Ornelas, Alice Maria; Morais, Enyara Rezende; de Souza Gomes, Matheus; de Paula Aguiar, Daniela; Magalhães, Lizandra Guidi; Rodrigues, Vanderlei

    2015-05-01

    The proteasome proteolytic system is the major ATP-dependent protease in eukaryotic cells responsible for intracellular protein turnover. Schistosoma mansoni has been reported to contain an ubiquitin-proteasome proteolytic pathway, and many studies have suggested a biological role of proteasomes in the development of this parasite. Additionally, evidence has suggested diversity in proteasome composition under several cellular conditions, and this might contribute to the regulation of its function in this parasite. The proteasomal system has been considered important to support the protein homeostasis during cellular stress. In this study, we described in vitro effects of oxidative stress, heat shock, and chemical stress on S. mansoni adults. Our findings showed that chemical stress induced with curcumin, IBMX, and MG132 modified the gene expression of the proteasomal enzymes SmHul5 and SmUbp6. Likewise, the expression of these genes was upregulated during oxidative stress and heat shock. Analyses of the S. mansoni life cycle showed differential gene expression in sporocysts, schistosomulae, and miracidia. These results suggested that proteasome accessory proteins participate in stress response during the parasite development. The expression level of SmHul5 and SmUbp6 was decreased by 16-fold and 9-fold, respectively, by the chemical stress induced with IBMX, which suggests proteasome disassembly. On the other hand, curcumin, MG132, oxidative stress, and heat shock increased the expression of these genes. Furthermore, the gene expression of maturation proteasome protein (SmPOMP) was increased in stress conditions induced by curcumin, MG132, and H₂O₂, which could be related to the synthesis of new proteasomes. S. mansoni adult worms were found to utilize similar mechanisms to respond to different conditions of stress. Our results demonstrated that oxidative stress, heat shock, and chemical stress modified the expression profile of genes related to the ubiquitin-proteasome

  12. The heme oxygenase system and its functions in the brain.

    PubMed

    Maines, M D

    2000-05-01

    The heme oxygenase (HO) system was identified in the early 1970s as a distinct microsomal enzyme system that catalyzes formation of bile pigments (Maines and Kappas, 1974). Up to the early 1990s the system was considered only as a "molecular wrecking ball" (Lane, 1998) for degradation of the heme molecule and production of toxic waste products, CO and bile pigments. For those years, the HO system remained relatively unknown to the research community. In a rather short span of the past 10 years following the discovery of high levels of a second form of the enzyme, HO-2, in the brain, suggesting that "heme oxygenase in the brain has functions aside from heme degradation" (Sun et al., 1990); concomitant with finding that another toxic gas, NO, is a signal molecule for generation of cGMP (Ignarro et al., 1982), the system was propelled into main stream research. This propulsion was fueled by the realization of the multiple and diverse functions of heme degradation products. Heme oxygenase has now found relevance in all kinds of human pathophysiology ranging from stroke, cancer, multiple sclerosis, and malaria to transplantation and immune response. As it turns out, its potential benefits are mesmerizing investigators in diverse fields (Lane, 1998). The most recent findings with HO-2 being a hemoprotein and potentially an intracellular "sink" for NO (McCoubrey et al., 1997a; Ding et al., 1999), together with the discovery of the third form of the enzyme, HO-3 (McCoubrey et al., 1997b), are likely to insure the widespread interest in the enzyme system in the coming years. The present review is intended to highlight molecular properties of HO isozymes and their likely functions in the brain. Extended reviews of the system are found in Maines (1992, 1997).

  13. Vaccine-enhanced artificial immune system for multimodal function optimization.

    PubMed

    Woldemariam, Kumlachew M; Yen, Gary G

    2010-02-01

    This paper emulates a biological notion in vaccines to promote exploration in the search space for solving multimodal function optimization problems using artificial immune systems (AISs). In this method, we first divide the decision space into equal subspaces. The vaccine is then randomly extracted from each subspace. A few of these vaccines, in the form of weakened antigens, are then injected into the algorithm to enhance the exploration of global and local optima. The goal of this process is to lead the antibodies to unexplored areas. Using this biologically motivated notion, we design the vaccine-enhanced AIS for multimodal function optimization, achieving promising performance.

  14. [Extranuclear functions of protein sumoylation in the central nervous system].

    PubMed

    Martin, Stéphane

    2009-01-01

    Post-translational protein modifications play essential roles in many aspects of cellular functions and therefore in the maintenance of cell integrity. These protein modifications are involved at all stages of neuronal communication within the central nervous system. Sumoylation is a reversible post-translational protein modification that consists in the covalent labelling of a small protein called SUMO to lysine residues of selected target proteins. Sumoylation is a well characterized regulator of nuclear functions and has recently emerged as a key factor for numerous extranuclear processes. Furthermore, sumoylation has recently been shown to modulate synaptic transmission and is also implicated in a wide range of neurodegenerative diseases.

  15. Altered expression of genes regulating skeletal muscle mass in the portacaval anastomosis rat.

    PubMed

    Dasarathy, Srinivasan; Muc, Sean; Hisamuddin, Kola; Edmison, John M; Dodig, Milan; McCullough, Arthur J; Kalhan, Satish C

    2007-04-01

    We examined the temporal relationship between portacaval anastomosis (PCA), weight gain, changes in skeletal muscle mass and molecular markers of protein synthesis, protein breakdown, and satellite cell proliferation and differentiation. Male Sprague-Dawley rats with end to side PCA (n=24) were compared with sham-operated pair-fed rats (n=24). Whole body weight, lean body mass, and forelimb grip strength were determined at weekly intervals. The skeletal muscle expression of the ubiquitin proteasome system, myostatin, its receptor (the activin 2B receptor) and its signal, cyclin-dependent kinase inhibitor (CDKI) p21, insulin-like growth factor (IGF)-I and its receptor (IGF-I receptor-alpha), and markers of satellite cell proliferation and differentiation were quantified. PCA rats did not gain body weight and had lower lean body mass, forelimb grip strength, and gastrocnemius muscle weight. The skeletal muscle expression of the mRNA of ubiquitin proteasome components was higher in PCA rats in the first 2 wk followed by a lower expression in the subsequent 2 wk (P<0.01). The mRNA and protein of myostatin, activin 2B receptor, and CDKI p21 were higher, whereas IGF-I and its receptor as well as markers of satellite cell function (proliferating nuclear cell antigen, myoD, myf5, and myogenin) were lower at weeks 3 and 4 following PCA (P < 0.05). We conclude that PCA resulted in uninhibited proteolysis in the initial 2 wk. This was followed by an adaptive response in the later 2 wk consisting of an increased expression of myostatin that may have contributed to reduced muscle protein synthesis, impaired satellite cell function, and lower skeletal muscle mass.

  16. Structural and functional features of central nervous system lymphatic vessels.

    PubMed

    Louveau, Antoine; Smirnov, Igor; Keyes, Timothy J; Eccles, Jacob D; Rouhani, Sherin J; Peske, J David; Derecki, Noel C; Castle, David; Mandell, James W; Lee, Kevin S; Harris, Tajie H; Kipnis, Jonathan

    2015-07-16

    One of the characteristics of the central nervous system is the lack of a classical lymphatic drainage system. Although it is now accepted that the central nervous system undergoes constant immune surveillance that takes place within the meningeal compartment, the mechanisms governing the entrance and exit of immune cells from the central nervous system remain poorly understood. In searching for T-cell gateways into and out of the meninges, we discovered functional lymphatic vessels lining the dural sinuses. These structures express all of the molecular hallmarks of lymphatic endothelial cells, are able to carry both fluid and immune cells from the cerebrospinal fluid, and are connected to the deep cervical lymph nodes. The unique location of these vessels may have impeded their discovery to date, thereby contributing to the long-held concept of the absence of lymphatic vasculature in the central nervous system. The discovery of the central nervous system lymphatic system may call for a reassessment of basic assumptions in neuroimmunology and sheds new light on the aetiology of neuroinflammatory and neurodegenerative diseases associated with immune system dysfunction.

  17. Functional self-assembled lipidic systems derived from renewable resources

    PubMed Central

    Silverman, Julian R.; Samateh, Malick; John, George

    2015-01-01

    Self-assembled lipidic amphiphile systems can create a variety of multi-functional soft materials with value-added properties. When employing natural reagents and following biocatalytic syntheses, self-assembling monomers may be inherently designed for degradation, making them potential alternatives to conventional and persistent polymers. By using non-covalent forces, self-assembled amphiphiles can form nanotubes, fibers, and other stimuli responsive architectures prime for further applied research and incorporation into commercial products. By viewing these lipid derivatives under a lens of green principles, there is the hope that in developing a structure–function relationship and functional smart materials that research may remain safe, economic, and efficient. PMID:26766923

  18. Alkylation damage by lipid electrophiles targets functional protein systems.

    PubMed

    Codreanu, Simona G; Ullery, Jody C; Zhu, Jing; Tallman, Keri A; Beavers, William N; Porter, Ned A; Marnett, Lawrence J; Zhang, Bing; Liebler, Daniel C

    2014-03-01

    Protein alkylation by reactive electrophiles contributes to chemical toxicities and oxidative stress, but the functional impact of alkylation damage across proteomes is poorly understood. We used Click chemistry and shotgun proteomics to profile the accumulation of proteome damage in human cells treated with lipid electrophile probes. Protein target profiles revealed three damage susceptibility classes, as well as proteins that were highly resistant to alkylation. Damage occurred selectively across functional protein interaction networks, with the most highly alkylation-susceptible proteins mapping to networks involved in cytoskeletal regulation. Proteins with lower damage susceptibility mapped to networks involved in protein synthesis and turnover and were alkylated only at electrophile concentrations that caused significant toxicity. Hierarchical susceptibility of proteome systems to alkylation may allow cells to survive sublethal damage while protecting critical cell functions.

  19. Systemic Modeling of Biological Functions in Consideration of Physiome Project

    NASA Astrophysics Data System (ADS)

    Minamitani, Haruyuki

    Emerging of the physiome project provides various influences on the medical, biological and pharmaceutical development. In this paper, as an example of physiome research, neural network model analysis providing the conduction mechanisms of pain and tactile sensations was presented, and the functional relations between neural activities of the network cells and stimulus intensity applied on the peripheral receptive fields were described. The modeling presented here is based on the various assumptions made by the results of physiological and anatomical studies reported in the literature. The functional activities of spinothalamic and thalamocortical cells show a good agreement with the physiological and psychophysical functions of somatosensory system that are very instructive for covering the gap between physiologically and psychophysically aspects of pain and tactile sensation.

  20. Systems and methods for producing low work function electrodes

    DOEpatents

    Kippelen, Bernard; Fuentes-Hernandez, Canek; Zhou, Yinhua; Kahn, Antoine; Meyer, Jens; Shim, Jae Won; Marder, Seth R.

    2015-07-07

    According to an exemplary embodiment of the invention, systems and methods are provided for producing low work function electrodes. According to an exemplary embodiment, a method is provided for reducing a work function of an electrode. The method includes applying, to at least a portion of the electrode, a solution comprising a Lewis basic oligomer or polymer; and based at least in part on applying the solution, forming an ultra-thin layer on a surface of the electrode, wherein the ultra-thin layer reduces the work function associated with the electrode by greater than 0.5 eV. According to another exemplary embodiment of the invention, a device is provided. The device includes a semiconductor; at least one electrode disposed adjacent to the semiconductor and configured to transport electrons in or out of the semiconductor.

  1. The evolution of the phage shock protein response system: interplay between protein function, genomic organization, and system function.

    PubMed

    Huvet, M; Toni, T; Sheng, X; Thorne, T; Jovanovic, G; Engl, C; Buck, M; Pinney, J W; Stumpf, M P H

    2011-03-01

    Sensing the environment and responding appropriately to it are key capabilities for the survival of an organism. All extant organisms must have evolved suitable sensors, signaling systems, and response mechanisms allowing them to survive under the conditions they are likely to encounter. Here, we investigate in detail the evolutionary history of one such system: The phage shock protein (Psp) stress response system is an important part of the stress response machinery in many bacteria, including Escherichia coli K12. Here, we use a systematic analysis of the genes that make up and regulate the Psp system in E. coli in order to elucidate the evolutionary history of the system. We compare gene sharing, sequence evolution, and conservation of protein-coding as well as noncoding DNA sequences and link these to comparative analyses of genome/operon organization across 698 bacterial genomes. Finally, we evaluate experimentally the biological advantage/disadvantage of a simplified version of the Psp system under different oxygen-related environments. Our results suggest that the Psp system evolved around a core response mechanism by gradually co-opting genes into the system to provide more nuanced sensory, signaling, and effector functionalities. We find that recruitment of new genes into the response machinery is closely linked to incorporation of these genes into a psp operon as is seen in E. coli, which contains the bulk of genes involved in the response. The organization of this operon allows for surprising levels of additional transcriptional control and flexibility. The results discussed here suggest that the components of such signaling systems will only be evolutionarily conserved if the overall functionality of the system can be maintained.

  2. Information theory as a general language for functional systems

    NASA Astrophysics Data System (ADS)

    Collier, John

    2000-05-01

    Function refers to a broad family of concepts of varying abstractness and range of application, from a many-one mathematical relation of great generality to, for example, highly specialized roles of designed elements in complex machines such as degaussing in a television set, or contributory processes to control mechanisms in complex metabolic pathways, such as the inhibitory function of the appropriate part of the lac-operon on the production of lactase through its action on the genome in the absence of lactose. We would like a language broad enough, neutral enough, but yet powerful enough to cover all such cases, and at the same time to give a framework form explanation both of the family resemblances and differences. General logic and mathematics are too abstract, but more importantly, too broad, whereas other discourses of function, such as the biological and teleological contexts, are too narrow. Information is especially suited since it is mathematically grounded, but also has a well-known physical interpretation through the Schrodinger/Brillouin Negentropy. Principle of Information, and an engineering or design interpretation through Shannon's communication theory. My main focus will be on the functions of autonomous anticipatory systems, but I will try to demonstrate both the connections between this notion of function and the others, especially to dynamical systems with a physical interpretation on the one side and intentional systems on the other. The former are based in concepts like force, energy and work, while the latter involve notions like representation, control and purpose, traditionally, at least in Modern times, on opposite sides of the Cartesian divide. In principle, information can be reduced to energy, but it has the advantage of being more flexible, and easier to apply to higher level phenomena.

  3. Classical action functional for the system of fields and wormholes

    SciTech Connect

    Hajicek, P.

    1982-12-15

    We lay down foundations of the quantum theory of wormholes for the model Einstein-Maxwell system. The generalization of the quantum theory of solitons to wormholes is not straightforward, because the fields are singular at r = 0. We propose to cut away the nonphysical part of the spacetime along the horizons and to impose boundary conditions at the resulting boundary of Cauchy surfaces. The boundary conditions are chosen such that (a) there is an action functional for the fields, (b) Poisson brackets of the boundary-fixed quantities with each other vanish, and (c) the soliton solution is unique. We study the action functional, find the surface terms, and, using the method of Regge and Teitelboim, extract the motion of the soliton. We show how the gauge group of the system is extended and find some properties of the additional gauge conditions. Finally, the soliton solution is written in the form in which all boundary and gauge conditions are satisfied.

  4. Transportation functions of the Civilian Radioactive Waste Management System

    SciTech Connect

    Shappert, L.B.; Attaway, C.R.; Pope, R.B. ); Best, R.E.; Danese, F.L. ); Dixon, L.D. , Martinez, GA ); Jones, R.H. , Los Gatos, CA ); Klimas, M.J. ); Peterson, R.W

    1992-03-01

    Within the framework of Public Law 97.425 and provisions specified in the Code of Federal Regulations, Title 10 Part 961, the US Department of Energy has the responsibility to accept and transport spent fuel and high-level waste from various organizations which have entered into a contract with the federal government in a manner that protects the health and safety of the public and workers. In implementing these requirements, the Office of Civilian Radioactive Waste Management (OCRWM) has, among other things, supported the identification of functions that must be performed by a transportation system (TS) that will accept the waste for transport to a federal facility for storage and/or disposal. This document, through the application of system engineering principles, identifies the functions that must be performed to transport waste under this law.

  5. Green's function approach of an anisotropic Heisenberg ferrimagnetic system

    NASA Astrophysics Data System (ADS)

    Mert, Gülistan

    2013-12-01

    We have investigated the influence of the exchange anisotropy parameter on the magnetization, critical and compensation temperatures and susceptibility of the anisotropic Heisenberg ferrimagnetic system with the single-ion anisotropy under an external magnetic field using the double-time temperature-dependent Green's function theory. In order to decouple the higher order Green's functions, Anderson-Callen's decoupling and random phase approximations have been used. This model is useful for understanding the temperature dependence of total magnetization of Lithium-chromium ferrites Li0.5Fe1.25Cr1.25O4 for which negative magnetization is characteristic. We observe that the critical temperature increases when the exchange anisotropy increases. When the system is under an external magnetic field, one obtains the first-order phase transition where the magnetization jumps for all the values of the exchange anisotropy parameters.

  6. Star product, discrete Wigner functions, and spin-system tomograms

    NASA Astrophysics Data System (ADS)

    Adam, P.; Andreev, V. A.; Isar, A.; Man'ko, V. I.; Man'ko, M. A.

    2016-03-01

    We develop the star-product formalism for spin states and consider different methods for constructing operator systems forming sets of dequantizers and quantizers, establishing a relation between them. We study the physical meaning of the operator symbols related to them. Quantum tomograms can also serve as operator symbols. We show that the possibility to express discrete Wigner functions in terms of measurable quantities follows because these functions can be related to quantum tomograms. We investigate the physical meaning of tomograms and spin-system tomogram symbols, which they acquire in the framework of the star-product formalism. We study the structure of the sum kernels, which can be used to express the operator symbols, calculated using different sets of dequantizers and also arising in calculating the star product of operator symbols, in terms of one another.

  7. Energy and enthalpy distribution functions for a few physical systems.

    PubMed

    Wu, K L; Wei, J H; Lai, S K; Okabe, Y

    2007-08-02

    The present work is devoted to extracting the energy or enthalpy distribution function of a physical system from the moments of the distribution using the maximum entropy method. This distribution theory has the salient traits that it utilizes only the experimental thermodynamic data. The calculated distribution functions provide invaluable insight into the state or phase behavior of the physical systems under study. As concrete evidence, we demonstrate the elegance of the distribution theory by studying first a test case of a two-dimensional six-state Potts model for which simulation results are available for comparison, then the biphasic behavior of the binary alloy Na-K whose excess heat capacity, experimentally observed to fall in a narrow temperature range, has yet to be clarified theoretically, and finally, the thermally induced state behavior of a collection of 16 proteins.

  8. Diverse Functions of Endothelial NO Synthases System: NO and EDH

    PubMed Central

    Godo, Shigeo

    2016-01-01

    Abstract: Endothelium-dependent relaxations are predominantly regulated by nitric oxide (NO) in large conduit arteries and by endothelium-dependent hyperpolarization (EDH) in small resistance vessels. Although the nature of EDH factors varies depending on species and vascular beds, we have previously demonstrated that endothelial NO synthases (eNOS)-derived hydrogen peroxide (H2O2) is an EDH factor in animals and humans. This vessel size-dependent contribution of NO and EDH is, at least in part, attributable to the diverse roles of endothelial NOSs system; in large conduit arteries, eNOS mainly serves as a NO-generating system to elicit soluble guanylate cyclase–cyclic guanosine monophosphate-mediated relaxations, whereas in small resistance vessels, it serves as a superoxide-generating system to cause EDH/H2O2-mediated relaxations. Endothelial caveolin-1 may play an important role for the diverse roles of NOSs. Although reactive oxygen species are generally regarded harmful, the physiological roles of H2O2 have attracted much attention as accumulating evidence has shown that endothelium-derived H2O2 contributes to cardiovascular homeostasis. The diverse functions of endothelial NOSs system with NO and EDH/H2O2 could account for a compensatory mechanism in the setting of endothelial dysfunction. In this review, we will briefly summarize the current knowledge on the diverse functions of endothelial NOSs system: NO and EDH/H2O2. PMID:26647119

  9. The Structure and Function of Type III Secretion Systems

    PubMed Central

    Notti, Ryan Q.; Stebbins, C. Erec

    2015-01-01

    ARTICLE SUMMARY Type III secretion systems (T3SS) afford gram-negative bacteria a most intimate means of altering the biology of their eukaryotic hosts — the direct delivery of effector proteins from the bacterial cytoplasm to that of the eukaryote. This incredible biophysical feat is accomplished by nanosyringe “injectisomes,” which form a conduit across the three plasma membranes, peptidoglycan layer and extracellular space that form a barrier to the direct delivery of proteins from bacterium to host. The focus of this chapter is T3SS function at the structural level; we will summarize the core findings that have shaped our understanding of the structure and function of these systems and highlight recent developments in the field. In turn, we describe the T3SS secretory apparatus, consider its engagement with secretion substrates, and discuss the post-translational regulation of secretory function. Lastly, we close with a discussion of the future prospects for the interrogation of structure-function relationships in the T3SS. PMID:26999392

  10. Combination of evidence in recommendation systems characterized by distance functions

    SciTech Connect

    Rocha, L. M.

    2002-01-01

    Recommendation systems for different Document Networks (DN) such as the World Wide Web (WWW), Digitnl Libarries, or Scientific Databases, often make use of distance functions extracted from relationships among documents and between documents and semantic tags. For instance, documents In the WWW are related via a hyperlink network, while documents in bibliographic databases are related by citation and collaboration networks.Furthermore, documents can be related to semantic tags such as keywords used to describe their content, The distance functions computed from these relations establish associative networks among items of the DN, and allow recommendation systems to identify relevant associations for iudividoal users. The process of recommendation can be improved by integrating associative data from different sources. Thus we are presented with a problem of combining evidence (about assochaons between items) from different sonrces characterized by distance functions. In this paper we summarize our work on (1) inferring associations from semi-metric distance functions and (2) combining evidence from different (distance) associative DN.

  11. Functional Requirements for an Electronic Work Package System

    SciTech Connect

    Oxstrand, Johanna H.

    2016-12-01

    This document provides a set of high level functional requirements for a generic electronic work package (eWP) system. The requirements have been identified by the U.S. nuclear industry as a part of the Nuclear Electronic Work Packages - Enterprise Requirements (NEWPER) initiative. The functional requirements are mainly applied to eWP system supporting Basic and Moderate types of smart documents, i.e., documents that have fields for recording input such as text, dates, numbers, and equipment status, and documents which incorporate additional functionalities such as form field data “type“ validation (e.g. date, text, number, and signature) of data entered and/or self-populate basic document information (usually from existing host application meta data) on the form when the user first opens it. All the requirements are categorized by the roles; Planner, Supervisor, Craft, Work Package Approval Reviewer, Operations, Scheduling/Work Control, and Supporting Functions. The categories Statistics, Records, Information Technology are also included used to group the requirements. All requirements are presented in Section 2 through Section 11. Examples of more detailed requirements are provided for the majority of high level requirements. These examples are meant as an inspiration to be used as each utility goes through the process of identifying their specific requirements. The report’s table of contents provides a summary of the high level requirements.

  12. The integumentary system: anatomy, physiology and function of skin.

    PubMed

    McLafferty, Ella

    2012-09-19

    This article, which forms part of the life sciences series, examines the anatomy and physiology of skin, also termed the integumentary system. Skin is composed of two main layers, the epidermis and dermis. The structure of the epidermis and dermis are described and their functions are discussed. Accessory structures, such as nails and hair are also considered. Although many diseases of the skin exist, two common conditions - psoriasis and decubitus ulcers - are described in this article.

  13. The integumentary system: anatomy, physiology and function of skin.

    PubMed

    McLafferty, Ella; Hendry, Charles; Alistair, Farley

    This article, which forms part of the life sciences series, examines the anatomy and physiology of skin, also termed the integumentary system. Skin is composed of two main layers, the epidermis and dermis. The structure of the epidermis and dermis are described and their functions are discussed. Accessory structures, such as nails and hair are also considered. Although many diseases of the skin exist, two common conditions--psoriasis and decubitus ulcers--are described in this article.

  14. Preliminary Design of Critical Function Monitoring System of PGSFR

    SciTech Connect

    2015-07-01

    A PGSFR (Prototype Gen-IV Sodium-cooled Fast Reactor) is under development at Korea Atomic Energy Research Institute. A critical function monitoring system of the PGSFR is preliminarily studied. The functions of CFMS are to display critical plant variables related to the safety of the plant during normal and accident conditions and guide the operators corrective actions to keep the plant in a safe condition and mitigate the consequences of accidents. The minimal critical functions of the PGSFR are composed of reactivity control, reactor core cooling, reactor coolant system integrity, primary heat transfer system(PHTS) heat removal, sodium water reaction mitigation, radiation control and containment conditions. The variables and alarm legs of each critical function of the PGSFR are as follows; - Reactivity control: The variables of reactivity control function are power range neutron flux instrumentation, intermediate range neutron flux instrumentation, source range neutron flux instrumentation, and control rod bottom contacts. The alarm leg to display the reactivity controls consists of status of control drop malfunction, high post trip power and thermal reactivity addition. - Reactor core cooling: The variables are PHTS sodium level, hot pool temperature of PHTS, subassembly exit temperature, cold pool temperature of the PHTS, PHTS pump current, and PHTS pump breaker status. The alarm leg consists of high core delta temperature, low sodium level of the PHTS, high subassembly exit temperature, and low PHTS pump load. - Reactor coolant system integrity: The variables are PHTS sodium level, cover gas pressure, and safeguard vessel sodium level. The alarm leg is composed of low sodium level of PHTS, high cover gas pressure and high sodium level of the safety guard vessel. - PHTS heat removal: The variables are PHTS sodium level, hot pool temperature of PHTS, core exit temperature, cold pool temperature of the PHTS, flow rate of passive residual heat removal system

  15. Quantitative Evaluation of the Reticuloendothelial System Function with Dynamic MRI

    PubMed Central

    Liu, Ting; Choi, Hoon; Zhou, Rong; Chen, I-Wei

    2014-01-01

    Purpose To evaluate the reticuloendothelial system (RES) function by real-time imaging blood clearance as well as hepatic uptake of superparamagnetic iron oxide nanoparticle (SPIO) using dynamic magnetic resonance imaging (MRI) with two-compartment pharmacokinetic modeling. Materials and Methods Kinetics of blood clearance and hepatic accumulation were recorded in young adult male 01b74 athymic nude mice by dynamic T2* weighted MRI after the injection of different doses of SPIO nanoparticles (0.5, 3 or 10 mg Fe/kg). Association parameter, Kin, dissociation parameter, Kout, and elimination constant, Ke, derived from dynamic data with two-compartment model, were used to describe active binding to Kupffer cells and extrahepatic clearance. The clodrosome and liposome were utilized to deplete macrophages and block the RES function to evaluate the capability of the kinetic parameters for investigation of macrophage function and density. Results The two-compartment model provided a good description for all data and showed a low sum squared residual for all mice (0.27±0.03). A lower Kin, a lower Kout and a lower Ke were found after clodrosome treatment, whereas a lower Kin, a higher Kout and a lower Ke were observed after liposome treatment in comparison to saline treatment (P<0.005). Conclusion Dynamic SPIO-enhanced MR imaging with two-compartment modeling can provide information on RES function on both a cell number and receptor function level. PMID:25090653

  16. Strengthening Rehabilitation in Health Systems Worldwide by Integrating Information on Functioning in National Health Information Systems.

    PubMed

    Stucki, Gerold; Bickenbach, Jerome; Melvin, John

    2016-12-15

    A complete understanding of the experience of health requires information relevant not merely to the health indicators of mortality and morbidity but also to functioning-that is, information about what it means to live in a health state, "the lived experience of health." Not only is functioning information relevant to healthcare and the overall objectives of person-centered healthcare but to the successful operation of all components of health systems.In light of population aging and major epidemiological trends, the health strategy of rehabilitation, whose aim has always been to optimize functioning and minimize disability, will become a key health strategy. The increasing prominence of the rehabilitative strategy within the health system drives the argument for the integration of functioning information as an essential component in national health information systems.Rehabilitation professionals and researchers have long recognized in WHO's International Classification of Functioning, Disability and Health the best prospect for an internationally recognized, sufficiently complete and powerful information reference for the documentation of functioning information. This paper opens the discussion of the promise of integrating the ICF as an essential component in national health systems to secure access to functioning information for rehabilitation, across health systems and countries.

  17. Expression Profile of Penaeus monodon Ubiquitin Conjugating Enzyme (PmUbc) at Protein Level in White spot syndrome virus Challenged Shrimp.

    PubMed

    Keezhedath, Jeena; Kurcheti, Pani Prasad; Pathan, Mujahid Khan; Babu, Gireesh P; Tripathi, Gayatri; Sudhagar, Arun; Rao, Srinivas P

    2013-06-01

    White spot syndrome virus (WSSV) is one of the major pathogens in shrimp aquaculture. Four proteins of WSSV are predicted to encode a RING H2 domain, which in presence of ubiquitin conjugating enzyme (E2) in shrimps can function as viral E3 ligase and modulate the host ubiquitin proteasome pathway. Modulation of host ubiquitin proteasome pathway by viral proteins is implicated in viral pathogenesis. In the present study, expression profile of Penaeus monodon Ubiquitin conjugating enzyme (PmUbc) was studied at protein level in WSSV challenged shrimp. A time point analysis of the expression of PmUbc was carried out at 0, 3, 6, 12, 24, 48 and 72 h post WSSV challenge in P. monodon. Recombinant PmUbc (rPmUbc) was produced in prokaryotic expression vector, BL21 (DE3) pLys S. The PmUbc expression pattern was studied by ELISA with rPmUbc antibodies raised in rabbit. A significant increase in PmUbc expression at 24 h post infection (hpi) was observed followed by a decline till 72 hpi. Since the up-regulation and a tremendous decline of PmUbc protein expression was observed at 24 and in 72 hpi respectively in ELISA, it can be speculated that these proteins might interact with host ubiquitination pathway for viral pathogenesis. Many findings have shown that viral infection can up-regulate expression of ubiquitin and that the ubiquitin system plays a key role in the course of viral infection. The present study reveals the expression patterns of PmUbc at protein level in WSSV infected P. monodon. However, further studies are to be carried out to unfold the molecular mechanism of interaction between host and virus to devise efficient control strategies for this major culprit in shrimp culture industry.

  18. Systemic regulation of photosynthetic function in field-grown sorghum.

    PubMed

    Li, Tao; Liu, Yujun; Shi, Lei; Jiang, Chuangdao

    2015-09-01

    The photosynthetic characteristics of developing leaves of plants grown under artificial conditions are, to some extent, regulated systemically by mature leaves; however, whether systemic regulation of photosynthesis occurs in field-grown crops is unclear. To explore this question, we investigated the effects of planting density on growth characteristics, gas exchange, leaf nitrogen concentration and chlorophyll a fluorescence in field-grown sorghum (Sorghum bicolor L.). Our results showed that close planting resulted in a marked decline in light intensity in lower canopy. Sorghum plants grown at a high planting density had lower net photosynthetic rate (Pn), stomatal conductance (Gs), and transpiration rate (E) than plants grown at a low planting density. Moreover, in the absence of mineral deficiency, close planting induced a slight increase in leaf nitrogen concentration. The decreased photosynthesis in leaves of the lower canopy at high planting density was caused mainly by the low light. However, newly developed leaves exposed to high light in the upper canopy of plants grown at high planting density also exhibited a distinct decline in photosynthesis relative to plants grown at low planting density. Based on these results, the photosynthetic function of the newly developed leaves in the upper canopy was not determined fully by their own high light environment. Accordingly, we suggest that the photosynthetic function of newly developed leaves in the upper canopy of field-grown sorghum plants is regulated systemically by the lower canopy leaves. The differences in systemic regulation of photosynthesis were also discussed between field conditions and artificial conditions.

  19. Robotic Mirror Therapy System for Functional Recovery of Hemiplegic Arms.

    PubMed

    Beom, Jaewon; Koh, Sukgyu; Nam, Hyung Seok; Kim, Wonshik; Kim, Yoonjae; Seo, Han Gil; Oh, Byung-Mo; Chung, Sun Gun; Kim, Sungwan

    2016-08-15

    Mirror therapy has been performed as effective occupational therapy in a clinical setting for functional recovery of a hemiplegic arm after stroke. It is conducted by eliciting an illusion through use of a mirror as if the hemiplegic arm is moving in real-time while moving the healthy arm. It can facilitate brain neuroplasticity through activation of the sensorimotor cortex. However, conventional mirror therapy has a critical limitation in that the hemiplegic arm is not actually moving. Thus, we developed a real-time 2-axis mirror robot system as a simple add-on module for conventional mirror therapy using a closed feedback mechanism, which enables real-time movement of the hemiplegic arm. We used 3 Attitude and Heading Reference System sensors, 2 brushless DC motors for elbow and wrist joints, and exoskeletal frames. In a feasibility study on 6 healthy subjects, robotic mirror therapy was safe and feasible. We further selected tasks useful for activities of daily living training through feedback from rehabilitation doctors. A chronic stroke patient showed improvement in the Fugl-Meyer assessment scale and elbow flexor spasticity after a 2-week application of the mirror robot system. Robotic mirror therapy may enhance proprioceptive input to the sensory cortex, which is considered to be important in neuroplasticity and functional recovery of hemiplegic arms. The mirror robot system presented herein can be easily developed and utilized effectively to advance occupational therapy.

  20. Comparative Study of Popular Objective Functions for Damping Power System Oscillations in Multimachine System

    PubMed Central

    Niamul Islam, Naz; Hannan, M. A.; Shareef, Hussain; Mohamed, Azah; Salam, M. A.

    2014-01-01

    Power oscillation damping controller is designed in linearized model with heuristic optimization techniques. Selection of the objective function is very crucial for damping controller design by optimization algorithms. In this research, comparative analysis has been carried out to evaluate the effectiveness of popular objective functions used in power system oscillation damping. Two-stage lead-lag damping controller by means of power system stabilizers is optimized using differential search algorithm for different objective functions. Linearized model simulations are performed to compare the dominant mode's performance and then the nonlinear model is continued to evaluate the damping performance over power system oscillations. All the simulations are conducted in two-area four-machine power system to bring a detailed analysis. Investigated results proved that multiobjective D-shaped function is an effective objective function in terms of moving unstable and lightly damped electromechanical modes into stable region. Thus, D-shape function ultimately improves overall system damping and concurrently enhances power system reliability. PMID:24977210

  1. Comparative study of popular objective functions for damping power system oscillations in multimachine system.

    PubMed

    Islam, Naz Niamul; Hannan, M A; Shareef, Hussain; Mohamed, Azah; Salam, M A

    2014-01-01

    Power oscillation damping controller is designed in linearized model with heuristic optimization techniques. Selection of the objective function is very crucial for damping controller design by optimization algorithms. In this research, comparative analysis has been carried out to evaluate the effectiveness of popular objective functions used in power system oscillation damping. Two-stage lead-lag damping controller by means of power system stabilizers is optimized using differential search algorithm for different objective functions. Linearized model simulations are performed to compare the dominant mode's performance and then the nonlinear model is continued to evaluate the damping performance over power system oscillations. All the simulations are conducted in two-area four-machine power system to bring a detailed analysis. Investigated results proved that multiobjective D-shaped function is an effective objective function in terms of moving unstable and lightly damped electromechanical modes into stable region. Thus, D-shape function ultimately improves overall system damping and concurrently enhances power system reliability.

  2. New adhesive systems based on functionalized block copolymers

    SciTech Connect

    Kent, M.; Saunders, R.; Hurst, M.; Small, J.; Emerson, J.; Zamora, D.

    1997-05-01

    The goal of this work was to evaluate chemically-functionalized block copolymers as adhesion promoters for metal/thermoset resin interfaces. Novel block copolymers were synthesized which contain pendant functional groups reactive toward copper and epoxy resins. In particular, imidazole and triazole functionalities that chelate with copper were incorporated onto one block, while secondary amines were incorporated onto the second block. These copolymers were found to self-assemble from solution onto copper surfaces to form monolayers. The structure of the adsorbed monolayers were studied in detail by neutron reflection and time-of-flight secondary ion mass spectrometry. The monolayer structure was found to vary markedly with the solution conditions and adsorption protocol. Appropriate conditions were found for which the two blocks form separate layers on the surface with the amine functionalized block exposed at the air surface. Adhesion testing of block copolymer-coated copper with epoxy resins was performed in both lap shear and peel modes. Modest enhancements in bond strengths were observed with the block copolymer applied to the native oxide. However, it was discovered that the native oxide is the weak link, and that by simply removing the native oxide, and then applying an epoxy resin before the native oxide can reform, excellent bond strength in the as-prepared state as well as excellent retention of bond strength after exposure to solder in ambient conditions are obtained. It is recommended that long term aging studies be performed with and without the block copolymer. In addition, the functionalized block copolymer method should be evaluated for another system that has inherently poor bonding, such as the nickel/silicone interface, and for systems involving metals and alloys which form oxides very rapidly, such as aluminum and stainless steel, where bonding strategies involve stabilizing the native oxide.

  3. A Functional-Phylogenetic Classification System for Transmembrane Solute Transporters

    PubMed Central

    Saier, Milton H.

    2000-01-01

    A comprehensive classification system for transmembrane molecular transporters has been developed and recently approved by the transport panel of the nomenclature committee of the International Union of Biochemistry and Molecular Biology. This system is based on (i) transporter class and subclass (mode of transport and energy coupling mechanism), (ii) protein phylogenetic family and subfamily, and (iii) substrate specificity. Almost all of the more than 250 identified families of transporters include members that function exclusively in transport. Channels (115 families), secondary active transporters (uniporters, symporters, and antiporters) (78 families), primary active transporters (23 families), group translocators (6 families), and transport proteins of ill-defined function or of unknown mechanism (51 families) constitute distinct categories. Transport mode and energy coupling prove to be relatively immutable characteristics and therefore provide primary bases for classification. Phylogenetic grouping reflects structure, function, mechanism, and often substrate specificity and therefore provides a reliable secondary basis for classification. Substrate specificity and polarity of transport prove to be more readily altered during evolutionary history and therefore provide a tertiary basis for classification. With very few exceptions, a phylogenetic family of transporters includes members that function by a single transport mode and energy coupling mechanism, although a variety of substrates may be transported, sometimes with either inwardly or outwardly directed polarity. In this review, I provide cross-referencing of well-characterized constituent transporters according to (i) transport mode, (ii) energy coupling mechanism, (iii) phylogenetic grouping, and (iv) substrates transported. The structural features and distribution of recognized family members throughout the living world are also evaluated. The tabulations should facilitate familial and functional

  4. Towards a Functionally-Formed Air Traffic System-of-Systems

    NASA Technical Reports Server (NTRS)

    Conway, Sheila R.; Consiglio, Maria C.

    2005-01-01

    Incremental improvements to the national aviation infrastructure have not resulted in sufficient increases in capacity and flexibility to meet emerging demand. Unfortunately, revolutionary changes capable of substantial and rapid increases in capacity have proven elusive. Moreover, significant changes have been difficult to implement, and the operational consequences of such change, difficult to predict due to the system s complexity. Some research suggests redistributing air traffic control functions through the system, but this work has largely been dismissed out of hand, accused of being impractical. However, the case for functionally-based reorganization of form can be made from a theoretical, systems perspective. This paper investigates Air Traffic Management functions and their intrinsic biases towards centralized/distributed operations, grounded in systems engineering and information technology theories. Application of these concepts to a small airport operations design is discussed. From this groundwork, a robust, scalable system transformation plan may be made in light of uncertain demand.

  5. [Functional characteristics of the basic internal system of hippocampal connections].

    PubMed

    Kichigina, V F; Bragin, A G

    1976-01-01

    Functional characteristics of two main intrahippocampal connections (dentate fascia-field CA3 and field CA3-field CA1) were studied in unanesthetized rabbits. Electrical stimulation of FD or CA3 was used during extracellular recording of the CA3 or CA1 neuronal activity, respectively. The system CA3-CA1 is a highly effective, with a very narrow threshold zone and wide range of active frequencies. The process of recruitment during continuous rhythmic stimulation is weak, any signs of prolonged potentiation are absent. The system FD-CA3 is characterized by low effeciency, a wide threshold zone, narrow range of active frequencies. It is able of gradual building up and prolonged preservation of potentiated state. The morphological reasons of these differences and possible role of these systems in the hippocampal activity are discussed.

  6. NGSI: FUNCTION REQUIREMENTS FOR A CYLINDER TRACKING SYSTEM

    SciTech Connect

    Branney, S.

    2012-06-06

    While nuclear suppliers currently track uranium hexafluoride (UF{sub 6}) cylinders in various ways, for their own purposes, industry practices vary significantly. The NNSA Office of Nonproliferation and International Security's Next Generation Safeguards Initiative (NGSI) has begun a 5-year program to investigate the concept of a global monitoring scheme that uniquely identifies and tracks UF{sub 6} cylinders. As part of this effort, NGSI's multi-laboratory team has documented the 'life of a UF{sub 6} cylinder' and reviewed IAEA practices related to UF{sub 6} cylinders. Based on this foundation, this paper examines the functional requirements of a system that would uniquely identify and track UF{sub 6} cylinders. There are many considerations for establishing a potential tracking system. Some of these factors include the environmental conditions a cylinder may be expected to be exposed to, where cylinders may be particularly vulnerable to diversion, how such a system may be integrated into the existing flow of commerce, how proprietary data generated in the process may be protected, what a system may require in terms of the existing standard for UF{sub 6} cylinder manufacture or modifications to it and what the limiting technology factors may be. It is desirable that a tracking system should provide benefit to industry while imposing as few additional constraints as possible and still meeting IAEA safeguards objectives. This paper includes recommendations for this system and the analysis that generated them.

  7. A simultaneous multimodal imaging system for tissue functional parameters

    NASA Astrophysics Data System (ADS)

    Ren, Wenqi; Zhang, Zhiwu; Wu, Qiang; Zhang, Shiwu; Xu, Ronald

    2014-02-01

    Simultaneous and quantitative assessment of skin functional characteristics in different modalities will facilitate diagnosis and therapy in many clinical applications such as wound healing. However, many existing clinical practices and multimodal imaging systems are subjective, qualitative, sequential for multimodal data collection, and need co-registration between different modalities. To overcome these limitations, we developed a multimodal imaging system for quantitative, non-invasive, and simultaneous imaging of cutaneous tissue oxygenation and blood perfusion parameters. The imaging system integrated multispectral and laser speckle imaging technologies into one experimental setup. A Labview interface was developed for equipment control, synchronization, and image acquisition. Advanced algorithms based on a wide gap second derivative reflectometry and laser speckle contrast analysis (LASCA) were developed for accurate reconstruction of tissue oxygenation and blood perfusion respectively. Quantitative calibration experiments and a new style of skinsimulating phantom were designed to verify the accuracy and reliability of the imaging system. The experimental results were compared with a Moor tissue oxygenation and perfusion monitor. For In vivo testing, a post-occlusion reactive hyperemia (PORH) procedure in human subject and an ongoing wound healing monitoring experiment using dorsal skinfold chamber models were conducted to validate the usability of our system for dynamic detection of oxygenation and perfusion parameters. In this study, we have not only setup an advanced multimodal imaging system for cutaneous tissue oxygenation and perfusion parameters but also elucidated its potential for wound healing assessment in clinical practice.

  8. Optimal Wonderful Life Utility Functions in Multi-Agent Systems

    NASA Technical Reports Server (NTRS)

    Wolpert, David H.; Tumer, Kagan; Swanson, Keith (Technical Monitor)

    2000-01-01

    The mathematics of Collective Intelligence (COINs) is concerned with the design of multi-agent systems so as to optimize an overall global utility function when those systems lack centralized communication and control. Typically in COINs each agent runs a distinct Reinforcement Learning (RL) algorithm, so that much of the design problem reduces to how best to initialize/update each agent's private utility function, as far as the ensuing value of the global utility is concerned. Traditional team game solutions to this problem assign to each agent the global utility as its private utility function. In previous work we used the COIN framework to derive the alternative Wonderful Life Utility (WLU), and experimentally established that having the agents use it induces global utility performance up to orders of magnitude superior to that induced by use of the team game utility. The WLU has a free parameter (the clamping parameter) which we simply set to zero in that previous work. Here we derive the optimal value of the clamping parameter, and demonstrate experimentally that using that optimal value can result in significantly improved performance over that of clamping to zero, over and above the improvement beyond traditional approaches.

  9. The function of BDNF in the adult auditory system.

    PubMed

    Singer, Wibke; Panford-Walsh, Rama; Knipper, Marlies

    2014-01-01

    The inner ear of vertebrates is specialized to perceive sound, gravity and movements. Each of the specialized sensory organs within the cochlea (sound) and vestibular system (gravity, head movements) transmits information to specific areas of the brain. During development, brain-derived neurotrophic factor (BDNF) orchestrates the survival and outgrowth of afferent fibers connecting the vestibular organ and those regions in the cochlea that map information for low frequency sound to central auditory nuclei and higher-auditory centers. The role of BDNF in the mature inner ear is less understood. This is mainly due to the fact that constitutive BDNF mutant mice are postnatally lethal. Only in the last few years has the improved technology of performing conditional cell specific deletion of BDNF in vivo allowed the study of the function of BDNF in the mature developed organ. This review provides an overview of the current knowledge of the expression pattern and function of BDNF in the peripheral and central auditory system from just prior to the first auditory experience onwards. A special focus will be put on the differential mechanisms in which BDNF drives refinement of auditory circuitries during the onset of sensory experience and in the adult brain. This article is part of the Special Issue entitled 'BDNF Regulation of Synaptic Structure, Function, and Plasticity'.

  10. Plant growth-promoting rhizobacteria and root system functioning

    PubMed Central

    Vacheron, Jordan; Desbrosses, Guilhem; Bouffaud, Marie-Lara; Touraine, Bruno; Moënne-Loccoz, Yvan; Muller, Daniel; Legendre, Laurent; Wisniewski-Dyé, Florence; Prigent-Combaret, Claire

    2013-01-01

    The rhizosphere supports the development and activity of a huge and diversified microbial community, including microorganisms capable to promote plant growth. Among the latter, plant growth-promoting rhizobacteria (PGPR) colonize roots of monocots and dicots, and enhance plant growth by direct and indirect mechanisms. Modification of root system architecture by PGPR implicates the production of phytohormones and other signals that lead, mostly, to enhanced lateral root branching and development of root hairs. PGPR also modify root functioning, improve plant nutrition and influence the physiology of the whole plant. Recent results provided first clues as to how PGPR signals could trigger these plant responses. Whether local and/or systemic, the plant molecular pathways involved remain often unknown. From an ecological point of view, it emerged that PGPR form coherent functional groups, whose rhizosphere ecology is influenced by a myriad of abiotic and biotic factors in natural and agricultural soils, and these factors can in turn modulate PGPR effects on roots. In this paper, we address novel knowledge and gaps on PGPR modes of action and signals, and highlight recent progress on the links between plant morphological and physiological effects induced by PGPR. We also show the importance of taking into account the size, diversity, and gene expression patterns of PGPR assemblages in the rhizosphere to better understand their impact on plant growth and functioning. Integrating mechanistic and ecological knowledge on PGPR populations in soil will be a prerequisite to develop novel management strategies for sustainable agriculture. PMID:24062756

  11. Energy Emergency Management Information System (EEMIS): functional requirements

    SciTech Connect

    Not Available

    1980-10-17

    This report deals with the functional requirements of the Energy Emergency Management Information System (EEMIS) as it is defined for State level use (EEMIS-S). This report provides a technical description of the EEMIS-S requirements. These guidelines state that in order to create the widest practicable competition the system's requirements, with few exceptions, must be expressed in functional terms without reference to specific hardware or software products, and that wherever exceptions are made a statement of justification must be provided. In addition, these guidelines set forth a recommended maximum threshold limit of annual contract value for schedule contract procurements. Section 2.0 presents a general overview of the EEMIS structure in terms of requirements for vendor support. The functional requirements for each component are developed by section as: Teleprocessing Monitor Requirements, Section 3.0; EEMIS File Requirements, Section 4.0; Data Base Management Requirements, Section 5.0; Application Program Requirements, Section 6.0; and Utility Program Requirements, Section 7.0. The final Section, 8.0, justifies the use of the GSA Teleprocessing Service Program - Multiple Award Schedule Contracts (TSP-MASC) procurement process. The intent of this section is to substantiate, in this instance, the desirability of obtaining time-sharing vendor services to support EEMIS under a schedule contract, even if certain TSP-MASC threshold limits might be exceeded.

  12. Plant growth-promoting rhizobacteria and root system functioning.

    PubMed

    Vacheron, Jordan; Desbrosses, Guilhem; Bouffaud, Marie-Lara; Touraine, Bruno; Moënne-Loccoz, Yvan; Muller, Daniel; Legendre, Laurent; Wisniewski-Dyé, Florence; Prigent-Combaret, Claire

    2013-09-17

    The rhizosphere supports the development and activity of a huge and diversified microbial community, including microorganisms capable to promote plant growth. Among the latter, plant growth-promoting rhizobacteria (PGPR) colonize roots of monocots and dicots, and enhance plant growth by direct and indirect mechanisms. Modification of root system architecture by PGPR implicates the production of phytohormones and other signals that lead, mostly, to enhanced lateral root branching and development of root hairs. PGPR also modify root functioning, improve plant nutrition and influence the physiology of the whole plant. Recent results provided first clues as to how PGPR signals could trigger these plant responses. Whether local and/or systemic, the plant molecular pathways involved remain often unknown. From an ecological point of view, it emerged that PGPR form coherent functional groups, whose rhizosphere ecology is influenced by a myriad of abiotic and biotic factors in natural and agricultural soils, and these factors can in turn modulate PGPR effects on roots. In this paper, we address novel knowledge and gaps on PGPR modes of action and signals, and highlight recent progress on the links between plant morphological and physiological effects induced by PGPR. We also show the importance of taking into account the size, diversity, and gene expression patterns of PGPR assemblages in the rhizosphere to better understand their impact on plant growth and functioning. Integrating mechanistic and ecological knowledge on PGPR populations in soil will be a prerequisite to develop novel management strategies for sustainable agriculture.

  13. Evolutionary ecology of mycorrhizal functional diversity in agricultural systems

    PubMed Central

    Verbruggen, Erik; Toby Kiers, E

    2010-01-01

    The root systems of most agronomic crops are colonized by diverse assemblages of arbuscular mycorrhizal fungi (AMF), varying in the functional benefits (e.g. nutrient transfer, pathogen protection, water uptake) provided to hosts. Little is known about the evolutionary processes that shape the composition of these fungal assemblages, nor is it known whether more diverse assemblages are beneficial to crop productivity. In this review we aim to identify the evolutionary selection pressures that shape AMF diversity in agricultural systems and explore whether promotion of AMF diversity can convincingly be linked to increases in agricultural productivity and/or sustainability. We then ask whether farmers can (and should) actively modify evolutionary selection pressures to increase AMF functioning. We focus on three agriculturally imposed selection regimes: tillage, fertilization, and continuous monoculture. We find that the uniform nature of these practices strongly selects for dominance of few AMF species. These species exhibit predictable, generally non-beneficial traits, namely heavy investment in reproduction at the expense of nutrient scavenging and transfer processes that are beneficial for hosts. A number of focus-points are given based on empirical and theoretical evidence that could be utilized to slow down negative selection pressures on AMF functioning, therein increasing crop benefit. PMID:25567946

  14. The integrated Earth System Model Version 1: formulation and functionality

    SciTech Connect

    Collins, William D.; Craig, Anthony P.; Truesdale, John E.; Di Vittorio, Alan; Jones, Andrew D.; Bond-Lamberty, Benjamin; Calvin, Katherine V.; Edmonds, James A.; Kim, Son H.; Thomson, Allison M.; Patel, Pralit L.; Zhou, Yuyu; Mao, Jiafu; Shi, Xiaoying; Thornton, Peter E.; Chini, Louise M.; Hurtt, George C.

    2015-07-23

    The integrated Earth System Model (iESM) has been developed as a new tool for pro- jecting the joint human/climate system. The iESM is based upon coupling an Integrated Assessment Model (IAM) and an Earth System Model (ESM) into a common modeling in- frastructure. IAMs are the primary tool for describing the human–Earth system, including the sources of global greenhouse gases (GHGs) and short-lived species, land use and land cover change, and other resource-related drivers of anthropogenic climate change. ESMs are the primary scientific tools for examining the physical, chemical, and biogeochemical impacts of human-induced changes to the climate system. The iESM project integrates the economic and human dimension modeling of an IAM and a fully coupled ESM within a sin- gle simulation system while maintaining the separability of each model if needed. Both IAM and ESM codes are developed and used by large communities and have been extensively applied in recent national and international climate assessments. By introducing heretofore- omitted feedbacks between natural and societal drivers, we can improve scientific under- standing of the human–Earth system dynamics. Potential applications include studies of the interactions and feedbacks leading to the timing, scale, and geographic distribution of emissions trajectories and other human influences, corresponding climate effects, and the subsequent impacts of a changing climate on human and natural systems. This paper de- scribes the formulation, requirements, implementation, testing, and resulting functionality of the first version of the iESM released to the global climate community.

  15. The integrated Earth system model version 1: formulation and functionality

    NASA Astrophysics Data System (ADS)

    Collins, W. D.; Craig, A. P.; Truesdale, J. E.; Di Vittorio, A. V.; Jones, A. D.; Bond-Lamberty, B.; Calvin, K. V.; Edmonds, J. A.; Kim, S. H.; Thomson, A. M.; Patel, P.; Zhou, Y.; Mao, J.; Shi, X.; Thornton, P. E.; Chini, L. P.; Hurtt, G. C.

    2015-07-01

    The integrated Earth system model (iESM) has been developed as a new tool for projecting the joint human/climate system. The iESM is based upon coupling an integrated assessment model (IAM) and an Earth system model (ESM) into a common modeling infrastructure. IAMs are the primary tool for describing the human-Earth system, including the sources of global greenhouse gases (GHGs) and short-lived species (SLS), land use and land cover change (LULCC), and other resource-related drivers of anthropogenic climate change. ESMs are the primary scientific tools for examining the physical, chemical, and biogeochemical impacts of human-induced changes to the climate system. The iESM project integrates the economic and human-dimension modeling of an IAM and a fully coupled ESM within a single simulation system while maintaining the separability of each model if needed. Both IAM and ESM codes are developed and used by large communities and have been extensively applied in recent national and international climate assessments. By introducing heretofore-omitted feedbacks between natural and societal drivers, we can improve scientific understanding of the human-Earth system dynamics. Potential applications include studies of the interactions and feedbacks leading to the timing, scale, and geographic distribution of emissions trajectories and other human influences, corresponding climate effects, and the subsequent impacts of a changing climate on human and natural systems. This paper describes the formulation, requirements, implementation, testing, and resulting functionality of the first version of the iESM released to the global climate community.

  16. The integrated Earth system model version 1: formulation and functionality

    DOE PAGES

    Collins, W. D.; Craig, A. P.; Truesdale, J. E.; ...

    2015-07-23

    The integrated Earth system model (iESM) has been developed as a new tool for projecting the joint human/climate system. The iESM is based upon coupling an integrated assessment model (IAM) and an Earth system model (ESM) into a common modeling infrastructure. IAMs are the primary tool for describing the human–Earth system, including the sources of global greenhouse gases (GHGs) and short-lived species (SLS), land use and land cover change (LULCC), and other resource-related drivers of anthropogenic climate change. ESMs are the primary scientific tools for examining the physical, chemical, and biogeochemical impacts of human-induced changes to the climate system. Themore » iESM project integrates the economic and human-dimension modeling of an IAM and a fully coupled ESM within a single simulation system while maintaining the separability of each model if needed. Both IAM and ESM codes are developed and used by large communities and have been extensively applied in recent national and international climate assessments. By introducing heretofore-omitted feedbacks between natural and societal drivers, we can improve scientific understanding of the human–Earth system dynamics. Potential applications include studies of the interactions and feedbacks leading to the timing, scale, and geographic distribution of emissions trajectories and other human influences, corresponding climate effects, and the subsequent impacts of a changing climate on human and natural systems. This paper describes the formulation, requirements, implementation, testing, and resulting functionality of the first version of the iESM released to the global climate community.« less

  17. System diagnostics using qualitative analysis and component functional classification

    DOEpatents

    Reifman, Jaques; Wei, Thomas Y. C.

    1993-01-01

    A method for detecting and identifying faulty component candidates during off-normal operations of nuclear power plants involves the qualitative analysis of macroscopic imbalances in the conservation equations of mass, energy and momentum in thermal-hydraulic control volumes associated with one or more plant components and the functional classification of components. The qualitative analysis of mass and energy is performed through the associated equations of state, while imbalances in momentum are obtained by tracking mass flow rates which are incorporated into a first knowledge base. The plant components are functionally classified, according to their type, as sources or sinks of mass, energy and momentum, depending upon which of the three balance equations is most strongly affected by a faulty component which is incorporated into a second knowledge base. Information describing the connections among the components of the system forms a third knowledge base. The method is particularly adapted for use in a diagnostic expert system to detect and identify faulty component candidates in the presence of component failures and is not limited to use in a nuclear power plant, but may be used with virtually any type of thermal-hydraulic operating system.

  18. System diagnostics using qualitative analysis and component functional classification

    DOEpatents

    Reifman, J.; Wei, T.Y.C.

    1993-11-23

    A method for detecting and identifying faulty component candidates during off-normal operations of nuclear power plants involves the qualitative analysis of macroscopic imbalances in the conservation equations of mass, energy and momentum in thermal-hydraulic control volumes associated with one or more plant components and the functional classification of components. The qualitative analysis of mass and energy is performed through the associated equations of state, while imbalances in momentum are obtained by tracking mass flow rates which are incorporated into a first knowledge base. The plant components are functionally classified, according to their type, as sources or sinks of mass, energy and momentum, depending upon which of the three balance equations is most strongly affected by a faulty component which is incorporated into a second knowledge base. Information describing the connections among the components of the system forms a third knowledge base. The method is particularly adapted for use in a diagnostic expert system to detect and identify faulty component candidates in the presence of component failures and is not limited to use in a nuclear power plant, but may be used with virtually any type of thermal-hydraulic operating system. 5 figures.

  19. Abnormal Default System Functioning in Depression: Implications for Emotion Regulation

    PubMed Central

    Messina, Irene; Bianco, Francesca; Cusinato, Maria; Calvo, Vincenzo; Sambin, Marco

    2016-01-01

    Depression is widely seen as the result of difficulties in regulating emotions. Based on neuroimaging studies on voluntary emotion regulation, neurobiological models have focused on the concept of cognitive control, considering emotion regulation as a shift toward involving controlled processes associated with activation of the prefrontal and parietal executive areas, instead of responding automatically to emotional stimuli. According to such models, the weaker executive area activation observed in depressed patients is attributable to a lack of cognitive control over negative emotions. Going beyond the concept of cognitive control, psychodynamic models describe the development of individuals’ capacity to regulate their emotional states in mother-infant interactions during childhood, through the construction of the representation of the self, others, and relationships. In this mini-review, we link these psychodynamic models with recent findings regarding the abnormal functioning of the default system in depression. Consistently with psychodynamic models, psychological functions associated with the default system include self-related processing, semantic processes, and implicit forms of emotion regulation. The abnormal activation of the default system observed in depression may explain the dysfunctional aspects of emotion regulation typical of the condition, such as an exaggerated negative self-focus and rumination on self-esteem issues. We also discuss the clinical implications of these findings with reference to the therapeutic relationship as a key tool for revisiting impaired or distorted representations of the self and relational objects. PMID:27375536

  20. Functional type 1 secretion system involved in Legionella pneumophila virulence.

    PubMed

    Fuche, Fabien; Vianney, Anne; Andrea, Claire; Doublet, Patricia; Gilbert, Christophe

    2015-02-01

    Legionella pneumophila is a Gram-negative pathogen found mainly in water, either in a free-living form or within infected protozoans, where it replicates. This bacterium can also infect humans by inhalation of contaminated aerosols, causing a severe form of pneumonia called legionellosis or Legionnaires' disease. The involvement of type II and IV secretion systems in the virulence of L. pneumophila is now well documented. Despite bioinformatic studies showing that a type I secretion system (T1SS) could be present in this pathogen, the functionality of this system based on the LssB, LssD, and TolC proteins has never been established. Here, we report the demonstration of the functionality of the T1SS, as well as its role in the infectious cycle of L. pneumophila. Using deletion mutants and fusion proteins, we demonstrated that the repeats-in-toxin protein RtxA is secreted through an LssB-LssD-TolC-dependent mechanism. Moreover, fluorescence monitoring and confocal microscopy showed that this T1SS is required for entry into the host cell, although it seems dispensable to the intracellular cycle. Together, these results underline the active participation of L. pneumophila, via its T1SS, in its internalization into host cells.